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Transgenic Mouse Models as Tools for Understanding How Increased Cognitive and Physical Stimulation Can Improve Cognition in Alzheimer's Disease.

ABSTRACT: Cognitive decline appears as a core feature of dementia, of which the most prevalent form, Alzheimer's disease (AD) affects more than 45 million people worldwide. There is no cure, and therapeutic options remain limited. A number of modifiable lifestyle factors have been identified that contribute to cognitive decline in dementia. Sedentary lifestyle has emerged as a major modifier and accordingly, boosting mental and physical activity may represent a method to prevent decline in dementia. Beneficial effects of increased physical activity on cognition have been reported in healthy adults, showing potential to harness exercise and cognitive stimulation as a therapy in dementia. 'Brain training' (cognitive stimulation) has also been investigated as an intervention protecting against cognitive decline with normal aging. Consequently, the utility of exercise regimes and/or cognitive stimulation to improve cognition in dementia in clinical populations has been a major area of study. However, these therapies are in their infancy and efficacy is unclear. Investigations utilising animal models, where dose and timing of treatment can be tightly controlled, have provided many mechanistic insights. Genetically engineered mouse models are powerful tools to investigate mechanisms underlying cognitive decline, and also how environmental manipulations can alter both cognitive outcomes and pathology. A myriad of effects following physical activity and housing in enriched environments have been reported in transgenic mice expressing Alzheimer's disease-associated mutations. In this review, we comprehensively evaluate all studies applying environmental enrichment and/or increased physical exercise to transgenic mouse models of Alzheimer's disease. It is unclear whether interventions must be applied before first onset of cognitive deficits to be effective. In order to determine the importance of timing of interventions, we specifically scrutinised studies exposing transgenic mice to exercise and environmental enrichment before and after first report of cognitive impairment. We discuss the strengths and weaknesses of these preclinical studies and suggest approaches for enhancing rigor and using mechanistic insights to inform future therapeutic interventions.

SUBMITTER: Shepherd A

PROVIDER: S-EPMC6296266 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Transgenic Mouse Models as Tools for Understanding How Increased Cognitive and Physical Stimulation Can Improve Cognition in Alzheimer's Disease.

Shepherd Amy A Zhang Tracy D TD Zeleznikow-Johnston Ariel M AM Hannan Anthony J AJ Burrows Emma L EL

Brain plasticity (Amsterdam, Netherlands) 20181212 1

Cognitive decline appears as a core feature of dementia, of which the most prevalent form, Alzheimer's disease (AD) affects more than 45 million people worldwide. There is no cure, and therapeutic options remain limited. A number of modifiable lifestyle factors have been identified that contribute to cognitive decline in dementia. Sedentary lifestyle has emerged as a major modifier and accordingly, boosting mental and physical activity may represent a method to prevent decline in dementia. Benef ...[more]

PMID: 30564551

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Project description:BACKGROUND:In spite of treatment advances, HIV infection is associated with cognitive deficits. This is even more important as many persons with HIV infection age and experience age-related cognitive impairments. Both computer-based cognitive training and transcranial direct current stimulation (tDCS) have shown promise as interventions to improve cognitive function. In this study, we investigate the acceptability and efficacy of cognitive training with and without tDCS in older persons with HIV. PATIENTS AND METHODS:In this single-blind randomized study, participants were 14 individuals of whom 11 completed study procedures (mean age =51.5 years; nine men and two women) with HIV-related mild neurocognitive disorder. Participants completed a battery of neuropsychological and self-report measures and then six 20-minute cognitive training sessions while receiving either active or sham anodal tDCS over the left dorsolateral prefrontal cortex. After training, participants completed the same measures. Success of the blind and participant reactions were assessed during a final interview. Assessments were completed by an assessor blind to treatment assignment. Pre- and post-training changes were evaluated via analysis of covariance yielding estimates of effect size. RESULTS:All participants believed that they had been assigned to active treatment; nine of the 11 believed that the intervention had improved their cognitive functioning. Both participants who felt the intervention was ineffective were assigned to the sham condition. None of the planned tested interactions of time with treatment was significant, but 12 of 13 favored tDCS (P=0.08). All participants indicated that they would participate in similar studies in the future. CONCLUSION:Results show that both cognitive training via computer game playing and tDCS were well accepted by older persons with HIV infection. Results are suggestive that tDCS may improve cognitive function in persons with HIV infection. Further study of tDCS as an intervention for HIV-related cognitive dysfunction is warranted.

Project description:BackgroundAging-related cognitive decline and cognitive impairment greatly impacts older adults' daily life. The worldwide ageing of the population and associated wave of dementia urgently calls for prevention strategies to reduce the risk of cognitive decline. Physical activity (PA) is known to improve cognitive function at older age through processes of neuroplasticity. Yet, emerging studies suggest that larger cognitive gains may be induced when PA interventions are combined with cognitive activity (CA). This meta-analysis evaluates these potential synergistic effects by comparing cognitive effects following combined PA + CA interventions to PA interventions (PA only), CA interventions (CA only) and control groups.MethodsPubmed, Embase, PsycInfo, CINAHL and Sportdiscus were searched for English peer-reviewed papers until April 2018. Data were extracted on cognition and factors potentially influencing the cognitive effects: mode of PA + CA combination (sequential or simultaneous), session frequency and duration, intervention length and study quality. Differences between older adults with and without mild cognitive impairments were also explored.ResultsForty-one studies were included. Relative to the control group, combined PA + CA intervention showed significantly larger gains in cognition (g = 0.316; 95% CI 0.188-0.443; p < .001). Studies that compared combined PA + CA with PA only, showed small but significantly greater cognitive improvement in favor of combined interventions (g = 0.160; 95% CI 0.041-0.279; p = .008). No significant difference was found between combined PA + CA and CA only interventions. Furthermore, cognitive effects tended to be more pronounced for studies using simultaneous designs (g = 0.385; 95%CI 0.214-0.555; p < .001) versus sequential designs (g = 0.114; 95%CI -0.102- 0.331, p = .301). Effects were not moderated by session frequency, session duration, intervention length or study quality. Also, no differences in effects were found between older adults with and without mild cognitive impairments.ConclusionFindings of the current meta-analysis suggest that PA programs for older adults could integrate challenging cognitive exercises to improve cognitive health. Combined PA + CA programs should be promoted as a modality for preventing as well as treating cognitive decline in older adults. Sufficient cognitive challenge seems more important to obtain cognitive effects than high doses of intervention sessions.

Project description:The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1-42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled 'cognitively impaired' subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory-Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1-42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1-42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.

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Transgenic Mouse Models as Tools for Understanding How Increased Cognitive and Physical Stimulation Can Improve Cognition in Alzheimer's Disease.

Publications

Transgenic Mouse Models as Tools for Understanding How Increased Cognitive and Physical Stimulation Can Improve Cognition in Alzheimer's Disease.

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