Petersen, Ronald C.

Abstract Introduction The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). Method We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high‐likelihood DLB cases, and 1049 controls. Result We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine‐mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). Discussion These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

ABSTRACT Background The clinical course of dementia with Lewy bodies patients is heterogeneous. The ability to more accurately prognosticate survival is important. Objective The objective of this study was to investigate hippocampal volume as a predictor of survival in dementia with Lewy bodies patients. Methods Survival analysis for time from onset of cognitive symptoms to death was carried out using Cox proportional hazards models. Given their age and total intracranial volume, patients were dichotomized into low/medium (0%‐66.7%) and high (66. 7%‐100%) hippocampal volume categories. The models using these categories to predict survival were adjusted for field strength, APOE ε4 status, and estimated onset age of cognitive problems. Results We investigated 167 consecutive patients with dementia with Lewy bodies. The median age at MRI was 72 years (interquartile range 67‐76), and 80% were male. The median time from estimated first cognitive symptom to death was 7.4 years (interquartile range:5.7‐10.2). Lower hippocampal volumes were significantly associated with higher risk of death (hazard ratio 1.28; 95% confidence interval 1.04‐1.58; P = .024). The predicted median survival for participants with onset of cognitive symptoms at age 68 was 10.63 years (95% confidence interval 8.66‐14.54) for APOE ε4 negative, high hippocampal volume participants; 8.89 years (95% confidence interval 7.56‐12.36) for APOE ε4 positive, high hippocampal volume participants; 8.10 years (95% confidence interval 7.34‐11.08) for APOE ε4 negative, low/medium hippocampal volume participants; and 7.38 (95% confidence interval 6.74‐9.29) years for APOE ε4 positive, low/medium hippocampal volume participants. Conclusions Among patients with clinically diagnosed dementia with Lewy bodies, those with neuroimaging evidence of hippocampal atrophy have shorter survival times. © 2016 International Parkinson and Movement Disorder Society

AbstractIntroductionThe clinical and pathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy‐confirmed Lewy Body pathology or AD pathology.MethodsWe identified four groups with available plasma 2 years before death: high (n = 12) and intermediate‐likelihood DLB (n = 14) based on the third report of the DLB consortium; dementia with Alzheimer's pathology (AD; n = 18); and cognitively normal with normal aging pathology (n = 21). Lipids were measured using ESI/MS/MS.ResultsThere were overall group differences in plasma ceramides C16:0, C18:1, C20:0, and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high‐likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group.DiscussionPlasma ceramides and monohexosylceramides are elevated in people with dementia with either high‐likelihood DLB or AD pathology.

AbstractIntroductionAccurate estimates of cognitive and clinical decline rates are essential to the design of clinical trials in Alzheimer's disease (AD) dementia.MethodsTo investigate the trajectories of individuals enrolled in therapeutic trials in mild‐to‐moderate AD, we analyzed the placebo arm data from 20 clinical trials including over 4500 subjects. We analyzed decline as measured by two cognitive instruments, the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAScog) and the Mini‐Mental State Examination, and one clinical rating scale, the Clinical Dementia Rating Sum of Boxes.ResultsTrajectories were generally similar across trials and nearly linear. Greater cognitive impairment at baseline, younger age, and greater education were associated with increased rate of cognitive decline. Effect sizes for the ADAScog were generated as a function of population characteristics.DiscussionThese data will inform the design of future studies of potential disease‐modifying therapies for mild‐to‐moderate AD dementia.

Objectives To characterize frailty in cognitively normal older adults at baseline and to investigate the relationship between frailty and mortality. Design Population‐based prospective cohort study: Mayo Clinic Study of Aging. Setting Olmsted County, Minnesota. Participants Cognitively normal older persons aged 70 and older (mean age 78.8 ± 5.2, 50.2% male; N = 2,356). Measurements Frailty was assessed at baseline using a 36‐item Frailty Index. Four frailty subgroups were identified based on the Frailty Index (≤0.10 (fit), 0.11–0.20 (at risk), 0.21–0.30 (frail), >0.30 (frailest)). All participants underwent comprehensive clinical and cognitive assessments. The association between frailty and mortality was assessed using Cox proportional hazards models. Results The median Frailty Index was 0.17 (interquartile range 0.11–0.22). Frailty increased with age and was more common in older men than in older women. Over a median follow‐up of 6.5 years (range 7 days to 8.9 years), 500 of the 2,356 participants died, including 292 men. The frailest participants had the greatest risk of death (hazard ratio ( HR ) = 3.91, 95% confidence interval ( CI ) = 2.69–5.68). The association was stronger in women ( HR = 5.26, 95% CI = 2.88–9.61) than men ( HR = 3.15, 95% CI = 1.98–5.02). Conclusion Baseline frailty was common, especially in older men, and increased with age. Frailty was associated with significantly greater risk of death, particularly in women. These sex differences should be considered when designing a geriatric care plan.