revista mexicana de neurocienciarevmexneurociencia.com/portadas/rmn_2019_3.pdfluis díaz-escobar,...

EditorialCommitment 129Gerónimo Aguayo-Leytte

Original Articles Frequency of hypertension, age, and gender in cerebrovascular disease in Paraguay 130Luis Díaz-Escobar, Alan Flores, Laia Seró-Ballesteros, Christian Otto, Ricardo Mernes, Fátima Pedrozo, Fabiola Riquelme, Romina González and Silvia González

Incidence rates of Parkinson’s disease in Mexico: Analysis of 2014-2017 statistics 136Mayela Rodríguez-Violante, Leora Velásquez-Pérez and Amin Cervantes-Arriaga

Efecto del estrés en la adquisición y consolidación de la memoria de reconocimiento de objetos en ratas 141María R. González-López, Norma L. García-Saldívar, José C. Arriaga-Ramírez and Sara E. Cruz-Morales

Review Articles Parálisis periódica tirotóxica: revisión de la literatura y reporte de caso en un hospital universitario mexicano privado de alta especialidad 149Manuel A. Sierra, Wallace R. Muñoz-Castañeda, Carlos Tolsa, Aldo E. Lara, Raúl Medina and Carolina Vega

Intervention programs on reading and writing processes in children with learning disorders: A review 155Cristian Villanueva-Bonilla and Ángela M. Ríos-Gallardo

Immunology of Alzheimer’s disease 162Lucila I. Sosa-García, Janeth Hernández-Jiménez, Diana I. Del Moral-Huerta, Charles Duyckaerts and Ana L. Calderón-Garcidueñas

Letter to Editor Subtipos motores en enfermedad de Parkinson y estudio REMPARK: ¿la resurrección de un proyecto olvidado? 171Carlos Zúñiga-Ramírez, Ingrid Estrada-Bellmann and Elisa Otero-Cerdeira

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VOLUME 20 - NUMBER 3 / May-June 2019 – ISSN: 1665-5044

eISSN: 2604-6180

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Revista Mexicana de

NeurocienciaPublicación oficial de la Academia Mexicana de Neurología A.C.

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Commitment Gerónimo Aguayo-Leytte*Neurology Service, Hospital Miguel Hidalgo, Aguascalientes, Mexico

Revista Mexicana de Neurociencia

EDITORIAL

Correspondence: *Gerónimo Aguayo-Leytte

E-mail: [email protected]

Available online: 18-06-2019

Rev Mex Neuroci. 2019;20(3):129-129


Date of reception: 06-05-2019

Date of acceptance: 07-05-2019

DOI: 10.24875/RMN.M19000047

We live in a time of definitions. I think that, as never before, so many contrasts are seen in technological advances in health, with potential and real benefits, but also the poor access of the majority of people to them. This technological development that can improve med-ical practice in our country runs into a great dissatis-faction from many patients who go to the public health system (IMSS, ISSSTE, Seguro Popular) and not, in-frequently, to the private. Long waiting times for con-sultation or surgery, and the physician-patient interview lasting for 10-15 min with a perception of a considerable distance from the first to the second, are common com-plaints that I hear.

In our beloved Mexico, the majority of the population lives in a certain degree of poverty. We as a guild who are interested in and practice the neurosciences (es-pecially the neurologists) are a fortunate group. We have had to study in prestigious institutions, and many have made subspecialties that they cultivate success-fully. Neurology has been erroneously recognized as a complex medical area, difficult to approach and prac-tice, both for students and physicians. It is up to us to modify this appreciation by sharing with our students and colleagues the study and practice of this fascinat-ing field of medicine.

The increasing influence and participation of medical cybernetics, (as Verghese points out when talking about artificial intelligence), and of so many new and impressive resources in revision methods, data analy-sis, and diagnostic and therapeutic procedures, compel

us to use these tools to optimize our work. However, this mush happen without subordinating ourselves to the systems and outshine and impede the real reason of our endeavor: attending to our patients, those who suffer and endure diseases that we should approach with a comprehensive view, recognizing the particular form of their affections by valuing their environment, their social and economic situation, their family ties, their aspirations, and desires.

This takes time, and it will be a challenge for us to demand to our public sector and private practice a per-formance that satisfies our patients – whom are not clients – and ourselves without discrimination.

This forces us to become more interested in issues of public health, epidemiology, sociology, history, phi-losophy, politics, and finally encouraging the human-ities further to expand our vision, and demand and participate as a group in the construction of a design health system for our population, without the vices of our current system as indicated by Viniegra (an Internist with a holistic approach to medicine) and several others.

The task before us is complex, delicate, and exciting; being physicians with the true vocation of service, from the clinic to assistance, teaching, and research, attend-ing, as previously mentioned, all the aspects that de-termine people’s suffering.

It is in our hands and in our trench to continue build-ing a better country of excellence and a higher high sense of the collective.

1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the terms of the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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http://dx.doi.org/10.24875/RMN.M19000047

http://crossmark.crossref.org/dialog/?doi=10.24875/RMN.M19000047&domain=pdf

http://creativecommons.org/licenses/by-nc-nd/4.0/

130

Frequency of hypertension, age, and gender in cerebrovascular disease in ParaguayLuis Díaz-Escobar, Alan Flores*, Laia Seró-Ballesteros, Christian Otto, Ricardo Mernes, Fátima Pedrozo, Fabiola Riquelme, Romina González and Silvia GonzálezUnidad de Ictus, Hospital de Clínicas, Servicio de Urgencias, Facultad de Ciencias Médicas, Universidad Nacional de Asunción. San Lorenzo, Paraguay


Abstract

Background: Hypertension, age, and gender are relevant factors associated to cerebrovascular disease. In Paraguay, cerebrovas-cular disease is the fourth cause of mortality; however, information about demographic and baseline characteristics are not widely knowledge. Our aim was to determinate the prevalence of hypertension, age, and gender in the setting of acute phase stroke in our population. Methods: This is a descriptive, single-center study. Data were collected from a prospective registry of stroke patients admitted in the stroke unit of our center, from April 2015 to December 2016. Results: From 996 stroke patients, 252 (25.3%) pre-sented intracerebral hemorrhage (ICH). 390 (39.1%) were female. The hypertension rate was 74% and 78% in ischemic stroke and ICH, respectively, being hypertensive hemorrhagic etiology, 79.5% of the ICH and lacunar infarct 11.6% of ischemic strokes. In ICH patients, mean age differences between genders were remarkable (mean years 55.41 [standard deviation (SD) ± 14.8] vs. 62.48 [SD ± 15.2], p ≤ 0.001). In the multivariate analysis, lower age than 60 years old (odds ratio [OR]: 4.893; confidence interval [CI] 95%: 1.772-13.509, p = 0.029) and higher systolic blood pressure at admission (OR: 1.098; CI 95% 1.044-1.155, p = 0.009) were independent factors associated to ICH. Conclusion: In our population, ICH rates are similar to regional findings, occurring an early age than other series, being remarkable in males. Hypertension rates in ischemic stroke and ICH are higher than other series and the variability of presumed hypertensive microangiopathy phenotype could be in relation to age (hypertensive hemorrhage vs. lacunar). These findings would be related to ethnic, social, environment, and geographic factors.

Key words: Stroke epidemiology. Hypertensive hemorrhage. Female stroke. Vascular risk factors. Intracerebral hemorrhage.

Frecuencia de la hipertensión, edad y género en la enfermedad cerebrovascular en Paraguay

Resumen

Resumen: La hipertensión, la edad y el género son factores relevantes asociados a enfermedad cerebrovascular(ECV). En Paraguay, la ECV es la cuarta causa de mortalidad, sin embargo, información sobre sus características no son de amplio co-nocimiento. Nuestro objetivo fue determinar la frecuencia de la hipertensión, la edad, el género en la ECV en fase aguda en


ORIGINAL ARTICLE


Rev Mex Neuroci. 2019;20(3):130-135




DOI: 10.24875/RMN.19000042

Correspondence: *Alan Flores

Unidad de Ictus, Hospital de Clínicas

Facultad de Ciencias Médicas

Universidad Nacional de Asunción

San Lorenzo, Paraguay


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http://crossmark.crossref.org/dialog/?doi=10.24875/RMN.19000042&domain=pdf



mailto:?subject=alanflo2507%40hotmail.com

131

L. Díaz-Escobar, et al.: Frequency of stroke risk factors in Paraguay

Introduction

Stroke is one of the diseases with the greatest impact on public health, being the third cause of mortality and leading cause of disability in the western world since most patients suffer sequels, which in 30% of cases disable them to perform daily activities1,2.

The proportion and frequency between the ischemic types and intracerebral hemorrhage (ICH) are variables according to a determined region; while in Spain, the rates of ICH are around to 12%3, in regions of South America such as Ecuador and Chile, the ICH reach rates between 37 and 46%4. In Paraguay, cerebrovas-cular disease is the fourth cause of death5. However, other data about the baseline characteristics in our population are not widely known.

Among the cardiovascular risk factors related to stroke, hypertension is the most frequent and important risk factor. The prevalence is around 70% in both isch-emic and hemorrhagic patients and its optimal control is possibly one of the most important interventions in secondary prevention for both types of stroke3,6. In Par-aguay, the prevalence of hypertension is high, with rates of 53% in men and 40% in women between 35 and 45 years, reaching up to 81% in the general population between 65 and 74 years7.

Another known and controversial stroke risk factor is gender and their disparities in baseline and clinical outcomes. Several descriptive studies have shown an association of older age, frequency of hypertension, obesity, and atrial fibrillation in women than in men8,9.

Objective

The objective of this study was to determine the rates of hypertension, age, gender, and other known risk

factors in patients with stroke in the acute phase in our environment.

Methods

This is a descriptive, observational study in a single center. Data were collected from a prospective of stroke patients admitted in the Stroke Unit of our center since April 2015-March 2019.

The known modifiable and non-modifiable risk factors have been recorded. In patients with hemorrhagic stroke, the etiology of hypertensive ICH has been de-termined according to the history of hypertension, the topography of the parenchymal lesion, and the vascular study10. The diagnosis of ischemic stroke was made according to the criteria of the Oxfordshire Community Stroke Project and the Trial of Org 10172 in acute stroke treatment11.

The descriptive statistical analysis was performed for all the parameters, which included measurements of the central tendency and dispersion for the quanti-tative variables, as well as absolute and relative fre-quencies for the qualitative variables, with their 95% confidence interval (CI) in both cases. If the data did not meet the assumptions of normality for the analysis, non-parametric statistical methods were used (Stu-dent’s t-test or Mann–Whitney U-test, respectively). The Chi-square test was applied for the comparison between the proportions. To determine the weight of each of the risk factors between ischemic and hemor-rhagic stroke, multiple logistic regression models were established, with a 95% CI. The statistical tests were performed with a significance level of 5%. The statis-tical program SPSS v. 23.0 was used to perform the analysis.

nuestra población. Métodos: Se trata de un estudio observacional descriptivo monocéntrico. Se recogieron datos de un regis-tro prospectivo de pacientes con ictus ingresados en la Unidad de Ictus de nuestro centro, desde abril del 2015 a marzo de 2019. Resultados: De 996 pacientes con ictus, 252(25,3%) presentaron hemorragia intracerebral (HIC). Trescientos noventa (39.1%) fueron mujeres. La tasa de hipertensión arterial fue elevada en isquémicos(74%) como hemorrágicos(78%), siendo la hemorragia hipertensiva el 79.5% de las HIC y los lacunares el 11.6% de ictus isquémicos. En pacientes con HIC, la diferencia de edad entre géneros fue significativa (media/años 55.41 (SD ± 14.8) Vs 62.48 (SD ± 15.2) p = <0.001). En el análisis multi-variante fueron factores independientes asociados a HIC una edad menor a 60 años (OR: 4.893;IC95%:1,772-13,509p=0.029) y una elevada presión arterial sistólica al ingreso(OR:1.098;IC95%1,044-1,155,p=0.009). Conclusión: En nuestra población, la frecuencia de HIC es similar a lo descrito en la región, observándose una edad más temprana que otras series, siendo remar-cable en el género masculino. La tasa de hipertensión en HIC e ictus isquémico es mayor que en otras series y la variación de distintos fenotipos por presunta microangiopatía hipertensiva estaría relacionado en parte a la edad (hemorragia hiperten-siva Vs. lacunares). Estos resultados podrían explicarse por razones étnicas, socio-ambientales y geográficas.

Palabras Clave: Ictus epidemiología. Hemorragia cerebral hipertensiva. Ictus en la mujer. Factores de riesgo. Hemorragia intracerebral.

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Rev Mex Neuroci. 2019;20

Results

From 996 patients with stroke, 744 (74.7%) were isch-emic and 252 (25.3%) ICH, 390 (39.1%) were women. The mean age was 62.8 years (standard deviation [SD] ± 15.3). From overall, 75.4% had known anteced-ent of hypertension, 27% diabetes mellitus (DM), and 6.4% dyslipidemia. The median baseline NIHSS was 8 (interquartile range [IQR]: 4-12).The baseline character-istics in general and of the ischemic and hemorrhagic groups are shown in Table 1.

In ischemic stroke patients, the mean age was 64.3 (SD ± 15.2) years, the median of NIHSS 8 (IQR 4-12), and 39.8% were women. Patients with ischemic stroke were significantly older (mean years 64.3 SD ± 15.2 vs. 58.1 SD ± 14.8), had higher glycemia at admission (mean mgr./dl 168.6 SD ± 97.7 vs. 155.9 SD ± 120.3, p = 0.513), frequency of DM (23.5% vs. 3.4%, p = 0.001), atrial fibrillation (13.6% vs. 1.3%, p = 0.001), prior his-tory of stroke (15.4% vs. 2.5%, p = 0.001), prior anti-platelet treatment (8.1% vs. 1.0%, p = 0.001), and lower systolic blood pressure on arrival than patients with ICH (mean mmHg, 169.8 SD ± 38.3 vs. 189.9 SD ± 43.2).

The most frequent etiology were (422 cases work-up performed) cardioembolic 41.2%, indeterminate in 24.1%, lacunar infarcts in 11.6%, and atherothrombotic in 21.5%. Hypertension was present in 91% of atherothrombotic strokes, 89.6% of lacunar strokes, 80.8% in cardioembol-ic, and 77.6% of indeterminate strokes, Figure 1.

ICH patients had a mean age of 58.1 (SD ± 14.8) years, the median of NIHSS was 9 (IQR 5-13), and

36.9% were women. From 142 cases with etiological work-up, 79.5% were due to hypertensive hemorrhage. The factors significantly related to hypertensive hemor-rhage (113 cases evaluated) were hypertension (p ≤ 0.001) and the lower age stratified by groups (p = 0.006), Figure 2.

In the multivariate analysis adjusted for sex, hyper-tension, DM, previous stroke, and atrial fibrillation, age < 60 years old (odds ratio [OR]: 4.893, 95% CI: 1.772-13.509, p = 0.029) and a higher systolic blood pressure at admission (OR: 1.098, 95% CI 1.044-1.155, p = 0.009) were independent factors associated with ICH.

In relation to gender, hypertension was present in 79.3% in men and 83.5% in women. In men, smoking habit was significantly more frequent (23.9% vs. 3.4%, p < 0.001) and they presented more ischemic heart disease (7.9% vs. 2.3%, p = 0.001) than women. Men were younger (61.75 SD ± 13.6 vs. 64.16 SD ± 17.4, p = 0.003), being in the ICH group, even more remark-able the difference (mean years 55.41 [SD ± 14.8] vs. 62.48 [SD ± 15.2], p ≤ 0.001), Figure 3.

Discussion

This is a descriptive study, with data from a prospec-tive cohort over a period of 41 months. In general, there is a higher proportion of men than women with stroke, and the mean age is significantly lower than in devel-oped countries1,3, but similar to the previous studies in Buenos Aires and Brasilia12,13. Hypertension is the most frequent risk factor, slightly higher than other series3,12-14.

Table 1. Baseline characteristics of all patients with stroke and subgroups, ischemic and hemorrhagic with their significance in the univariate analysis

All(n = 996)

Ischemic(n = 744)

ICH(n = 252)

p value

Age, year 62.8 DS ± 15.3 64.3DS ± 15.2 58.1 ± 14.8 < 0.001

Glycemia at admission mgr/dl. (n: 169) 165.4DS ± 120.3 168.6DS ± 97.7 155.9DS ± 120.3 0.513

Female gender n (%) 390 (39.1) 295 (39.6) 93 (36.9) 0.585

Hypertension n (%) 749 (75.2) 553 (74.3) 195 (77.3) 0.102

Diabetes mellitus n (%) 237 (23.6) 206 (23.5) 30 (3.4) < 0.001

Dyslipidemia n (%) 56 (5.6) 47 (5.4) 9 (1) 0.144

Atrial fibrillation 128 (12.7) 117 (13.6) 11 (1.3) < 0.001

Prior antiplatelet treatment 996 (99.1) 81 (8.1) 10 (1.0) 0.003

Prior stroke 150 (14.9) 129 (15.4) 21 (2.5) 0.001

Baseline NIHSS median (interquartile range) 8 (4) 8 (4) 9 (4) 0.796

Systolic blood pressure at admission 169.8 ± 38.3 161.4 ± 32.5 189.9 ± 43.2 < 0.001

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Another risk factors rate such as DM, previous stroke, and atrial fibrillation was similar to prior studies; howev-er, the frequency of dyslipidemia, known ischemic

cardiopathy, and smoking was strikingly lower3,12-14. Possible explanations (in addition to the inherent biases and limitations from the nature of this study) are that our

Figure 2. Graphic bar showing number of cases of intracerebral hemorrhage according to stratified age group.

Figure 1. Graphic bar showing number of cases of ischemic stroke etiology according to prior hypertension status.

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center, although it is located in an urban center, is a reference center that receives patients from the rural area also, and this could affect our results. Another reason would be the lack of knowledge of the risk fac-tors of our population (less than half of men know about their blood cholesterol levels7).

The rate of HIC is significantly higher than that de-scribed in developed countries3,12 and is consistent with results from our region in studies conducted in Chile, Ecuador, and Argentina14-16. These results are ex-plained by the high prevalence rate of hypertension in our population, especially manifests at early ages in the adult7.

In relation to ischemic stroke, the etiology by TOAST (in 422 cases) showed a high rate of cardioembolic (41.2%), however, a lower frequency of atheromatous disease (21.5%) and lacunar (11.6%). These results are more similar with those found in Santiago14 than in those shown in Brasilia, Guayaquil, and Buenos Ai-res13,15,16. It should be noted that in South America, the frequency in relation to the etiology of stroke is very heterogeneous and diverse, mainly due to ethnic, geo-graphical, and sociocultural differences4. Finally, the relative high rate of indeterminate etiology would be related in many cases to an incomplete study and is a clear limitation at the present study.

Interestingly, while hypertension rates are high (79.3%) in ischemic patients, the percentage of lacunar strokes for presumed hypertensive microangiopathy as a cause is lower than expected (11.6%). In contrast, hypertensive hemorrhage represents the cause of up to 79.5% of ICH. The previous studies in relation to this possible common substrate have shown that the cere-bral vascular phenotype (ICH vs. lacunar infarcts) due to hypertensive microangiopathy would be related in part to age and cholesterol levels17,18. Therefore, a pos-sible explanation to our findings could be related to age

(remarkably younger patients) and the lower frequency of dyslipidemia (5.6%) known in our population. Another possible explanation would be in relation to the less severe clinical deficit associated with lacunar stroke19, which may affect the arrival or referral of these patients. These results are consistent in the region with the pre-vious studies in Santiago de Chile and Bogotá13,20. Unfortunately, the body mass index, which has been shown to be a prognostic factor for the development of ICH or lacunar infarctions in hypertensive microangiop-athy18, has not been evaluated in the present study. Future prospective and comparative studies should be taken into account to confirm these findings.

Regarding gender, women presented a stroke less frequently, with greater age (according to literature8,21,22) and significantly less known cardiovascular risk factors than men, which is also consistent with the previous studies. Factors such as hypertension and atrial fibrilla-tion, which in other series showed a significantly higher frequency in women, have not been seen in our study8,9. The age difference in HIC is remarkable among gen-ders, being the higher hypertension prevalence in early age7 and the hypothetical hormonal preventive effect in women20,21 probable reasons of this finding.

As a relevant limitation at the present study, it is a monocentric study, involving patients from urban and rural areas that may not represent a specific geograph-ic area.

In this prospective study in our country, hypertension is a risk factor highly related to stroke with a higher frequency of hypertensive hemorrhages in younger pa-tients than other series, especially in men. The frequen-cy of different stroke subtypes would be related to environmental, sociocultural, and biological factors. Multicenter and comparative studies are warranted to confirm these findings. The intensification of public health programs focused on the control of risk factors,

Figure 3. Bars showing the mean age according to gender in overall (A), ischemic (B), and intracerebral hemorrhage (C) stroke patients.

A B C

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especially hypertension, is necessary to prevent cere-brovascular disease in our environment.

Funding

There was no particular funding source for this sci-entific report.

Conflicts of interest

The authors declare that in this study, there are no relevant conflicts of interest.

References 1. Bonita R. Epidemiology of stroke. Lancet. 1992;339:342-4. 2. Truelsen T, Piechowski-Jóźwiak B, Bonita R, Mathers C, Bogousslavs-

ky J, Boysen G, et al. Stroke incidence and prevalence in Europe: a review of available data. Eur J Neurol. 2006;13:581-98.

3. Arias-Rivas S, Vivancos-Mora J, Castillo J, En Nombre de Los Investi-gadores Del Registro Epices. Epidemiology of the subtypes of stroke in hospitalised patients attended by neurologists: results of the EPICES registry (I). Rev Neurol. 2012;54:385-93.

4. Saposnik G, Brutto OH, Iberoamerican Society of Cerebrovascular Di-seases. Stroke in South America: a systematic review of incidence, prevalence, and stroke subtypes. Stroke. 2003;34:2103-7.

5. Boletín de Vigilancia. Enfermedades no Transmisibles y Factores de Riesgo. Ministerio de Salud Pública y Bienestar Social; 2015. Available from: http://www.mspbs.gov.py.

6. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Eze-kowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare profes-sionals from the American heart association/American stroke association. Stroke. 2014;45:2160-236.

7. Primera Encuesta Nacional de Factores de Riesgo de Enfermedades No Transmisibles. Primera Edición. Asunción, Ministerio de Salud Pública y Bienestar Social; 2012. Available from: http://www.mspbs.gov.py.

8. Andersen KK, Andersen ZJ, Olsen TS. Age and gender-specific preva-lence of cardiovascular risk factors in 40,102 patients with first-ever is-chemic stroke: a nationwide Danish study. Stroke. 2010;41:2768-74.

9. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Ly-nch G, et al. Sex differences in stroke: epidemiology, clinical presenta-tion, medical care, and outcomes. Lancet Neurol. 2008;7:915-26.

10. Lang EW, Ya ZR, Preul C, Hugo HH, Hempelmann RG, Buhl R, et al. Stroke pattern interpretation: the variability of hypertensive versus amyloid angiopathy hemorrhage. Cerebrovasc Dis. 2001;12:121-30.

11. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991;337:1521-6.

12. Saposnik G, Caplan LR, Gonzalez LA, Baird A, Dashe J, Luraschi A, et al. Differences in stroke subtypes among natives and Caucasians in Boston and Buenos Aires. Stroke. 2000;31:2385-9.

13. Carod-Artal FJ, Lanchipa JO, Ramírez LM, Pérez NS, Aguayo FM, Mo-reno IG, et al. Stroke subtypes and comorbidity among ischemic stroke patients in Brasilia and cuenca: a Brazilian-Spanish cross-cultural study. J Stroke Cerebrovasc Dis. 2014;23:140-7.

14. Nogales-Gaete J, Núñez L, Arriagada C, Sáez D, Figueroa T, Fernán-dez R, et al. Caracterización clínica de 450 pacientes con enfermedad cerebrovascular ingresados a un hospital público durante 1997. Rev Med Chil. 2000;128:1227-36.

15. Del Brutto OH, Mosquera A, Sánchez X, Santos J, Noboa CA. Stroke subtypes among hispanics living in Guayaquil, ecuador. Results from the Luis Vernaza hospital stroke registry. Stroke. 1993;24:1833-6.

16. Saposnik G, Gonzalez L, Lepera S, Luraschi A, Sica RE, Caplan LR, et al. Southern buenos aires stroke project. Acta Neurol Scand. 2001;104:130-5.

17. Labovitz DL, Boden-Albala B, Hauser WA, Sacco RL. Lacunar infarct or deep intracerebral hemorrhage: who gets which? The northern Manhat-tan study. Neurology. 2007;68:606-8.

18. Lioutas VA, Beiser A, Himali J, Aparicio H, Romero JR, DeCarli C, et al. Lacunar infarcts and intracerebral hemorrhage differences: a nested ca-se-control analysis in the FHS (Framingham heart study). Stroke. 2017; 48:486-9.

19. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689-701.

20. Peña I, Ruiz C, Morillo LE, Pedraza OL, Sánchez E, Santín LC, et al. Clasificación del TOAST en la práctica clínica de un hospital universita-rio. Acta Neurol Colombiana. 2001;17:304-30.

21. Alonso de Leciñana M, Egido JA, Fernández C, Martínez-Vila E, San-tos S, Morales A, et al. Risk of ischemic stroke and lifetime estrogen exposure. Neurology. 2007;68:33-8.

22. Murphy SJ, McCullough LD, Smith JM. Stroke in the female: role of biological sex and estrogen. ILAR J. 2004;45:147-59.

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Incidence rates of Parkinson’s disease in Mexico: Analysis of 2014-2017 statisticsMayela Rodríguez-Violante1*, Leora Velásquez-Pérez2 and Amin Cervantes-Arriaga1,3

1Movement Disorders Clinic; 2Department of Epidemiology; 3Clinical Neurodegenerative Diseases Research Unit, National Institute of Neurology and Neurosurgery. Mexico City, Mexico


ORIGINAL ARTICLE

Abstract

Objective: The objective of this study was to estimate and analyze the incidence and incidence rates of Parkinson’s disease (PD) in Mexico. Methods: Data on new cases of PD from January 2014 to December 2017 were extracted from the electronic Morbidity Annals and Epidemiological Bulletin published by the Secretary of Health. Crude and age-standardized incidence and incidence rate were calculated and compared with reports from other countries. Results: The overall incidence rate for the 2014-2017 period was 37.92/100,000 (incidence density of 9.48/100,000 person-years). The incidence rate in the 65+ population was 313.94/100,000. The incidence rate was higher in men than in women (42.22 vs. 34.78/100,000, respectively). Conclusion: The incidence rate in Mexican population increases with age, and it is slightly more frequent in men but is lower in comparison to developed countries. Differences in incidence rates between developed and underdeveloped countries merit further studies.

Key words: Parkinson’s disease. Incidence. Rate. Mexico.

Tasa de incidencia de la enfermedad de Parkinson en México: Análisis de 2014-2017

Resumen

Objetivo: Estimar y analizar las tasas de incidencia e incidencia de la enfermedad de Parkinson en México. Métodos: Se extrajeron los datos sobre nuevos casos de enfermedad de Parkinson de enero de 2014 a diciembre de 2017 de los Anales de Morbilidad y del Boletín Epidemiológico publicados por el Secretario de Salud. Se calculó la incidencia y la tasa de incidencia bruta y estandarizada por edad; y se compararon con informes de otros países. Resultados: La tasa de incidencia global para el período 2014-2017 fue de 37.92 por 100.000 (densidad de incidencia de 9.48 por 100,000 personas-año). La tasa de inciden-cia en la población de más de 65 años fue de 313.94 por 100,000. La tasa de incidencia fue más alta en hombres que en mujeres (42.22 vs. 34.78 por 100,000, respectivamente). Conclusión: La tasa de incidencia en la población mexicana aumenta con la edad y es ligeramente más frecuente en los hombres, pero es menor en comparación con los países desarrollados. Las diferencias en las tasas de incidencia entre los países desarrollados y subdesarrollados merecen un mayor estudio.

Palabras clave: Enfermedad de Parkinson. Incidencia. Tasa. México.

Correspondence: *Mayela Rodríguez-Violante

Clínica de Trastornos del Movimiento

Instituto Nacional de Neurología y Neurocirugía

Insurgentes Sur, 3877

Col. La Fama

C.P. 14269, Mexico City, Mexico



Rev Mex Neuroci. 2019;20(3):136-140




DOI: 10.24875/RMN.M19000043


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137

M. Rodríguez-Violante, et al.: PD incidence in Mexico

Introduction

Parkinson’s disease (PD) is the second most com-mon neurodegenerative disease after Alzheimer’s dis-ease. PD is rare before age 50 but increases dramati-cally after age 60. Its prevalence rises from 107/100,000 in persons between 50 and 59 years old up to 1087/100,000 in persons > 70 years1. Furthermore, PD is more frequent in men than women2.

Due to changing patterns of population age distribu-tions and life expectancy, it is expected that the inci-dence of PD will increase exponentially in the next couple of decades. It has been projected that the num-ber of persons with PD will double from 2005 to 20303. Moreover, modification of other related factors such as smoking prevalence may result in up to a 10% increase is such estimates4. Currently, no proven neuroprotec-tive or disease-modifier treatment for PD is available. Consequently, PD will still be considered a health prob-lem affecting the quality of life of those who have the disease, as well as their relatives and carers.

Epidemiological data regarding PD in Latin America are scarce. At 1,960,189 km2 and with over 119 million people, Mexico is the third largest country and the third most populated in Latin America (14th and 11th world-wide, respectively). In addition, Mexico harbors an ex-traordinary ethnic and genetic diversity5.

The objective of this paper is to describe the incidence of PD using data for a nation-wide electronic database.

Materials and methods

The incidence of PD in Mexico was estimated over the period from January 2014 to December 2017 using a national electronic database. Since 1994, the General Direction of Epidemiology enabled the Epidemiological Surveillance Automated System (SUAVE), an electronic system developed for collection, recording, analysis, and dissemination of data. However, it was until 2014 that PD (ICD-10 Code G20) was included in the weekly report form. Currently, all new cases of PD are reported on weekly basis categorized by state, sex, age group, and institution of the National Health System using a standardized procedure. In addition, data are regularly evaluated for compliance and consistency. Yearly data are summarized and published on the first trimester of the following year in the Morbidity Annals6. In addition, weekly data are published as an electronic Epidemio-logical Bulletin and made publicly available at the Sec-retary of Health website7. The SUAVE system covers 78.46% of the Mexican population.

Demographic groups were predefined by age as follows: 20-24, 25-44, 45-49, 50-59, 60-64, and 65+. Estimates of population were obtained from the projections of popu-lation growth 2010-2050 of the National Council for Pop-ulation available to the public at their website8. There was no requirement for ethical approval for this study. A waiver of informed consent was approved by the local ethics com-mittee due to the retrospective nature of the study and the fact that no identifying information was used.

Statistical analysis

Incidence proportion (cumulative incidence) was cal-culated using the number of new cases of PD during a 4-year period (2014-2017) as numerator and the popu-lation at the start of time interval as denominator. Inci-dence rates were calculated by dividing the number of new cases of PD by the estimated mid-year population. Incidence rates were computed per 100,000 individu-als. Confidence intervals (95% CI) were calculated as-suming a Poisson distribution, as the event of interest was rare. Stratified incidence rates were calculated across gender, age band, and time. Incidence density (average rate) was calculated by dividing the number of new cases of PD during the specified time interval by the summed person-years of observation (per-son-years at risk). The average annual percent change (AAPC) was calculated as described by Fay et al9.

Results

Data quality

The summarized reports (by gender and age group) from the Morbidity Annals 2014-2017 were reviewed. In addition, a total of 208 weekly reports from January 2014 to December 2017 were collected. Seven reports were not available online (two from 2014, four from 2015, and one from 2016); however, since each bulletin included the accumulated frequencies, the missing data could be inferred. In addition, data were complet-ed for gender. In the case of age groups, 70 cases (16 in 2014, 23 in 2015, 13 in 2016, and 28 in 2017) were not categorized due to missing data and were excluded from age group analyses.

Overall incidence

The total number of new (incident) cases between 2014 and 2017 was 28,457. The incidence proportion for the specified time interval was 0.04%. The overall

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incidence rate for the 2014-2017 period was 37.92/100,000 with an incidence density of 9.48/100,000 person-years. Table 1 summarizes the annual incidence and incidence rate by gender and age group, and table 2 includes the annual incidence by state. The AAPC drawn from the data was 26.70% for the period 2014-2017. Neverthe-less, the percentage change from 2014 to 2015 was 43.82%, while the change from 2015 to 2016 and from 2016 to 2017 was 10.13% in both the cases.

Incidence by gender

A total of 14,914 men were diagnosed with PD during the 4-year period for an incidence rate of 42.22/100,000. On the other hand, 13,543 women were diagnosed with PD, with an incidence rate of 34.78/100,000. The male-to-female ratio was 1.10.

Incidence by age group

As mentioned before, 70 (0.25%) cases could not be classified by age group. Consequently, a total of 28,387

incident cases were included for this analysis. Stratified according to age the incidence rate increased sharply in the > 60 groups. The incidence rate in people ≥ 45 years of age was 94.86/100,000 (incidence density of 23.72/100,000 person-years), while incidence rate in the 65+ group was 313.94/100,000 (incidence density of 78.49/100,000 person-years). Conversely, incidence rate in people < 45 years was 1.66/100,000 (incidence density of 0.42/100,000 person-years).

Discussion

Neurodegenerative diseases such as PD are expect-ed to become more prevalent as population ages. PD prevalence has been reported to be between 217.22 and 308/100,000 persons10,11. PD incidence in Europe, Asia, and North America varies widely. The parkinsonism in-cidence in Northeast (PINE) Scotland (a total population of 311,357) study (PINE) reported an overall annual in-cidence of 17.9/100,00012, while a similar study carried out in the Northeast of England (total population of 488,576) reported a crude incidence of 15.9/100,000

Table 1. Overall and annual incidence of Parkinson’s disease in subgroups by gender and age

Incidence 2014 2015 2016 2017

OverallIncident casesIncidence rate*

50576.74 (95% CI 6.57‑6.93)

72739.52 (95% CI 9.30‑9.74)

800910.30 (95% CI 10.07‑10.53)

811810.26 (95% CI 10.04‑10.49)

By genderMale

Incident casesIncidence rate*

FemaleIncident casesIncidence rate*

26667.47 (95% CI 7.26‑7.84)

23916.08 (95% CI 5.89‑6.39)

384810.60 (95% CI 10.03‑11.04)

34258.54 (95% CI 8.34‑8.92)

416811.28 (95% CI 6.57‑6.93)

38419.41 (95% CI 9.20‑9.81)

423211.27 (95% CI 10.92‑11.60)

38869.36 (95% CI 9.06‑9.65)

By age group20‑24

Incident casesIncidence rate*

25‑44Incident casesIncidence rate*




65+Incident casesIncidence rate*

200.19 (95% CI 0.11‑0.29)

1490.42 (95% CI 0.35‑0.49)

1582.28 (95% CI 1.94‑2.66)

6356.04 (95% CI 5.58‑6.53)

67218.28 (95% CI 16.92‑19.71)

340742.63 (95% CI 41.21‑44.08)

300.28 (95% CI 0.18‑0.40)

2330.65 (95% CI 0.57‑0.74)

2333.27 (95% CI 2.86‑3.71)

9588.83 (95% CI 8.28‑9.41)

96225.12 (95% CI 23.56‑26.76)

483458.55 (95% CI 56.91‑60.22)

180.17 (95% CI 0.09‑0.26)

1370.38 (95% CI 0.31‑0.45)

2613.57 (95% CI 3.15‑4.03)

10389.27 (95% CI 8.72‑9.85)

99224.89 (95% CI 23.37‑26.49)

555065.20 (95% CI 64.34‑67.83)

220.22 (95% CI 0.14‑0.33)

1510.42 (95% CI 0.35‑0.49)

2933.92 (95% CI 3.49‑4.39)

10709.26 (95% CI 8.72‑9.83)

105825.56 (95% CI 24.04‑27.12)

549662.23 (95% CI 60.60‑63.89)

*Per 100,000 persons. CI: Confidence interval

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M. Rodríguez-Violante, et al.: PD incidence in Mexico

persons-years13. On the other hand, a study in France using a health-care insurance database reported an an-nual incidence of PD of 49/100,000 person-years10.

In Mexican population, we found an incidence of PD from 2014 to 2017 of 37.92/100,000 persons aged 20 or over. The incidence density of 9.48/100,000 per-son-years is significantly lower in comparison with other reports.

Overall, the highest incidence rate has been reported in China; a recent meta-analysis found an incidence of PD from 1983 to 2009 of 362/100,000 person-years14. Canada is second with an incidence density of 252/100,000 persons15. On the other hand, India has the lowest incidence density (5.7/100,000 person-year)16. Regarding Latin America, Bauso et al. reported a crude incidence density of 31.2/100,000 person-years in Argentina17.

PD is more common in men than in women. For in-stance, the PINE study found an incidence of 21.1 per 100,000 in men and 14.7 per 100,000 in women; similar rates were also reported in the Northeast of England study (17.7 in men and 14.0 in women). The incidence rates in the Mexican population maintained the expected sex ratio with PD being slightly more common in men.

It is well known that PD rarely occurs before age 50 years and sharply increases after the age of 60 years18; in Mexican population, incidence was higher in people over 45 years and over 65 years over the 4-year period (94.86 and 313.94/100,000, respectively). An annual incidence of 232/100,000 persons has been reported in the 65 years or older Navajo population despite having a lower annual crude incidence of 22.5/100,00019.

On the other hand, the incidence rate in Mexican population < 45 years of age was of 1.66/100,000. In comparison, a study in Finland population reported an incidence of early onset PD (< 55 years of age at the time of diagnosis) of 3.3/100,000 between 1995 and 2006. Interestingly, the incidence increased from 2.1 to 4.5/100,000 during this period20. In our population, the incidence rate had a 1.5-fold increase from 2014 to 2016 but maintained stable afterward. More recently, Savica et al. analyzed trends in PD incidence rates in Minnesota from 1976 to 2005; they observed an in-crease in incidence from 10.1 to 18.5/100,000 per-son-years21. Conversely, a study in English population from 1999 to 2009 found a downward trend with inci-dence rates declining between 1% and 6% depending on the case definition used22.

There are several hypotheses on this time-trends including a longer life expectancy, better symptom awareness by the patient leading to earlier diagnosis, and change in smoking habits increasing the risk of PD. It should be pointed that, in our results, there was an

Table 2. Overall and annual incidence of Parkinson’s disease by state and year

State Incidence rate per 100,000 habitants

2014 2015 2016 2017

Aguascalientes 1.96 5.12 12.76 12.37

Baja California 13.08 11.30 9.82 8.20

Baja California Norte 10.03 11.93 8.53 55.00

Campeche 0.71 10.56 11.01 9.12

Coahuila 16.84 1.70 1.93 15.65

Colima 26.20 19.18 25.82 23.82

Chiapas 6.26 3.79 5.94 5.23

Chihuahua 12.19 8.99 22.34 22.58

Mexico City 3.40 9.14 9.38 8.28

Durango 9.28 27.30 21.11 21.25

Guanajuato 0.95 3.10 3.61 5.25

Guerrero 3.11 8.60 7.38 7.68

Hidalgo 10.90 7.34 8.02 8.73

Jalisco 5.65 16.52 17.01 18.47

Estado de México 5.47 5.13 5.65 4.49

Michoacan 7.64 7.77 10.02 9.38

Morelos 20.22 19.59 18.05 16.33

Nayarit 15.64 13.57 14.02 11.47

Nuevo León 1.44 11.51 8.37 9.39

Oaxaca 7.71 12.35 10.59 6.91

Puebla 4.30 10.30 8.13 7.78

Querétaro 0.74 6.71 5.86 4.96

Quintana Roo 8.68 6.36 6.24 6.13

San Luis Potosí 3.19 9.41 10.30 13.79

Sinaloa 21.76 27.70 33.44 26.82

Sonora 12.39 11.98 13.43 14.10

Tabasco 6.91 5.91 6.99 8.23

Tamaulipas 3.87 13.67 12.87 13.45

Tlaxcala 4.05 8.06 11.76 8.21

Veracruz 4.30 9.07 11.66 12.29

Yucatán 11.32 7.37 7.45 6.33

Zacatecas 2.72 2.17 4.37 5.71

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evident increase in the incidence rate from 2014 to 2015 followed by a pronounced decrease from 2015 to 2016 and the stabilizing. We cannot rule out a bias due to underreporting during the 1st year of the inclusion of PD coding in the weekly report forms.

Our report has a number of limitations. First, coding errors and misdiagnosis cannot be ruled out. Most of the patients were diagnosed by a generalist possibly diminishing diagnostic accuracy. For example, the PINE study reported that 8.8% of the subjects changed diag-nosis from PD to another disorder during follow-up12. Likewise, the National Epidemiological Surveillance System considers acceptable when 80% of the weeks are consistent in terms of diagnoses notified in a timely manner, so it is possible to have a variation of up to 20%.

Second, age groups were used as provided in the database, thus limiting further analysis. Nevertheless, the correlation of age with PD incidence is non-linear and the groups of 50-59, 60-64, 65 and over were ap-propriate for the objectives of the study. Third, available data comprised only 4 years which prevent us from properly analyzing trend, although it allows to observe differences between age and sex groups. Furthermore, due to the pre-specified age groups, juvenile parkin-sonism (age of onset < 21 years) is not recorded. Fi-nally, data collected only included incident cases, no information on pre-existing cases was available; con-sequently, point or period prevalence cannot be prop-erly estimated.

To the best of our knowledge, this is the first report of PD incidence rate in Mexico as a whole. The 2014-2017 crude incidence rate of 37.92/100,000 or 9.48/100,000 person-years is lower than those reported in most developed countries, but when stratified by age, the incidence rate of 23.72/100,000 person-years in people ≥ 45 years is more in line with other reports. Differences in incidence rates between developed and under-developed countries merit further studies.

Sex ratio is also consistent with the current literature. Since nation-wide PD data collection is relatively new in Mexico, future analysis will be required to estimate trends.

Acknowledgments

The authors thank Dr. Gabriela del Carmen Nu-camendi for her assistance regarding the use of Sec-retary of Health databases and General Direction of Epidemiology data.


The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References 1. Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkin-

son’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583-90.

2. Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson’s disease. Rev Neurol (Paris). 2016;172:14-26.

3. Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 throu-gh 2030. Neurology. 2007;68:384-6.

4. Rossi A, Berger K, Chen H, et al. Projection of the prevalence of Parkin-son’s disease in the coming decades: revisited. Mov Disord. 2018;33:156-9.

5. Moreno-Estrada A, Gignoux CR, Fernández-López JC, et al. Human genetics. The genetics of Mexico recapitulates native American substruc-ture and affects biomedical traits. Science. 2014;344:1280-5.

6. Secretaría de Salud. Anuarios de Morbilidad. Dirección General de Epi-demiología; 2018. Available from: http://www.epidemiologia.salud.gob.mx/anuario/html/anuarios.html. [Last accessed on 2018 Mar 08].

7. Matus CR, Herrera AR. Boletín Epidemiológico, Sistema Nacional de Vigilancia Epidemiológica Sistema Único de Información. Secretaría de Salud; 2017. Available from: https://www.gob.mx/salud/acciones-y-pro-gramas/direccion-general-de-epidemiologia-boletin-epidemiologico. [Last accessed on 2018 Mar 08].

8. CONAPO. Proyecciones de la Población 2010-2050; 2018. Available from: http://www.conapo.gob.mx/es/CONAPO/Proyecciones. [Last ac-cessed on 2018 Mar 08].

9. Fay MP, Tiwari RC, Feuer EJ, Zou Z. Estimating average annual percent change for disease rates without assuming constant change. Biome-trics. 2006;62:847-54.

10. Blin P, Dureau-Pournin C, Foubert-Samier A, et al. Parkinson’s disease incidence and prevalence assessment in France using the national heal-thcare insurance database. Eur J Neurol. 2015;22:464-71.

11. Enders D, Balzer-Geldsetzer M, Riedel O, et al. Prevalence, duration and severity of Parkinson‘s disease in germany: a combined meta-analysis from literature data and outpatient samples. Eur Neurol. 2017;78:128-36.

12. Caslake R, Taylor K, Scott N, et al. Age-, gender-, and socioeconomic status-specific incidence of Parkinson’s disease and parkinsonism in Northeast Scotland: the PINE study. Parkinsonism Relat Disord. 2013; 19:515-21.

13. Duncan GW, Khoo TK, Coleman SY, et al. The incidence of Parkinson’s disease in the North-East of England. Age Ageing. 2014;43:257-63.

14. Ma CL, Su L, Xie JJ, et al. The prevalence and incidence of Parkinson’s disease in China: a systematic review and meta-analysis. J Neural Transm (Vienna). 2014;121:123-34.

15. Allyson Jones C, Wayne Martin WR, Wieler M, King-Jesso P, Voaklander DC. Incidence and mortality of Parkinson’s disease in older Canadians. Parkinsonism Relat Disord. 2012;18:327-31.

16. Gourie-Devi M. Epidemiology of neurological disorders in India: review of background, prevalence and incidence of epilepsy, stroke, Parkinson’s disease and tremors. Neurol India. 2014;62:588-98.

17. Bauso DJ, Tartari JP, Stefani CV, et al. Incidence and prevalence of Parkinson’s disease in Buenos Aires city, Argentina. Eur J Neurol. 2012; 19:1108-13.

18. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525-35.

19. Gordon PH, Mehal JM, Holman RC, et al. Incidence and prevalence of Parkinson’s disease among Navajo people living in the Navajo nation. Mov Disord. 2015;30:714-20.

20. Ylikotila P, Tiirikka T, Moilanen JS, et al. Epidemiology of early-onset Parkinson’s disease in Finland. Parkinsonism Relat Disord. 2015;21938-42.

21. Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA. Time trends in the incidence of Parkinson disease. JAMA Neurol. 2016;73:981-9.

22. Horsfall L, Petersen I, Walters K, Schrag A. Time trends in incidence of Parkinson’s disease diagnosis in UK primary care. J Neurol. 2013;260: 1351-7.

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Efecto del estrés en la adquisición y consolidación de la memoria de reconocimiento de objetos en ratasMaría R. González-López, Norma L. García-Saldívar, José C. Arriaga-Ramírez y Sara E. Cruz-Morales*Psicofarmacología, Unidad de Investigación Interdisciplinaria en Ciencias de la Salud y Educación (UIICSE), FES-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla. Ciudad de México, México


ARTíCuLO ORIGINAL

Resumen

Introducción: Muchas tareas utilizadas en la evaluación del aprendizaje y memoria tienen componentes estresantes. Esto dificulta la interpretación de resultados de los efectos del estrés sobre la mejoría, el deterioro o la ausencia de efecto en la memoria. Se considera que la tarea de reconocimiento de objetos (RO) no contiene estímulos estresantes, por lo que pue-de ser útil en el estudio del efecto del estrés sobre la memoria. Objetivo: Evaluar el efecto del estrés por restricción (R) (15 min) sobre la adquisición y consolidación de la memoria en RO. Adicionalmente se evaluó la posible activación del eje hipotálamo pituitario adrenal como consecuencia del entrenamiento en RO. Método: Ratas machos Wistar asignadas a cuatro grupos ejecutaron la tarea de RO: dos con R pre o posentrenamiento (R+RO, RO+R), otro recibió corticosterona (C) intraperitonealmente preentrenamiento (C+RO) y uno solo RO. Al concluir la tarea, fueron sacrificados inmediatamente y se cuantificó la C plasmática por ensayo por inmunoabsorción ligado a enzimas (ELISA). Para descartar el efecto estresor del entrenamiento en RO, se midió la C en cuatro grupos: uno intacto (I), dos entrenados en RO sacrificados 0 o 24 h después (ERO-0 y ERO-24) y otro restringido 15 min (R15), sacrificado inmediatamente después. Resultados: La R deterioró la adquisición en los grupos R+RO y RO+R; la concentración de C aumentó en R+RO y C+RO. En los grupos ERO-0 y R15 aumentó la concentración de C plasmática. Conclusiones: La R deterioró la adquisición en RO. El entrenamiento en RO aumentó la concentración de C en plasma similar a R15, indicando la naturaleza estresante de la tarea. Es probable que el deterioro de memoria en el grupo R+RO se deba a la suma de la elevación de la C inducida por la R y a los cambios in-ducidos por el entrenamiento en RO. La inyección de C no modificó la memoria.

Palabras clave: Memoria de reconocimiento. Adquisición. Estrés. Corticosterona. Restricción.

The effect of stress on acquisition and consolidation of object recognition memory in rats

Abstract

Introduction: Many tasks used in the evaluation of learning and memory have stressful components. This makes it difficult to interpret the effects of stress on improvement, impairment or no effect on memory. It is considered that the object recog-nition task (RO) contain no stressful stimuli; therefore, it can be useful in the study of the effect of stress on memory. Objective: To evaluate the effect of restraint stress (R) (15 min) on acquisition and consolidation of memory in RO. In

1665-5044/© 2018. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Correspondence: *Sara Eugenia Cruz-Morales

Psicofarmacología, UIICSE, FES-Iztacala

Universidad Nacional Autónoma de México

Av. de los Barrios, 1

C.P. 54090, Tlalnepantla, Méx., México


Disponible en internet: 18-06-2019

Rev Mex Neuroci. 2019;20(3):141-148


Fecha de recepción: 4-06-2018

Fecha de aceptación: 30-11-2018

DOI: 10.24875/RMN.M19000045

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Introducción

El estrés facilita, deteriora o no influye en las etapas de la memoria en ratas1-3 y humanos4, su efecto inter-viene en los circuitos cerebrales involucrados5,6. La respuesta depende de las características del estresor7, la duración y naturaleza de la tarea8-10, y factores fisio-lógicos del sujeto que influyen en las respuestas neu-roendocrinas y conductuales11.

El estrés provoca liberación de corticosterona (C) por las glándulas suprarrenales12,13. Niveles de estrés alto o bajo deterioran la memoria y un nivel moderado la mejora14. La administración de C puede mejorar15 o deteriorar la memoria14,16,17, lo que depende de la dosis, la experiencia emocional o la fase de la memoria estudiada18,19.

La naturaleza de la tarea es importante. En el estudio de la memoria de procedimiento hemos utilizado dos tareas: la de evitación inhibitoria (EI) y el laberinto ele-vado en T (LET). En la EI, la administración del choque provoca que los animales aprendan a evitar el estímulo aversivo durante el entrenamiento. Con esta tarea se han estudiado diferentes estructuras cerebrales y la participación de sistemas de neurotransmisión como el colinérgico20,21. Anticolinérgicos como la escopolamina administrada intraperitonealmente22 o intraestriatal in-dujeron amnesia23. La escopolamina posentrenamien-to no produjo amnesia en intensidades de 1 y 1.5 mA; con intensidades de 2 y 2.5 mA produjo amnesia22 y altas intensidades, 2.8 y 3.0 mA, no deterioraron la memoria. Se ha propuesto que con altas intensidades de choque, la actividad colinérgica no es necesaria para la consolidación24. Estudios realizados con ago-nistas GABAérgicos demostraron quela administración de muscimol indujo amnesia25 y potenció la amnesia inducida por escopolamina, con intensidades bajas26.

Los componentes aversivos de la tarea con el LET fueron comparados con estresores como la restricción de movimiento (R)27, estresor traumático para los

roedores28 que activa el eje hipotálamo pituitario adre-nal (HPA)27. La exposición pre entrenamiento a 6029 o 15 min de R30 deterioraron la memoria pero no la ex-posición posentrenamiento31. Estas dos tareas son consideradas aversivas por la presencia de los espa-cios abiertos y el choque, componentes considerados estresores intrínsecos32. La exposición al entrenamien-to en LET activa el eje HPA33 y el choque en EI au-menta la concentración de C30, por lo que los resulta-dos podrían interpretarse como la suma de los estresores intrínsecos más el estresor extrínseco con efecto en el entrenamiento.

La tarea de reconocimiento de objetos (RO) evalúa la memoria declarativa mediante la preferencia por la novedad34,35. Tiene la ventaja de que los ensayos pue-den ser modificados para examinar diferentes compo-nentes de la memoria, el efecto del estrés y la libera-ción de hormonas. Se ha propuesto que carece de estímulos aversivos por no requerir de privación de agua y comida36,37. El objetivo de este trabajo fue eva-luar en una tarea de memoria de reconocimiento de objetos, el efecto del estrés por R (15 min) sobre la adquisición y consolidación de la memoria y estudiar la posible activación del eje HPA como consecuencia del entrenamiento de la tarea.

Método

Sujetos

Los experimentos fueron realizados siguiendo las normas establecidas por las guías de conducta ética en el cuidado y uso de animales no humanos de la Society for Neuroscience. Se utilizaron ratas Wistar machos adultos ingenuos experimentalmente (250-270 g) provenientes del bioterio de la Universidad Nacional Autónoma de México, FES-Iztacala. Los su-jetos fueron alojados en el bioterio, con agua y alimento ad libitum, con un ciclo de luz-oscuridad (8:00 a

addition, the possible activation of the hypothalamic-pituitary-adrenal axis was evaluated as a consequence of the training in RO. Methods: Male Wistar rats assigned to four groups carried of the task of RO: two with R pre or post-training (R+RO, RO+R), another received corticosterone (C) intraperitoneally pre-training (C+RO) and one RO only (RO). Thereafter, they were immediately sacrificed and plasma C was quantified. To exclude the stressor effect of training in RO, C was measured in four groups: one intact (I), two trained in RO sacrificed 0 or 24 h later (ERO-0 and ERO-24) and another restricted 15 min (R15), sacrificed immediately after. Results: The R impaired the acquisition in the groups R+RO and RO+R; the con-centration of C increased in R+RO and C+RO. In ERO-0 and R15, the plasma C increased. Conclusions: The pre-training R impaired memory. Training in RO increased the plasma C similar to R15 indicating the stressful nature of the task. The C injection did not modify memory.

Key words: Recognition memory. Acquisition. Stress. Corticosterone. Restriction.

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MR. González-López, et al.: Estrés y memoria de reconocimiento en ratas

20:00 h), donde permanecieron en estas condiciones durante cinco días previos al experimento. Al inicio de los experimentos los sujetos (n = 56) se asignaron aleatoriamente a diferentes grupos. Los grupos experimentales que ejecutaron la tarea de memoria de reconocimiento recibieron una sesión de habituación de 10 min en la caja de reconocimiento libre de objetos un día previo al entrenamiento.

Fármaco

Corticosterona en polvo C2505 (Sigma-Aldrich).

Aparatos

– Restrictores. Se emplearon contenedores de acrílico cilíndricos (Plas-Labs, Inc™) con hoyos ajustables a la talla del sujeto experimental. Los sujetos fueron restringidos en un cuarto con luz natural durante 15 min.

– Lector de placas. Para medir la concentración de C se utilizó un lector de placas (H Reader 1 de HLAB), con filtro de 405 a 630 nm y una resolución de 0.0001 de absorbancia.

– Cámara de reconocimiento de objetos. Se empleó una cámara construida de PVC blanco (100 x 100 x 50 cm), con el piso cuadriculado (10 cm) que permitió colocar los objetos siempre a la misma distancia. Una cámara de circuito cerrado (AVTECH de 4 ca-nales AVTECH AVC792DBKIT) grabó los ensayos de los sujetos con el fin de visualizar y hacer mediciones mediante un software para colección y análisis de datos Observer38.

– Objetos familiares y novedosos. Se utilizaron legos infantiles de plástico de color azul para los objetos familiares (Fig. 1A) variando el color y la forma para el objeto novedoso (Fig. 1B). La parte interna de los legos se saturaron de acrílico dental con el fin de que pesaran y la rata no los moviera.

– Tarea de RO. Las sesiones experimentales se reali-zaron entre las 8:00 y 11:00 h. En los ensayos de entrenamiento se colocó al sujeto en la cámara con dos objetos idénticos (F1 y F2) y se les permitió ex-plorarlos en una prueba de familiarización durante 5 min. La exploración se definió como el acercamien-to de los sujetos dirigiendo la nariz hacia los objetos en un rango de 2 cm o cuando olfateaban. Dar la vuelta a/o sentarse sobre el objeto no se considera-ron una conducta de exploración39,40. El criterio de inclusión en el grupo fue que los sujetos exploraran por lo menos 10 s durante los ensayos de

entrenamiento solo en los grupos que no hubieran sido expuestos a tratamiento antes del entrenamien-to. En los grupos con tratamiento previo al entrena-miento, se respetaron los tiempos de exploración como efecto de este.En el ensayo de prueba después de un periodo de

retardo de 24 h posteriores al entrenamiento se expuso a los sujetos a un objeto familiar (OF) y a un objeto novedoso (ON) durante 5 min.

Se registró el tiempo de exploración al objeto nove-doso (TN) y al objeto familiar (TF) y se calculó un ín-dice de discriminación para cada sujeto que se expresó como ID = 100 * (TN – TF)/(TN + TF), donde TF = tiem-po dedicado a explorar al objeto familiar y TN = tiempo dedicado a explorar al objeto novedoso. El índice de discriminación (ID) mayor a cero, muestra que los ani-males exploraron más al ON que al OF, por lo que se considera buena memoria, mientras que una propor-ción cercana a cero indica que los animales exploraron el mismo tiempo a los dos objetos, lo que se considera deterioro de la memoria35,36.

Cuantificación de la corticosterona

Al concluir las sesiones experimentales, los sujetos se sacrificaron por decapitación entre las 8:00 y 11:00 h, se obtuvieron muestras de sangre del tronco (3 ml) que fueron centrifugadas a 3,000 rpm. Inmedia-tamente después el suero se mantuvo a –20 °C hasta ser procesado, por medio de una prueba de enlace de inmunoensayo (Assay Designs, Catálogo n.º 900-097 EV, Ann Arbor, Michigan, EE.UU.); los resultados ana-líticos son expresados en ng/ml. El límite bajo de de-tección fue de 0.027 ng/ml y el porcentaje inter e in-traensayo tuvo un coeficiente de variación de 5.3 y 9.87 respectivamente.

Figura 1. Objetos utilizados en la tarea de reconocimiento de objetos. A: objeto familiar (OF). B: objeto novedoso (ON).

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Procedimiento

Se utilizaron 32 sujetos asignados a cuatro grupos (n = 8) que recibieron los siguientes tratamientos: un grupo que ejecutó la tarea de RO; dos grupos que realizaron el entrenamiento de la tarea de RO con la diferencia que uno fue sometido a R antes del entre-namiento (estrés en la fase de adquisición) (R+RO) y otro fue entrenado e inmediatamente después someti-do a R (estrés en la fase de consolidación) (RO+R); a un cuarto grupo se le administró 5 mg/kg intraperito-neal (ip) antes del entrenamiento para simular la C li-berada por la exposición a R (C+RO). La prueba de memoria se realizó en todos los grupos 24 h después del entrenamiento. Los animales fueron sacrificados después de la prueba.

Adicionalmente se evaluó la liberación de C en plas-ma después de exponer a los sujetos al entrenamiento de RO para descartar que la sola exposición al entre-namiento active el eje HPA como ocurre en otras ta-reas33. Se asignaron 24 ratas a cuatro grupos (n = 6), que recibieron los siguientes tratamientos: un grupo intacto (I), sin ningún tratamiento, un grupo expuesto a 15 min de R sacrificado inmediatamente después (R15); otros dos grupos expuestos solo al entrenamiento en RO sacrificados 0 o 24 h después (ERO-0 y ERO-24).

Estadística

Dado que se confirmó la homogeneidad de las va-rianzas, para analizar los efectos en el total del TN y el ID entre grupos, se empleó un análisis de varianza de una vía (ANOVA), cuando hubo diferencias se utilizó

una prueba post hoc de Honestly Significant Difference (HSD) de Tukey. Para analizar las diferencias entre TN y TF de cada grupo se realizaron pruebas de t de Stu-dent pareada. Como los datos de la concentración de C no presentaron homogeneidad de varianzas, se rea-lizó una prueba de Kruskal-Wallis seguida de una prue-ba U de Mann-Whitney. Todos los análisis estadísticos se realizaron mediante el software STATISTICA® (ver-sión 7).

Resultados

En la figura 2A se muestra el tiempo de exploración al objeto novedoso de los diferentes tratamientos. Se observaron diferencias significativas (F [3, 28] = 7.60; p < 0.001) entre los grupos. Los sujetos de los grupos R+RO y RO+R permanecieron menos tiempo exploran-do el ON (p < 0.01) respecto al que ejecutó la tarea sin R. La administración de C antes del entrenamiento no tuvo efecto. En la figura 2B se muestra el ID, se en-contraron diferencias significativas entre los grupos (F [3, 28] = 5.37; p < 0.01); el grupo R+RO difirió de todos los grupos (p < 0.05), mostrando una menor dis-criminación al ON. Los grupos de RO+R y de C+RO no presentaron diferencias respecto a RO.

La prueba t de Student mostró que el grupo que ejecutó la tarea de RO sin ningún tratamiento exploró más el ON (t [7] = 3.53; p < 0.01). Hubo menor explo-ración de los objetos en los grupos que fueron some-tidos a R o que recibieron C. No obstante, se observó que en el grupo de R+RO el TN y el TF fueron similares (t [7] = 0.2; p = 0.843). La exploración al ON fue mayor

Figura 2. Gráficas que muestran a sujetos expuestos a restricción (R) antes o después del entrenamiento (R+RO, RO+R) o de la administración de corticosterona (5 mg/kg) (C+RO). A: media (± EEM) del tiempo de exploración al objeto novedoso (TN). B: media (± EEM) del índice de discriminación (ID) en la tarea de RO.*p < 0.01.†p < 0.05.

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en los grupos que recibieron R después del entrena-miento o C (t [7 = 2.93; p < 0.05) (Fig. 3).

La concentración de C en plasma presentó diferen-cias significativas entre los grupos (H [3, n = 31] = 15.727; p < 0.001). Los sujetos que fueron sometidos a R o a la administración de C antes del entrenamiento mostraron mayor concentración de C plasmática (p < 0.05), mien-tras que en el grupo expuesto a R posentrenamiento la concentración fue parecida al grupo RO (Fig. 4).

Finalmente, la figura 5 muestra la concentración de C en plasma de los grupos expuestos al entrenamiento en RO o a la R 15 min; se observaron diferencias (H [4, n = 30] = 13.21; p < 0.05). Los grupos que reci-bieron R o el entrenamiento en RO y que fueron sacri-ficados inmediatamente después mostraron mayor concentración de C respecto al grupo intacto (p < 0.05), no así los que fueron sacrificados a las 24 h, lo que denota que el entrenamiento en la tarea de RO esti-mula al eje HPA de forma similar a la exposición a R cuando se registra inmediatamente.

Discusión

Nuestros resultados demostraron deterioro en la ad-quisición de la memoria de reconocimiento de los su-jetos expuestos a R antes del entrenamiento, evalua-dos en la fase de prueba 24 h después, según el TN y el ID, parámetros empleados en esta prueba. Lo anterior es consistente con lo reportado en otros estu-dios41 donde demostraron que el efecto de R en RO provocó deterioro cuando se aplicó antes del entrena-miento y la fase de prueba se realizó en intervalos de 3 h, pero no cuando se realizó la prueba 5 min des-pués. Efectos similares se encontraron en este labora-torio con la exposición a 15 min de R preentrenamiento y una demora de fase de prueba de dos horas que también provocó deterioro de la memoria de RO42. Como puede observarse para esta tarea las demoras entre la fase de entrenamiento y la prueba son deter-minantes para poder evaluar el ID y el TN43, ya que los intervalos largos pueden influir en la reducción del ID39; sin embargo, con esta tarea se pudieron observar efec-tos del estrés 24 h después. La exposición a R antes del entrenamiento se ha observado en otras tareas como LET, ya que 15 o 60 min de R ocasionaron de-terioro de la memoria cuando el entrenamiento se rea-lizó inmediatamente después29,30.

En la consolidación de RO no se observó un efecto significativo en el ID, lo que implica que los sujetos discriminaron en forma similar al grupo que realizó la tarea sin R. Cuando se compararon TN y TF durante

la prueba, los sujetos del grupo RO+R visitaron más el ON, pero exploraron menos que el grupo sin R, esto puede estar relacionado con un efecto de ansiedad inducido por la caja utilizada para desarrollar la tarea, ya que los sujetos muestran menor tiempo de explora-ción. El efecto de R sobre la consolidación evaluado con el ID, coincide con los resultados obtenidos en otros estudios con 60 min de R precedidos por el en-trenamiento en RO en ratones2.

Figura 4. Medianas de la concentración de corticosterona (C) en plasma de sujetos que realizaron la tarea de reconocimiento de objetos sin restricción (RO), expuestos a restricción preentrenamiento o posentrenamiento (R+RO, RO+R) o 5 mg/kg de C preentrenamiento (C+RO).*p < 0.05 frente al grupo de RO.

Figura 3. Medias (± EEM) del tiempo de exploración al objeto novedoso (TN) o al objeto familiar (TF) en sujetos sin restricción (RO), expuestos a restricción preentrenamiento o posentrenamiento (R+RO, RO+R) o 5 mg/kg de corticosterona (C) preentrenamiento (C+RO) que realizaron la tarea de RO.*p < 0.01 frente a TN de su grupo.†p < 0.05 frente a TN de su grupo.

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Los sujetos a los que se les administró C preentrenamiento no presentaron deterioro de RO; efectos similares se han reportado en una tarea de alternación espacial18. La concentración en plasma medida 24 h después en los grupos que realizaron la tarea de RO aumentó solo en los grupos que fueron expuestos a R o C preentrenamiento. Esto implica que la sola elevación de C no es suficiente para generar cambios en la memoria de RO y aunque la concentra-ción es similar parece que el efecto en la memoria dependió del momento de la presentación de la R.

Hay tareas que por sus características aversivas ge-neran activación del eje HPA durante el entrenamien-to31,33. En diversos estudios que utilizan la tarea de RO para evaluar la memoria emplean una caja cuadrada o rectangular, esta misma tarea se ha utilizado como campo abierto para evaluar la respuesta de ansiedad44,45.

El efecto del estrés por R en la adquisición de la memoria en RO se puede explicar por el estado emo-cional del animal durante el entrenamiento46. Existen estudios que relacionan la presentación de estresores como la restricción, cercanos a la fase de la adquisi-ción con la expresión diferencial de receptores a glu-cocorticoides bajos y receptores a mineralocorticoides altos en hipocampo, que pueden generar alteración en el procesamiento de la información47. En nuestros re-sultados es probable que el efecto de la R se sume al estrés producido durante el entrenamiento en RO y que ambos modifiquen la codificación de la información emocional en las estructuras cerebrales involucradas durante la adquisición48.

Los resultados obtenidos en el ID y el TN sugieren que para que ocurra deterioro de memoria se requiere que los sujetos sean expuestos a la suma de factores estresantes; en este caso el estrés extrínseco produ-cido por la R e intrínseco ocasionado por el entrena-miento en RO. En estas condiciones es probable que se modifique el estado emocional durante el entrena-miento en RO y sensibilice el eje HPA, de tal forma que durante la exposición en la sesión de prueba de RO se favorezca la liberación de C49.

La cercanía entre ambos estresores es fundamental, porque en otros estudios, cuando se administraron 60 o 75 min de R antes del entrenamiento en RO, no se vio efecto en la memoria,2 tampoco 60 min de R apli-cados 24 h antes en la tarea de alternación espacial tuvieron efecto18.

En el presente estudio se observó mayo concentra-ción de C en los animales evaluados inmediatamente después del entrenamiento, respecto a los evaluados 24 h después. Los resultados muestran que el entre-namiento en la tarea de RO activa la respuesta de estrés en los periodos inmediatos a la tarea y se com-porta como un estresor que se restablece por retroali-mentación negativa, ya que a las 24 h la concentración de C vuelve a condiciones basales.

Aunque los sujetos fueron habituados a la cámara 24 h antes del entrenamiento durante 10 min, la reex-posición a la cámara de RO provocó activación del eje HPA el día del entrenamiento. El animal en el entrena-miento se enfrenta a dos objetos similares que son extraños o novedosos para él, la liberación de C es un índice importante de estrés en ratas y sugiere que el confinamiento en un ambiente nuevo es estresante50. La respuesta del sujeto a una cámara que durante la habituación estaba vacía y durante el entrenamiento se expone a dos objetos, implica un nuevo contexto, y es probable que esta exposición le provoque activación de la atención, la ansiedad y de factores relacionados con la respuesta de estrés como la liberación de glucocorticoides41,42.

