to Promote Cognitive and Brain in Vascular … to Promote Cognitive and Brain Plasticity in Vascular...

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Exercise to Promote Cognitive and Brain Plasticity in Vascular Cognitive Impairment Teresa LiuAmbrose, PhD, PT Canada Research Chair University of British Columbia [email protected]

Transcript of to Promote Cognitive and Brain in Vascular … to Promote Cognitive and Brain Plasticity in Vascular...

Page 1: to Promote Cognitive and Brain in Vascular … to Promote Cognitive and Brain Plasticity in Vascular Cognitive Impairment Teresa Liu‐Ambrose, PhD, PT Canada Research Chair ... Disclosure

Exercise to Promote Cognitive and Brain Plasticity in Vascular Cognitive Impairment

Teresa Liu‐Ambrose, PhD, PTCanada Research Chair

University of British [email protected]

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RESULTS:  Tr ia l  Complet ion   (6  Months)Funding:  Heart  and  Stroke  Foundat ion  of  Canada  and  Canadian  Stroke  Network

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Disclosure of current conflicts of interestName of speaker/moderator: Teresa Liu‐Ambrose, PhD, PT

I have no current conflict of interest with the content of this 

presentation.

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The  Problem• Worldwide, one new case of dementia is detected every 3‐4 seconds.

• Most common types:1. AD2. Vascular cognitive 

impairment

Alzheimer’s Disease International, “The Global Impact of Dementia 2013‐2015.”

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Vascular  Cognit ive   Impairment

• Includes all levels of cognitive decline from mild to severe/advanced (i.e., dementia) due to vascular burden of the brain– Overt: clinical stroke– Covert: lesions in subcortical white matter due to small vessel disease

» Gorelick et al., Stroke, 2011

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Vascular  Cognit ive   Impairment

• Covert ischemic lesions may outnumber overt strokes by 5:1 and are associated with increased dementia risk.

» Vermeer et al., 2007

• Thus, the prevention and treatment of covert ischemic lesions is now a recognized priority.

» Middleton et al., 2013

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Subcortical   Ischemic  VCI   (SIVCI)

Risk factors• Age• Hypertension• Diabetes• Dyslipidemia

Lacunes

White Matter Lesions

Images from Patel et al., 2011, International Journal of Stroke

Small Vessel D

isease

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Exercise  and  VCI

• Key risk factors for VCI, such as hypertension, are largely modifiable– Regular physical activity

• Few randomized controlled trials (RCTs) have examined the potential benefit of exercise on cognitive function in VCI– In particular, those with covert subcortical ischemic lesions (i.e., SIVCI)

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PROMoTE Study:  A  6 ‐Month  Proof ‐of ‐Concept  RCT

• Does 3x/week of aerobic training benefit cognitive function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI)?

» NCT01027858» Liu‐Ambrose et al., Neurology, 2016» Hsu et al., BJSM, 2017» Barha et al., JAD, 2017

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Study  DesignBaseline 

Measurement

Aerobic Training (AT)

6‐Month Measurement

12‐Month Measurement

Education (ED)

6‐Month Measurement

12‐Month Measurement

71 Randomized

Intervention

Follow‐Up

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Study  Partic ipantsInclusion Criteria

• Clinical diagnosis of VCI‐ND• Small Vessel Ischemic Disease: 

periventricular or deep WML, plus at least one lacunar infarct

» Erkinjuntti et al., Semin ClinNeuropsychiatry, 2003

• Cognitive Syndrome:Montreal Cognitive Assessment score less than 26/30 at screening

• Mini‐Mental State Examination score of greater or equal to 20 at screening 

• Provide informed consent

Exclusion Criteria• Diagnosed with another type of 

dementia or other neurological conditions

• Plan to participate in another intervention study

• Unable to exercise safely– Physician clearance was 

required

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• Usual Care• Progressive walking program, up to 65‐70% HRR

• 3x/week • 60 min/class

Aerobic Training Education

• Usual care• Educational seminar or 

hands‐on session on nutrition

• 1x/month• 60 min/class

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Aerobic  Training  (AT)  Group• Moderate intensity, 3x/week, 60 min/class• Karvonen formula used

