is semantic impairment a predictive sign for alzheimer disease?

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Revista de Logopedia, Foniatría y Audiología (2014) xxx, xxx---xxx

Revista de

LOGOPEDIA, FONIATRÍA y AUDIOLOGÍAwww.elsevier.es/logopedia

REVIEW ARTICLE

Is semantic impairment a predictive sign for Alzheimerdisease?

Yeison Guerrero

Universidad Nacional de Colombia, Bogotá, Cundinamarca, Colombia

Received 25 December 2012; accepted 21 October 2013

KEYWORDSSemanticimpairment;Alzheimer’s disease;Mild cognitiveimpairment;Verbal fluency;Visual confrontationnaming

Abstract This review describes the performance of persons with Alzheimer disease and mildcognitive impairment in some semantic tasks reported in the literature due to their diagnos-tic and prognostic values. Most of the studies reviewed included visual confrontation namingand verbal fluency tasks. There is a controversy about whether naming deficits are due to adegradation of semantic contents, difficulties in accessing contents, and an inability to accessto word form, or whether they are due to failed connections between the semantic system andphonological and lexical representations. It is necessary to explore in detail the process of thelinguistic system and its relationship with other biological and cognitive markers during pre-dementia phases and progression to dementia, as well as to evaluate new treatment options,in order to decrease cognitive deterioration and prevent or delay progression to dementia.Semantic verbal fluency tasks and event-related potentials (N400 and P600 components) mightbe useful in the search for therapeutic possibilities.© 2012 AELFA. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVEDeterioro semántico;Enfermedad deAlzheimer;Deterioro cognitivoleve;Fluidez verbal;Denominación por

¿Es el deterioro semántico un signo predictor de la enfermedad de Alzheimer?

Resumen La presente revisión describe el desempeno de sujetos con enfermedad deAlzheimer y deterioro cognitivo leve en algunas tareas de naturaleza semántica reportadaspor la literatura por su valor pronóstico y de diagnóstico. La mayoría de los estudios revisadosincluyen pruebas de denominación por confrontación visual y fluidez verbal. Existe controver-sia en cuanto a si el origen los déficits en denominación es dado por una degradación de loscontenidos a nivel semántico, dificultades en el acceso a ellos, imposibilidad de acceder a

Please cite this article in press as: Guerrero, Y. Is semantic impairment a predictive sign for Alzheimer disease? Revistade Logopedia, Foniatría y Audiología (2014). http://dx.doi.org/10.1016/j.rlfa.2013.10.001

confrontación visual la forma de la palabra o por fallos en las conexiones entre el sistema semántico y las rep-resentaciones léxicas o fonológicas. Se destaca la necesidad de explorar detalladamente losprocesos del sistema lingüístico y su relación con otros marcadores biológicos y cognitivosdesde fases predemenciales y durante la progresión a demencia, así como la exploración denuevas posibilidades terapéuticas que permitan disminuir el deterioro cognitivo y evitar o pro-longar su posible evolución a demencia. La tarea de fluidez verbal semántica y los potenciales

E-mail address: [email protected]

0214-4603/$ – see front matter © 2012 AELFA. Published by Elsevier España, S.L. All rights reserved.http://dx.doi.org/10.1016/j.rlfa.2013.10.001

dx.doi.org/10.1016/j.rlfa.2013.10.001

dx.doi.org/10.1016/j.rlfa.2013.10.001

http://www.elsevier.es/logopedia

mailto:[email protected]

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2 Y. Guerrero

relacionados con eventos (componentes N400 y P600), pueden ser útiles en la búsqueda deposibilidades terapéuticas.© 2012 AELFA. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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ntroduction

ementia is a syndrome that could be caused by aumber of progressive alterations, affecting cognitive func-ions (including language), behavior, and the capability ofoing activities of daily living (Ardila & Ostrosky, 2012;rganización mundial de la salud [OMS], 2007).

