Combined Aerobic Exercise and Cognitive Training in Seniors at Increased Risk for Alzheimer's Disease

Official title

Combined Aerobic Exercise and Cognitive Training for Alzheimer's Disease Prevention in At-Risk Seniors Estimated by An Exosomal Synaptic Protein Model: Cognition and Exosomal Synaptic Proteins Effects

Overview

The study aims to investigate the effect of a long-term combined aerobic exercise and cognitive training program on cognitive function and blood exosomal synaptic protein levels in seniors at increased risk for Alzheimer's Disease.

Detailed description

Alzheimer's disease (AD) is the most common cause of dementia in people older than 65 years worldwide. The neuropathological changes of AD occur decades before the onset of cognitive impairment, suggesting that early identification and timely intervention may postpone the clinical progress. In addition to its characteristic amyloid β and tau pathology, AD is also marked by synaptic dysfunction. Abnormal synaptic protein levels, such as growth associated protein 43 (GAP43), neurogranin, synaptotagmins, and synaptosome associated protein 25 (SNAP25) have been observed in the brain tissue and cerebrospinal fluid (CSF). Blood neuro-exosomal synaptic proteins have emerged as promising predictors for AD and cognitive decline. Particularly, the investigators previously reported a combination of blood neuro-exosomal protein (GAP43, neurogranin, SNAP25, and synaptotagmin 1) can predict AD 5 to 7 years before the clinical onset.

Both physical exercise and cognitive training have been demonstrated to improve cognitive function in AD and to exert a protective effect against developing dementia in the normal aging population. Furthermore, cognitive stimulation is an established modulator of synaptic plasticity and physical exercise might regulate synapse functional and structural change. However, whether cognitive training and physical exercise can alter exosomal synaptic protein levels and the relationship of biomarker changes to cognitive function in those seniors at increased risk for AD remain unclear.

In this study, the investigators aim to

1. assess the effects of a long-term combined aerobic exercise and cognitive training program on cognitive function and the predictive biomarkers (blood neuro-exosomal synaptic proteins: GAP43, neurogranin, SNAP25, and synaptotagmin 1) in seniors at increased risk of AD with abnormally decreased levels of the biomarkers. 2. determine the relationship of biomarker changes with cognitive function in these people. 3. confirm the predictive value of the blood neuro-exosomal synaptic proteins for AD in a longitudinal setting.

Interventions

• Behavioral Combined aerobic exercise and cognitive training program
  Participants will take part in a combined aerobic exercise and cognitive training program. The program will include moderate cycling exercise and cognitive game resolving at the same time. The tasks will be instructed and supervised by a fitness expert and a trained clinical neuropsychologist.

Primary outcome measures

• Change in cognitive function over time as assessed by the Montreal Cognitive Assessment (MoCA) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Mini Mental State Examination (MMSE) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Clinical Dementia Rating (CDR) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Verbal Fluency Test [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Digit Span Test-Forward and Backward [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Trail-Making Test Parts A and B (TMT-A and TMT-B) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by Boston Naming Test (BNT) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by the Rey-Osterrieth Complex Figure Test (ROCF) [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Change in cognitive function over time as assessed by California Verbal Learning Test (CVLT) [Time frame: baseline time, year 1, year 3, year 5, year 7]

Secondary outcome measures (5)

• Changes in concentrations of blood neuro-exosomal GAP43 over time [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Changes in concentrations of blood neuro-exosomal neurogranin over time [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Changes in concentrations of blood neuro-exosomal SNAP25 over time [Time frame: baseline time, year 1, year 3, year 5, year 7]
• Changes in concentrations of blood neuro-exosomal synaptotagmin1 over time [Time frame: baseline time, year 1, year 3, year 5, year 7]
• The area under curve of the blood neuro-exosomal synaptic proteins (GAP43, neurogranin, SNAP25, and synaptotagmin1) for the accurate diagnosis of AD [Time frame: up to 7 years]

Eligibility criteria

Inclusion criteria

• Mandarin-speaking subjects.
• Not clinically demented.
• Meeting the cutoff values of MMSE and CDR.
• With low levels of blood neuro-exosomal synaptic proteins (GAP43<1983pg/ml, synaptotagmin 1<431pg/ml, neurogranin<1433pg/ml, SNAP25<448pg/ml)

Exclusion criteria

• Had major neurologic diagnosis (e.g., Alzheimer's disease, Parkinson's disease, stroke, encephalitis, and epilepsy) or other condition that might impair cognition or confound assessments.
• Had a history of psychotic episodes or had major depression (Hamilton Depression Rating Scale score > 24 points).
• Had severe systemic diseases, such as tumors, cardiovascular or orthopedic disorders that can affect the ability to perform the proposed intervention tasks.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

China · 1 center

• Xuanwu Hospital — Beijing

Publications

• Jia L, Zhu M, Kong C, Pang Y, Zhang H, Qiu Q, Wei C, Tang Y, Wang Q, Li Y, Li T, Li F, Wang Q, Li Y, Wei Y, Jia J. Blood neuro-exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage. Alzheimers Dement. 2021 Jan;17(1):49-60. doi: 10.1002/alz.12166. Epub 2020 Aug 10. PMID 32776690
• Jia L, Quan M, Fu Y, Zhao T, Li Y, Wei C, Tang Y, Qin Q, Wang F, Qiao Y, Shi S, Wang YJ, Du Y, Zhang J, Zhang J, Luo B, Qu Q, Zhou C, Gauthier S, Jia J; Group for the Project of Dementia Situation in China. Dementia in China: epidemiology, clinical management, and research advances. Lancet Neurol. 2020 Jan;19(1):81-92. doi: 10.1016/S1474-4422(19)30290-X. Epub 2019 Sep 4. PMID 31494009
• Chatzi C, Zhang Y, Hendricks WD, Chen Y, Schnell E, Goodman RH, Westbrook GL. Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L. Elife. 2019 Jun 24;8:e45920. doi: 10.7554/eLife.45920. PMID 31232686
• Lopez-Ortiz S, Valenzuela PL, Seisdedos MM, Morales JS, Vega T, Castillo-Garcia A, Nistico R, Mercuri NB, Lista S, Lucia A, Santos-Lozano A. Exercise interventions in Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. Ageing Res Rev. 2021 Dec;72:101479. doi: 10.1016/j.arr.2021.101479. Epub 2021 Sep 30. PMID 34601135
• He Z, Gao Y, Alhadeff AL, Castorena CM, Huang Y, Lieu L, Afrin S, Sun J, Betley JN, Guo H, Williams KW. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab. 2018 Dec;18:107-119. doi: 10.1016/j.molmet.2018.08.011. Epub 2018 Sep 12. PMID 30292523
• Chapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, Keebler MW, Gardner CM, Strain JF, DeFina LF, Lu H. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015 Feb;25(2):396-405. doi: 10.1093/cercor/bht234. Epub 2013 Aug 28. PMID 23985135
• Hill NT, Mowszowski L, Naismith SL, Chadwick VL, Valenzuela M, Lampit A. Computerized Cognitive Training in Older Adults With Mild Cognitive Impairment or Dementia: A Systematic Review and Meta-Analysis. Am J Psychiatry. 2017 Apr 1;174(4):329-340. doi: 10.1176/appi.ajp.2016.16030360. Epub 2016 Nov 14. PMID 27838936

Identifiers

NCT: NCT05163626 · ICND20210920

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