Exercise to Promote Cognitive and Brain Plasticity in Vascular Cognitive Impairment

Transcription

1 Exercise to Promote Cognitive and Brain Plasticity in Vascular Cognitive Impairment Teresa Liu Ambrose, PhD, PT Canada Research Chair University of British Columbia

2 RESULTS: Trial Completion (6 Months) Funding: Heart and Stroke Foundation of Canada and Canadian Stroke Network

3 Disclosure of current conflicts of interest Name of speaker/moderator: Teresa Liu Ambrose, PhD, PT I have no current conflict of interest with the content of this presentation.

4 The Problem Worldwide, one new case of dementia is detected every 3 4 seconds. Most common types: 1. AD 2. Vascular cognitive impairment Alzheimer s Disease International, The Global Impact of Dementia

5 Vascular Cognitive 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

6 Vascular Cognitive 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

7 Subcortical Ischemic VCI (SIVCI) Risk factors Age Hypertension Diabetes Dyslipidemia Small Vessel Disease White Matter Lesions Lacunes Images from Patel et al., 2011, International Journal of Stroke

8 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)

9 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)?» NCT » Liu Ambrose et al., Neurology, 2016» Hsu et al., BJSM, 2017» Barha et al., JAD, 2017

10 Study Design Baseline Measurement 71 Randomized Aerobic Training (AT) 6 Month Measurement Education (ED) 6 Month Measurement Intervention 12 Month Measurement 12 Month Measurement Follow Up

11 Study Participants Inclusion Criteria Clinical diagnosis of VCI ND Small Vessel Ischemic Disease: periventricular or deep WML, plus at least one lacunar infarct» Erkinjuntti et al., Semin Clin Neuropsychiatry, 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

12 Aerobic Training Education Usual Care Progressive walking program, up to 65 70% HRR 3x/week 60 min/class Usual care Educational seminar or hands on session on nutrition 1x/month 60 min/class

13 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% HRR 50% 55% 60% 65% 65 70% HRR=Heart Rate Reserve

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15 Usual care 1x/month Nutrition Education (NE) Group Education seminars Cooking classes with registered dietician

16 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

17 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)

18 Secondary: fmri Subset of participants Modified Ericksen Flanker Task 6 blocks 16 trials/block

19 fmri Analysis: Contrasts of Interest Baseline 6 Months Congruent Trials < Incongruent Trials < Congruent Trials < Incongruent Trials 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.

20 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

21 RESULTS: Trial Completion (6 Months) RESULTS: Trial Completion (6 Months)

22 Results: Participants

23 Results: Participants NE Group n = 35 AT group n = 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%

24 Results: Treatment Fidelity Change from Baseline to Trial Completion Adjusted within group change (SE) Adjusted between group difference (95% CI) Variable NE Group AT Group AT ED p value 6 Minute Walk Test (meters) 3.91 (9.00) (8.47) (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

25 Results: ADAS Cog Change 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

26 Exploring Associations Change in ADAS Cog associated with change in diastolic blood pressure (r=0.29, p=0.02)

27 Results: Improved Set Shifting in Females Only

28 Results: Increased BDNF in Females Only * BDNF=brain derived neurotrophic factor

29 Results: fmri 21 in final analysis 11 NE Group 10 AT Group

30 Results: Flanker Performance Baseline Mean (SD) 6 Month Mean (SD) Adjusted 6 Month Change * Mean (SE) NE Group Flanker task Congruent (ms) (254.2) (76.2) 40.9 (17.2) Flanker task Incongruent (ms) (109.7) (70.5) 7.5 (20.7) White Matter Lesion (mm^3) (3671.7) AT Group Flanker task Congruent (ms) (96.8) 636.3(71.3) (18. 1) ** Flanker task Incongruent (ms) (119.7) 708.0(74.4) 86.8 (21.9) ** White Matter Lesion (mm^3) (4344.9) *Adjusted for baseline MoCA, baseline WML, and baseline performance **p<0.05 for between group difference

31 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

32 Results: fmri Lateral Occipital Cortex Superior Temporal Gyrus Compared with the NE group, the AT group demonstrated reduced activation in the left lateral occipital cortex and right superior temporal gyrus.

33 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 better incongruent trial performance at trial completion.

34 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

35 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

36 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

37 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

38 Resistance Training & WMLs Compared with BAT, 2x/week RT significantly reduced WML progression» Bolandzadeh et al., JAGS, 2015

39 Trainees 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 Acknowledgements 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!