According to the international report about Alzheimer,t is calculated that more than 35.6 millions of people liveith this syndrome and it generated a total cost of more than00 billion dollars in 2010 (Alzheimer’s Disease InternationalADI], 2010). AD is the most common type of dementia, rep-esenting between 50 and 56% of the cases identified byutopsies and clinical semiology (Querfurth & Frank, 2010).he main risk factor is person’s age since its incidence isoubled every 5 years after an age of 65; thus, 1275 newases are reported every year per 100,000 people older than5 (Hirtz, Thurman, Gwinn-Hardy, Chaudhuri, & Zalutsky,007).

In a strict way AD is not an illness but a progressivenatomic-clinic syndrome that is pathologically character-zed by neuronal loss on the entorhinal and transentorhinalegions and on the hippocampus; this neuronal loss wille posteriorly extended onto the neocortex (Kowalewski

Murphy, 2012). The principal histopathological findingsnclude accumulation of brain plaques charged of �-amiloideA�) peptide and prominent neurofibrillary tangles in theedial part of the temporal lobe (Querfurth & Frank, 2010).hese findings have been associated with synaptic dys-unctions and neural degeneration that entails cognitivempairment (Weiner et al., 2012).

Currently, it does not exist a cure for AD, neither a treat-ent that slow down the progression of this disorder (Weiner

t al., 2012); one of the main obstacles in the developmentf therapeutic treatments is that AD’s diagnosis is performedt advanced stages, when both behavior and central ner-ous system (CNS) are already affected (Lara et al., 2006).his has led to many investigations to focus on identify-

ng markers at early phases of the disease (Frisoni et al.,009).

AD could start 10 years before clinical manifestationsre presented (Barandiaran, 2011). In fact, the term ‘‘mildognitive impairment’’ (MCI) is used to differentiate theoundary between non-pathological aging and dementiaRodríguez, Juncos-Rabadán, & Facal, 2008). MCI repre-ents a diagnostic entity that is applied to people who haveognitive difficulties above the expectancy for their age,ven though this does not interfere with their daily lifectivities. At this stage, progression of AD is about 15%

Please cite this article in press as: Guerrero, Y. Is semantic imde Logopedia, Foniatría y Audiología (2014). http://dx.doi.org

er year, whereas 1.2% is reported for the general pop-lation, and impairments could be detected at cognitiver biological level (Taler & Phillips, 2008). Regarding therst one, memory, executive functions, perceptual speed,

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isuospatial skills, attention and the domain of languageould be affected (Sabbagh et al., 2007).

During the process of non-pathologic aging, language isne of the latest cognitive functions that are affected;nstead, language impairment is considered as one of theost usual manifestations in AD (Subirana, Bruna, Puyuelo,

Virgili, 2009). Thereby, it could be obvious at early stages,ven before noticing any clinical manifestation that char-cterize the beginning of the most evident deteriorationCullell, Bruna, & Puyuelo, 2006). In fact people with MCI,ho have multiple affections including language, have aigher risk of progressing to an AD than those who have ansolated memory alteration (amnesic SCI), (Rey Pérez andleó Bisa, 2010; Taler & Phillips, 2008). This confirms themportance of evaluating language when AD is suspected.

First signs of deterioration are evident in the semanticomponent of language (Juncos-Rabadán, Pereiro, Facal, &odríguez, 2010). A detailed examination of linguistic dif-culties indicates that conceptual and lexical organizationsre the main alterations (Garrard, Lambon Ralph, Patterson,ratt, & Hodges, 2005). This is specially reflected on the dif-culty to find words (Fisher, Rourke, & Bieliauskas, 1999) andn the verbal disfluency (Henry, Crawford, & Phillips, 2004).

This literature review aims to describe the performancef people with AD and MCI at some semantic tasks reportedy the literature due to their diagnostic and prognosticalue.

earch strategy to identify the selected studies

ubMed (MedLine), LILACS, y EBSCO HOST were theatabases used in this study. The articles included encom-assed dates from 1993 to February 2013. The key wordssed were ‘‘Alzheimer’’, ‘‘semantics’’ and ‘‘mild cognitivempairment’’; ‘‘OR’’ and ‘‘AND’’ were connecting wordslso used. This electronic searching was complementedy eligible original studies reviewed at the bibliographicesources of the National University of Colombia. Further-ore, experts on the field were contacted in order to seek

or information about potential studies that had not beendentified through the strategies previously described.

