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