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Motoric Cognitive Risk SyndromeMotor Ways to Dementia
Joe Verghese, MBBS, MS.
Integrated Divisions of Cognitive & Motor Aging (Neurology) and Geriatrics
(Medicine)Albert Einstein College of Medicine,
Bronx, NY
Faculty/Presenter Disclosure
• Faculty: Joe Verghese
• Relationships with financial sponsors:National institutes of Health, USA
Disclosure of Financial Support• This program has not received any financial support
• Potential for conflict(s) of interest:None
Funding received from:NIH: RO1-AGO25119(NIA), RO1-AGO39330(NIA), RO1-AGO36921(NIA/Fogarty), RO1-AGO4407(NIA), RO1-AG050448 (NIA), R56AG057548(NIA) and UG3NS105565 (NINDS)Saint Care Corporation, Japan
Outline• Motoric impairments in pre-clinical dementia
Clinical and quantitative gait
Walking while talking
Spatial navigation
• Motoric Cognitive risk syndrome
• Clinical applications: interventions
follow up time (years)
surv
ival
pro
babi
lity
0 5 10 15 20
0.0
0.2
0.4
0.6
0.8
1.0
Normal gait (n = 337)
Abnormal gait (n = 85)
Bronx Aging Study: Older adults with neurological gait abnormalities are twice likely to develop dementia
Hazard Ratio 1.96 (95% CI 1.3-2.96)*Adjusted for age, sex, education, medical illnesses, and Blessed scores.
Verghese, N Engl J Med 2002
Buracchio, T. et al. Arch Neurol 2010;67:980-986.
Change point for gait speed in MCI converters in relation to the mean age at conversion in men and women
He’s a nice guy, but he played too much football with his helmet off.
…. so dumb he can't walk and chew gum at the same time.
aAAA, C, E…
40 feet: sec
Complex
Walking While Talking Test
Verghese et al. J Am Geriatr Soc 2002
WWT-complex 33
Log rank < .0001
Time to fall in weeks
6050403020100
Fall
free
surv
ival
1.1
1.0
.9
.8
.7
.6
.5
.4
.3
.2Log rank < .0001
WWT-complex 33s
WWT-complex < 33s
Verghese, J Am Geriatr Soc 2002Ayers, Gerontology 2014
Older adults who had difficulty walking while talking were 13 times more likely to fall over the next year.
N = 60
EAS: Mobility Stress Test Approach to Predicting Frailty, Disability, and Mortality in High Functioning Older Adults
Einstein Aging Study
Verghese et al. JAGS 2012
WWT predicts vascular dementiaCeïde. J Geriatr Psych Neurology 2018
What happens at or before when gait slows?
Brain changesBiological derangements
Imaging Motion:Functional Near Infra-red Spectroscopy (fNIRS))
Holtzer et al. J Gerontol Med Sci 2012, Neuroimage 2015
Walking at normal pace without talking
Walking while talking
H Blumen et al. Human Brain Mapp 2014
fMRI activation patterns during imagined WWT
Prefrontal activation on fNIRS during WWT predicts falls in high functioning older adults
Model adjustments Fall risk : HR per SD unit, 95% CI
Age, gender, education, illness, cognition
1.32, 1.01 – 1.71
+ fNIRS activation during normal walk and talk alone
1.30, 1.00 – 1.45
+ Digit symbol substitution test 1.32, 1.02 – 1.69
+ WWT velocity 1.37, 1.05 – 1.79
166 high functioning older persons Mean age 75, 51% womenNo dementia and disability, normal gait
Neurology 2017
Exocentric navigation: Floor maze test
124 subjects• 101 error free• 16 with errors• 7 failures
PlanningImmediateDelayed
Sanders A, et al. JGMS 2008
Maze navigation:
an early marker of cognitive decline?
