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Background: Despite considerable heritability, previous smaller genome‐wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. Objective: The objective of this study was to perform a large‐scale GWAS in a well‐characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. Methods: Array‐based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. Results: This GWAS identified no common genome‐wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. Conclusions: Moderate single‐nucleotide polymorphism–based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence‐based GWASs (eg, by whole‐genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36‐month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores.Patients clustered into two neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36‐month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36‐month neurodevelopmental group with 82% accuracy and an area under the curve of .86.These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion X‐linked dystonia‐parkinsonism (XDP), a neurodegenerative movement disorder endemic to the Philippines, is primarily investigated in patients from Panay Island and the Greater Manila area. However, individuals residing in geographically distant regions may exhibit different clinical or genetic characteristics compared to those documented in earlier reports.The aim was to investigate the relationship of XDP clinical features in a Mindanao cohort with modifiers of age at onset (AAO) variability and utilization of a previously reported AAO model.We investigated clinical and genetic features in 27 XDP patients from southern Mindanao. In all patients, we genotyped the 4 polymorphisms linked to AAO.The XDP‐relevant hexanucleotide repeat number significantly correlated with AAO in the 27 patients and explained about 68% of AAO variability. There is no statistical difference between the predicted and actual AAO.The AAO model may provide reliable predictions by employing the effect of XDP genetic modifiers of AAO variability. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion To study the changes in incidence, age at onset and severity of visual impairment (VI) due to retinitis pigmentosa (RP) in the Years 1980–2019, and the incidence and age at diagnosis of hereditary retinal dystrophy (HRD) diagnoses coded by ICD10 H35.5 in the Years 1998–2019 in Finland.A total of 1606 persons with VI due to RP registered by the Finnish Register of Visual Impairment and total of 4291 HRD diagnoses registered by the Care Register of the Finnish Institute for Health and Welfare were included. VI was classified according to the Finnish national definitions derived from the WHO definitions. The significance of the changes in incidence and age at onset were tested with statistical tests (Kruskal–Wallis, Mann–Whitney U and Cochran‐Armitage). Two‐tailed p‐value below 0.05 was considered significant.The incidence of VI due to RP has decreased from 0.96/100 000 in the 1980s to 0.55/100 000 in the 2010s (p 0.004). The age at onset of VI has increased from 41.6 to 50.3 years. The severity of VI has not changed. The incidence of HRD diagnoses has decreased from 3.66/100 000 in the 2000s to 2.86/100 000 in the 2010s (p 0.024). The age at diagnosis has risen in male patients from 42.1 to 44.5 years (p 0.024).The VI caused by RP in Finland has decreased. It develops at an older age than in the past. We hypothesize that this trend may be attributed to informed decisions by visually impaired persons to refrain from having offspring to prevent the transmission of hereditary mutations. The severity of VI due to RP has remained relatively unchanged. The incidence of HRD diagnoses has decreased, and the diagnosis occurs at an older age among men. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We first examined the role of age at cardiovascular disease (CVD) onset for incident dementia, and then examined whether lifestyle factors at guideline‐recommended levels in individuals with CVD mitigates dementia risk. METHODS: We used population‐based data (Whitehall II: n = 10,308/baseline 1985–1988/examinations every 4–5 years). Lifestyle factors (non‐smoking, body mass index [BMI], physical activity, diet) were extracted post‐CVD. RESULTS: Over a median of 31.6 years, 3275 (32.1%) developed CVD. At age 70, risk of dementia was higher in individuals with CVD onset before (hazard ratio [HR] of incident dementia for participants with CVD before age 60, using participants without CVD at age 70 as the reference: 1.56, 95% confidence interal [CI] 1.18–2.08) but not after 60 years. In participants with CVD, a greater number of lifestyle factors at recommended levels post‐CVD was associated with a lower dementia risk (per lifestyle factor at recommended level HR: 0.73, 95% CI 0.59–0.92). DISCUSSION: Our results suggest that early onset CVD is associated with a higher dementia risk at older ages. In those with CVD, the dementia risk was lower if lifestyle factors are at recommended levels following CVD diagnosis. Highlights: CVD in midlife but not in late life is associated with a higher risk of dementia.Dementia risk in CVD patients is lower if their lifestyle factors are at recommended levels.These findings provide evidence to promote CVD prevention in midlife or earlier.Study findings also show the importance of a healthy lifestyle in those with CVD. [ABSTRACT FROM AUTHOR]

Objective: Glucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical characteristics at baseline and cognitive and motor progression over time among patients having GBA‐related PD (GBA‐PD), early‐onset idiopathic PD (early‐iPD), and late‐onset idiopathic PD (late‐iPD). Methods: We recruited 88 GBA‐PD, 167 early‐iPD, and 488 late‐iPD patients in this study. A subset of 50 GBA‐PD, 81 early‐iPD, and 223 late‐iPD patients was followed up at least once, with a 3.0‐year mean follow‐up time. Linear mixed‐effects models helped evaluate the rate of change in the Unified Parkinson's Disease Rating Scale motor and Montreal Cognitive Assessment scores. Results: At baseline, the GBA‐PD group showed more severe motor deficits and non‐motor symptoms (NMSs) than the early‐iPD group and more NMSs than the late‐iPD group. Moreover, the GBA‐PD group had more significant cognitive and motor progression, particularly bradykinesia and axial impairment, than the early‐iPD and late‐iPD groups at follow‐up. However, the early‐onset GBA‐PD (early‐GBA‐PD) group was similar to the late‐onset GBA‐PD (late‐GBA‐PD) group in baseline clinical features and cognitive and motor progression. Conclusion: GBA‐PD patients exhibited faster cognitive and motor deterioration than early‐iPD and late‐iPD patients. Thus, subtype classification based on genetic characteristics rather than age at onset could enhance the prediction of PD disease progression. [ABSTRACT FROM AUTHOR]