Ennaceur39 considera que la tarea de RO se realiza en bajas condiciones de estrés y otros autores señalan que la habituación al contexto experimental reduce la respuesta de agitación51. Sin embargo, los resultados de nuestro estudio indican lo contrario, ya que la situación emocional del sujeto persiste en el entrenamiento de la tarea de RO, lo que permite disociar el estrés intrínseco, inherente a la tarea o situación de aprendizaje32, ya que la exposición solo al entrenamiento es comparable al efecto ocasionado por la R.

Figura 5. Medianas de la concentración de corticosterona (C) en plasma de ratas sometidas a restricción (R15) o entrenamiento en reconocimiento de objetos (RO) sin restricción (I) (ERO‑0 y ERO‑24), sacrificadas a las 0 o 24 h.*p < 0.05 frente a I.

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Conclusiones

Los resultados obtenidos en este estudio sugieren que 15 min de R antes del entrenamiento en RO dete-rioran la memoria declarativa a las 24 h y desencade-nan la liberación de C en plasma. La inyección de C pre entrenamiento en dosis de 5 mg/kg reproduce las concentraciones plasmáticas bajo estrés, pero no tiene efecto sobre la memoria. Se demostró el efecto estre-sor del entrenamiento de la tarea de RO.

Financiamiento

El estudio se realizó con el apoyo del Programa de Apoyo a Proyectos de Investigación e Innovación Tec-nológica (PAPIIT) de la Universidad Nacional Autóno-ma de México, con el número de proyecto IN306216 otorgado a Sara Eugenia Cruz Morales.

Conflicto de intereses

Los autores declaran no tener conflicto de intereses.

Bibliografía 1. Bisaz R, Conboy L, Sandi C. Learning under stress: A role for the neural

cell adhesion molecule NCAM. Neurobiol Learn Mem. 2009;91:333-42. 2. Li S, Fan YX, Wang W, Tang YY. Effects of acute restraint stress on

different components of memory as assessed by object-recognition and object-location tasks in mice. Behav Brain Res. 2012;227(1):199-207.

3. Wirth M. Hormones, stress, and cognition: The effects of glucocorticoids and oxytocin on memory. Adapt Human Behav Physio. 2015;1(2):177-201.

4. Corbett B, Winberg L, Duarte A. The effect of mild acute stress during memory consolidation on emotional recognition memory. Neurobiol Learn Mem. 2017 145:33-44.

5. Butler RK, Oliver EM, Sharko AC, Parrilla-Carrero J, Kaigler KF, Fadel JR, et al. Activation of corticotrophin releasing factor-containing neurons in the rat central amygdale and bed nucleus of the stria terminalis following exposure to two different anxiogenic stressors. Behav Brain Res. 2016; 304:92-101.

6. Ness D, Calabrese P. Stress effects on multiple memory system interac-tions. Neural Plast. 2016;2016:4932128.

7. Howland JG, Cazakoff BN. Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object–place recognition me-mory. Neurobio Learn Mem. 2010;93:261-7.

8. Cazakoff BN, Johnson KJ, Howland JG. Converging effects of acute stress on spatial and recognition memory in rodents: A review of recent behavioural and pharmacological findings. Pro Neuropsychopharmacol Biol Psychiatry. 2010;34:733-41.

9. Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10(6):459-66.

10. Sardari M, Rezayof A, Khodagholi F. Hippocampal signaling pathways are involved in stress-induced impairment of memory formation in rats. Brain Res. 2015;1625:54-63.

11. Joëls M, Sarabdjitsingh RA, Karst H. Unraveling the time domains of corticosteroid hormone influences on brain activity: Rapid, slow and chronic modes. Pharmacol Rev. 2012;64:901-38.

12. Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress res-ponse. Compr Physiol. 2016;6(2):603-21.

13. Wolf OT. Stress and memory retrieval: mechanisms and consequences. Behav Sci. 2017;14:40-6.

14. Vargas-López V, Torres-Berrio A, González-Martínez L, Múnera A, Lam-prea MR. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res. 2015; 291:60-6.

15. Barsegyan A, Mackenzie SM, Kurose BD, McGaugh JL, Roozendaal B. Glucocorticoids in the prefrontal cortex enhances memory consolidation

and impair working memory by a common neural mechanism. Proc Natl Acad Sci U S A. 2010;107(38):16655-60.

16. Atsak P, Guenzel FM, Kantar-Gok D, Zalachoras I, Yargicoglu P, Meijer OC, et al. Glucocorticoids mediate stress-induced impairment of retrieval of stimulus-response memory. Psychoneuroendocrinolo-gy. 2016;67:207-15.

17. Roozendaal B. Stress and memory: Opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem. 2002;78:578-95.

18. Sadowski RN, Jackson GR, Wieczorek LA, Gold PE. Effects of stress, corticosterone, and epinephrine administration on learning in place and response tasks. Behav Brain Res. 2009;205:19-25.

19. Yang Ch, Liu J, Chai B, Fang Q, Chai N, Zhao LY, et al. Stress within a restricted time window selectively affects the persistence of long-term memory. PLoS One. 2013;8:e59075.

20. Prado-Alcalá RA, Cruz-Morales SE, López-Miro FA. Differential effects of cholinergic blockade of anterior and posterior caudate nucleus on avoidance behaviors. Neurosci Lett. 1980;18:339-45.

21. Prado-Alcalá RA. Is cholinergic activity of the caudate nucleus involved in memory? Life Sci. 1985;37:2135-42.

22. García-Saldívar NL. Efecto de agonistas y antagonistas GABAérgicos sobre la amnesia inducida por escopolamina, en ratas sometidas a un condicionamiento de evitación pasiva en condiciones de bajo reforza-miento [Tesis de Maestría en Internet]. México: Universidad Nacional Autónoma de México, Programa de Maestría y Doctorado en Psicología; 2002. Disponible en: http://132.248.9.195/pdtestdf/0302175/Index.html

23. González-López MRA, García-Saldívar NL, Gómez-Romero JG, Arria-ga-Ramírez PA, Cruz-Morales SE. Modulación de la actividad GABAér-gica del estriado sobre la amnesia inducida por escopolamina. Rev Mex Psicol. 2003;20:283-9.

24. Cruz-Morales SE, Durán-Arévalo M, Díaz del Guante MA, Quirarte G, Prado-Alcalá RA. A threshold for the protective effect of over-reinforced passive avoidance against scopolamine-induced amnesia. Behav Neural Biol. 1992;57:256-9.

25. Veloz-Gómez L. Interacción colinérgica y GABAérgica en una tarea de evitación inhibitoria entrenada con bajas intensidades [Tesis de Licen-ciatura en Internet]. México: Universidad Nacional Autónoma de México; 1999. Disponible en: http://132.248.9.195/pd1999/271194/Index.html

26. Cruz-Morales SE. Interacción de los sistemas colinérgico y GABAérgico en la consolidación de una respuesta de evitación inhibitoria [Tesis de Doctorado en Internet] México: Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México; 1992. Disponi-ble en: http://132.248.9.195/pmig2016/0183543/Index.html

27. García-Saldívar NL, González-López MR, Monroy J, Dominguez R, Cruz-Morales SE. Restriction stress modifies monoamines activity in the prefrontal cortex of rats submitted to an inhibitory avoidance task. Annual Meeting SfN 2014; Sn. Diego, Cal., USA, 628.26. Abstract.

28. Armario A, Escorihuela RM, Nadal. Long-term neuroendocrine and be-havioural effects of a single exposure to stress in adult animals. Neuros-ci Biobehav Rev. 2008;32:1121-35.

29. Cruz-Morales SE, García-Saldívar NL, González-López MR, Castillo-Ro-berto G, Monroy J, Domínguez R. Acute restriction impairs memory in the elevated T-maze (ETM) and modifies serotonergic activity in the dorsolateral striatum. Behav Brain Res. 2008;195:187-91.

30. García-Saldívar NL. Efecto del estrés agudo por restricción sobre la memoria y la ansiedad: participación de la noradrenalina en la CPF y núcleo estriado [Tesis de Doctorado en Internet]. México: Programa de Maestría y Doctorado en Psicología, Universidad Nacional Autónoma de México; 2017. Disponible en: http://132.248.9.195/ptd2017/febre-ro/070501788/Index.html

31. Favila GP. Efectos de la administración de corticosterona e inducción de estrés por restricción en una prueba de LET sobre la consolidación y recuperación de la memoria [Tesis de Licenciatura en Internet]. México: Facultad de Psicología, Universidad Nacional Autónoma de México; 2015. Disponible en: http://132.248.9.195/ptd/2015/agosto/307075374/Index.html

32. Sandi C, Pinelo-Nava MT. Stress and memory: Behavioral effects and neurobiological mechanisms. Neural Plast. 2007;2007:78970.

33. Graeff FG, Zangrossi Jr. H. The hypothalamic-pituitary-adrenal axis in anxiety and panic. Psychol Neurosci. 2010;3(1):3-8.

34. Cohen SJ, Stackman Jr RW. Assessing rodent hippocampal involvement in the novel object recognition task: A review. Behav Brain Res. 2015; 285:105-17.

35. Nava-Mesa MO, Lamprea MR, Múnera A. Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation. Neurobiol Learn Mem. 2013; 106:185-92.

36. Jurado-Berbel P, Costa-Miserachs D, Torras-Garcia M, Coll-Andreu M, Portell-Cortés I. Standard object recognition memory and “what” and “where” components: Improvement by post-training epinephine in highly habituated rats. Behav Brain Res. 2010;207:44-50.

37. Luine, V. Recognition memory task in neuroendocrine research. Behav Brain Res. 2015;285:158-64.

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er.

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2019

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38. Observer, Software de dominio público del Laboratorio de Psicobiología de la Universidad de Säo Paulo, Brazil.

39. Ennaceur A. One trial object recognition in rats and mice: Methodological and theoretical issues. Behav Brain Res. 2010;215:244-54.

40. Zhao X Li Y, Peng T, Seese RR, Wang Z. Stress impairs consolidation of recognition memory after blocking drug memory reconsolidation. Neu-rosci Lett. 2011;501:50-4.

41. Baker KB, Kim JJ. Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats. Learn Mem. 2002;9:58-65.

42. González-López MR, García-Saldívar NL, González-Sánchez DJ, Gas-cón-Enríquez O, Romero-Guadiana JC, Cruz-Morales SE. Efectos del estrés agudo sobre la memoria declarativa y la ansiedad en ratas: efec-tos de género 2017; LX Congreso Nacional de Ciencias Fisiológicas, Nuevo León, Monterrey, México Abstract.

43. Sutcliffe JS, Marshall KM, Neill JC. Influence of gender on working and spatial memory in the novel object recognition task in the rat. Behav Brain Res. 2007;177:117-25.

44. Harro H. Animals, anxiety, and anxiety disorders: How to measure anxie-ty in rodents and why. Behav Brain Res. 2018;352:81-93.

45. Lamprea MR, Cardenas FP, Setem J, Morato S. Thigmotatic responses in an open-field. Braz J Med Biol Res. 2008;41:135-40.

46. Woodson JC, Macintosh D, Fleshner M, Diamond DM. Emotion-induced amnesia in rats: working memory-specific impairment, corticosterone-me-mory correlation, and fear versus arousal effects on memory. Learn Mem. 2003;10:326-36.

47. Harris AP, Holmes MC, de Kloet ER, Chapman KE, Seckle JR. Minera-locorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour. Psychoneuroendocrinology. 2013;38:648-58.

48. Schulz K, Korz V. Emotional and cognitive information processing: Rela-tions to behavioral performance and hippocampal long-term potentiation in vivo during a spatial water maze training in rats. Learn Mem. 2010; 17:552-60.

49. Muñoz-Abellán C, Rabasa, Daviu N, Nadal R, Armario A. Behavioral and endocrine consequences of simultaneous exposure to two different stres-sors in rats: Interaction or independence? Plos One. 2011;6(6):e21426.

50. Bevins RA, Besheer J, Palmatie MI, Jensen HC, Pickett KS, Eurek S. Novel-object place conditioning: Behavioral and dopaminergic processes in expression of novelty reward. Behav Brain Res. 2002;129:41-50.

51. Okuda S, Roozendaal B, McGaugh JL. Glucocorticoid effects on object recognition memory require training-associated emotional arousal. Proc Natl Acad Sci U S A. 2004;101(3):853-8.

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Parálisis periódica tirotóxica: revisión de la literatura y reporte de caso en un hospital universitario mexicano privado de alta especialidadManuel A. Sierra1,2, Wallace R. Muñoz-Castañeda1*, Carlos Tolsa1, Aldo E. Lara1, Raúl Medina1 y Carolina Vega2

1Departamento de Neurología; y 2Departamento de Medicina Interna, Hospital Clínica Médica Sur; 3Departamento de Neurología, Instituto Nacional de Neurología y Neurocirugía, Hospital Manuel Velasco Suárez. Ciudad de México, México


ARTíCuLO DE REvIsIóN

Resumen

La parálisis periódica tirotóxica (PTT) es una complicación mortal de la tirotoxicosis caracterizada por hipopotasemia súbi-ta, parálisis muscular y tirotoxicosis. La PTT, aunque cada vez es más frecuente en nuestro medio, todavía no diagnostica de forma oportuna debido a la falta de familiaridad y la sutileza de la sintomatología referida. El reconocimiento temprano por parte del médico de primer contacto puede prevenir la mortalidad de dicha enfermedad. Se presenta un caso típico de parálisis tirotóxica en un hospital universitario privado mexicano y se realiza una revisión de la literatura más actual. Reali-zamos una revisión de la literatura en PubMed y EMBASE. Se analizaron características clínicas, bioquímicas y diagnósticas, la terapéutica y el pronóstico. La PPT es una entidad clínica que se presenta de forma rara en la población mexicana, sin embargo es importante encontrarse familiarizado con el diagnóstico ya que el tratamiento es diferente al de otras parálisis periódicas hipopotasémicas.

Palabras clave: Parálisis. Tirotoxicosis. Periódica. Hipopotasemia. Arreflexia.

Thyrotoxic periodic paralysis: review of the literature and case report in a high specialty Mexican university hospital

Abstract

Thyrotoxic periodic paralysis (TPP) is a fatal complication of thyrotoxicosis, characterized by sudden hypokalemia, muscle paralysis and thyrotoxicosis. TPP, although it is becoming more frequent in our country, is still not diagnosed in a timely man-ner due to the lack of familiarity and the subtlety of the referred symptomatology. Early recognition by the first contact phy-sician can prevent the mortality of said disease. A typical case of thyrotoxic paralysis is presented in a private Mexican university hospital and a review of the most current literature is made. We conducted a review of the literature in PubMed and EMBASE. Clinical, biochemical, diagnostic, therapeutic and prognostic characteristics were analyzed. TPP is a clinical

Correspondencia: *Wallace Rafael Arturo Muñoz-Castañeda

Departamento de Medicina Interna

Hospital Médica Sur

Sillón de Mendoza, 110

Col. Toriello Guerra, Del. Tlalpan

Ciudad de México, México



Rev Mex Neuroci. 2019;20(3):149-154




DOI: 10.24875/RMN.M19000046

1665-5044/© 2018. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Introducción

La asociación de parálisis periódica y tirotoxicosis fue documentada por Rosenfeld en 1902. Mundialmen-te, los asiáticos orientales son la población más afec-tada; en ellos la incidencia es de alrededor del 2%. En México se desconoce la incidencia real1,2,3. La PPT se caracteriza por la tríada de: hipopotasemia grave, debilidad muscular profunda y presencia de tirotoxico-sis3,4. La hipopotasemia en la PPT resulta de un des-plazamiento intracelular de potasio inducido por la sen-sibilización de la bomba Na+/K+-ATPasa por la hormona tiroidea4. El diagnóstico precoz no solo ayuda en el tratamiento definitivo con betabloqueadores no selectivos y en la corrección del hipertiroidismo, sino que también previene el riesgo de hiperpotasemia de rebote debido al reemplazo excesivo de potasio. La TTP es curable una vez que se logra un estado eutiroideo4.

Presentación de caso clínico

Mujer de 33 años de edad, hispana, sin anteceden-tes heredofamiliares de importancia. Niega anteceden-tes personales patológicos, incluyendo el consumo de medicamentos de uso crónico.

Inició su padecimiento actual en noviembre del 2017 a las 20:00 h, al presentar de forma súbita parestesias en extremidades inferiores en región distal, bilateral y simétrica con irradiación a muslos. Tres horas después se agregó disminución de la fuerza en ambas extremi-dades inferiores que impedía la deambulación, por lo cual acude a otra institución (no especificada) donde se administró ketorolaco 30 mg vía intravenosa dosis única sin mejoría de la sintomatología. Seis horas des-pués del inicio del padecimiento se agrega pérdida de fuerza de extremidades superiores, así como cervical-gia, bradilalia y disnea de pequeños esfuerzos. Por lo anterior sus familiares la traen a Urgencias de nuestra institución.

A su llegada a Urgencias se encontró estable hemo-dinámicamente, signos vitales dentro de parámetros normales. Alerta, orientada, facies álgica, pares cra-neales sin alteraciones, cuadriplejia, arreflexia, sin presencia de reflejos patológicos. Cardiopulmonar sin alteraciones. Abdomen asignológico. Al interrogatorio

directo refirió episodios aislados de diaforesis profunda persistente de 48 h de evolución, pérdida de 15 kg de peso no intencionada de 3 meses de evolución; cefalea y palpitaciones, así como diarrea sin moco ni sangre de 1 semana de evolución.

En los laboratorios generales destacó: hiperglucemia (195.4 mg/dl) e hipopotasemia severa (1.42). El electro-cardiograma evidenció bloqueo AV de segundo grado Mobitz II. Se decidió colocación de catéter venoso cen-tral, así como reposición vía intravenosa de potasio. Pun-ción lumbar sin alteraciones (glucosa 86, proteínas 23, sin microorganismos teñidos con Gram). Por los hallaz-gos anteriores se decidió traslado a la Unidad de Terapia Intensiva para continuar abordaje y tratamiento.

Después de la reposición de potasio la paciente evo-lucionó con hiperreflexia generalizada y recuperación de la fuerza muscular (4/5) en las 4 extremidades. Como principal sospecha de una parálisis periódica de causa tirotóxica se solicitó perfil tiroideo, así como an-ticuerpos antitiroideos, reportando TSH suprimida y hormonas tiroideas aumentadas (TSH < 0.003, T3 2.85, T4L 4.27, T4 16.71, anticuerpos antiperoxidasa positi-vos). Se calculó el gradiente transtubular de potasio, siendo del 12% (sugerente de pérdida renal) y también la puntuación en la escala de Burch-Wartofsky, siendo de 35 (elevado riesgo para tormenta tiroidea incipien-te). Se inició tratamiento con tiamazol, propranolol y colestiramina, con buena tolerancia. Posteriormente presentó cifra de potasio de control dentro de rangos normales (5.16), fuerza muscular en las cuatro extre-midades de manera total. Con lo anterior se integró hipertiroidismo autoinmunitario con parálisis hipopota-sémica. La paciente fue egresada 48 h después de su ingreso con adecuada evolución, asintomática y con laboratorios dentro de rangos normales.

Definición

La parálisis tirotóxica (PT) es una complicación po-tencialmente fatal del hipertiroidismo (tirotoxicosis), reversible y caracterizada por parálisis muscular e hi-popotasemia severa.

La parálisis periódica tirotóxica (PPT) corresponde a un tipo de parálisis hipopotasémica que constituye la principal causa de parálisis periódica hipopotasémica

entity that occurs rarely in the Mexican population, however it is important to be familiar with the diagnosis since the treatment is different from other periodic hypokalemic paralysis..

Key words: Paralysis. Thyrotoxicosis. Periodic. Hypokalemia. Areflexia.

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WR. Muñoz-Castañeda, et al.: Parálisis periódica tirotóxica

en países asiáticos, a diferencia de la parálisis periódica hipopotasémica familiar, que es la causa más común en países occidentales de herencia autosómica dominante1,2,3.

Epidemiología

Debido a su baja prevalencia en los países occiden-tales y a la sutileza de su presentación, la tirotoxicosis a menudo no se reconoce3. A pesar de que se ve co-múnmente en la enfermedad de Graves, la PPT no se encuentra relacionada con la etiología, la gravedad y la duración de la tirotoxicosis. Generalmente no hay antecedentes familiares de parálisis periódica. Algunos subtipos de antígenos HLA tales como DRw8, A2, BW22, Aw19, B17 B5 y Bw46 en ciertas poblaciones étnicas pueden hacerlos más susceptibles al PPT4,5.

La incidencia de PPT en pacientes tirotóxicos chinos y japoneses se ha informado en el 1.8 y el 1.9%, res-pectivamente, y en EE.UU. entre el 0.1 y el 0.2%. En México no existen datos sobre la incidencia de esta relación. La relación entre hombres y mujeres va de 17:1 a 70:1, a pesar de que el hipertiroidismo es más común en las mujeres (proporción de mujeres a hom-bres de 9:1)4,5,6.

Etiología

La causa más común de tirotoxicosis es la enferme-dad de Graves, sin embargo, se han reportado casos de PT en pacientes con bocio tóxico nodular, tirotoxi-cosis inducida por yodo, tiroiditis linfocítica, adenomas secretores de tirotropina e incluso tiroiditis inducida por amiodarona1.

Fisiopatogenia

La fisiopatología de la PPT es multifactorial y aún no se comprende por completo. Se sabe que la PPT se debe a la disminución de potasio intracelular y no a la depleción de potasio corporal. Muchas teorías han tra-tado de definir la fisiopatología de la PPT. Una de las teorías más aceptadas es el incremento de la actividad de la bomba Na+/K+-ATPasa, encontrándose una tasa de actividad de hasta un 80% mayor en los pacientes diagnosticados con PPT. La bomba Na+/K+-ATPasa se activa mediante distintos estímulos entre los cuales destacan: la insulina, el ejercicio, la estimulación adre-nérgica, las hormonas tiroideas y la testosterona. Los estrógenos y la progesterona han demostrado dismi-nuir la actividad de la bomba Na+/K+-ATPasa, lo que

podría explicar la mayor incidencia de PPT en el sexo masculino7,8 (Fig. 1). Actualmente existen mutaciones bien conocidas que influyen en la fisiopatogenia de la PPT; un ejemplo claro es la mutación de Kir 2.6, un canal de potasio regulado por hormonas tiroideas lo-calizado en el músculo esquelético. El hipertiroidismo puede provocar un estado hiperadrenérgico que puede conducir a la activación de la bomba de Na+/K+-ATPa-sa y dar como resultado la captación celular de pota-sio. Se ha encontrado que los pacientes con PPT tie-nen hiperinsulinemia durante los episodios de parálisis. Esto puede explicar los ataques después de las comi-das con alto contenido de carbohidratos12.

Manifestaciones clínicas y diagnóstico

La parálisis periódica puede manifestarse con cual-quier condición asociada con hipopotasemia (Tabla 1). El diagnóstico de una PPT se basa en la presentación de parálisis flácida de comienzo súbito en el contexto de hipopotasemia e hipertiroidismo. Este cuadro clínico suele presentarse en individuos de la tercera a la quinta década de la vida, con una mayor incidencia en hom-bres, lo que contrasta con la parálisis periódica familiar (PPF), que suele tener un inicio más temprano9.