MAZE Normal Mild impaired(Blessed ≥4)
P-value
Immediate trial, sec 22.9 29.9 0.008
Delayed trial, sec 16.3 20.2 0.002
Maguire E et al. J Neurosci 1997, Proc Natl Acad Sci USA 2000
O'Keefe, J. & Dostrovsky, J. Brain research 1971Nakazawa et al. Nature Reviews Neuroscience 2004
Mild Cognitive Impairment (MCI) syndrome
• Subjective cognitive complaints• Objective cognitive • Preserved ADL• Absence of dementia
Buracchio, T. et al. Arch Neurol 2010;67:980-986.
Gait speed declines early in the course of cognitive decline
Motoric Cognitive Risk (MCR) syndrome
• Subjective cognitive complaints• Objective motoric: slow gait
(1 SD below age and sex adjusted means)• Preserved ADL• Absence of dementia
J Gerontol Med Sci 2013
Why have another pre-dementia syndrome?
Benign senescent forgetfulness (Kral 1962)Age Associated Memory Impairment (Crook 1987)Age associated Cognitive Decline (WHO 1992)Mild Cognitive Disorder (ICD-10, 1993)Cognitive Impairment No Dementia (Graham 1997)Preclinical/prodromal AD (Dubois 2010)MCI syndrome (Reisberg 1987)
Non‐Amnestic MCI
MCRAmnestic MCI
0
2
4
6
8
10
12
14
DementiaAlzheimer Vascular
Hazard Ra
tioEinstein Aging
J Gerontol Med Sci 2013
MCR project: global prevalence study
22 sites worldwide. 26,802 participants
MCI (2596) MCR(1810)674
Healthy MCR TotalHealthy 17932 1810 19742MCI 2596 674 3270Total 20528 2484 23012
Study N Cognitive
impairment
(MMSE ≥5 points)*
Dementia*
mory & Aging Project, USA 1280 1.49 (1.08-2.07) 2.10 (1.43-2.09)
eligious Orders Study, USA 1013 1.90 (1.44-2.51) 1.98 (1.44-2.74)
Hispanic EPESE, USA 1562 1.48 (1.16-1.88) 1.79 (1.31-2.44)
InCHIANTI, Italy 700 2.74 (1.54-4.86)
NCGG-SGS Japan 4235 2.49 (1.52-2.02)
CR patients are at high risk of developing gnitive decline, dementia and AD
azard ratios with 95% CI adjusted for age, sex, education, presence of vascular ease and MMSE scores
MCR: Incidence rates
EAS LonGenity MAP ROSSite Bronx NY Chicago Multi-site
N 813 573 1020 722
ncidence/ 1000 py 55.0 50.8 79.6 68.6
5% CI 45.4 – 65.0 32.8 – 75.0 71.4 – 88.5 61.4 – 76.2
What drives MCR transition to dementia?
y Follow‐up Incident Dementia, n
Velocity;HR (95% CI), p‐value
General CognitionScore; HR (95% CI), p‐value
1.92 ± 2.19 16 1.01 (0.96‐1.01), 0.759
0.73(0.58‐0.93), 0.010
P 2.28 ± 2.53 59 0.98(0.94‐1.02), 0.307
0.84(0.76‐0.93), 0.001
5.75 ± 4.89 51 0.97(0.94‐1.00.), 0.039
0.68(0.52‐0.88), 0.003
MA 1.96 ± 1.59 8 1.00(0.93‐1.07), 0.973
0.68 (0.51‐0.91), 0.009
analyses are adjusted for age, sex and education
U bli h d d t
CR subtypes and 1-year cognitive decline (RBANS)
Global Memory Attention Language Visuospatiallocity 0.001 0.002 <0.001ride length 0.003 0.02 <0.001
wing timeride riability
wing riability
<0.001 0.029 0.02 <0.001 0.006
Allali G et al J Gerontol Med Sci 2016
Significant p-values shown
Association of Maze Completion Time with MCR
IMT DMT
10 20 30 40 50Time (months)
0 10 20 30 40 500
20
40
60
80
100
Time (months)
Cum
ulat
ive
Haz
ard
Adjusted HR (95% CI), p-valueercentile Ref.