375 articles were found and 40 of them were included inhis literature review. Studies had to have a task that eval-ated semantic processing in AD and/or MCI. Observationaltudies were included in order to help evaluating the pro-nostic value and the diagnosis of semantic processing. Somether inclusion criteria were: studies had to be published in

thesis or a journal; they had to include mean and standard

pairment a predictive sign for Alzheimer disease? Revista/10.1016/j.rlfa.2013.10.001

eviation and; data had to be compared by age range andevel of schooling. In some cases semantic processing tasksere part of a neuropsychological test. Single case studiesere excluded since they present very partial aspects on the

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Is semantic impairment a predictive sign for Alzheimer disea

prognostic and diagnostic value of the tasks used. Articleswith insufficient information were also excluded.

Results

Semantic processing

Most of the studies reviewed include confrontation nam-ing and verbal fluency tasks, used to assess the access tothe word’s meaning in patients with AD and MCI. The mainfindings will be described below.

Visual confrontation naming

Visual confrontation naming tasks (VCN) require that thepatient names a stimulus presented visually. This is a processthat involves visual perception, image recognition, accessto the object’s name, inhibition of irrelevant words, pho-netic analysis, and correct word’s articulation (Romo, Cifras,González, & Pino, 2008). Furthermore it involves an inten-tional processing (different from lexical decision tasks thatrequire automatic processing) and lower demand of execu-tive functions regarding to the verbal fluency tests (Taler &Phillips, 2008).

The normal process of aging produces slight changes onthe accuracy of object’s naming; specially, it involves dif-ficulties to remember a known word. However, with someeffort the word could be remembered. Patients with ADpresent those difficulties but in a more evident way. As men-tioned before, problems finding words is a symptom welldocumented at early stages of the disease (Duong, Giroux,Tardif, & Ska, 2005; Ehrlich, Obler, & Clark, 1997; Fisheret al., 1999). Those deficits are highly related to dementia’sseverity (Penaloza, 2004) and they seem to be more associ-ated with deterioration of semantic organization than witha perceptual process (Rodríguez et al., 2008).

Although many experts think that naming errors in ADpatients are caused by a semantic deficit, some authorsclaim that those difficulties are due to a lexical retrievaldeficit (Fernández-Turrado et al., 2006). Moreaud, David,Chamallet and Pellat (2001) analyzed the AD patient’sresponse in a VCN task but they implemented some vari-ations: if patients could not name an objected presentedthrough images, they were asked to produce the object’ssound (e.g. cow, train, whistle, etc.). Authors observed thatmany of them could access this information but not to theform of the word. According to this they concluded that withsome items there was a deficit in lexical retrieval instead ofa difficulty in semantic access.

The Boston naming test (BNT) (Kaplan, Goodglass, &Weintraub, 1983 is one of the most used visual confrontationnaming tasks in the clinical field; this along with some otherdiagnostic indicators help detecting cognitive deteriorationand dementia (Vigliecca & Aleman, 2007). The original ver-sion of the BNT consists of 85 images to be named, rangingfrom the most frequently presented until the most infre-


quent; some modified versions include abbreviations of 15,30 and 60 items (Hobson et al., 2011). Studies have demon-strated the utility of the BNT and other naming tests todifferentiate AD patients from control groups (Gale, Irvine,

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aws, & Ferrissey, 2009; Karrasch et al., 2010; Larrain &imino, 1998).

Naming has also been studied in order to distinguishetween control groups without cognitive impairment andCI or between MCI and AD. It has been also used to evalu-te the progression of people with MCI to dementia. Duong,hitehead, Hanratty and Chertkow (2006) found that peo-

le with MCI has lower scores on BNT and even though theyesponded equally fast than control groups, people with MCIade significantly more errors at semantic knowledge items.More recent studies have investigated semantic and

honologic access in individuals with MCI through a VCNf famous people and a paradigm called the tip-of-the-ongue phenomenon (TOT), which facilitates production ofvents. Authors suggest that individuals with MCI have moreifficulties in transmitting from semantic to phonologicalepresentations than the ones presented at the normalging. Thus, proposing that naming deficits in MCI are due tohonological access impairment and those could be the firsttep in progressing from MCI to AD (Juncos-Rabadán, Facal,ojo-Seoane, & Pereiro, 2013; Juncos-Rabadán, Rodríguez,acal, Cuba, & Pereiro, 2011; Rodríguez et al., 2008).

