Physical a ctivity and c ognitive stimulation: Effects on c ognition a nd p lasma BDNF levels i n h ealthy o

1. School of Psychiatry and Clinical Neurosciences School of Medical Sciences Physical activity and cognitive stimulation: Effects oncognition and plasma BDNF levels in healthy older adults T Shah, G Verdile, H Sohrabi, E Putland, C Cheetham, C Gregory, A Mondal, R.N. Martins* *School of Medical Sciences, Edith Cowan University, Perth, Western Australia

2. Lifestyle Interventions – An International Priority Physical Activity (PA) Observational and Interventional Studies • PA reduces risk of cognitive decline and dementia by 30-50% (Barnes, 2007) • PA increases cardiorespiratory fitness which coincides with improvements in cognitive capacity with the largest effects on motor function and auditory attention (Angevaren et al., 2008) • Higher levels of fitness is associated with reduced brain atrophy in AD (Burns et al., 2008) • Older adults participating in an aerobic exercise intervention for six months increased brain volume (Colcombe et al., 2006). • Randomized controlled trial of 24 week of walking on 170 participants improved scores on ADAS-Cog in the exercise group post intervention (Lautenschlager et al., 2008) • Aerobic exercise training increased anterior hippocampal volume by 2%, thus reversing age related loss in volume by 1-2 yrs and also improved spatial memory (Erickson et al., 2011)

3. PA Interventions in Animal Models • PA increasesnumber of synapses per neuron, enhancesmemoryfunction, improveslearning, increasessurvival of cells in thedentategyrusandenhancesrecoveryfromlesion-inducedmemorydeficits (Cotman & Berchtold, 2007) • 5 months of voluntary PA or environmental enrichment in AD transgenic mice reduces cerebral Aβ levels (Adlard et al., 2005, Lazarov et al., 2005) Adlard et al., 2005 Lazarov et al., 2005

4. Physical Activity, Plasma Aβ and Hippocampal Volume Brown et al., manuscript in preparation

5. Cognitive Stimulation (CS): Cognitive Training Interventions ACTIVE trial, n=2837 (randomized, controlled, single blind trial) Compared to contact control group, all 3 intervention groups improved Memory, reasoning and processing (Ball et al., 2008). IMPACT trial, n=487 (randomized, controlled double blind trial) Compared to Active control group, Brain training improved memory/ attention and processing speed (Smith et al., 2009). Smith et al., 2009

6. Combination of Physical Activity and Cognitive Stimulation • Physical activity and cognitive stimulation intervention trials in healthy elderly have shown improvements in cognitive functioning. • Limited studies on whether the improvements observed in PA or CS intervention trials correlate in changes in blood biomarkers. • Varying intensity, type, duration and frequency not determined in the majority of studies. • Studies investigating whether a combination of PA and CS intervention leads to a further improvement in cognition (eg. Oswald et al., 2006, Fabre et al., 2002) are either small sample sized or did not use computerized programs for brain training in healthy elderly. • Previous studies did not investigate whether a combination lead to changes in blood biomarkers.

7. Brain Derived Neurotropic Factor (BDNF) • Promotes the growth and differentiation of new neurons and synapses. • Increased aerobic fitness results in an activation of growth factors like BDNF which mediate structural changes such as capillary density in rodents (Cotman,2002; Aleman et al., 2000; Mcauley et al.,2004; Prins 2002; Rogers et al., 1990). • Exercise also increases BDNF in the hippocampus, an area involved in learning and memory formation (Neeper et al., 1997; Vaynman et al., 2003). • A novel combination of PA and CS showed improvement in learning and memory abilities independent of activity intensity, BDNF and pCREB protein levels in rodents (Langdon & Corbett, 2011) . • A recent human trial involving cyber cyclists vs traditional cycling showed increased levels of plasma BDNF levels in cyber cyclists. However, BDNF was measured only on a small sample size (n=30) in this study (Anderson-Hanley et al., 2012)

8. Physical Activity And Cognitive Stimulation (PEACS) Study The overall aim of the PEACS study is to establish the clinical significance of physical activity and computerized brain training on cognitive functioning and AD related blood biomarkers in the elderly. Objective of current study To assess cognitive functioning and plasma levels of brain derived neurotrophic factor (BDNF) following a 16 week intervention of physical activity, computerized cognitive stimulation or a combination of both in healthy older adults

9. PEACS Study Plan 800 Healthy Community Dwelling Older Adults Contacted in Perth, Western Australia 660 Yes To the Study 107 Refused Participation 660 Telephone Screening 589 Eligible 383 Information Packs Sent 37 could not be Recontacted 106 Denied Participation 240 Yes to Baseline Appointment 194 Completed Intervention & 2nd Follow Up PA=47 CS=51 PA+CS=46 CONTROL=50 199 Completed 1st Follow Up 224 Recruited & Randomized 221 Completed Baseline Appointment 27 Withdrew/Dropouts