La parálisis se caracteriza por debilidad muscular de inicio abrupto de predominio proximal, principalmente en miembros inferiores. En la mayoría de los casos es si-métrica y está acompañada de hiporreflexia/arreflexia.

Figura 1. Mecanismo de la parálisis periódica tirotóxica (adaptada de Abhishek, et al., 20042).

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Dicha parálisis puede llegar a progresar hasta cuadripa-resia. De manera excepcional se ven afectados la sensibilidad, las funciones mentales y los músculos ocu-lares, bulbares o respiratorios10. Dichos episodios pueden tener una duración de minutos a días sin tratamiento. En algunos casos se ha llegado a reportar que horas a días previos a los episodios los pacientes pueden manifestar mialgias, rigidez, calambres o debilidad leve que se au-tolimitan antes de presentar la parálisis11.

La mayoría de los casos reportados de esta parálisis suelen ser en los meses calurosos del año y su horario de presentación es predominantemente de la noche a primeras horas de la mañana12. Una de las caracterís-ticas clínicas que podría ayudar a diferenciar la PPF y la PPT es la presencia de taquicardia y la tendencia a la hipertensión sistólica en los pacientes con diagnós-tico de PPT13.

La hipopotasemia suele estar presente en la gran mayoría de los episodios de parálisis y el nivel elevado de potasio sérico (5 mmol/l) suele correlacionar con la gravedad del cuadro. En la mayoría de las series de casos el nivel de potasio sérico promedio llega a rondar entre 1.9 y 2.4 mmol/l; sin embargo, se han reportado casos con potasio sérico dentro de valores normales o con niveles de hipopotasemia extremadamente bajos. La excreción urinaria de potasio suele estar disminuida, lo que ayuda a diferenciar la PPT de otras causas de parálisis hipopotasémica. Esto debe ser demostrado utilizando la relación potasio/creatinina y el gradiente transtubular de potasio, ya que la cuantificación aleato-ria de potasio urinario suele ser un método inexacto para calcular la excreción renal de potasio13,14,15.

Otras alteraciones de electrólitos séricos descritas en estos pacientes suelen ser la hipofosfatemia e hi-pomagnesemia leves15. A nivel urinario se ha llegado a reportar que los pacientes con PPT presentan au-mento del índice calcio/creatinina y disminución del índice fosfato/creatinina. Basándose en estos hallaz-gos, Lin, et al. proponen que la relación calcio urinario/fosfato urinario con un valor mayor de 1.7 mg/mg po-dría tener una sensibilidad y especificidad del 100 y el 96% respectivamente para el diagnóstico de PPT en relación con otras causas de parálisis hipopotasémica. La presencia de hipertiroidismo, caracterizado por un perfil tiroideo sérico con T3 y/o T4 aumentadas con TSH disminuida, es un criterio fundamental para el diagnóstico de esta entidad. Sin embargo, no se ha encontrado relación entre los niveles de hormonas ti-roideas y la gravedad de la parálisis10,11.

En diferentes estudios se ha aproximado que más del 50% de los pacientes presentan PPT sin contar con un diagnóstico previo o cuadro clínico sugerente de hipertiroidismo. Dicho hallazgo fue corroborado en un estudio en el que utilizando el índice de Wayne se de-terminó que solo el 17% de los pacientes de dicha población presentaba síntomas o signos francos de hipertiroidismo (índice de Wayne > 19). Mientras que el 38% de los pacientes se podían clasificar como clí-nicamente eutiroideos (índice de Wayne < 11)12.

Dadas las alteraciones electrolíticas características de esta entidad, los cambios electrocardiográficos son comunes en esta enfermedad. Conocer la prevalencia de dichos cambios es importante para el clínico, para el correcto tratamiento y vigilancia del paciente. Dichos cambios varían en frecuencia y van desde la taquicar-dia sinusal hasta arritmias fatales y usualmente no correlacionan con la intensidad de los síntomas15.

En la mayoría de los casos, se observan cambios consistentes con niveles séricos bajos de potasio como depresión del segmento ST, taquicardia sinusal y on-das U. En algunas series se reportan arritmias severas, las cuales resultan menos frecuentes pero suelen tener desenlaces fatales como bloqueo AV de segundo gra-do, fibrilación ventricular y taquicardia ventricular16. Por lo anterior, se recomienda monitoreo continuo electro-cardiográfico de estos pacientes en una unidad crítica, así como controles de electrólitos séricos de manera seriada17. En la mayoría de los pacientes los estudios electrodiagnósticos como la electromiografía (EMG), no son necesarios. Sin embargo, la EMG realizada durante los episodios de debilidad típicamente revelan cambios miopáticos con amplitud disminuida del poten-cial de acción muscular (CMAP), así como disminución

Tabla 1. Diagnósticos diferenciales de parálisis hipopotasémica

– Medicamentos tocolíticos– Toxicidad por teofilina– Toxicidad de la cloroquina– Hiperinsulinemia– Parálisis periódica tirotóxica– Diuréticos– Hiperaldosteronismo primario– Regaliz– Síndrome de Bartter, síndrome de Gitelman– Acidosis tubular renal– Síndrome nefrótico– Necrosis tubular aguda– Cetoacidosis diabética– Enfermedad celíaca– Esprue tropical– Diarrea infecciosa (Salmonella, Strongyloides, Yersinia,

Campylobacter)– Síndrome de intestino corto

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WR. Muñoz-Castañeda, et al.: Parálisis periódica tirotóxica

del reclutamiento motor o silencio eléctrico dependiendo de la severidad de la debilidad. Otros hallazgos des-critos menos frecuentes incluyen aumento de la activi-dad de inserción, aumento de los potenciales polifásicos de la unidad motora y reducción de la velocidad de conducción de la fibra muscular. Dichos cambios no se modifican con la estimulación con epinefrina. En cuan-to al estudio de la conducción nerviosa, de manera general resultan sin alteraciones.

En algunos casos, la actividad física puede desenca-denar ataques de debilidad, con cambios consistentes en la EMG. Una técnica de EMG que puede usarse para ayudar a confirmar el diagnóstico entre ataques es la «prueba de ejercicio». Los CMAP que siguen un solo estímulo eléctrico supramáximo se registran en reposo y posteriormente de manera seriada con el ejer-cicio. Una reducción gradual de más del 40% en la amplitud motora evocada después de 30 a 40 min es compatible con un diagnóstico de parálisis periódica, pero no es específico. Se ha reportado una sensibilidad del 71% de esta prueba, pero disminuye cuando los ataques no han sido recientes. Todos estos cambios mejoran cuando se restablece la función tiroidea18-24.

Tratamiento

El tratamiento inicial en el paciente con parálisis pe-riódica secundaria a tirotoxicosis se centra en mejorar los niveles séricos de potasio. Es importante destacar que los pacientes con PPT no tienen un déficit del po-tasio corporal total, por lo que la administración de potasio debe ser controlada para evitar hiperpotasemia de rebote25.

La suplementación con potasio para el tratamiento de la PPT ha demostrado disminuir el tiempo de recu-peración y disminuir complicaciones cardiopulmona-res. La administración de potasio puede llevarse a cabo por vía oral o vía intravenosa. Sin embargo, existe una serie de casos en los cuales se observó un menor tiempo de respuesta en los sujetos que fueron tratados con potasio intravenoso en comparación con potasio vía oral. Se recomienda que la velocidad de infusión de cloruro de potasio no sea mayor de 10 mmol/h y se ha llegado a recomendar no superar una dosis de 50 mmol en 24 h. Estas recomendaciones se basan en publicaciones que llegan a reportar hiperpotasemia de rebote en el 40 hasta el 80% de los pacientes que re-ciben más de 90 mmol de cloruro de potasio en un periodo de 24 h26-30.

Aunque no existen ensayos clínicos controlados que demuestren el beneficio del uso de betabloqueadores

no selectivos en el tratamiento agudo de la PPT, existen múltiples reportes de casos en los cuales la adminis-tración de propranolol, ya sea por vía intravenosa o vía oral, se ha asociado a reversibilidad del cuadro, tanto como terapia inicial como en pacientes en los que no se observó mejoría posterior a la reposición de potasio.

Dicho tratamiento puede ser iniciado de manera simul-tánea o utilizarse en caso de resistencia al tratamiento inicial. Las dosis mencionadas en diferentes reportes van de 3 mg/kg de propranolol vía oral y de 1 mg de propranolol intravenoso cada 10 min sin superar la dosis total de 3 mg. En la mayoría de los casos no se ha asociado el uso de betabloqueadores no selectivos a hiperpotasemia de rebote31,32.

Tratamiento preventivo

El objetivo primordial del tratamiento preventivo se centra en lograr el retorno al eutiroidismo, dicha medida evitará la recurrencia de los episodios de parálisis. La tasa de recurrencia puede llegar a ser de hasta el 60% en los pacientes que aún no se encuentran eutiroideos, presentando el mayor riesgo los primeros 3 meses tras el diagnóstico de PPT. El tratamiento del hipertiroidismo se puede llevar a cabo por cualquiera de los métodos estándar de tratamiento: farmacológico, quirúrgico o yodo radioactivo. Existen estudios que han demostrado que según la etiología del hipertiroidismo pueden existir terapéuticas más apropiadas que otras en cuestión de disminuir la recurrencia de la parálisis. Siendo los más recomendados los métodos definitivos como la ablación con yodo radioactivo o la tiroidectomía. Sin embargo, existen asociaciones de recurrencia de la parálisis pos-terior al uso de yodo radioactivo33,34.

En el periodo en el que se consigue la normalización de las hormonas tiroideas, el uso de betabloqueadores no selectivos puede disminuir la frecuencia de los epi-sodios de parálisis. Aunque no existe una dosis esta-blecida de propranolol, en un estudio clínico la dosis de 40 mg de propranolol vía oral cada 6 h se asoció a una disminución del 71% de la PPT inducida por car-bohidratos. De igual forma se tiene que evitar la exposición a condiciones predisponentes: dieta alta en carbohidratos, consumo excesivo de sal, alcohol o ejer-cicio intenso mientras los niveles séricos de hormonas tiroideas no se encuentren dentro de los valores nor-males. Por último, es importante mencionar que el uso de acetazolamida y la suplementación de potasio vía oral como tratamiento preventivo puede precipitar los episodios de parálisis, en contraste con su utilidad en la parálisis periódica hipopotasémica familiar35,36.

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Financiamiento

La presente investigación no ha recibido ayudas es-pecíficas provenientes de agencias del sector público, sector comercial o entidades sin ánimo de lucro.

Conflicto de intereses

Los autores declaran no tener conflicto de intereses.

Bibliografía 1. Morales-Victorino N, Guevara-Arnal L, Almeda-Valdés P. Parálisis tiro-

tóxica: informe de un caso y revisión de la literatura. Rev Medica Sur. 2008;15(2):81-5.

2. Vijayakumar A, Ashwath G, Thimmappa D. Thyrotoxic periodic paralysis: Clinical J Thyroid Res. 2014;2014:649502.

3. Patel H, Wilches LV, Guerrero J. Thyrotoxic periodic paralysis: Diversity in America. J Emerg Med. 2014;46(6):760-2.

4. Lam L, Nair RJ, Tingle L. Thyrotoxic periodic paralysis. Proc (Bayl Univ Med Cent). 2006;19(2):126-9.

5. Pothiwala P, Levine SN. Analytic review: thyrotoxic periodic paralysis: a review. J Intensive Care Med. 2010;25:71.

6. Pompeo A, Nepa A, Maddestra M, Feliziani V, Genovesi N. Thyrotoxic hypokalemic periodic paralysis: An overlooked pathology in western countries. Eur J Intern Med. 2007;18:380-90.

7. Guerra M, Rodriguez Del Castillo A, Battaner E, Mas M. Androgens stimulate preoptic area Na+-K+ATPase activity in male rats. Neurosci Lett. 1987;78(1):97-100.

8. Feely J. Potassium shift in thyrotoxic periodic paralysis. Postgrad Med J. 1981;57:238-9.

9. Lee KO, Taylor EA, Oh VM, Cheah JS, Aw SE. Hyperinsulinemia in thyrotoxic hypokalemic periodic paralysis. Lancet. 1991;337(8749):1063-4.

10. Lin S-H. Thyrotoxic periodic paralysis. Mayo Clin Proc. 2005;80(1):99-105.

11. Salih M, van Kinschot CMJ, Peeters RP, de Herder WW, Duschek EJJ, van der Linden J, et al. Thyrotoxic periodic paralysis: an unusual presen-tation of hyperthyroidism. Neth J Med. 2017;75(8):315-20.

12. Chang CC, Cheng CJ, Sung CC, Chiueh TS, Lee CH, Chau T, et al. A 10-year analysis of thyrotoxic periodic paralysis in 135 patients: focus on symptomatology and precipitants. Eur J Endocrinol. 2013;169(5):529-36.

13. Goldberger ZD. Images in cardiovascular medicine. An electrocardiogram triad in thyrotoxic hypokalemic periodic paralysis. Circulation. 2007;115:e179.

14. Hsu YJ, Lin YF, Chau T, Kuo SW, Lin SH. Electrocardiographic manifes-tations in patients with thyrotoxic periodic paralysis. Am J Med Sci. 2003;326:128.

15. Areta-Higuera JD, Algaba-Montes M, Oviedo-García AA. Parálisis perió-dica hipopotasémica. A propósito de un caso. SEMERGEN. 2014;40:4.

16. Fisher J. Thyrotoxic periodic paralysis with ventricular fibrillation. Arch Intern Med. 1982;142:1362-4.

17. Loh KC, Pinheiro L, Ng KS. Thyrotoxic period paralysis complicated by near-fatal ventricular arrhythmias. Singapore Med J. 2005;46:88-9.

18. Ryzen E, Servis KL, Rude RK. Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium con-centrations measured by nuclear magnetic resonance. J Am Coll Nutr. 1990;9:114-9.

19. Tengan CH, Antunes AC, Gabbai AA, Manzano GM. The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neu-ral Neurosurg Psychiatry. 2004;75:497-9.

20. Kung AWC. Thyrotoxic periodic paralysis: A diagnostic challenge. J Clin Endocrinol Metab. 2006;91:2490-5.

21. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, et al. The primary periodic paralyses: diagnosis, pathogenesis and treat-ment. Brain. 2006;129:8.

22. Sharma CM, Nath K, Parekh J. Reversible electrophysiological abnorma-lities in hypokalemic paralysis: Case report of two cases. Ann Indian Acad Neurol. 2014;17:100.

23. Tengan CH, Antunes AC, Gabbai AA, Manzano GM. The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neu-rol Neurosurg Psychiatry. 2004;75:497.

24. Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A, et al. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve. 2000;23:1089.

25. Lin SH, Lin YF, Halperin ML. Hypokalaemia and paralysis. QJM. 2001;94(3):133-9.

26. Cesur M, Bayram F, Temel MA, Ozkaya M, Kocer A, Ertorer ME, et al. Thyrotoxic hypokalaemic periodic paralysis in a Turkish population: three new case reports and analysis of the case series. Clinical Endocrinology. 2008;68:143-52.

27. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med. 1999;159:601.

28. Lin S-H, Chu P, Cheng C-J, Chu S-J, Hung Y-J, Lin Y-F. Early diagnosis of thyrotoxic periodic paralysis: spot urine calcium to phosphate ratio. Crit Care Med. 2006;34(12):2984-9.

29. Hsieh MJ, Lyu RK, Chang WN, Chang KH, Chen CM, Chang HS, et al. Hypokalemic thyrotoxic periodic paralysis: clinical characteristics and predictors of recurrent paralytic attacks. Eur J Neurol. 2008;15(6):559-64.

30. Lu KC, Hsu YJ, Chiu JS, Hsu YD, Lin SH. Effects of potassium supple-mentation on the recovery of thyrotoxic periodic paralysis. Am J Emerg Med. 2004;22(7):544-7.

31. Lin SH, Lin YF. Propranolol rapidly reverses paralysis, hypokalemia, and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis. 2001;37(3):620.

32. Shayne P, Hart A. Thyrotoxic periodic paralysis terminated with intrave-nous propranolol. Ann Emerg Med. 1994;24(4):736.

33. Chang RY, Lang BH, Chan AC, Wong KP. Evaluating the efficacy of primary treatment for Graves’ disease complicated by thyrotoxic periodic paralysis. Int J Endocrinol. 2014;2014:949068.

34. Akar S, Comlekci A, Birlik M, Onen F, Sari I, Gurler O, et al. Thyrotoxic periodic paralysis in a Turkish male; the recurrence of the attack after radioiodine treatment. Endocr J. 2005;52(1):149-51.

35. Vijayakumar A, Ashwath G, Thimmappa D. Thyrotoxic periodic paralysis: clinical challenges. J Thyroid Res. 2014;2014:649502.

36. Yeung RT, Tse TF. Thyrotoxic periodic paralysis. Effect of propranolol. Am J Med. 1974;57(4):584-90.

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Intervention programs on reading and writing processes in children with learning disorders: A reviewCristian Villanueva-Bonilla1,2* and Ángela M. Ríos-Gallardo1

1Grancolombiano Polytechnic University Institution, Bogotá; 2Young Researchers and Innovators Programme Colciencias, Universidad Surcolombiana, Neiva. Colombia


REvIEW ARTICLE

Abstract

Reading comprehension is the goal of all reading and constitutes one of the fundamental axes of cognitive development in early childhood. The learning problems are manifested essentially in the school environment and significantly hinder academic activities that include reading and writing processes. This review identifies and compares published research on intervention processes in children with learning difficulties, specifically addressing dyslexia and dysgraphia. We selected eight studies in Spanish at a Latin American level and 23 studies in English at a global level. In conclusion, the current state of empirical research published in Spanish in intervention processes in children with learning difficulties is fewer in number in the past 10 years compared to literature in English, as evidenced by the search. The comparison established with literature published in English and worldwide indicates progressive advances of the Latin American literature in the subject addressed by this review, specifically in intervention programs focused on specific difficulties associated with lear-ning disorders.

Key words: Learning problems. Reading comprehension. Intervention. Dyslexia. Dysgraphia.

Programas de intervención sobre procesos de lecto-escritura en niños con trastornos del aprendizaje: Una revisión

Resumen

La comprensión lectora es el objetivo de toda lectura y se constituye como uno de los ejes fundamentales del desarrollo cognitivo en la primera infancia. Los problemas de aprendizaje se manifiestan esencialmente en el ámbito escolar y obsta-culizan de forma significativa las actividades académicas que incluyen procesos de lectura y escritura. La presente revisión identifica y compara las investigaciones publicadas sobre procesos de intervención en población infantil con dificultades del aprendizaje, abordando específicamente la dislexia y la disgrafia. Se seleccionaron 8 estudios en español a nivel lati-noamericano y 23 estudios en inglés a nivel mundial. En conclusión, el estado actual de la investigación empírica publicada en español en procesos de intervención en población infantil con dificultades del aprendizaje son menores en número en

Correspondence: *Cristian Villanueva-Bonilla

Faculty of Health, Surcolombian University

Hernando Moncaleano University Hospital

Calle 9, carrera 4

Neiva, Huila, Colombia



Rev Mex Neuroci. 2019;20(3):155-161




DOI: 10.24875/RMN.M18000059


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http://dx.doi.org/%2010.24875/RMN.M18000059



156


Introduction

Reading comprehension is the goal of all reading and is one of the fundamental axes of cognitive development in early childhood1. Reading is an active process of preparation and interpretation of written language, which produces new meanings from the union between the reader’s previous information and the (interactive) text. In addition, the author defines it as a strategic process that varies according to the reader’s purpose and implies control of cognitive abilities that contribute to the final comprehension of the text (metacognition)2.

Language literacy is a capacity that has recently con-solidated3. Every day people are exposed to various activities where skills related to reading are implicit. However, the development of such capabilities has be-come a difficulty for parents, teachers, and students. The learning problems are manifested essentially in the school environment and significantly hinder academic activities that include reading and writing processes4-6.

Research in the 70s focused on describing the pop-ulation with reading and writing difficulties, investigating the possibility of designing specific intervention strate-gies; in the 1980s, experimental research began with different strategies focused on improving the specific difficulties of learning disorders7. Later, in the 90s, in-tervention programs and strategies were designed for class situations, taking as an axis the social and moti-vational conditions of students with such difficulties. Greater attention was given to the methods and mate-rials teachers used to teach their students, including the necessary teaching materials and group work8.

School requirements have increased significantly in society in recent years; currently, the starting age of primary education has declined. Schooling begins be-fore entering school, in institutions such as nursery, garden, and preschool, which serve as a prelude to formal education9. Appropriately, it has been estab-lished in the Colombian population as in other Latin American countries (Argentina, Brazil, Chile, Mexico, Peru, and Uruguay), the commitment to the improve-ment of reading skills through national and international initiatives aimed at the development whole of the children10.

They have been initially implemented two programs to meet the reader level assessment of children. In recent years, these programs have shown disturbing figures of Colombian and Latin American children who obtain low scores in international and national tests of reading performance10. Overall, Latin America is below in PISA scores (2000-2012) average reading and math-ematics so their world regions (Eastern and Western Europe, Anglo-Saxon countries, Asia-Pacific, and Nor-dics)10. However, the upward trend in average scores is an indicator of progress in skills such as reading.

Latin American countries also differ from each other, Colombia ranks sixth among the seven countries men-tioned above in TERCE scores in reading for the third grade of schooling. Chile presents an average marked-ly superior to the other countries, followed by Uruguay, Peru, Mexico, Brazil, and finally Argentina10. Taking into account the same test (TERCE) applied in sixth grade, and for the same year, Colombia climbs to fourth place, and Chile maintains its average score. In the PISA tests (2000-2012), there is a similar situation10.

Despite the improvement evidenced in the mentioned results, the difficulties of reading and writing have had an impact on the increase of learning problems, caus-ing school failures and generating an increase in the incidence of the diagnosis of learning disorders. School failure is directly related to difficulties in areas such as literacy and mathematics, thematic axes in most Co-lombian and Latin American schools that impede the development of other skills necessary for the full devel-opment of children (kinesthetic, spatial, musical, artis-tic, and among others)11. In other words, education is not adapted to the cognitive, social, and emotional needs of the child9,12.

The mentioned difficulties affect the adequate capac-ity to read and understand a written text. For this reason, the prevalence of learning disorders in school-children has increased, ranging from 15% to 20%, char-acterized by low school performance and loss of academic years13. One of the most common diagnoses is developmental dyslexia (DD), identified as being a neuropsychological disorder that presents difficulties in phonological processing (phonological awareness and

los últimos 10 años en comparación con la literatura en inglés, como lo evidencia la búsqueda realizada. La comparación establecida con la literatura publicada en inglés y a nivel mundial indica avances progresivos de la literatura latinoamerica-na en el tema abordado por esta revisión, específicamente en programas de intervención enfocados en dificultades espe-cíficas asociadas a los trastornos de aprendizaje.

Palabras clave: Problemas de aprendizaje. Comprensión de lectura. Intervención. Dislexia y disgrafia.