Jager and Budge (2005) evaluated during 6 years howersons with MCI progressed to dementia. They periodicallyerformed assessments every 2 years and one of the testsncluded were VCN; it was composed by 30 images orderedn an ascending difficulty (Naming Test Graded). Authorseported that VCN was predictive of MCI progressing to AD,n all assessments. However, some other studies suggest thatCN tasks do not predict dementia’s incidence (Albert, Moss,anzi, and Jones, 2001; Caselli et al.) and they claim thathere is no significant difference either between patientsith MCI and control groups (Brouillette et al., 2011; Joubertt al., 2008; Van der Vlies et al., 2007; Vigliecca & Aleman,007), or between MCI and AD (Joubert et al., 2010). To sum-arize, VCN permits discriminate between non-pathological

ging and AD; however, results seem contradictory regardingifferentiation between normal aging and MCI, between MCInd AD and also about progression of MCI to dementia.

erbal fluency

erbal fluency tests (VF) evaluate individual’s capability ofetrieve and produce the greatest number of words accord-ng to a specific criterion given over a period of time.

Those tests are widely used during neuropsychologicalssessment or as a screen test for MCI and dementia (Chia-en, Shuu-Jiun, Ling, & Jong-Ling, 2010; Fernández, Marino,

María, 2004). Reasons for being broadly used are: simple todminister, short time of application and more discrimina-ive validity than longer and more complex tests such as Miniental State Examination (MMSE) or Folstein test, according

o some articles (Carnero et al., 2007).There are two important aspects to assess in verbal

uency: phonological verbal fluency (FVF) through Con-rolled Oral Word Association Test (COWA) (Benton, 1968),


or instance. This test requires the person names the largestumber of words (excluding nouns) that begin with a specificord, during a period of time; and semantic verbal fluency

SVF) through Isaacs Set Test (Isaacs & Kennie, 1973), for

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xample, in which the patient is asked to name as manytems as possible that belong to a specific category.

Both, FVF and SVF are associated with multiple cogni-ive processes, including semantic memory search, selectedemantic representation, access to the correspondinghonemic representation, motor planning, articulation ofhe selected words (Henry et al., 2004), memory and inhi-ition of words previously named (Davis et al., 2010). Bothests have been reported by literature as sensitive to alter-tions in frontal and temporal areas. In fact, activation inemporal and frontal lobes has been reported while peo-le perform animals fluency tasks (SVF-an); this, througherebral blood flow measurements (Ardila, Ostrosky-Solís,

Bernal, 2006).Similarly, both semantic fluency and phonological fluency

ave been determined as a sign of semantic deteriorationt the early stages of AD and MCI (Laws, Duncan, & Gale,010). Lower semantic fluency performance, in comparisonith phonological fluency, has been reported in AD (Butters,ranholm, Salmon, Grant, & Wolfe, 1987; Suhr & Jones,998; Taler & Phillips, 2008). Possible explanation is thatemantic fluency requires greater demands on the integrityf semantic network, even though both measurements arequivalent in sensitivity of executive control processes andf recovery effort (Henry et al., 2004).

