Citations

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

Elevation of circulating fatty acids (FA) during fasting supports postprandial (PP) insulin secretion that is critical for glucose homeostasis and is impaired in diabetes. We tested our hypothesis that lipid droplet (LD) protein perilipin 5 (PLIN5) in β-cells aids PP insulin secretion by regulating intracellular lipid metabolism. We demonstrated that PLIN5 serves as an LD protein in human islets. In vivo, Plin5 and triglycerides were increased by fasting in mouse islets. MIN6 cells expressing PLIN5 (adenovirus [Ad]-PLIN5) and those expressing perilipin 2 (PLIN2) (Ad-PLIN2) had higher [3H]FA incorporation into triglycerides than Ad-GFP control, which support their roles as LD proteins. However, Ad-PLIN5 cells had higher lipolysis than Ad-PLIN2 cells, which increased further by 8-Br-cAMP, indicating that PLIN5 facilitates FA mobilization upon cAMP stimulation as seen postprandially. Ad-PLIN5 in islets enhanced the augmentation of glucose-stimulated insulin secretion by FA and 8-Br-cAMP in G-protein–coupled receptor 40 (GPR40)- and cAMP-activated protein kinase–dependent manners, respectively. When PLIN5 was increased in mouse β-cells in vivo, glucose tolerance after an acute exenatide challenge was improved. Therefore, the elevation of islet PLIN5 during fasting allows partitioning of FA into LD that is released upon refeeding to support PP insulin secretion in cAMP- and GPR40-dependent manners.

ABSTRACTBackgroundWe have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders.MethodsWe screened 488 autopsy‐confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat‐primed polymerase chain reaction assay.ResultsNo larger (intermediate or expanded) repeats were found in these autopsy‐confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002).ConclusionsOur results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy‐confirmed PD. © 2014 International Parkinson and Movement Disorder Society

Fronto-temporal lobar degeneration (FTLD) is a form of dementia which may manifest through symptoms similar to Alzheimer’s, including language-specific impairment. Linguistic manifestations of the disorder are often described in subjective assessments of the disorder, but not always easily quantifiable using objective tests. This paper investigates a speech characteristic not yet assessed in FTLD patients, that of “temporal cycles” [Henderson et al. (1966); Butterworth and Goldman-Eisler (1979)]. Temporal cycles in the speech of healthy adults consist of alternating and roughly equal periods of fluent and hesitant speech [Roberts and Kirsner (2000)]. A time series analysis of temporal cycles was conducted using spontaneous speech from 45 adults diagnosed with FTLD. Patients’ cognitive functioning was assessed using the language-specific clinical dementia rating (CDR) scale by board-certified neurologists. Periodicity of temporal cycles was quantified using the proportion of the energy in the highest peak to the total energy in the power spectrum. It was found that this measure was correlated with independent CDR assessments. The results of this study indicate that temporal cycles may be used to characterize the effects of neurodegenerative disorders on speech communication. [Work supported by US NIA Grants Nos. R01-AG023195, P50-AG16574, P30-AG19610, and NIH NIA-1R01AG026390, and Univ. of MN Academic Health Center.]

OBJECTIVE—The aim of this study was to examine associations between diabetes and clinical markers of benign prostatic hyperplasia (BPH) in community-dwelling white and black men aged 40–79 years. RESEARCH DESIGN AND METHODS—Data from the Olmsted County Study of Urinary Symptoms and Health Status and the Flint Men's Health Study were combined for a total study sample of 2,484 men. Severity of lower urinary tract symptoms (LUTS), peak urinary flow rates, prostate volume, and serum prostate-specific antigen (PSA) levels were examined by self-reported physician-diagnosed diabetes. RESULTS—Overall, 170 men (6.8%) reported a history of diabetes. Increased irritative LUTS and specifically nocturia were positively associated with diabetes. These patterns were consistent across race and persisted after adjustment for age, BMI, and various indicators of socioeconomic status. Furthermore, the relationship between irritative LUTS and diabetes was greater in black men. No significant associations were observed between diabetes and prostate volume, PSA level, and peak urinary flow rate. CONCLUSIONS—Our multiethnic community-based study demonstrates positive associations between diabetes and irritative LUTS and nocturia. Moreover, the association between irritative LUTS and diabetes is increased in black men. There was no strong evidence for an association between diabetes and BPH across measures more specific to BPH (i.e., prostate volume, PSA, and peak urinary flow rate). Taken together, our findings suggest that the presence of diabetes may be less related to prostate growth and more related to the dynamic components of lower urinary tract function. Further evaluations of the association between diabetes and BPH and related racial variations are warranted.