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C. Villanueva-Bonilla and AM. Ríos-Gallardo: Learning disorders

mastery of grapheme-phoneme relationship) and com-prising a specific difficulty of the language of neurobi-ological origin14,15. On the other hand, dysgraphia is characterized by difficulties in motor skills that affect the graphic quality of writing with a general origin of functional etiology16-18.

Since this is a phenomenon that requires prompt intervention by professionals in health sciences, includ-ing the psychologist, it is essential to know the different intervention processes on reading and writing skills in children with learning disorders. For this reason, the purpose of this review is to identify and compare re-search published in Spanish and Latin American jour-nals in the past 10 years with publications made in English and published in different journals worldwide during the past 2 years, about processes of intervention in children with learning difficulties, specifically ad-dressing dyslexia and dysgraphia.

Methodology

The methodology used to search for literature written in Spanish and English is described below:

Search for literature

Intervention studies written in English that was pub-lished from January 2015 to May 2016 and written in

Spanish studies were searched from January 2007 to May 2016. Figure 1 summarizes the process of study selection.

The databases consulted to identify the articles in English were Scopus, PubMed, and ScienceDirect with the following search terms: “dyslexia” or “dysgraphia” or “developmental dysgraphia” or “agraphia” or “alexia” or “developmental agraphia” or “developmental reading disorder” or “DD” or “developmental reading disability” or “reading disorder” or “spelling disorder” or “develop-mental spelling disorder” or “specific spelling disorder” combined with “intervention” or “training” and including the population under study, “children” or “child.” The terms in English were extracted from Mesh Browser and the articles identified in the initial literature review and final selection of 23 studies of 16 journals (Table 1).

For the search in Spanish, the databases of Redalyc, Scielo, Dialnet, and the Google Scholar search engine were selected, and the following search terms were used: “dislexia,” “Incapacidad Lectora Durante el Desar-rollo,” “Dislexia del Desarrollo,” “Trastorno de la Lectura,” “Alexia,” “Trastorno del Desarrollo de la Lectura,” “Agra-fia,” “Disgrafia,” “Agrafia Pura,” “Disgrafia del desarrollo,” “Trastorno de la escritura,” “Trastorno de la expresión escrita,” combined with “intervención” o “entrenamiento,” together with the population, “niños” o “niñ?” The terms in Spanish were extracted from descriptors in health sciences and the articles identified in the first literature

Figure 1. Flow diagram of the selection process of the studies.

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review. Primary studies were reviewed (clinical trial or controlled clinical trial or randomized controlled trial or case reports). Consisting of 35 articles that were found in the 22 indexed psychology journals that were con-sulted (Table 2) and final selection of eight studies.

Criteria for the selection of studies

For this review, the following criteria were considered: (a) the objective of the study was to identify and review the interventions carried out on the reading and writing processes in children with learning disorders; (b) the articles were written in Spanish or English; (c) primary studies (clinical trial or controlled clinical trial or ran-domized controlled trial or case reports) are included; and (d) the interventions were aimed at children.

Organization of information

The organization of the information was done in an excel matrix; the following information was collected

from each of the studies (title, author, year, objective, sample, instruments, intervention process, results, find-ings, and bibliography).

Results

Once the articles of the search were selected using the aforementioned methodology (eight in Spanish and 23 in English), the following sections characterize Latin American and worldwide research at a first moment, after which the state of the research carried out is com-pared, including the relevance of the interventions and the results presented.

Latin American literature (Spanish)

In general, the research carried out specifically on intervention with children with learning difficulties is found in smaller numbers at a Latin American level (literature in Spanish) compared to the world literature; however, the authors referenced below focus on im-portant aspects that contribute to the promotion of reading and writing skills, favoring the adaptation of children to their school contexts, including parents and

Table 1. Indexed journals and articles in English subject of the study

ISSN number Title of the journal N (articles)

10769242 Dyslexia 1

02667363 Educational psychology in practice

1

16641078 Frontiers in Psychology 4

19411243 J. Occup. Ther. Sch. early intervention

2

02782626 Brain and cognition 1

00066761 BPA applied psychology bulletin 1

21678359 PeerJ 1

00222194 Journal of learning disabilities 1

19326203 Plos One 4

07369387 Annals of dyslexia 1

22131582 NeuroImage: clinical 1

22119493 Trends in neuroscience and education

1

10870547 Journal of attention disorders 1

18632653 Brain structure and function 1

23171782 Codas 1

00315125 Perceptual and motor skills 1

Total 23

Table 2. Indexed journals and articles in Spanish found

ISSN number Title of the journal N (articles)

1794‑4724 Avances en Psicología Latinoamericana

4

0120‑0534 Revista Latinoamericana de Psicología

3

1657‑9267 Universitas Psychologica 1

1657‑8961 Pensamiento Psicológico 3

0123‑9155 Acta Colombiana de Psicología 5

0124‑0137 Psicogente 4

0121‑5469 Revista Colombiana de Psicología

8

2027‑1786 Revista Iberoamericana de Psicología

3

0124‑7816 Katharsis 1

1900‑2386 Psychología: Avances de la Disciplina

1

1900‑3099 Pensando Psicologia 1

2145‑3535 Informes Psicológicos 1

Total 35

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teachers so that the changes made can also be present in their social context.

Initially, the execution of a neuropsychological intervention program was highlighted through game activities that sought to improve the abilities related to the reading process, such as accuracy, speed of read-ing, comprehension of texts, and phonological aware-ness. The children were evaluated through tests of cognitive assessment and IQ that showed improvement in their reading performance (child neuropsychological assessment – ENI and WISC IV)19.

In this sense, other investigations developed literacy programs focused on the phonological awareness com-ponent. Different visopráxicas activities and the spatial location were presented to strengthen the corporal and spatial scheme to generate changes in the phonological processing of the words. The authors concluded that this type of intervention programs has a positive impact on the skills that ensure success in learning to read20-22. In addition, the implementation of different activities based on materials such as board games, didactic sup-ports is highlighted. In addition, the implementation of different activities based on materials such as board games, didactic supports and inferential questionnaires is highlighted, which allowed children to develop skills in orality and the elaboration of narrative texts, fostering creativity and imagination together23,24.

The results of psychoeducational programs are pos-itive; there are changes in phonological knowledge and development, language as a social practice, and in semantic and morphosyntactic aspects. The evalua-tions carried out indicate improvement with respect to control groups in said abilities related to reading and writing25,26.

An intervention program was established based on training processes based on rehabilitation tasks in chil-dren with deficiencies in the quality of handwriting, the ability to understand and dominate the text. In the in-tervention, activities and active participation in reading processes (occupation and participation approach to reading intervention) were developed, which allowed to integrate different perspectives in the treatment, education, occupational cognitive psychology, and cog-nitive neuroscience. The results obtained showed an improvement in the objective skills of the intervention in relation to the control group27-29.

The results of intervention programs to reduce the difficulties associated with dyslexia are evaluated through multiple instruments that allow obtaining valid and reliable results. Software was used to train reading skills that showed positive changes in fluency,

accuracy, and speed of reading, general knowledge of vocabulary and comprehension of written texts30.

In this thematic line, an intervention program that implemented visuomotor coordination exercises were carried out, which showed that the strategies were effective to improve the deficits associated with chil-dren with DD (skills of visual discrimination, visual memory, Visual Spatial Relationship, visual closure, phonological awareness, and quality of writing)31,32.

Other investigations have demonstrated the effective-ness of interventions focused on cognitive abilities (attention, memory, executive functions, and among others), using different methodological strategies and evaluating changes through instruments such as func-tional magnetic resonance33-36. In these studies, the effects of intervention programs on functional connec-tivity in areas related to learning processes in children with dyslexia and attention deficit hyperactivity (ADHD) are described. The results showed better functional connectivity in the cingulate-opercular, anterior cingu-late cortex, decrease of components N100 and P300, as well as increase in the accuracy of the writing and decrease in the reaction time (processing speed)33-38.

Music-based programs were also identified that were intended to help improv brain circuits that are common to music and language processes, which in theory could have a positive effect on the specific difficulties in some types of dyslexia. Positive changes were evi-denced in categorical and auditory perception, auditory attention, phonological awareness, reading skills, rep-etition of pseudowords, temporal processing, and rhythm skills39,40.

Continuing with the interventions based on improving the reading processing, specifically in the graph-eme-phoneme, using essentially game strategies. Positive results were shown in the ability to read and decode words in relation to the control group41. In sim-ilar investigations, positive results were presented after the intervention program in phonetic reading, visual words, and reading fluency42-44.

On the other hand, research formulated from a rhyth-mic program of reading education (rhythmic reading training), contributed positive effects in the reading and speaking process (sound, word coding capacity, cate-gorical, and auditory perception as well as in the tem-poral component of expression), and the authors conclude that the rhythm facilitates the development of reading skills due to the temporal structure that modu-lates the decoding of words45,46.

Regarding longitudinal investigations, a 5-year fol-low-up to a reading intervention program was carried

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out with children of the third grade of schooling (n = 2212), positive changes were generated in spelling, decoding of words and reading comprehension in rela-tion to with the control group. There were no significant differences in vocabulary. For future studies, the author suggests the systematic inclusion of intervention activ-ities but at a lower intensity, in stages that follow the development of reading skills47.

Finally, the intervention programs focused on the family are also necessary. In this sense, training aimed at parents was implemented, which consisted of infor-mation or psychoeducation on the characteristics and management of children with dyslexia, in addition to presenting strategies of promotion of prosocial behav-ior, aimed at reducing behavioral difficulties. In the final evaluation, the parents reported positive changes in their children’s emotional and social skills based on the knowledge and implementation of the strategies learned during the program48,49.

Discussion

According to the review of literature, the various inter-ventions in the child population show significant advanc-es in the implementation of pedagogical strategies and cognitive stimulation through didactic games, which al-low children to improve the understanding and expres-sion of language (acquisition of vocabulary, understand-ing of texts, and among others). Activities related to music were also implemented to improve reading skills, the components of phonological awareness, spatial lo-cation, and indispensable aspects in the development of phonoarticulation related to the reading process.

It is important to mention that most intervention pro-grams allowed the promotion of reading and writing skills, although the research that presented results that were not improved from the activities carried out in their intervention programs is also highlighted. The interven-tion processes demonstrate the effectiveness of vari-ous processes aimed at improving learning problems. Among them, the use of pedagogy, music, and cogni-tive stimulation is mentioned as a complement to basic school skills. This implementation allowed advances in students with learning difficulties.

In general, the investigations are highlighted for their methodological quality (pre-post or repeated measure-ment designs, broad samples, random assignation of the participants to the experimental and control groups, instruments with validity and reliability data, and among others). It is taken into account that despite the few results of the search conducted in Spanish in the past

10 years, the research carried out contributes to the development of increasingly specific intervention pro-grams for children with learning disorders, including different methodological strategies. The intervention programs include children with difficult socioeconomic characteristics and contribute not only in the school environment but also in social contexts.

The studies published in English mostly present the methodological characteristics that identify a quality article. The presence of Latin American authors is high-lighted in the revised articles in English, which denotes the collaboration of authors from different regions of the world to produce knowledge that contributes to the needs and/or particular difficulties of children with learning difficulties.

Finally, the articles in English and Spanish included in the results of the study differ essentially in the meth-odological aspects, the Latin American studies with intervention programs focused on the literacy process-es in children with learning difficulties present small samples, evaluation instruments not validated in His-panic-Latin American population and without reliability data, the children that make up each of the experimen-tal and control groups are not randomized; therefore, the results are not generalizable.

Conclusion

The current state of empirical research published in Spanish in intervention processes in children with learning difficulties is fewer in number in the past 10 years compared to literature in English, as evidenced by the search performed. The comparison established with literature published in English indicates progres-sive advances of Latin American scholarship in the topic addressed in this review, specifically in interven-tion programs focused on specific difficulties associat-ed with learning disorders and the characteristics presented by each of the children.

References 1. Bruner J. Desarrollo Cognitivo y Educación. Madrid: Morata; 1998. 2. Pinzás J. Metacognición y Lectura. Lima: Fondo Editorial PUCP; 2003. 3. Talero C, Espinosa A, Vélez A. Dificultad del aprendizaje de la lectura

en las escuelas de una localidad de Bogotá. Acta Neurol Colomb. 2005; 21:280-8.

4. Ardila A, Rosselli M. Neuropsicología Clínica. México: Manual Moderno; 2007.

5. Matute E, Ardila M, Roselli A. Trastorno de la lectura. In: Roselli M, Matute y ME, Ardila A, editors. Neuropsicología del Desarrollo Infantil. México: Manual Moderno; 2010. p. 139-60.

6. Matute E, Roselli A, Ardila M. Trastorno de la expresión escrita. En: Roselli A, Matute y ME, Ardila A, editors. Neuropsicología del Desarrollo Infantil. México: Manual Moderno; 2010. p. 161-80.

7. Paris SG, Paris AH. Classroom applications of research on self-regulated learning. Educ Psychol. 2001;36:89-101.

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er.

©

Per

man

yer

2019

161


8. Álvarez-Otero B, Monereo C. Evaluación del conocimiento estratégico de los alumnos a través de tareas auténticas de escritura en clase de ciencias naturales. Av Psicol Latinonot. 2010;28:251-64.

9. Lopera F. Dificultades del aprendizaje. In: Díaz R, Cornejo W, editors. Neurología Infantil. Medellín: Universidad de Antioquia; 2002. p. 224-42.

10. Rivas A. América Latina Después de PISA: lecciones Aprendidas de la Educación en Siete Países (2000-2015). Argentina: Fundación CIPPEC; 2015.

11. Aponte-Henao M, Zapata-Zabala ME. Caracterización de las funciones cog-nitivas de un grupo de estudiantes con trastornos específicos del aprendiza-je en un colegio de la ciudad de Cali, Colombia. Psychologia. 2013;7:23-34.

12. Sattler J, Weyandt L. Discapacidades específicas para el aprendizaje. Evaluación infantil: aplicaciones Conductuales y Clínica. Vol. 2. México: El Manual Moderno; 2003. p. 293-349.

13. Pardo NA. Prevalencia del Trastorno Específico de la Lectura en una Muestra de Instituciones Educativas de la Localidad 19 de Bogotá. Co-lombia: Universidad Nacional de Colombia; 2015.

14. Defior S, Serrano F. Dislexia en español: bases para su tratamiento y diagnóstico. Dislexia definición e intervención en hispanohablantes. En: Matute E, Guajardo S, editors. Dislexia: definición e Intervención en Hispanohablantes. México: Manual Moderno; 2012. p. 15-35.

15. Artigas-Pallarés J. Dislexia: enfermedad, trastorno o algo distinto. Rev Neurol. 2009;48:63-9.

16. Portellano Pérez J. La Disgrafía. España: Editorial Paidós; 1985. 17. Dueñas M. Tengo un Hijo Disléxico. Madrid: Temas de Hoy; 1987. 18. Fabelo S, del Carmen M. Prevención de las disgrafías escolares: nece-

sidad de la escuela actual para la atención a la diversidad: una mirada desde Cuba. Nóesis Rev Ci Soc Humanit. 2006;15:117-33.

19. Cadavid-Ruiz N, Rosas R, Quijano-Martínez MC, Tenorio M. El juego como vehículo para mejorar las habilidades de lectura en niños con di-ficultad lectora. Pensamiento Psicol. 2015;12:23-38.

20. Flórez-Romero R, Restrepo MA, Schwanenflugel P. Promoción del alfa-betismo inicial y prevención de las dificultades en la lectura: una experien-cia pedagógica en el aula de preescolar. Av Psicol Latinonot. 2009;27:79-96.

21. Córdova E. Intervención de la lectoescritura en una niña con dislexia. Pensamiento Psicol. 2014;12:55-69.

22. Vargas A, Villamil W. Diferencias en el rendimiento lector entre dos grupos de niños de transición debidas a una intervención promotora del alfabetismo emergente en el aula. Rev Colomb Psicol. 2007;16:65-76.

23. Castilla C, Amaya MY, Amaya YP, Laguna YV. Influencia del juego como pilar de la educación en el desarrollo del lenguaje oral y escrito por medio de los juegos de mesa. Rev Iberoam Psicol. 2014;7:39-48.

24. Duque-Aristizábal C. Exploración de la comprensión inferencial de textos narrativos en niños de preescolar. Rev Colomb Psicol. 2010;19:21-35.

25. Morales D, de Delia J, Mota MC, García EZ. La práctica social del len-guaje como base para la enseñanza de la lectoescritura. Rev Iberoam Psicol. 2012;5:59-66.

26. Valenzuela MJ, Ruiz IM, Ríos MD. Intervención temprana de la lectoes-critura en sujetos con dificultades de aprendizaje. Rev Latinoam Psicol. 2011;43:35-44.

27. Grajo LC, Candler C. An occupation and participation approach to rea-ding intervention (OPARI) Part II: pilot clinical application. J Occup Ther Sch Early Interv. 2016;9:86-98.

28. Grajo LC, Candler C. An occupation and participation approach to rea-ding intervention (OPARI) Part I: defining reading as an occupation. J Occup Ther Sch Early Interv. 2016;9:74-85.

29. Baldi S, Nunzi M, Brina CD. Efficacy of a task-based training approach in the rehabilitation of three children with poor handwriting quality: a pilot study. Percept Mot Skills. 2015;120:323-35.

30. Tucci R, Savoia V, Bertolo L, Vio C, Tressoldi PE. Efficacy and efficien-cy outcomes of a training to ameliorate developmental dyslexia using the online software reading trainer®. BPA Appl Psychol Bull. 2015;64:53-60.

31. Qian Y, Bi HY. The effect of magnocellular-based visual-motor intervention on Chinese children with developmental dyslexia. Front Psychol. 2015;6:1-7.

32. Fusco N, Germano GD, Capellini SA. Efficacy of a perceptual and vi-sual-motor skill intervention program for students with dyslexia. Codas. 2015;27:128-34.

33. Horowitz-Kraus T. Differential effect of cognitive training on executive functions and reading abilities in children with ADHD and in children with ADHD comorbid with reading difficulties. J Atten Disord. 2015;19:515-26.

34. Horowitz-Kraus T. Improvement in non-linguistic executive functions fo-llowing reading acceleration training in children with reading difficulties: an ERP study. Trends Neurosci Educ. 2015;4:77-86.

35. Horowitz-Kraus T, DiFrancesco M, Kay B, Wang Y, Holland SK. Increa-sed resting-state functional connectivity of visual and cognitive-control brain networks after training in children with reading difficulties. Neuroi-mage Clin. 2015;8:619-30.

36. Horowitz-Kraus T, Holland SK. Greater functional connectivity between reading and error-detection regions following training with the reading acceleration program in children with reading difficulties. Ann Dyslexia. 2015;65:1-23.

37. Moreau D, Waldie KE. Developmental learning disorders: from generic interventions to individualized remediation. Front Psychol. 2016;6:1-8.

38. Horowitz-Kraus T, Toro-Serey C, Difrancesco M. Increased resting-state functional connectivity in the cingulo-opercular cognitive-control network after intervention in children with reading difficulties. PLoS One. 2015;10:1-21.

39. Habib M, Lardy C, Desiles T, Commeiras C, Chobert J, Besson M, et al. Music and dyslexia: a New musical training method to improve reading and related disorders. Front Psychol. 2016;7:26.

40. Flaugnacco E, Lopez L, Terribili C, Montico M, Zoia S, Schön D, et al. Music training increases phonological awareness and reading skills in developmental dyslexia: a randomized control trial. PLoS One. 2015; 10:e0138715.

41. Jeffes B. Raising the reading skills of secondary-age students with se-vere and persistent reading difficulties: evaluation of the efficacy and implementation of a phonics-based intervention programme. Educ Psy-chol Pract. 2016;32:73-84.

42. Fraga-Gonzalez G, Zaric G, Tijms J, Bonte M, Blomert L, Leppanen P, et al. Responsivity to dyslexia training indexed by the N170 amplitude of the brain potential elicited by word reading. Brain Cogn. 2016;106:42-54.

43. McArthur G, Castles A, Kohnen S, Larsen L, Jones K, Anandakumar T, et al. Sight word and phonics training in children with dyslexia. J Learn Disabil. 2015;48:391-407.

44. McArthur G, Kohnen S, Jones K, Eve P, Banales E, Larsen L, et al. Replicability of sight word training and phonics training in poor readers: a randomised controlled trial. Peer J. 2015;2015:1-21.

45. Bonacina S, Cancer A, Lanzi PL, Lorusso ML, Antonietti A. Improving reading skills in students with dyslexia: the efficacy of a sublexical training with rhythmic background. Front Psychol 2015;6:1510.

46. Cancer A, Bonacina S, Lorusso ML, Lanzi PL, Antonietti A. Rhythmic reading training (RRT): a computer-assisted intervention program for dyslexia. In: Giakoumis D, Lopez G, Matic A, Serino S, Cipresso P, editors. 5th International Conference on Pervasive Computing Paradigms for Mental Health, Mind Care 2015. Tokyo, Japan: Springer Verlag; 2016. p. 249-58.

47. Wolff U. Effects of a randomized reading intervention study aimed at 9-year-olds: a 5-year follow-up. Dyslexia. 2016;22:85-100.

48. Heim S, Pape-Neumann J, van Ermingen-Marbach M, Brinkhaus M, Grande M. Shared vs. specific brain activation changes in dyslexia after training of phonology, attention, or reading. Brain Struct Funct. 2015; 220:2191-207.

49. Multhauf B, Buschmann A. Parent training programme for dyslexia recog-nising changes in children’s behaviour. LOGOS Interdiszip. 2016;24:4-14.

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Immunology of Alzheimer’s diseaseLucila I. Sosa-García1, Janeth Hernández-Jiménez1, Diana I. Del Moral-Huerta1, Charles Duyckaerts2

and Ana L. Calderón-Garcidueñas3*1Doctoral Program in Biomedical Sciences, Institute of Biomedical Research, Universidad Veracruzana, Xalapa; 2Departament of Neuropathology, Hôpital Universitaire Pitié-Salpêtrière, Paris, France; Faculty of Medicine, Universidad Veracruzana, Región Veracruz. Mexico


REvIEW ARTICLE

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology. Neuroinflammation is an early event of the presymp-tomatic stages in AD and contributes to its progression. We review the participation of astrocytes, microglia and blood-brain barrier cells, the mechanisms of cell death and the inflammatory factors such as chemokines, interferons and Toll-like recep-tors involved in progression and perpetuation of AD. Some of its prognostic and therapeutic possibilities are also mentioned. Identifying the different actors involved in inflammation and the main mechanisms of damage might allow the development of preventive strategies and treatments to fight against this devastating disease.

Key words: Immunology. Alzheimer’s disease. Microglia. Innate immunity. Lymphocytes.

Inmunología de la enfermedad de Alzheimer

Resumen

La enfermedad de Alzheimer (EA) es una patología neurodegenerativa multifactorial. La neuroinflamación es un evento temprano de las etapas presintomáticas en la EA y contribuye a su progresión. En este trabajo revisamos la participación de astrocitos, microglia y células de la barrera hematoencefálica, los mecanismos de muerte celular y los factores inflama-torios como las quimiocinas, los interferones y los receptores tipo Toll que participan en la progresión y la perpetuación de esta enfermedad. También se mencionan algunas de sus posibilidades pronósticas y terapéuticas. La identificación de los diferentes actores involucrados en la inflamación y de los principales mecanismos de daño podrían permitir el desarrollo de estrategias y tratamientos preventivos para combatir esta enfermedad devastadora.

