Neurobiology of aging
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TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p. R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). ⋯ Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p. S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
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Neurobiology of aging · Jun 2014
Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention.
Recent studies have found an association between a variant in triggering receptor expressed on myeloid cells 2 (TREM2) (rs75932628-T) and both Alzheimer's disease (AD) and cognitive function in individuals aged 80-100 years. The role of TREM2 in younger, asymptomatic individuals is unknown. We examined this variant in 1148 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. ⋯ Carriers were more likely to have a parental history of AD (100% of carriers vs. 70% of noncarriers; p = 0.01) and, among the parental history subset, families with a TREM2 carrier had a younger maternal age of AD onset than noncarriers (67.9 vs. 75.6 years; p = 0.03). There was no significant association between TREM2 carrier status and cognitive function or decline. In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.
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Age-associated white matter degeneration has been well documented and is likely an important mechanism contributing to cognitive decline in older adults. Recent work has explored a range of noninvasive neuroimaging procedures to differentially highlight alterations in the tissue microenvironment. Diffusional kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI) that accounts for non-Gaussian water diffusion and can reflect alterations in the distribution and diffusion properties of tissue compartments. ⋯ DKI metrics were additionally useful in combination with DTI metrics for the classification of regions according to their multivariate "diffusion footprint", or pattern of relative age effect sizes. It is possible that the specific multivariate patterns of age-associated changes measured are representative of different types of microstructural pathology. These results suggest that DKI provides important complementary indices of brain microstructure for the study of brain aging and neurologic disease.
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Neurobiology of aging · Jun 2014
Dysregulated physiological stress systems and accelerated cellular aging.
Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. ⋯ LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively.