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