Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI

Kathryn M Broadhouse; Maria Fiatarone Singh; Chao Suo; Nicola Gates; Wei Wen; Henry Brodaty; Nidhi Jain; Guy C Wilson; Jacinda Meiklejohn; Nalin Singh; Bernhard T Baune; Michael Baker; Nasim Foroughi; Yi Wang; Nicole Kochan; Kevin Ashton; Matt Brown; Zhixiu Li; Yorgi Mavros; Perminder S Sachdev; Michael J Valenzuela

doi:10.1016/j.nicl.2020.102182

Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI

Neuroimage Clin. 2020:25:102182. doi: 10.1016/j.nicl.2020.102182. Epub 2020 Jan 14.

Authors

Kathryn M Broadhouse¹, Maria Fiatarone Singh², Chao Suo³, Nicola Gates⁴, Wei Wen⁵, Henry Brodaty⁶, Nidhi Jain⁷, Guy C Wilson⁷, Jacinda Meiklejohn⁷, Nalin Singh⁷, Bernhard T Baune⁸, Michael Baker⁹, Nasim Foroughi¹⁰, Yi Wang¹¹, Nicole Kochan¹², Kevin Ashton¹³, Matt Brown¹⁴, Zhixiu Li¹⁵, Yorgi Mavros¹⁶, Perminder S Sachdev¹², Michael J Valenzuela¹⁷

Affiliations

¹ Nola Thompson Centre for Advanced Imaging, Sunshine Coast Mind and Neuroscience Thompson Institute, University of the Sunshine Coast, QLD, Australia; Regenerative Neuroscience Group, Brain and Mind Centre and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. Electronic address: kbroadhouse@usc.edu.au.
² Physical Activity, Lifestyle, Ageing and Wellbeing Faculty Research Group, Faculty of Health Sciences and Sydney Medical School, The University of Sydney, Lidcombe, NSW, Australia; Hebrew SeniorLife and Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
³ Regenerative Neuroscience Group, Brain and Mind Centre and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Melbourne, VIC, Australia.
⁴ Regenerative Neuroscience Group, Brain and Mind Centre and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁵ School of Psychiatry, University of New South Wales, Sydney, NSW, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
⁶ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia; Dementia Collaborative Research Centre, University of New South Wales, Sydney, NSW, Australia.
⁷ Physical Activity, Lifestyle, Ageing and Wellbeing Faculty Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia.
⁸ Department of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁹ Physical Activity, Lifestyle, Ageing and Wellbeing Faculty Research Group, Faculty of Health Sciences and Sydney Medical School, The University of Sydney, Lidcombe, NSW, Australia; School of Exercise Science, Australian Catholic University, Strathfield, NSW, Australia.
¹⁰ Clinical and Rehabilitation Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia.
¹¹ Clinical and Rehabilitation Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia; Department of Medicine and the Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
¹² Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
¹³ Biomedical Sciences, Faculty of Health Sciences and Medicine, Bond University, QLD, Australia.
¹⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, QLD, Australia; King's College London National Institutes of Health Biomedical Research Centre, UK.
¹⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, QLD, Australia.
¹⁶ Physical Activity, Lifestyle, Ageing and Wellbeing Faculty Research Group, Faculty of Health Sciences and Sydney Medical School, The University of Sydney, Lidcombe, NSW, Australia.
¹⁷ Regenerative Neuroscience Group, Brain and Mind Centre and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: michael.valenzuela@sydney.edu.au.

Abstract

Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training. One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT+CCT), (2) PRT+Sham CCT, (3) CCT+Sham PRT, (4) Sham physical+sham cognitive training (SHAM+SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures. PRT but not CCT or PRT+CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM+SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation. Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.

Keywords: Hippocampus; Mild cognitive impairment; Plasticity; Randomised controlled trial; Resistance exercise; Subfields.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cognitive Dysfunction / diagnostic imaging
Cognitive Dysfunction / pathology
Cognitive Dysfunction / physiopathology
Cognitive Dysfunction / rehabilitation*
Cognitive Remediation*
Combined Modality Therapy
Connectome*
Female
Hippocampus* / diagnostic imaging
Hippocampus* / pathology
Hippocampus* / physiopathology
Humans
Longitudinal Studies
Male
Middle Aged
Nerve Net* / diagnostic imaging
Nerve Net* / pathology
Nerve Net* / physiopathology
Neuronal Plasticity* / physiology
Outcome Assessment, Health Care*
Placebos
Resistance Training*

Substances

Placebos