CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity.

Chromosomal instability (CIN) is a hallmark of many cancers. Restricting the localization of centromeric histone H3 variant CENP-A to centromeres prevents CIN. CENP-A overexpression (OE) and mislocalization have been observed in cancers and correlate with poor prognosis; however, the molecular consequences of CENP-A OE on CIN and aneuploidy have not been defined. Here, we show that CENP-A OE leads to its mislocalization and CIN with lagging chromosomes and micronuclei in pseudodiploid DLD1 cells and xenograft mouse model. CIN is due to reduced localization of proteins to the kinetochore, resulting in defects in kinetochore integrity and unstable kinetochore-microtubule attachments. CENP-A OE contributes to reduced expression of cell adhesion genes and higher invasion of DLD1 cells. We show that CENP-A OE contributes to aneuploidy with karyotypic heterogeneity in human cells and xenograft mouse model. In summary, our results provide a molecular link between CENP-A OE and aneuploidy, and suggest that karyotypic heterogeneity may contribute to the aggressive phenotype of CENP-A-overexpressing cancers.

Interaction Between Physical Activity and Genes Related to Neurotrophin Signaling in Late-Life Cognitive Performance: The Cache County Study.

Research indicates that lifestyle and genetic factors influence the course of cognitive impairment in aging, but their interactions have not been well-examined. This study examined the relationship between physical activity and genotypes related to brain-derived neurotrophic factor (BDNF) in predicting cognitive performance in a sample of older adults with up to 12 years of follow-up. Physical activity levels (sedentary, light, and moderate/vigorous) were determined for the sample of 3,591 participants (57% female) without dementia. The genotypes examined included BDNF gene single nucleotide polymorphisms (SNPs) (rs6265 and rs56164415) and receptor gene SNPs (NTRK2 rs2289656 and NGFR rs2072446). Cognition was assessed triennially using the Modified Mini-Mental State Exam. Unadjusted linear mixed models indicated that sedentary (ß = -5.05) and light (ß = -2.41) groups performed worse than moderate-vigorous (p < .001). Addition of interaction effects showed significant differences in rate of decline between activity levels, particularly among males (p = .006). A three-way interaction with sex, NGFR SNP rs2072446, and physical activity suggested that the C/C allele was associated with better cognitive performance among males engaging in light activity only (p = .004). Physical activity and sex, but not BDNF-related SNPs, predicted rate of cognitive decline in older adults, while NGFR rs2072446 may modify main effects.

Neuropsychiatric symptoms in patients with dementia and the longitudinal costs of informal care in the Cache County population.

INTRODUCTION: Severity of dementia and neuropsychiatric symptoms contribute to increasing informal care costs. We examined which neuropsychiatric symptoms subdomains (NPS-SD) were associated with informal costs in a population-based sample. METHODS: Dementia progression and informal costs (2015 dollars) were estimated from the Cache County Dementia Progression Study. Overall NPS and specific NPS-SD were assessed with the Neuropsychiatric Inventory. Generalized Estimating Equations (GEE with gamma-distribution/log-link) modeled the relationship between NPS-SDs and informal cost trajectories. RESULTS: Two hundred eighty participants (52.1% female; age M = 85.67, SD = 5.60) exhibited an adjusted cost increase of 5.6% (P = .005), 6.4% (P < .001), 7.6% (P = .030), and 13% (P = .024) for every increasing Neuropsychiatric Inventory unit in psychosis-SD, affective-SD, agitation/aggression-SD, and apathy-SD, respectively. An increase in each unit of apathy was associated with a 2% annual decrease in costs (P = .040). DISCUSSION: We extend our prior work on informal costs and dementia severity by identifying NPS-SD associated with informal costs. Interventions targeting NPS-SD may lower informal costs.

Nutritional Status is Associated With Severe Dementia and Mortality: The Cache County Dementia Progression Study.

PURPOSE: Studies have reported faster cognitive/functional decline in persons with dementia (PWD) with malnutrition. We investigated whether baseline nutritional status predicted severe dementia and mortality in a population-based sample. PATIENTS: A maximum of 300 PWD were assessed annually for up to 8.6 years. METHODS: Nutritional status was assessed using a modified Mini-Nutritional Assessment (mMNA). Severe dementia was defined as: "severe" rating on the Clinical Dementia Rating or Mini-Mental State Examination score ≤10. Using Cox proportional hazards models, we examined the association between baseline mMNA score (or its subcomponents) with each outcome. Covariates included demographics; dementia onset age, type, and duration; APOE genotype; and residency with caregiver. RESULTS: Compared with "well-nourished," "malnourished" PWD had 3-4 times the hazard of severe dementia [hazard ratio (HR), 4.31; P=0.014] and death (HR, 3.04; P<0.001). Those "at risk for malnutrition" had twice the hazard of severe dementia (HR, 1.98; P=0.064) and 1.5 times the hazard of death (HR, 1.46; P=0.015). mMNA subcomponents of food group intake, weight loss, body mass index, mobility, health status, protein consumption, and mid-arm circumference predicted one or both outcomes. CONCLUSIONS: Nutritional status is an important predictor of clinical outcomes in dementia and may provide an avenue for intervention.