Palabras clave: Inmunología. Enfermedad de Alzheimer. Microglia. Inmunidad innata. Linfocitos.

Correspondencia: *Ana Laura Calderón-Garcidueñas

Facultad de Medicina

Agustín de Iturbide, s/n

Zona Centro

C.P. 91700, Veracruz, México



Rev Mex Neuroci. 2019;20(3):162-170




DOI: 10.24875/RMN.19000010

1665-5044/© 2019. Academia Mexicana de Neurología A.C. A.C. Published by Permanyer México. This is an Open Access article under the terms of the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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mailto:acald911%40hotmail.com?subject=

http://dx.doi.org/10.24875/RMN.19000010

http://crossmark.crossref.org/dialog/?doi=10.24875/RMN.19000010&domain=pdf


163

L.I. Sosa-García, et al.: Immunology of AD

Introduction

Alzheimer’s disease (AD) is the most common de-mentia. It is characterized by abnormal protein aggre-gates of tau protein (tubulin-associated) and β-amyloid (Aβ). Tau aggregates acting as “seeds” may propagate pathology by spreading from cell to cell in a “prion-like” manner1. It occurs in two forms, early onset, that is, genetically determined and late onset that is more fre-quent and mutifactorial2. Late-onset AD is genetically complex with 56-79% heritability3. Regardless of the initial trigger that initiates the abnormal aggregation of proteins, there seems to be an inflammatory back-ground that contributes to the perpetuation of neuronal damage2. The importance of the immune response in AD has been evidenced with genomic studies in late-on-set AD. These studies have shown at least four func-tional pathways of susceptibility to AD, the immune re-sponse, the regulation of endocytosis, the transport of cholesterol, and the ubiquitination of proteins4. The aim of this work is to review the most important immunolog-ical aspects in AD and its possible therapeutic implications.

Development

The immune system identifies foreign elements (i.e., different from the self) to mount a defense re-sponse against them. Natural or innate immunity is not specific and does not require an external challenge to be involved; acquired immunity is specific and keeps the memory of previous challenges. The immune sys-tem seems to contribute to the perpetuation of damage in Alzheimer’s disease (AD). Some recent research suggests that the manipulation of some of these par-ticipants in the immune response such as microglia and cytokines could have beneficial therapeutic effects. In-flammation in AD involves both the innate and the ac-quired immune system5.

Participating cells

Astrocytes

Astrocytes are the most abundant glial cells. They contribute to the support of the neurons, but it is now known that they can perform other functions including providing the biochemical support of the endothelial cells that are part of the blood–brain barrier (BBB); they participate in the maintenance of the extracellular ionic balance and the repair and healing process of the brain

parenchyma. The astrocytes can clean detritus by phagocytosis and support neuronal nutrition; but also, they are mediators of inflammation and are involved in the formation of reactive oxygen species. They have multiple roles in the development of AD: astrocytes de-grade Aβ without the need for opsonins or cytokines6. They contribute to the clearance of β-amyloid protein (Aβ) and limit brain inflammation. If they dysfunction, they can also participate in neurodegeneration, releas-ing toxins, and altering basic metabolic pathways7.

Astrocytes, as well as monocytes/macrophages and endothelial cells, secrete, monocyte chemoattractant protein-1 (MCP-1); this secretion is mediated by the stimulation of Aβ and depends on the physical contact between monocytes and astrocytes. MCP-1 facilitates the formation of Aβ oligomers in microglia. The concen-tration of MCP-1 in serum and cerebrospinal fluid (CSF) is elevated in patients with AD; the higher plasma con-centration of MCP-1, the greater the severity of the disease, and the greater the cognitive deterioration8.

In cell cultures of astrocytes, it has been shown that it is possible to inhibit inflammation induced by Aβ by pyrrolidine dithiocarbamate acid, indicating that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is probably involved in the inflammatory pro-cess9. Resveratrol reduces inflammation in rat astro-cytes probably by inhibiting NF-κB9.

Interleukin 8 (IL-8) was the first chemokine identified in the brain. Astrocytes, neurons, and microglia are capable of producing IL-8 in vitro, whereas IL-8 receptor or CXCR2 is located in the neuritic portion of the plaques around Aβ deposits in tissues of patients with AD. Type 2 diabetes mellitus is a risk factor for demen-tia. It has been shown that hyperglycemia increases the expression of IL-6 mRNA and the astrocytic secretion of IL-6 and IL-8, contributing to astrocyte-mediated neuroinflammation10.

Microglia

Microglia are resident myeloid cells of the brain ca-pable of recognizing endogenous and exogenous in-sults and initiating an immune response. They promote phagocytic cleaning and provide trophic support to ensure tissue repair and maintain homeostasis. In ad-dition, they participate actively in the remodeling of synapses with the release of brain-derived neurotroph-ic factor (BDNF) that contributes to the formation of memory circuits.11 Microglial cells originate from the yolk sac during primitive hematopoiesis12. Their differ-entiation need the PU.1 transcription factor and the

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regulatory factor of interferon 8 or IRF8; to survive, they also require the signaling of the colony stimulating factor 1 receptor (CSF1R)13. The release of IL-10 by the microglia causes an increase in the number of dendritic spines. AD is associated with apolipoprotein E ε4 (APOE4) while APOE2 has a protective nature. Both astrocytes and microglia express APOE under the control of nuclear hormone receptors. In AD, the in-flammatory activity of the microglia is increased. The microglial cells mount an immune response against the misfolded Aβ protein. The deposit of Aβ induces inflam-matory changes in the brain parenchyma, and activa-tion of the microglia has been demonstrated with an increase in the levels of pro-inflammatory cytokines in the regions characteristically most affected in the dis-ease14. If the problem is not solved and the stimulus continues, the activity of the microglia deviates from its physiological and beneficial functions. To recognize aggressions, the microglia have different types of re-ceptors, some designed to identify molecular patterns associated with pathogens (PAMPS) and damage, known as PAMPS/DAMPS. It also presents the class 1-scavenger receptor, CD36 (Cluster designa-tion/differentiation), CD14, integrin α6β1, CD47 (integ-rin-associated protein), and Toll-like receptors (TLR2, TLR4, TLR6, and TLR9)14. The amyloid precursor pro-tein (APP) is an integral membrane protein expressed in many tissues and concentrated in the neuronal syn-apse where it probably has a trophic and regulatory function with both extracellular and intracellular inter-action with different signal transduction pathways15. It seems to participate in the development of the neural stem cell, in neuronal survival, and the growth and repair of neurites. APP is cut by some enzymes, giving rise to peptides, some of which are released outside the cell16. Two of these fragments, or peptides that leave the cell are:– Soluble sAPP that promotes the growth of nerve cells

and can play an important role in the formation of neurons, both before and after birth.

– Aβ, a peptide of 36-43 amino acids that activates ki-nases. Oligomeric Aβ42 enhances Ras (contraction of Rat Sarcoma)/ERK signaling cascade and glycogen synthase kinase-3 (GSK-3) activation. Both ERK and GSK-3 induce hyperphosphorylation of tau and APP at Thr66817 and could be related to cholesterol metab-olism. In fact, inhibition of cholesterol biosynthesis reduces γ-secretase activity and Aβ generation18 It is also believed that it may have some antimicrobial ac-tivity (it intervenes in the inflammatory action)16.

APP undergoes two consecutive cuts by two mem-brane-bound proteases. It is initially cut by BACE1 (β-site APP-cleaving enzyme 1). Subsequently, a sec-ond cut is made by the secretase γ (gamma) complex within the transmembrane region of the APP resulting in fragments of 37-42 amino acids at the C-terminal end called Aβ. In particular, the Aβ of 42 amino acids (Ab1-42) has a tendency to form soluble oligomers and fibrils16.

The binding of Aβ to CD36, TLR4, and TLR6 acti-vates microglia and with it, the production of pro-inflam-matory cytokines and chemokines. Microglial cells ingest Aβ fibrils that enter the endosomal/lysosomal pathway. However, these fibrils are resistant to enzy-matic degradation unlike soluble Aβ that is degraded by extracellular proteases. Preliminary studies have demonstrated that CNP520, a BACE-1 inhibitor, re-duced the amount of Aβ in CSF and in the brain paren-chyma of healthy rats and dogs, and the deposit of Aβ in the plaques of transgenic-APP mice. In adults over 60, it was well tolerated and it reduced Aβ concentra-tion in the CSF. These studies are still in progress19.

Microglia are able to release the insulin-degrading enzyme (IDE) that degrades insulin, amylin, and Aβ. IDE seems to be the main regulator of Aβ levels in mi-croglia and neurons. In animal models, the homozy-gous deletion of the IDE gene results in a 50% de-crease in the degradation of Aβ and in a similar deficit in the breakdown of insulin in the liver with an accumu-lation of Aβ in the brain. A meta-analysis demonstrated recently that AD patients have lower protein levels of IDE in comparison with controls (mRNA levels were not systematically lower)20.

It has also been shown that IDE degrades the APP intracellular domain (AICD). IDE regulates the levels of non-phosphorylated AICD. It seems that phosphoryla-tion protects AICD from its breakdown by IDE. The IDE could be a therapeutic target in AD21.

ApoE gene, which codes for ApoE, the most important genetic risk for AD seems to have an immunomodula-tory function. This function is related to the activation of triggering receptor expressed on myeloid cells2 (TREM2) expressed by microglia22.

Mutations in the extracellular domain of TREM2 con-fer an elevated risk of developing late-onset AD. A risk allele (R47H) of TREM2 had an effect similar to ApoE4 (odds ratio 2.90-5.05) in a Colombian population23. TREM2 is a receptor expressed in macrophages in-cluding microglia in the brain. TREM2 participates in the survival and proliferation of microglia, chemotaxis, and phagocytosis23. In murine models of AD, the loss of TREM2 causes increased deposits of Aβ in the

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hippocampus due to a dysfunctional response of the microglia to Aβ suggesting that TREM2 facilitates the clearance of Aβ by these cells24.

The microglial response mediated by TREM2/DAP12 (DNA activation protein of 12kDa) limits the diffusion and toxicity of the amyloid plaques forming a protective barrier. TREM2 propagates its signal through the adapter protein DAP12, which, in turn, activates several signaling pathways including Spleen tyrosine kinase, phosphoinositide 3-kinase, and the mitogen-activated protein kinase (MAPK) which culmi-nates in increased phagocytosis and an anti-inflam-matory profile in the microglia24. On the other hand, dendritic cells deficient in TREM2 secrete more tumor necrosis factor-alpha (TNF-α), IL6 and IL-12 compared to wild type, especially when activated by lipopolysac-charides; this suggests that there may be a shift to-ward a more inflammatory profile in the absence of TREM225.

The loss of TREM2 in microglia confers an increased risk of developing late-onset AD and is associated with loss of endothelial homeostasis25.

In AD, there is over-regulation of TREM2 that seems to serve as a compensatory response to Aβ1−42 and protects against the progression of the disease by mod-ulating the functions of microglia. TREM2 promotes the survival of microglia by activating the Wnt/β-catenin signaling pathway. The manipulation of TREM2/Wnt/β-catenin may be a therapeutic target in AD26.

It is known that all isoforms of apoE are an agonist of TREM227. APOE3 maintains lipid homeostasis and has a protective cardiovascular effect. APOE2 is asso-ciated with dysbetalipoproteinemia and APOE4 is a risk factor for AD27. Microglial cells are able to produce nitric oxide (NO), TNF-α, and IL-1β and promote the gener-ation of antibodies against Aβ, stimulating the clear-ance of amyloid plaques. The soluble Aβ oligomers and the Aβ fibrils have the ability to bind to receptors ex-pressed in the microglia, such as CD14, CD36, CD47 integrin α6β1, the Class A eliminator receptor, the re-ceptor for advanced glycation end products (RAGE), and TLR. In macrophages and microglia, classical M1 activation is characterized by a pro-inflammatory profile of cytokines including TNF-α, interleukins 1 (IL-1), 6 (IL-6), 12, and 18, and it is accompanied by a deficient phagocytic capacity, while the M2 profile is character-ized by secretion of anti-inflammatory cytokines IL-4, IL-10, and IL-13 and transforming growth factor-beta (TGF-β) and by a high phagocytic capacity without NO production. A third phenotype is a deactivated state associated with corticosteroids or with TGF-β. In vitro,

bipolar/rod-shaped microglia are highly proliferative, ex-press various M1/M2 markers and are quickly trans-formed into amoeboid microglia within 30 min of lipo-polysaccharide treatment, leading to the upregulation of pro-inflammatory cytokine gene expression and the activation of Jak/STAT signaling pathway (Janus ki-nase-signal transducer and activator of transcription)28. Markers of microglial phenotypes in human brains are still limited; the most widely used marker to describe activated microglia, particularly in diseased brains, has been HLA-DR, or major histocompatibility complex II protein. Ionized calcium binding adaptor molecule-1 (IBA1) and CD68 are generic markers of microglia and recruited monocytes29. In patients with AD, Stages V-VI of Braak, degeneration of the microglia has been ob-served, especially in the dentate gyrus, probably due to the accumulation of toxic tau-soluble species30. There are agents capable of increasing phagocytosis of Aβ in phagocytic cells, such as Lipoxin A4 (LXA4), an endogenous lipid mediator with anti-inflammatory properties. It has been shown in mice that the admin-istration of aspirin (15 μg/kg) twice a day, through the activation of LXA4, reduces the activation of NF-κB and the levels of pro-inflammatory cytokines, and produces an increase in IL-10 with anti-inflammatory action and in TGF-b. This was translated to the brain level in the recruitment of microglia with a phenotype characterized by the upregulation of YM1 lectin protein, and arginase 1 and low-regulation of the inducible synthase expres-sion of NO. With this phenotype, the microglia presented a better phagocytic function with an efficient clearance of Aβ, reduction of synaptotoxicity, and improvement of cognition31.

In transgenic mice bearing a mutated gene of tau (p301s MAPT), the elimination of astrocytic and microg-lial senescent cells (that accumulate p16INK4A), with first-generation senolytics drugs (drugs that cause se-nescent cells to become susceptible to their own pro-apoptotic microenvironment)32, preserves the cog-nitive function; a therapy focused on senescent cells (with irreversible arrest of the cell cycle) could be useful in AD33.

BBB

The BBB protects the central nervous system from the entry of substances that can be potentially harmful and maintains homeostasis and communication be-tween the brain and the peripheral blood. In addition to affecting neurons, astrocytes, and microglia, AD also damages the vascular cells of the neurovascular unit

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such as endothelial cells, pericytes, and vascular smooth muscle cells34. The interaction of Aβ with endo-thelial cells produces structural and functional changes in the BBB. It is now known that C-reactive protein (CRP), a member of the pentraxin superfamily involved in innate immune response, acts as a direct mediator of inflammatory reactions. The inert circulating pentam-eric form (pCRP) is transformed into the pro-inflamma-tory isoform pCRP and finally into the monomeric form (CRPm) in the presence of amyloid beta and activated endothelial cells. It will then contribute to the inflamma-tion in AD35.

Aβ in CSF is rapidly cleared into the bloodstream. Aβ in the brain parenchyma is cleared across the BBB through the low-density lipoprotein receptor-related protein-1 (LRP-1)36.

The luminal-to-abluminal transcytosis of Aβ is medi-ated by a transporter identified as the receptor for advanced glycation end products (RAGE). RAGE up-regulation has been observed in the CNS microvascu-lature of humans with AD by histochemical methods in autopsy material37.

Decreased expression of low-density lipoprotein re-ceptor-related to protein 1 (LPR-1) in the outer or ablu-minal part of cerebral capillary cells and decreased levels of multidrug transporter p-glycoprotein (P-gp) in the luminal plasma membrane of the capillaries lead to a decrease in the flow of Aβ from the brain to the blood38.

On the other hand, it has been observed that Catal-pol, an iridoid glycoside extracted from the root of Reh-mannia glutinosa Libosch, has a neuroprotective effect in AD. The protective mechanism seems to depend on a decrease in the levels of metalloproteinases (MMPs), MMP-2, MMP-9, and RAGE, as well as an increase in the concentration of proteins of the narrow junctions (zonula occludens-1, ocludin, and claudin-5), the LPR-1 and the glycoprotein P, so that the Catalpol could have utility in the early treatment of AD39. The endothelial cells of the BBB can also be damaged by high concen-trations of low-density proteins (LDL). Statins decrease the inflammatory effects of oxidized LDL in the microvasculature40.

Lymphocytes

AD appears to be a systemic pathology in which some of the dysfunctions found in the brain are pres-ent in peripheral tissues. Lymphocytes from patients with AD have an increased susceptibility to death in-duced by hydrogen peroxide (H2O2) that is related to

the severity of dementia and appears to depend on deregulation of the p53 pathway with increased ex-pression of p5341. Various alterations in the lympho-cytes of patients with AD have been described, includ-ing a systemic decrease in B and T lymphocytes. The peripheral CD4 + and CD19 + lymphocytes in the early stages of AD show mitochondrial depletion. Lympho-cytes T-helper 17 are found in the brain parenchyma of AD and IL-17A is located around the Aβ deposits. Overexpression of IL-17 improves glucose metabolism, amyloid angiopathy and learning in rats exposed to ozone, a murine model of oxidative stress and de-creases soluble Aβ in the hippocampus and the CSF42. More recently, it has been found that micro-RNA Let-7b levels increase with the progression of the disease and this is parallel to the increase in the number of CD4 + T lymphocytes in the CSF. This microRNA cor-relates positively with the expression of t-Tau and p-Tau and is being studied as a possible biomarker of progression43.

In the late stages of the disease, CD8 + T lympho-cytes are increased in number in the hippocampus of subjects with AD compared to subjects without demen-tia. The numerical density of T-lymphocytes correlates with the tau pathology (AT8 staining)44.

It is known that Vitamin D deficiency is a risk factor for cognitive deterioration and that this vitamin is in-volved in the clearance of Aβ from the brain. In subjects with mild cognitive impairment, their lymphocytes are more susceptible to oxidative damage, which improves with treatment with Vitamin D for 6 months as well as the plasma concentration of Aβ and cognitive function45.

It has been proposed that the T cell profile may change depending on the stage of the evolution of AD, with an increase in pro-inflammatory activity as the disease progresses. Neurodegeneration, in general, has been linked to an imbalance between effector T cells that release IFNγ or IL17 and T-lymphocytes reg, which leads to a decrease in neuroprotection and in-creases neuronal damage46.

Mechanisms of Cell Death

Apoptosis and necrosis

In the context of AD, although death due to apoptosis seems to prevail, necrosis also contributes to neurode-generation. In familial Alzheimer’s, some genes in-volved (presenilin 1 and 2) make neurons more sus-ceptible to apoptosis2.

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On the other hand, greater expression of Bak and Bad pro-apoptotic proteins, activation of caspases and decreased expression of the antiapoptotic gene NCK-associated protein 1 has been demonstrated in affected brains2.

Neuronal autophagy

Excessive accumulation of autophagic vacuoles and toxic substances such as misfolded proteins or dam-aged organelles can lead to cell death by self-destruc-tion. Autophagosomes are frequent in AD. The beclin-1 protein plays an important role in autophagy and is di-minished in AD. In fact, patients with AD show accumulation of autophagy markers such as sequesto-some 1/p62 (ubiquitin-binding protein) and LC3 (Micro-tubule-associated protein 1A/1B-light chain 3) and these markers colocalize with the Aβ marker-6E10 and hyperphosphorylated tau47.

The intracellular Aβ alters the retrograde transport mediated by dynein. The neurons must transport the autophagosomes generated in the distal axons to the soma or neuronal body. This retrograde transport starts with the recruitment of the late endosome complex (LE)-loaded with dynein and with SNAPIN (SNAP-as-sociated protein) after fusion of LE with autophagic vacuoles to form amphysomes. However, in AD, auto-phagic vacuoles accumulate massively within dystro-phic neurites. Aβ is associated with an increased den-sity of LEs or multivesicular bodies. It has been shown in animal models that Dynein intermediate chain 1, axonemal interacts with Aβ _ interacts with Aβ. This binding competitively disrupts the formation of dynein-SNAPIN complexes, and therefore the recruit-ment of dynein motors to LEs-loaded with SNAPIN (am-physomes), is markedly reduced48.

Inflammation

In the development of AD, Aβ, and Tau protein can act as pro-inflammatory factors. In fact, the deposition of Aβ in the brain is associated with the activation of astrocytes and microglia. The soluble isoforms of Aβ are phagocytosed by microglia while the insoluble de-posits activate microglia by binding to TLRs. In these cells, Aβ activates MAPKs and favors the expression of a pro-inflammatory profile with the secretion of cy-tokines and chemokines that amplify the inflammatory process49. The misfolded protein aggregates activate the NLRP3 (cryopyrin) inflammosome. NLRP3 inflam-masome is a multiprotein complex expressed in

myeloid cells and has an important role in the activation of caspase-1 by Aβ50.

Glia maturation factor (GMF) is a regulator of the actin cytoskeleton with a unique role in remodeling actin network architecture; it does not bind actin but instead binds the Arp2/3 complex. GMF catalyzes the deb-ranching of actin filament networks and inhibits actin nucleation by Arp2/3 complex. GMF is also a pro-inflam-matory molecule present in glial cells and some neu-rons. Its over-expression causes inflammation. It is lo-calized and expressed in the neighborhood of Aβ and tau in the temporal cortex of patients with AD. GMF could be a therapeutic target in AD51.

Dendritic cells (DC) appear to regulate the entry of T-lymphocytes into the perivascular and leptomenin-geal spaces. Their protective properties in AD are related to their ability to clear Aβ. Aβ significantly de-creases the expression of brain-derived neurotrophic factor (BDNF) in DCs derived from AD patients but not from control subjects, AD-linked dysregulated im-mune mechanisms lead to dendritic cell-mediated over-activation of inflammation and impaired antigen presentation, thus supporting the idea that immune cell activation could play an important role in AD pathogenesis52.

Recently, elevated levels of CSF biomarkers such as heparin and chitin-binding glycoprotein (YKL-40), inter-cellular adhesion molecule-1, vascular adhesion mole-cule-1, IL-15, and fms-related tyrosine kinase-1 have been described, both during the preclinical phase and in the dementia phase of AD. These levels correlate with the total concentration of tau in the CSF53.

Chemokines

Chemokines, belonging to the cytokine family, are small proteins that bind to heparin and are chemoat-tractants; some are pro-inflammatory while others control the migration of cells during development. Chemokines are classified according to their primary protein structure that is based on the number of amino acids that separate two cysteine residues; thus, four groups are recognized, α (CXC), β (CC), γ (CX3C), and δ (C). Chemokine receptors are designated CX-CR1-CXCR6, CCR1-CCR11, CX3CR1, and XCR. Chemokines and their receptors represented by MCP-1 (also called chemokine (C-C motif) ligand 2 [CCL2] and its receptor (CCR2) are considered biomarkers to monitor progression in AD since the progression of the disease seems to be related to the expression of chemokines14.