Percentile 1.70 (0.57-5.08), p = 0.341ercentile 5.84 (2.08-16.37), p = 0.001
Adjusted HR (95% CI), p-value1st Percentile Ref.2nd Percentile 2.72 (0.91-8.08), p = 0.0723rd Percentile 6.58 (2.15-20.10), p = 0.001
otoric Cognitive Risk syndrome
ny older patient without dementia)
esenting with slow ait and cognitive mplaints.
MCR and risk of incident falls. Results adjusted for age and sex.
MCR syndrome and risk of mortality. d ratios adjusted for age, sex, education, medical illnesses, BMI, hospital stays, and use of a mobility aid
Ayers & Verghese. Alzheimers Dement. 2016.
Summary: 1
MCR syndrome: Is it Alzheimer's or vascular?What is the underlying pathology?
eauchet, Allali, Annweiler, Verghese. ssociation of Motoric Cognitive Risk Syndrome With rain Volumes: Results From the GAIT Study.
J Gerontol A Biol Sci Med Sci. 2016
ang, Allali, Kesavadas, Noone, Pradeep, Blumen, Verghese. erebral Small Vessel Disease and Motoric Cognitive Risk yndrome: Results from the Kerala-Einstein Study.
J Alzheimers Dis. 2016
hite matter hyperintensities not related to MCRJ Neuroimaging Psychiatry Neurology, in press
arkinsonian pathology?
MCR Consortium
CCMA study (Westchester, USA)Einstein Aging Study (Bronx, USA)LonGenity (NY, USA)Kerala-Einstein Study (Kerala, India)NuAge (Montreal, Canada)GAIT (Angers, France)NCGG-SGS (Obu, Japan)TASCOG (Tasmania, Australia)
1R56AG057548-01: NIA
MCR: Einstein Aging Study, CCMA, GAIT
Bl t l i i
MCR & Alzheimer pathology
follow-up time in years
0 1 2 3 4
8590
9510
0
gh homocysteine level (>15 mol/liter) vs. normal
• IL-6 but not TNF-alpha linked to gait decline
J Gerontol Med Sci 2012
• HS-CRP predicts gait decline (not in vascular disease)Age Ageing 2011
• High homocysteine levels predict gait declineJ Amer Geriatr Soc 2010
IL6 levels in MCR vs. Normal
instein Aging Study (n=337)
N Log IL-6 P-valueMCR 50 1.37 ± 0.55
0.003ormal 287 1.06 ± 0.70
10 polymorphisms predict incident MCR onGenity study)
Sathyan et al. Neurobiol Aging 2017
0 Ashkenazi Jewish seniorsincident MCR over 3 years
MCR: Polygenic risk scores
POLYGENIC SCORE B Sig. Exp(B)95% C.I.for EXP(B)Lower Upper
1 GENERAL COGNITION POLYGENIC SCORE ‐0.022 0.735 0.979 0.863 1.1102 BODY MASS INDEX (BMI) POLYGENIC SCORE 0.148 0.018 1.160 1.026 1.3123 HEIGHT POLYGENIC SCORE 0.006 0.937 1.006 0.866 1.1694 DIASTOLIC BLOOD PRESSURE (DBP) POLYGENIC SCORE 0.025 0.676 1.025 0.912 1.1535 SYSTOLIC BLOOD PRESSURE (SBP) POLYGENIC SCORE 0.038 0.525 1.039 0.924 1.1686 MEAN ARTERIAL PRESSURE (MAP) POLYGENIC SCORE 0.019 0.753 1.019 0.907 1.1457 PULSE PRESSURE (PP) POLYGENIC SCORE 0.032 0.596 1.032 0.918 1.1608 MAJOR DEPRESSIVE DISORDER (MDD) POLYGENIC SCORE ‐0.019 0.760 0.981 0.870 1.1079 SCHIZOPHRENIA POLYGENIC SCORE ‐0.012 0.907 0.988 0.810 1.20610 EDUCATIONAL ATTAINMENT (YRS EDUCATION) POLYGENIC SCORE ‐0.024 0.707 0.977 0.863 1.10511 EVER SMOKER POLYGENIC SCORE CREATED ‐0.012 0.857 0.988 0.867 1.12612 ALZHEIMERS DISEASE (AD) POLYGENIC SCORE 0.097 0.107 1.102 0.979 1.24113 NEUROTICISM POLYGENIC SCORE 0.106 0.150 1.112 0.962 1.28514 SUBJECTIVE WELL‐BEING POLYGENIC SCORE ‐0.029 0.655 0.972 0.856 1.10215 WAIST CIRCUMFERENCE POLYGENIC SCORE 0.156 0.014 1.169 1.033 1.32416 WAIST‐TO‐HIP RATIO (WHR) POLYGENIC SCORE ‐0.023 0.711 0.977 0.863 1.10617 DEPRESSIVE SYMPTOMS POLYGENIC SCORE ‐0.019 0.767 0.981 0.866 1.112