10. Intervention Protocol

11. Study Assessments (Baseline, 16wk) • Fasting blood sample for measurement of plasma BDNF, beta amyloid, cortisol, insulin and lipid profile • Neuropsychological tests - Cambridge Cognitive Examination-revised (CAMCOG-R; baseline & 16 week), Rey auditory verbal learning test (RAVLT), Controlled Oral Word Association Test (COWAT), CogState (CogState, Australia) • Physical fitness assessments (incremental shuttle walk test, 1 repetition maximum strength testing, Borg scale) and monthly PA training by exercise physiologists • Monitoring and training of intervention in monthly group meetings and also recording in daily log book along with routine recreational physical and mental activities • Fortnightly phone calls to address any technical issues related to the intervention protocol

12. BASELINE DEMOGRAPHICS

13. Other Baseline Characteristics

14. EFFECTS OF INTERVENTIONS ON COGNITIVE OUTCOMES Paired t test examined the within-group’s pre and post intervention performances. General cognitive funciton (CAMCOG) improved from baseline in all three intervention groups Verbal Memory (RAVLT) and Fluency (COWAT) improved from baseline in intervention and Control groups

15. EFFECTS OF INTERVENTIONS ON COGNITVE OUTCOMES Independent t test examined for intervention groups compared to control

16. Physical Activity + Cognitive Stimulation Increases Plasma BDNF Levels p= 0.02 Plasma BDNF Levels (pg/ml)

17. EFFECTS OF INTERVENTIONS ON BLOOD BIOMARKERS

18. Summary of Results • Comparisons of baseline with a 16 week intervention of physical activity (PA), cognitive stimulation (CS) or a combination of both revealed: • General cognitive function significantly improved with all three interventions. No significant improvement was observed in the control group • Verbal memory and Fluency improved from baseline in all three intervention groups and the control group. However, the intervention groups showed a trend towards a greater percent change than the controls in delayed recall with the greatest change observed with a combination of PA and CS (p=0.05). • Visual memory and learning (CPAL, p=0.023) and attention (ONB, p=0.024) significantly improved with cognitive stimulation only. • The interventions showed an improvement in percent change from baseline in visual learning and memory (OCL) in the combined group and in visual attention (IDN) in the PA and CS group only. • Speed of processing (DET) declined from baseline in control group (p<0.05), but did not significantly change in the intervention groups. • The combination of PA and CS significantly increased serum BDNF levels (p=0.02).

19. Conclusions and Future Directions • Preliminary analysis of a 16 week intervention of PA, CS or combination improves cognition from baseline. • Activities – physical or mental, led to improvement in general cognitive functions including delayed recall, visual learning and memory, visual attention, working memory. • The combination of PA and CS combination led to a significant increase in plasma BDNF levels. • Follow-up analysis include: Interventions on AD blood biomarkers, brain glucose metabolism (FDG-PET) and body composition (DEXA analysis). • PEACS Study has just completed its 52 week longitudinal follow-up with neuropsychological assessments and currently we are in the process of analysing our main study objectives.

20. Acknowledgements • The PEACS Participants • Clinical Research Team at Edith Cowan University / McCusker Foundation • Western Australia Cardiac Rehabilitation Services A/Prof Craig Cheetham and his team • Hollywood Private Hospital • Sir Charles Gardner Hospital • University of Western Australia • Edith Cowan University Special Thanks Dr Giuseppe Verdile, Mr Kevin Taddei, Dr Hamid Sohrabi, Ellen Putland

21. Eligibility • Male/female, aged 58 - 85 years • Able to communicate, understand and give written consent in English • Living independently and able to perform daily activities • No history of tremors • No visual impairment (a vision of 6/6 or corrected vision) to complete neuropsychological testing and undergo the intervention • No auditory impairment to complete neuropsychological testing and undergo the intervention • Having access to personal computer with internet facility at home • Computer literate (can move mouse or work with keyboard) • Willing to allocate their time for 16 weeks of the intervention • Willing to participate in the longitudinal follow up

22. Inclusion - Exclusion Criteria Inclusion Criteria • MMSE ≥ 24 • Personal physician fitness certificate stating that the participant is fit to take part in a home based physical activity intervention program for duration of 16 week Exclusion Criteria • Diagnosis of any type of dementia including AD • Uncontrolled medical condition–physical or mental that could lead to difficulty complying with the protocol including history of myocardial infarction, unstable or severe cardiovascular disease including angina or congestive heart failure, schizophrenia, bipolar disorder, anxiety neurosis or depression • Arthritis causing any disability or restricted movements • History of any learning or developmental disability • Going to the gym since last six months

23. EFFECTS OF INTERVENTIONS ON COGNITVE OUTCOMES - CogState Paired t test examined the within-group’s pre and post intervention performances.

24. EFFECTS OF INTERVENTIONS ON COGNITVE OUTCOMES % of Change from Baseline when Compared to Controls