This differentiation has been used to distinguish AD fromther types of dementia (Araujo et al., 2011; Marczinski &ertesz, 2006). Sometimes even this aspect is considereds a criterion to diagnose AD (Rascovsky, Salmon, Hansen,hal, & Galasko, 2007); in fact, recently, SVF has beeneported as the only semantic functioning task that differ-ntiates individuals with MCI and control groups (Joubertt al., 2008). Thus, it gives a predictive value of patientsith MCI who 5 years later developed dementia (Ingles,entzel, Fisk, & Rockwood, 2002). Furthermore, perfor-ance of individuals with AD at animal fluency task does not

mprove with practice, even in a very short interval betweennitial and final evaluations; this could be useful at search-ng therapeutic strategies (Taler, Klepousniotou, & Phillips,009). However, few studies report that the differentiationetween FVF and SVF does not discriminate either betweenD and elderly controls (Laws et al., 2010) or with otherementias (Suhr & Jones, 1998). To sum up, several articlesave reported differences in verbal fluency between controlroups and AD, control groups and MCI and between AD andCI. SVF is altered from predemented phases and is predic-

ive of AD progression. However, results related to FVF andVF differentiation, as a criterion to discriminate AD fromther dementias, are contradictory.

valuation of semantic processing usingvent-related potentials

n important characteristic of language processing is thepeed in which it performs; even though fluency and visualonfrontation naming are the widest tasks used to eval-


ate language in AD and MCI, those only include theesult of information processing, in contrast to some neu-ophysiological recording techniques such as event-relatedotentials (ERPs).

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ERP are a manifestation of the brain electric activity thats recorded on the scalp and is displayed as voltage changeshat are synchronized to internal or external stimuli; theyonstitute a non-invasive method that permits monitoringerebral processes in real time. Furthermore, according touiroz (2003) they are the most likely technique in neuropsy-hological research of cognitive processes.

ERP could be classified as endogenous, those that appearithin the first 100 ms after stimulus presentation and;xogenous, those of later onset. Regarding nomenclature,he term component is usually used for a portion of brainlectrical activity registration, sensible to a concrete exper-mental manipulation and which is considered a reflex of

particular process or a group of processes. Those com-onents could be named depending on their polarity andatency; P (if they show positive polarity) and N (if there isegative polarity) plus the time, taken in milliseconds, fromtimulus presentation to maximum or minimum amplitudeoint during a concrete latency. For instance, N400 compo-ent is a negative polarity wave that appears approximately00 ms after stimulus presentation.

N400 component is considered as an indicator of seman-ic processing (Nunez Pena, Corral, & Escera, 2004) and itas been used in some studies of AD and MCI. Castaneda,strosky, Feggy Perez, Bobesb, and Rangel (1997) eval-ated electrophysiological response of 10 patients withrobable AD and 10 asymptomatic individuals, using ERP,uring a semantic categorization task, presenting congru-nt images (e.g. guitar---violin) and incongruent images (e.g.elmet-violin) as stimuli. They found significant differencesn incongruent responses between patients and controls; aecrease in N400 component from the group of patients waseported (Castaneda et al., 1997). It decreased even morefter a second evaluation performed two years later with theame group of patients (Castaneda, Ostrosky, Perez, Rangel,

Maria, 1999). Authors associate those results with difficul-ies to access and use semantic information in AD patientsOlichney et al., 2006).

In Colombia, a study about AD, developed in thentioquia department, performed three experiments thatvaluated naming process in three phases: (1) spontaneousaming, (2) naming with semantic cues and (3) naming withhonological cues. The purpose of this research was toetermine the presence of different brain systems involvedn naming process through ERP. Researchers found differentctivation centers for the three naming phases evaluated.qually, they reported that semantic and phonologic sys-ems are differentially altered in AD; they concluded thatemantic system is compromised earlier than the phono-ogical during the course of cognitive deterioration in ADQuiroz, Bobbes, & Lopera, 2002); this is consistent witherbal reports presented by several studies.

On the other hand, Olichney et al. (2002) examinedhe electrophysiological response of people with MCI andlderly controls; 216 phrases adjusted by frequencynd which described one category (e.g. ‘‘breakfast food’’)ollowed by one congruent (e.g. ‘‘pancake’’) or incongruentord (Olichney et al., 2002). They found that individuals


ith MCI manifested a delayed N400 component; controlshowed a positive component delayed for new words, whichs significantly reduced when a word was repeated. This rep-tition effect was even weaker for participants with MCI

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and almost completely absent in those who converted toAD. Authors report significant differences on the repetitioneffect between patients with MCI who converted to AD andthose who did not; contrary to what was observed throughthe MMSE which did not discriminate between these groups.