ble.: Logistic regression analysis of polygenic score of multiple phenotypes with motoric cognitive risk syndrome usted for age, gender, education and genetic ancestry
ealth & Retirement StudyMCR 300 Healthy 4779 Unpublished data
Health & Retirement study
MCR 300Normal 4,779
MCR (cognitive frailty): evolving definitions el Motor Cognitive/other Time Application
Slow gait Self‐report (MCR)
1‐2 min Community screening
Population research
Resource poor settings
Slow gait
Spatial navigation
Dual task
Frailty
Cognitive tests
MCI
5‐30 min Memory clinics
Research
Gait
MCR
Biomarkers• Blood• CSF• Imaging
Research
Summary: 2
an we prevent cognitive decline via otor pathways?
MCRDepressive symptoms (HR 1.22, 95% CI:
1.14-1.32)
Age (HR 1.04, 95% CI:
General Mental Status
HR 0.82, CI:0.75- 0.90)
Stroke(HR 1.73, 95% CI:
1.20-2.50)PD
(HR 2.71, 95% CI
1.82-4.02)
Education(HR 0.97, 95% CI:
0.95-0.99)
Obesity(HR 1.60, 95% CI:
1.19-2.15)
hysical Activity
R 1.95, 5% CI: 61-2.36)
ifiable Risk Factors
modifiable Risk Factors
riable Adjusted HR (95% CI)* P-valuegnitive Activity Scale 0.95 (0.91-1.00) 0.040ysical Activity Scale 0.94 (0.88-1.00) 0.036mber of High Contact Roles 0.78 (0.64-0.95) 0.016
ze of Social Network 0.95 (0.91-0.99) 0.008
Association of social and leisure activities with incident MCR
djusted for age, sex, and education years
CMA study
tiglioni et al. Lancet 2000Glei et al. Int J Epidemiol 2005
England: Men: spouse, women: friends
Taiwan: Friends not family
n: network size
Dancing and risk of dementia Adjusted Hazard Ratio 0.24 (0.06-0.99)
ects of Cognitive Activity Programs on gnition in MCI
Doi, Verghese, et al. JAMDA 2017
MCI. 40 week training. 60 min/week.
ce group improved story memory recall compared to control 0.011), but not music group.
h groups improved on MMSE compared to controls (dance; P=0.026, sic; P=0 008)
Attention training: rationale
Observational studiesCommon brain substratesCommon risk factors: genetics, vascularCognitive-motor responds to treatment: Methylphenidate, DBS, dopamineDual task training: balance
Journal of Gerontology: Medical Sciences 2010
rain games and mobility in frail seniors
nt ge in elocity
± SEM
Effect on Gait Velocity
Time: 0 3 months 6 months(baseline) (Post-trial) (3-month follow-up)
N 12/12 10/10 9/9
ent ge
ity
±
Time: 0 3 months 6 months(baseline) (Post-trial) (3-month follow-up)
WWT: Walking while reciting alternate alphabets
M i JAMDA i
01 AG050448-01 (Verghese/Holtzer):Cognitive tervention to improve simple and complex walking
420 sedentary seniors
Far transferchallenge
NeurodegenerDis Manag 2016
85: Fencing100: Bicycling110: Nursing home 117: Stooped smoking119: Wheelchair. 45 lb120: Time’s mistress122: mentally intact
DietOlive oilPort wineChocolate 1lb/week
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