– HRR = Max HR + Rest HR– Target training HR = %HRR + Rest HR

• Nordic poles introduced at 3 months• Heart rate monitors, Borg, and “Talk Test”40%‐45%

HRR40%‐45%

HRR50%50% 55%55% 60%60% 65%65% 65‐70%65‐70%

HRR=Heart Rate Reserve

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Nutrit ion  Education  (NE)  Group

• Usual care• 1x/month

– Education seminars– Cooking classes with registered dietician

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Primary  Outcome  Measure

• Alzheimer Disease Assessment Scale (ADAS‐Cog) – 11 brief cognitive tests assessing memory, language, and praxis

– Scores range from 0 to 70, with higher scores indicating greater severity of cognitive impairment. 

– An outcome measure in AD trials but also trials with vascular dementia and MCI

» Orgogozo et al., Stroke, 2002» Lautenschlager et al., JAMA, 2008

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Secondary  Outcome  Measures

Executive Functions• Set shifting

– Trail Making Tests (A & B)• Response inhibition & conflict resolution– Stroop Colour Word Test

• Working Memory– Verbal Digits (Forward & Backward)

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• Subset of participants• Modified Ericksen Flanker Task

– 6 blocks• 16 trials/block

Secondary:   fMRI

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Baseline 

Incongruent Trials 

Congruent Trials  <

6 Months 

Incongruent Trials 

Congruent Trials  <<

fMRI Analysis: Contrasts of Interest

Entered into a higher‐level mixed‐effects (FMRIB's Local Analysis of Mixed Effects or FLAME) group analysis to provide an accurate estimation of group 

differences in neural activity across time.

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Flanker Task Analysis

fMRI Data• Motion corrected• FSL-FLIRT registered• Spatially smoothed – Gaussian

kernel 6.0mm FWHM• Event-related data convolved with

double-gamma function• Fixed-effects Contrasts

• Incongruent > Congruent• 6-month > Baseline

• Mixed-effects Contrasts• AT > ED; ED > AT

Behavioural Data

• Reaction time (RT) and accuracy during 96 trials assessed

• Only trials corresponding to correct responses were considered

• Mean RT for each condition calculated

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RESULTS:  Tr ia l  Complet ion   (6  Months)RESULTS:  Tr ia l  Complet ion   (6  Months)

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Results:  Partic ipants

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Results:  Partic ipantsNE Groupn = 35

AT groupn = 35

Variable Mean (SD) or n (%) Mean (SD) or n (%)

Age, years 73.7 (8.3) 74.8 (8.4)Gender, female 17 (49%) 19 (54%)

Education, > High School 27 (82%) 24 (69%)# of Meds for Cardiovascular Health 1.9 (1.5) 2.0 (1.6)

Functional Comorbidity Index 2.8 (2.2) 2.8 (1.5)Mini‐Mental State Examination 26.4 (3.1) 26.3 (2.7)Montreal Cognitive Assessment 21.7 (4.4) 20.7 (3.3)

Beta Blockers, yes 7 (20%) 7 (20%)% of Classes Attended (max = 78) ‐‐ 69%

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Results:  Treatment  Fidel ityChange from Baseline to Trial Completion

Adjusted within‐group change (SE) Adjusted between‐group difference (95% CI)

Variable NE Group AT Group AT ‐ EDp‐value

6‐Minute Walk Test (meters)

‐3.91(9.00)

26.44(8.47)

30.34(5.83, 54.86)

.02

Resting Systolic BP (mm Hg)

‐1.59(3.28)

‐6.67(3.05)

‐5.08(‐13.97, 3.81)

.26

Resting Diastolic BP (mm Hg)

1.81(2.07)

‐5.09(1.94)

‐6.89(‐12.52, ‐1.26)

.02

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Results:  ADAS ‐CogChange from Baseline to Trial Completion

Adjusted within‐group change (SE) Adjusted between‐group difference (95% CI)

ADAS‐Cog NE Group AT Group AT ‐ NE

p‐value

Intention to Treat(n = 70)

0.10 (0.53)

‐1.61(0.50)

‐1.71(‐3.15, ‐0.26)

.02

Complete Case(n = 58)

0.32 (0.56)

‐1.61(0.49)

‐1.94(‐3.42, ‐0.46)

.01

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Exploring  Associations• Change in ADAS‐Cog associated with change in diastolic blood 

pressure (r=0.29, p=0.02)

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Results:   Improved  Set  Shift ing   in  Females  Only

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*

Results:   Increased  BDNF   in  Females  Only

BDNF=brain derived neurotrophic factor

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Results:   fMRI

• 21 in final analysis– 11 NE Group– 10 AT Group

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Results:  Flanker  PerformanceBaselineMean (SD)

6‐MonthMean (SD)

Adjusted 6‐Month Change*

Mean (SE)

NE Group

Flanker task – Congruent (ms) 805.2 (254.2) 681.3 (76.2) ‐40.9 (17.2)

Flanker task – Incongruent (ms) 823.7 (109.7) 764.4 (70.5) ‐7.5 (20.7)

White Matter Lesion (mm^3) 2106.2 (3671.7) ‐‐ ‐‐

AT Group

Flanker task – Congruent (ms) 681.7 (96.8) 636.3(71.3) ‐136.7 (18. 1) **

Flanker task – Incongruent (ms) 737.9 (119.7) 708.0(74.4) ‐86.8 (21.9) **

White Matter Lesion (mm^3) 4012.5 (4344.9) ‐‐ ‐‐

*Adjusted for baseline MoCA, baseline WML, and baseline performance**p<0.05 for between‐group difference

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Results:   fMRI

• NE>AT; 6M>Baseline; Incon>Con• 3 significant clusters

– Occipital pole– Lateral occipital cortex– Superior temporal gyrus

• After adjusting for covariates– Lateral occipital cortex– Superior temporal gyrus

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Lateral Occipital Cortex Superior Temporal Gyrus

Results:   fMRI

Compared with the NE group, the AT group demonstrated reduced activationin the left lateral occipital cortex and right superior temporal gyrus. 

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Results:  Neural  Activity  &  Flanker  Performance  

• Reduced % signal change of left lateral occipital cortex and superior temporal gyrus were significantly associated with better congruent trial performance at trial completion.

• Reduced % signal change of superior temporal gyrus was significantly associated with betterincongruent trial performance at trial completion.

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Discussion

• Preliminary evidence for the efficacy of aerobic training for cognitive function in older adults with mild SIVCI, relative to usual care plus nutrition education.

• Memory has been shown to be particularly impaired in persons with small subcortical strokes

» Jacova et al., Annals of Neurology, 2012

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Discussion

• Difference of 1.61 points observed on the ADAS‐Cog falls within the range observed in previous pharmaceutical trials among individuals with vascular dementia or mild SIVCI (1 to 2 points)

• Less than minimal clinically important difference (3 points)

» Shrag et al., 2012

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Discussion

• Benefit of aerobic exercise for executive functions may be moderated by sex

» Colcombe and Kramer, Psychol Sci, 2003

• Aerobic exercise among older adults with mild SIVCI may improve neural efficiency. 

• Efficiency = same level of performance requiring less neural resource

» Yaakov Stern, Columbia University

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Limitations

• This is a proof‐of‐concept study, larger and longer trials are needed.

• Better understanding of moderators and mediators

• Other types of training, such as resistance training, should also be examined– May reduce the progression of the lesions

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Compared with BAT, 2x/week RT significantly reduced WML progression

» Bolandzadeh et al., JAGS, 2015

Resistance  Training  &  WMLs

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AcknowledgementsTrainees and Research Staff• John Best, PhD, PDF• Jennifer Davis, PhD, PDF• Cindy Barha, PhD, PDF• Liang Hsu, MSc, PhD• Elizabeth Dao, BA, MSc• Shirley Wang, Undergrad• Bryan Chiu, Undergrad• Lisanne ten Brinke, MSc• Michelle Munkacsy, MA• Winnie Cheung, BA

Co‐Investigators• Robin Hsiung, MD• Claudia Jacova, PhD • Philip Li, MD• Howard Feldman, MD• Lara Boyd, PT, PhD• Janice Eng, PT/OT, PhD• Penny Brasher, PhD• Lindsay Nagamatsu, PhD

Huge thanks to all the participants for their time and commitment!