Similarly, Olichney et al. (2008) performed a study of par-ticipants with MCI, during a period of 3 years, with annualreviews of the N400 and P600 components. They found thatabnormal ERP (P600 and N400), represent a risk of 81% ofconversion to AD in the following three years.

Recently, Saavedra, Iglesias, and Olivares (2012)introduced various known and unknown faces to patientswith MCI and AD on tasks of explicit and implicit familiarity.Authors reported decrease in ERP (P100, N170, N250 andN400) associated with a selective loss knowledge regardingfacial identification. To summarize, ERP findings are pre-sented as potential clinical markers of AD and MCI as wellas progress from MCI to AD.

Conclusions

VCN allows discrimination between non-pathological agingand AD; however, results seem contradictory regarding tothe differentiation between normal aging and MCI, betweenMCI and AD and progression of MCI to dementia. Those resultscould be partly due to variability among test used, applica-tion and scoring criteria, familiarity of items and samplesize. Regarding naming deficits, it is unclear whether theorigin is given by degradation of contents at semantic level,difficulties to access to those contents, inability to accessto the word’s form or due to failed connections betweensemantic system and phonological or lexical representa-tions. New research that address in detail processes ofthe linguistic system, from predemented phases and theirchanges during the progression of dementia could contributeto a better understanding of the origin of language difficul-ties in AD.

Differences in verbal fluency between controls and AD,between controls and MCI and AD are widely reported. SVF isthe most altered in predemented phases and thus, it showsa higher predictive value, in comparison with FVF, in pro-gression of MCI to AD. In fact, deficits in semantic verbalfluency have been correlated with the presence of neurofib-rillary tangles in the lateral portion of the temporal lobe atearly stages of AD (Laws et al., 2010).

Results in terms of differentiation between SVF and FVF,as a criterion to discriminate AD from other dementias arecontradictory. However, SVF is constituted as an importantscreening tool for detecting AD, MCI and its progression todementia. Thus, since it is simple and quick to apply, andit reaches clinical, regulatory, experimental and psycho-metric criteria that are characteristic of a cognitive test(Ardila et al., 2006). As expected, diagnosis of a neurolog-ical disease cannot be only based on the result of a testor a neuropsychological assessment, even if those are wide(Vega, Menéndez González, & Calatayud Noguera, 2007), butthey do increase the likelihood of success in the diagnosis at


early stages of the disease.ERPs are presented as potential clinical markers of AD

and MCI and even of its progression to AD. However, prospec-tive studies with larger samples, developed in different

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ountries and cultural contexts are needed. Those could alsoe correlated with other biological markers and cognitiveests.

At the genetic level, the major susceptibility factor inate onset of AD (after 65 years), known so far, is the pres-nce of the APOE �4 allele (Martinez, 2003). It increasesrom 4 to 13 times the risk of developing the diseaseQuerfurth & Frank, 2010). It seems coherent to think that aenotype that is associated with an increased risk of devel-ping AD could be equally associated with an impairmentf cognitive functions (among them language), therefore,tudies with rigorous paradigms that correlate biologicalarkers, such as APOE �4, with tasks that permit extract-

ng information about neurological and linguistic processing,uch as: VCN, the Verbal Fluency and/or ERP and/or imagingechniques, would increase our understanding of the influ-nce of genotypic changes in the linguistic profile of AD andhe origin of its language difficulties. Furthermore, likeli-ood of an opportune diagnosis would increase and thus,reater chances of treatment could be offered. It would alsoermit giving families and caregivers management strate-ies depending on each particular case.

Finally, the decrease of N400 component in the coursef the disease, changes in N400 and P600 component inatients with MCI and the null improvement with practicen SVF tasks in individuals with AD are aspects that coulde useful to prove the effectiveness of diverse therapeuticossibilities in order to decrease cognitive impairment andrevent or prolong its possible evolution to dementia.

unding

rant Jóvenes Investigadores e Innovadores (Colciencias)olombia.

onflicts of interest

he authors have no conflicts of interest to declare.

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