Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer\u27s disease?

Western countries are experiencing aging populations and increased longevity; thus, the incidence of dementia and Alzheimer\u27s disease (AD) in these countries is projected to soar. In the absence of a therapeutic drug, non-pharmacological preventative approaches are being investigated. One of these approaches is regular participation in physical activity or exercise. This paper reviews studies that have explored the relationship between physical activity and cognitive function, cognitive decline, AD/dementia risk and AD-associated biomarkers and processes. There is now strong evidence that links regular physical activity or exercise to higher cognitive function, decreased cognitive decline and reduced risk of AD or dementia. Nevertheless, these associations require further investigation, more specifically with interventional studies that include long follow-up periods. In particular, relatively little is known about the underlying mechanism(s) of the associations between physical activity and AD neuropathology; clearly this is an area in need of further research, particularly in human populations. Although benefits of physical activity or exercise are clearly recognised, there is a need to clarify how much physical activity provides the greatest benefit and also whether people of different genotypes require tailored exercise regimes.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.162

Bilingualism Is Associated with a Delayed Onset of Dementia but Not with a Lower Risk of Developing it: a Systematic Review with Meta-Analyses.

Some studies have linked bilingualism with a later onset of dementia, Alzheimer's disease (AD), and mild cognitive impairment (MCI). Not all studies have observed such relationships, however. Differences in study outcomes may be due to methodological limitations and the presence of confounding factors within studies such as immigration status and level of education. We conducted the first systematic review with meta-analysis combining cross-sectional studies to explore if bilingualism might delay symptom onset and diagnosis of dementia, AD, and MCI. Primary outcomes included the age of symptom onset, the age at diagnosis of MCI or dementia, and the risk of developing MCI or dementia. A secondary outcome included the degree of disease severity at dementia diagnosis. There was no difference in the age of MCI diagnosis between monolinguals and bilinguals [mean difference: 3.2; 95% confidence intervals (CI): -3.4, 9.7]. Bilinguals vs. monolinguals reported experiencing AD symptoms 4.7 years (95% CI: 3.3, 6.1) later. Bilinguals vs. monolinguals were diagnosed with dementia 3.3 years (95% CI: 1.7, 4.9) later. Here, 95% prediction intervals showed a large dispersion of effect sizes (-1.9 to 8.5). We investigated this dispersion with a subgroup meta-analysis comparing studies that had recruited participants with dementia to studies that had recruited participants with AD on the age of dementia and AD diagnosis between mono- and bilinguals. Results showed that bilinguals vs. monolinguals were 1.9 years (95% CI: -0.9, 4.7) and 4.2 (95% CI: 2.0, 6.4) older than monolinguals at the time of dementia and AD diagnosis, respectively. The mean difference between the two subgroups was not significant. There was no significant risk reduction (odds ratio: 0.89; 95% CI: 0.68-1.16) in developing dementia among bilinguals vs. monolinguals. Also, there was no significant difference (Hedges' g = 0.05; 95% CI: -0.13, 0.24) in disease severity at dementia diagnosis between bilinguals and monolinguals, despite bilinguals being significantly older. The majority of studies had adjusted for level of education suggesting that education might not have played a role in the observed delay in dementia among bilinguals vs. monolinguals. Although findings indicated that bilingualism was on average related to a delayed onset of dementia, the magnitude of this relationship varied across different settings. This variation may be due to unexplained heterogeneity and different sources of bias in the included studies. Registration: PROSPERO CRD42015019100

Election Reform in Virginia: Deliberation and Incremental Change

Several key factors explain the incremental approach to election law after the 2000 presidential election. The close election in Florida spurred lawmakers in Virginia to create the Joint Subcommittee Studying Virginia\u27s Election Process and Voting Technologies. This special subcommittee was formed to learn more about the capacity of election administration. Through that process, Virginia officials concluded that the election system was fundamentally sound, though they identified a need for additional resources to increase staff, improve polling place access for disabled voters, and clean up registration rolls. A declining fiscal outlook limited budget resources and constrained the legislature from adopting the joint subcommittee\u27s modest recommendations for additional spending. Interestingly, partisan differences over the most controversial issue-recounting ballots-were overcome as a result of deliberation. The joint subcommittee\u27s study created a forum within which a leading Republican senator changed his initial preference for how to recount ballots, and his view prevailed against the wishes of the Republican majority in the House of Delegates. Thus, in the case of Virginia, the deliberative process altered the policy views of a key committee leader, who in turn affected the outcome of the legislative process during the 2002 session. The legislature continued to pass incremental changes to upgrade the electoral system during 2003

Resurrecting Brinley Plots for a Novel Use: Meta-Analyses of Functional Brain Imaging Data in Older Adults

By plotting response times of young and older adults across a variety of tasks, Brinley spurred investigation and debate into the theory of general cognitive slowing. Though controversial, Brinley plots can assess between-task differences, the impact of increasing task demand, and the relationship between responses in two groups of subjects. Since a relationship exists between response times and the blood-oxygen level dependent (BOLD) signal of functional MRI (fMRI), Brinley's plotting method could be applied as a meta-analysis tool in fMRI studies of aging. Here, fledgling “Peiffer plots” are discussed for their potential impact on understanding general cognitive brain activity in aging. Preliminary results suggest that general cognitive slowing may be localized at the sensorimotor transformation in the precentral gyrus. Although this meta-analysis method is naturally used with imaging studies of aging, theoretically it may be applied to other study pairs (e.g., schizophrenic versus normal) or imaging datasets (e.g., PET)

Pre-Clinical Research and Development of Novel FKBP12 Antagonists for Enhanced Wound Healing and Regenerative Therapy

The combination of AMD3100 and low-dose FK506 has been shown to accelerate wound healing in vivo. Though AMD3100 is known to work by releasing hematopoietic stem cells into circulation, the mechanism of FK506 in this setting has remained unknown. In this study, we investigated the activities of FK506 in human cells and a diabetic-rat wound model using a non-immunosuppressive FK506 analog named FKVP. While FKVP was incapable of inhibiting calcineurin, wound healing enhancement with AMD3100 was unaffected. Further study showed that both FK506 and FKVP activate BMP signaling in multiple cell types through FKBP12 antagonism. Furthermore, selective inhibition of BMP signaling abolished stem cell recruitment and wound healing enhancement by combination treatment. These results shed new light on the mechanism of action of FK506 in BMP-mediated acceleration of wound healing, and raised the possibility that less toxic non-immunosuppressive FKBP ligands such as FKVP can replace FK506 as novel leads for wound healing. Moreover, new synthetic techniques and in vitro screening systems have translated into a methodology for the production and identification of additional non-immunosuppressive analogs to be tested in vivo. Further study shows that FKBP12 protein degradation can be chemically-induced using either a specialized FK506 analog or SNAP protein substrate. This technique generated our most potent BMP-activator, as well as a new method for identifying protein-protein interactions in live cells