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In studies of clinical follow-up of patients with a cog-nitive neurological deficit, it has been seen that those with the highest tertile of MCP-1 in CSF showed a sig-nificant cognitive decrease and developed dementia in a shorter time than those in the lowest tertile14.

The chemotactic cytokines stimulate and control the movement of leukocytes from the blood to the tissues. In the context of AD, the most studied chemokine is CCL5 (RANTES) that regulates the expression and se-cretion of T cells14. Curcumin increases neuronal sur-vival in the toxicity model induced by N-methyl-d-aspar-tic acid by inducing the expression of RANTES in astrocytes through the phosphatidylinositol 3-kinase and MAPK pathways54.

In AD increased concentrations of CCL5 of astroglial origin have been described in the cerebral microcircu-latory system in response to the increase in reactive oxygen species-mediated by cytokines.

It has been described in patients with AD that levels of MCP-1 and IL8 are increased in serum, CSF and parenchyma; on the other hand, levels of fractalkine and stromal cell-derived factor 1 are decreased in se-rum. Fractalkine (CX3CL1) is made by neurons, and its receptor (CX3CR1) is expressed by microglia; there-fore, fractalkine/receptor interactions are a neuron–mi-croglial signaling system55.

MIP-1 and RANTES levels are elevated in the brain parenchyma. MCP-1, IL-6, and IL-8 are over-expressed in brain tissue in AD. Immunohistochemical studies have confirmed the increase and localization of these three factors in neurons56, whereas in astrocytes MCP-1 and IL-6 were detected. MCP-1 and IL-8 have been observed in senile plaques.

Interferons (IFN)

IFN are cytokines made up of glycoproteins used for communication between cells; they activate the immune system in case of aggression. They are divided into three classes: types I, II, and III. Type I IFN in humans is IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω; produced by fibroblasts and monocytes; they are activated in viral infections. Type II or IFN-γ in humans is activated by IL-12 and produced by helper T-lymphocytes type 1 (Th1) and natural killer cells. Type III IFNs are charac-terized by having CRF2-4 and CRF2-12 receptors. The expression of IFNs Type I and III can be induced in virtually all cell types after recognition of viral compo-nents, while the production of IFN Type II is restricted to immune cells.

Type I IFNs are pleiotropic cytokines that control the secretion of pro-inflammatory cytokines and regulate the immune response that contributes to progression in AD. IFN beta 1a has been used in patients with AD in early stages; an improvement in the instrumental activities of daily life has been observed in these patients57.

TLRs

TLRs are Type I transmembrane proteins with ect-odomains that contain leucine-rich repeats that medi-ate the recognition of molecular PAMP; they are ho-mologous to toll, a receptor found in insects, which participate both in the establishment of dorsoventral polarity during embryogenesis and in the immune response against fungal infections. 12 TRLs have been described in mice and 10 in humans; TLR1-9 are conserved in both. Fibrillar Aβ can interact directly with TLR2, TLR4, and CD14 to induce phagocytosis of Aβ by microglia in the early stages and neuroin-flammatory responses in the advanced stages. In the early stages, the signal mediated by TLR3 increases the autophagy of Aβ; it increases neuronal apoptosis in the late stages. Furthermore, TLR7, TLR8, and TLR9 can increase phagocytosis of Aβ early, to later contribute to neuroinflammation. TLR2 and TLR4 can be a target of therapeutic intervention in AD58. It has also been described that the polymorphism of TLR2 -196-174del is a risk factor for late-onset AD in some populations59.

It seems today well established that chronic inflam-matory reactions are present in Alzheimer disease and are important factors that accelerate the progression of the disease. Receptors of innate immunity such as TLRs and RAGE play a central role in the perpetuation of inflammation. RAGE activation is a primary mecha-nism which determines self-perpetuated chronic inflam-mation, and RAGE cooperation with TLRs amplifies inflammatory signaling49.

Conclusions

AD is multifactorial neurodegenerative pathology. Neuroinflammation is an early event of the presymp-tomatic stages in AD and contributes to the progression of the disease53.

To identify the different actors participating in the inflammation and the mechanisms of damage involved can allow the development of treatments and preven-tive strategies in the fight against this disease.

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There are no potential conflicts of interest for any of the authors in this scientific report.

Funding source

None.

Acknowledgment

To CONACYT, for the doctorate grants awarded to SGLI, HJJ, and DMHDI.

References 1. Lewis J, Dickson DW. Propagation of tau pathology: hypotheses, disco-

veries, and yet unresolved questions from experimental and human bra-in studies. Acta Neuropathol. 2016;131:27-48.

2. Balin BJ, Hudson AP. Etiology and pathogenesis of late-onset alzhei-mer’s disease. Curr Allergy Asthma Rep. 2014;14:417.

3. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining alzheimer disease. Arch Gen Psychiatry. 2006;63:168-74.

4. International Genomics of Alzheimer’s Disease Consortium (IGAP). Con-vergent genetic and expression data implicate immunity in alzheimer’s disease. Alzheimers Dement. 2015;11:658-71.

5. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflam-mation in alzheimer disease. Nat Rev Neurosci. 2015;16:358-72.

6. Liu C, Cui G, Zhu M, Kang X, Guo H. Neuroinflammation in alzheimer’s disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol. 2014;7:8342-55.

7. Birch AM. The contribution of astrocytes to alzheimer’s disease. Biochem Soc Trans. 2014;42:1316-20.

8. Lee WJ, Liao YC, Wang YF, et al. Plasma MCP-1 and cognitive decline in patients with alzheimer’s disease and mild cognitive impairment: a two-year follow-up study. Sci Rep. 2018;8:1280.

9. Zhao H, Wang Q, Cheng X, et al. Inhibitive effect of resveratrol on the inflammation in cultured astrocytes and microglia induced by Aβ1-42. Neuroscience. 2018;379:390-404.

10. Bahniwal M, Little JP, Klegeris A. High glucose enhances neurotoxicity and inflammatory cytokine secretion by stimulated human astrocytes. Curr Alzheimer Res. 2017;14:731-41.

11. Parkhurst CN, Yang G, Ninan I, et al. Microglia promote learning-depen-dent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596-609.

12. Melchior B, Puntambekar SS, Carson MJ. Microglia and the control of autoreactive T cell responses. Neurochem Int. 2006;49:145-53.

13. Kierdorf K, Erny D, Goldmann T, et al. Microglia emerge from erythrom-yeloid precursors via pu.1-and irf8-dependent pathways. Nat Neurosci. 2013;16:273-80.

14. Guedes JR, Lao T, Cardoso AL, El Khoury J. Roles of microglial and monocyte chemokines and their receptors in regulating alzheimer’s di-sease-associated amyloid-β and tau pathologies. Front Neurol. 2018; 9:549.

15. Lanni C, Fagiani F, Racchi M, et al. Beta-amyloid short-and long-term synaptic entanglement. Pharmacol Res. 2019;139:243-60.

16. Gay M, Evrard C, Descamps F, et al. A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: toward a new profile of indirect β-secreta-se inhibitors. Eur J Med Chem. 2018;159:104-25.

17. Kirouac L, Rajic AJ, Cribbs DH, Padmanabhan J. Activation of ras-ERK signaling and GSK-3 by amyloid precursor protein and amyloid beta fa-cilitates neurodegeneration in alzheimer’s disease. ENeuro. 2017; 4:ENEURO.0149-16.2017.

18. Kim Y, Kim C, Jang HY, Mook-Jung I. Inhibition of cholesterol biosynthe-sis reduces γ-secretase activity and amyloid-β generation. J Alzheimers Dis. 2016;51:1057-68.

19. Neumann U, Ufer M, Jacobson LH, et al. The BACE-1 inhibitor CNP520 for prevention trials in alzheimer’s disease. EMBO Mol Med. 2018; 10:e9316.

20. Zhang H, Liu D, Huang H, Zhao Y, Zhou H. Characteristics of insulin-de-grading enzyme in alzheimer’s disease: a meta-analysis. Curr Alzheimer Res. 2018;15:610-7.

21. Kazkayasi I, Burul-Bozkurt N, Ismail MA, et al. Insulin deprivation decrea-ses insulin degrading enzyme levels in primary cultured cortical neurons and in the cerebral cortex of rats with streptozotocin-induced diabetes. Pharmacol Rep. 2018;70:677-83.

22. Shi Y, Holtzman DM. Interplay between innate immunity and alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018; 18:759-72.

23. Arboleda-Bustos CE, Ortega-Rojas J, Mahecha MF, et al. The p.R47H variant of TREM2 gene is associated with late-onset alzheimer disease in colombian population. Alzheimer Dis Assoc Disord. 2018;32:305-8.

24. Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213:667-75.

25. Li JT, Zhang Y. TREM2 regulates innate immunity in alzheimer’s disease. J Neuroinflammation. 2018;15:107.

26. Zheng H, Jia L, Liu CC, et al. TREM2 promotes microglial survival by activating wnt/β-catenin pathway. J Neurosci. 2017;37:1772-84.

27. Jendresen C, Årskog V, Daws MR, Nilsson LN. The alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J Neuroinflammation. 2017;14:59.

28. Tam WY, Ma CH. Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes. Sci Rep. 2014;4:7279.

29. Krbot K, Hermann P, Skorić MK, et al. Distinct microglia profile in creut-zfeldt-jakob disease and alzheimer’s disease is independent of disease kinetics. Neuropathology. 2018;38:591-600.

30. Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in alzheimer’s disease. Acta Neuropathol. 2009;118:475-85.

31. Medeiros R, Kitazawa M, Passos GF, et al. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces alzheimer di-sease-like pathology in mice. Am J Pathol. 2013;182:1780-9.

32. Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017;21:21-8.

33. Bussian TJ, Aziz A, Meyer CF, et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018; 562:578-82.

34. Snyder HM, Corriveau RA, Craft S, et al. Vascular contributions to cog-nitive impairment and dementia including alzheimer’s disease. Alzhei-mers Dement. 2015;11:710-7.

35. McFadyen JD, Kiefer J, Braig D, et al. Dissociation of C-reactive protein localizes and amplifies inflammation: evidence for a direct biological role of C-reactive protein and its conformational changes. Front Immunol. 2018;9:1351.

36. Shibata M, Yamada S, Kumar SR, et al. Clearance of alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106:1489-99.

37. Jeynes B, Provias J. Evidence for altered LRP/RAGE expression in al-zheimer lesion pathogenesis. Curr Alzheimer Res. 2008;5:432-7.

38. Erickson MA, Banks WA. Blood-brain barrier dysfunction as a cause and consequence of alzheimer’s disease. J Cereb Blood Flow Metab. 2013;33:1500-13.

39. Liu C, Chen K, Lu Y, Fang Z, Yu G. Catalpol provides a protective effect on fibrillary Aβ1-42 -induced barrier disruption in an in vitro model of the blood-brain barrier. Phytother Res. 2018;32:1047-55.

40. Wong WB, Lin VW, Boudreau D, Devine EB. Statins in the prevention of dementia and alzheimer’s disease: a meta-analysis of observational stu-dies and an assessment of confounding. Pharmacoepidemiol Drug Saf. 2013;22:345-58.

41. Salech F, Ponce DP, SanMartín CD, et al. PARP-1 and p53 regulate the increased susceptibility to oxidative death of lymphocytes from MCI and AD patients. Front Aging Neurosci. 2017;9:310.

42. Solleiro-Villavicencio H, Rivas-Arancibia S. Systemic th17/IL-17A res-ponse appears prior to hippocampal neurodegeneration in rats expo-sed to low doses of ozone. Neurologia. 2017. pii: S0213-4853(17) 30194-9.

43. Derkow K, Rössling R, Schipke C, et al. Distinct expression of the neu-rotoxic microRNA family let-7 in the cerebrospinal fluid of patients with alzheimer’s disease. PLoS One. 2018;13:e0200602.

44. Merlini M, Kirabali T, Kulic L, Nitsch RM, Ferretti MT. Extravascular CD3+ T cells in brains of alzheimer disease patients correlate with tau but not with amyloid pathology: an immunohistochemical study. Neurodegener Dis. 2018;18:49-56.

45. SanMartin CD, Henriquez M, Chacon C, et al. Vitamin D increases aβ140 plasma levels and protects lymphocytes from oxidative death in mild cognitive impairment patients. Curr Alzheimer Res. 2018;15:561-9.

46. Sommer A, Winner B, Prots I. The trojan horse-neuroinflammatory impact of T cells in neurodegenerative diseases. Mol Neurodegener. 2017;12:78.

47. Ahmed ME, Iyer S, Thangavel R, et al. Co-localization of glia maturation factor with NLRP3 inflammasome and autophagosome markers in human alzheimer’s disease brain. J Alzheimers Dis. 2017;60:1143-60.

48. Tammineni P, Cai Q. Defective retrograde transport impairs autophagic clearance in alzheimer disease neurons. Autophagy. 2017;13:982-4.

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er.

©

Per

man

yer

2019

170


49. Navarro V, Sanchez-Mejias E, Jimenez S, et al. Microglia in alzheimer’s disease: activated, dysfunctional or degenerative. Front Aging Neurosci. 2018;10:140.

50. Shao BZ, Cao Q, Liu C. Targeting NLRP3 inflammasome in the treatment of CNS diseases. Front Mol Neurosci. 2018;11:320.

51. Raikwar SP, Thangavel R, Dubova I, et al. Targeted gene editing of glia maturation factor in microglia: a novel alzheimer’s disease therapeutic target. Mol Neurobiol. 2019;56:378-93.

52. Ciaramella A, Salani F, Bizzoni F, et al. The stimulation of dendritic cells by amyloid beta 1-42 reduces BDNF production in alzheimer’s disease patients. Brain Behav Immun. 2013;32:29-32.

53. Janelidze S, Mattsson N, Stomrud E, et al. CSF biomarkers of neuroin-flammation and cerebrovascular dysfunction in early alzheimer disease. Neurology. 2018;91:e867-77.

54. Lin MS, Hung KS, Chiu WT, et al. Curcumin enhances neuronal survival in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in

astrocytes via PI-3K and MAPK signaling pathways. Prog Neuropsy-chopharmacol Biol Psychiatry. 2011;35:931-8.

55. Ransohoff RM, El Khoury J. Microglia in health and disease. Cold Spring Harb Perspect Biol. 2015;8:a020560.

56. Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and alzheimer’s disease brains. Am J Pathol. 1998;153:31-7.

57. Grimaldi LM, Zappalà G, Iemolo F, et al. A pilot study on the use of interferon beta-1a in early alzheimer’s disease subjects. J Neuroinflammation. 2014;11:30.

58. Rubio-Araiz A, Finucane OM, Keogh S, Lynch MA. Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocyto-sis of β-amyloid. J Neuroinflammation. 2018;15:247.

59. Sohrabifar N, Gharesouran J, Talebi M, Ghojazadeh M, Mohaddes Ar-debili SM. Association of CLU and TLR2 gene polymorphisms with la-te-onset alzheimer disease in a Northwestern Iranian population. Turk J Med Sci. 2015;45:1082-6.

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subtipos motores en enfermedad de Parkinson y estudio REMPARK: ¿la resurrección de un proyecto olvidado?

Motor subtypes in Parkinson’s disease and REMPARK study: the resurrection of a forgotten project?

Carlos Zúñiga-Ramírez1*, Ingrid Estrada-Bellmann2 y Elisa Otero-Cerdeira3

1Unidad de Movimientos Anormales y Enfermedades Neurodegenerativas, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, 2Servicio de Neurología, Hospital Universitario José E. González, Monterrey, Nuevo León, 3Unidad de Trastornos del Movimiento y Neurociencias (UTMON), Hospital Español, Ciudad de México. México


CARTA AL EDITOR



DOI: 10.24875/RMN.M19000044

Hemos leído recientemente el artículo de Alvara-do-Franco, et al. denominado Análisis de subtipos motores en la enfermedad de Parkinson: Registro Mexicano de Enfermedad de Parkinson (ReMePARK)1. En él se habla de un estudio de cohorte (prospectivo por definición) donde se utilizó la base de datos del estudio ReMePARK2, con la finalidad de observar cam-bios en las manifestaciones clínicas motoras de los sujetos incluidos en dicho reporte. La población de sujetos que conformaron el estudio ReMePARK prove-nía de cinco centros de referencia en el país, donde al menos tres de estos centros no han proporcionado información de seguimiento (follow-up) acerca de la evolución que han tenido los pacientes a lo largo de su enfermedad. De manera más importante, en el es-tudio ReMePARK2 la manera de obtener los datos (un formato de registro tomado en una sola ocasión) lo convierte más bien en un estudio de corte transversal y no de cohorte. Por estas razones, desconocemos por completo a qué población se refieren los autores del

artículo en cuestión cuando mencionan que se trata de un subanálisis del estudio original ReMePARK2.

Referente al cambio de manifestaciones clínicas de la enfermedad de Parkinson a lo largo de su evolución, existen varios puntos a discutir. En los estudios de tipo prospectivo se puede estar incurriendo en un sesgo de anticipación (lead time bias)3 al asumir de forma prema-tura que una presentación clínica tiene la capacidad de cambiar de un fenotipo a otro. Es bien sabido que la enfermedad de Parkinson es progresiva e invariable-mente se añadirán otros signos y síntomas a lo largo de su evolución, esto no quiere decir que cambie radical-mente de fenotipo, sino que la progresión de la enfer-medad implica empeoramiento motor y no motor. De acuerdo con esto, y tal como lo mencionan Simuni, et al.4, es posible que la enfermedad no haya llegado a «madurar» en el momento de recolectar los datos inicia-les de forma muy temprana, lo que pueda estar condi-cionando los hallazgos que comentan Alvarado-Franco, et al. en su estudio. La edad de presentación de la

1665-5044/© 2019. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).


Rev Mex Neuroci. 2019;20(3):171-172


Correspondencia: *Carlos Zúñiga-Ramírez

Unidad de Movimientos Anormales y

Enfermedades Neurodegenerativas

Hospital Civil de Guadalajara Fray Antonio Alcalde

Av. Rubén Darío, n.º 1208, piso 2 interior 1

Col. Italia Providencia

C.P. 44648, Guadalajara, Jalisco, México


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http://dx.doi.org/ 10.24875/RMN.M18000044



mailto:?subject=c.zuniga.ramirez%40gmail.com

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enfermedad es un factor bien reconocido a fecha de hoy en cuanto a velocidad de progresión se refiere: en las formas de inicio temprano (Young-Onset Parkinson Di-sease, YOPD) la discapacidad progresa en forma más lenta que en las de inicio tardío (Late-Onset Parkinson Disease, LOPD). En las formas YOPD predominan clíni-camente la rigidez y la distonía, en tanto que en las formas LOPD predomina el fenotipo de inestabilidad postural y alteraciones de la marcha (postural instability and gait disorders). En las primeras es más espectacu-lar la respuesta a la terapia dopaminérgica, pero tam-bién se conoce que desarrollarán fluctuaciones motoras, no motoras y discinesias de manera más temprana que las variantes tardías de la enfermedad. Este patrón clí-nico es bien conocido y hasta ahora no se ha observado que cambie con el tiempo de evolución de la enferme-dad. Otro punto determinante en la clasificación del fe-notipo motor consiste en el tiempo de la evaluación: no es lo mismo evaluar a un individuo en on, en off de menos de 12 horas o en off de más de 12 horas de duración. El momento de recolección de datos motores no se menciona en el artículo en cuestión.

De mayor controversia aún resultan estudios como el de Selikhova, et al.5, donde realizan un estudio post mortem de 242 sujetos con enfermedad de Parkinson definida y encuentran patología tipo alfa-sinucleína y tau variable, con diferente grado y zonas de afectación de acuerdo con el fenotipo clínico observado. Esto úl-timo iría totalmente en contra de la teoría de «cambio de fenotipo» en tan poco tiempo de evolución, ya que los cambios observados por histopatología y la impli-cación del sistema nervioso en esta y otras enferme-dades neurodegenerativas toma años para definirse por completo. Si hablamos de variabilidad genética y fenotipo motor, lamentablemente en este estudio y en los hasta ahora publicados con respecto al cambio de fenotipo con el paso del tiempo, no cuentan con ningún biomarcador, estudio post mortem o de genética que ayude a correlacionar sus hallazgos. En este contexto, la enfermedad, o más bien el síndrome parkinsoniano,

puede catalogarse actualmente en forma clínica, gené-tica y patológica, con patrones bien definidos desde cada punto de vista6.

Retomando el estudio actual, el cual genera dudas en cuanto a su diseño, ya que inicialmente lo nombran como prospectivo y en la discusión hablan de «la na-turaleza retrospectiva del estudio», nosotros pensamos más bien que se trata de un estudio retrospectivo (cor-te transversal si en efecto se utilizó la base de datos del estudio original ReMePARK, o de series de tiempo si se utilizó una población diferente al ReMePARK), donde no está de más remarcar un posible sesgo de mala clasificación (misclassification bias)7. Dicho ses-go es el más frecuente dentro de los estudios retros-pectivos, donde pudieron malinterpretarse los datos iniciales de la población estudiada y posteriormente «reclasificar» estos.

Por todas estas razones, creemos que se puede incurrir en interpretaciones prematuras acerca de la progresión clínica de la enfermedad con los datos pre-sentados en el estudio de Alvarado-Franco, et al. Será interesante observar en el futuro estudios que correla-cionen sus hallazgos clínicos de cambio en la fenome-nología motora de la enfermedad con biomarcadores, genética e histopatología.

Bibliografía 1. Alvarado-Franco NL, Olguín-Ramírez L, Eisinger RS, Ramírez-Zamora A,

Cervantes-Arriaga A, Rodríguez-Violante M, et al. Análisis de subtipos motores en la enfermedad de Parkinson: Registro Mexicano de Enfer-medad de Parkinson (ReMePARK). Rev Mex Neuroci. 2018;19(5):3-8

2. Cervantes-Arriaga A, Rodríguez-Violante M, López-Ruiz M, Estrada-Be-llmann I, Zúñiga-Ramírez C, Otero-Cerdeira E, et al. Caracterización de la enfermedad de Parkinson en México: estudio ReMePARK. Gac Med Mex. 2013;149(5):497-501.

3. Prorok PC. The theory of periodic screening I: Lead time and proportion detected. Adv Appl Prob. 1976;8:127-43.

4. Simuni T, Caspell-García C, Coffey C, Lasch S, Tanner C, Marek K, et al. How stable are Parkinson’s disease subtypes in de novo patients: Analy-sis of the PPMI cohort? Parkinsonism Relat Disord. 2016;28:62-7.

5. Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A clinico-pathological study of subtypes in Parkinson’s disease. Brain. 2009;132(Pt 11):2947-57.

6. Thenganatt MA, Jankovic J. Parkinson disease subtypes. JAMA Neuro-logy. 2014;71(4):499-504.

7. Copeland KT, Checkoway H, McMichael AJ, Holbrook RH. Bias due to misclassification in the estimation of relative risk. Am J Epidemiol. 1977;105(5):488-95.

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