Background: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. Methods: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. Results: The HP polymorphism significantly impacts AD risk in European‐descent individuals (and in meta‐analysis with African‐descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. Discussion: The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Intervention of Alzheimer's dementia hinges on early diagnosis and advanced planning. This work utilizes the cognitive clock, a novel indicator of brain health, to develop a dementia prediction model that can be easily applied in broad settings. METHODS: Data came from over 3000 community‐dwelling older adults. Cognitive age was estimated by aligning Mini‐Mental State Examination (MMSE) scores to a clock that represents the typical cognitive aging profile. We identified a mean cognitive age at Alzheimer's dementia onset and predicted the corresponding chronological age at person‐specific level. RESULTS: The mean chronological age at baseline was 78 years. A total of 881 (28%) participants developed Alzheimer's dementia. The mean cognitive age at onset was 91 years. The predicted chronological age at onset had a mean (standard deviation) of 87.6 (6.7) years. The model's prediction accuracy was supported by multiple testing statistics. DISCUSSION: Our model offers an easy‐to‐use tool for predicting person‐specific age at Alzheimer's dementia onset. [ABSTRACT FROM AUTHOR]

Introduction: Our understanding of the genetic predisposition for age‐at‐onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex‐specific effects. Methods: Genome‐wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome. Results: We identified 11 genome‐wide significant loci (P < 5 × 10−8), including six known AD‐risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex‐specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males. Discussion: Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD. [ABSTRACT FROM AUTHOR]

Background: To explore whether the age at onset (AAO) of Chinese patients with moyamoya disease (MMD) increased over time due to a reduced exposure to leptospiral infection. Methods: We performed an independent, multicenter, retrospective study based on data from patients with MMD who initially attended four tertiary hospitals in Hubei, China, from 1996 to 2020. After stratifying the year of MMD onset into five periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, and 2016–2020), we analyzed the temporal trends in AAO and compared different classes of AAO (early‐onset, < 20 years; intermediate‐onset, 20–49 years; late‐onset, ≥ 50 years) in each period. Results: We included 1858 patients in this study, with 878 women and 980 men. Their median (IQR) AAO was 47 (39‒55) years. The case AAO significantly increased at the rate of 0.94 years per year (r = 0.406, p <.0001), while no trend was observed in birth years through time (p =.512). The birth cohorts who grew up in the leptospirosis epidemic years was stably susceptible to MMD. The median (IQR) AAO has increased significantly from 26 (14–37) years (1996–2000) to 51 (43–57) years (2016–2020) (p <.0001). The proportion of early‐onset MMD was significantly higher in 1996–2000 (33.3%, p <.0001) and 2001–2005 (10.4%, p <.001). The AAO shows an aging trend that the proportion of late‐onset MMD went from 4.5% (2001–2005) to 54.5% (2016–2020) (p <.0001). Conclusions: The AAO of MMD was increasing during a recent 25‐year period in China, which may reflect a birth cohort effect that resulted from environmental changes. The disparity risk of birth cohorts with MMD changed with leptospirosis epidemics, suggesting leptospiral exposure might be a potential risk factor. [ABSTRACT FROM AUTHOR]

Introduction: Residential instability (RI) during adolescence is associated with poor health outcomes. Also, extraversion has been shown to be a moderator of these associations. However, the associations between RI, extraversion, and age at onset of psychosis (AOP) remain unknown. Methods: Data were collected from patients with first‐episode psychosis (FEP). Linear regression models assessed the association between RI during adolescence and AOP. Extraversion was tested as a moderator using the interaction term RI‐by‐extraversion. Results: Among 89 participants with FEP, both RI (adjusted β = −.278, p =.006) and the interaction term RI‐by‐extraversion (adjusted β =.290, p <.001) were associated with earlier AOP. Stratified analyses showed that RI was only significantly associated with earlier AOP among those with low extraversion (adjusted β = −.598, p <.001). Conclusions: RI predicted earlier AOP and this association was moderated by extraversion. These findings suggest that extraversion may buffer the negative relationship between RI and AOP. Future research should replicate these findings. [ABSTRACT FROM AUTHOR]

Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI. Methods: A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed‐effects models examined association between age and single nucleotide variants (SNVs). Results: Three SNVs were significantly associated (P < 5 × 10–8) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late‐Onset Alzheimer's Disease dataset. Discussion: The replicated genome‐wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post‐synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objectives: Late-onset bipolar disorder (LOBD) represents a significant subgroup of bipolar disorder (BD). However, knowledge for this group is mostly extrapolated from small studies in subjects with early/mixed age of illness onset. In this global sample of older adults with BD (OABD: ≥50 years old) we aim to characterize the sociodemographic and clinical presentation of LOBD (≥40 years at BD onset) compared to early-onset BD (EOBD: <40 years at BD onset).Methods: The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data on 437 older age bipolar disorder participants. We compared LOBD versus EOBD on depression, mania, functionality, and physical comorbidities. Exploratory analyses were performed on participants with BD onset ≥50 years old.Results: LOBD (n = 105) did not differ from EOBD (n = 332) on depression, mania, global functioning, nor employment status (p > 0.05). Late-onset bipolar disorder was associated with higher endocrine comorbidities (odds ratio = 1.48, [95%CI = 1.0,12.1], p = 0.03). This difference did not remain significant when subjects with BD onset ≥50 years old were analyzed.Limitations: This study is limited by the retrospective nature of the variable age of onset and the differences in evaluation methods across studies (partially overcame by harmonization processes).Conclusion: The present analysis is in favor of the hypothesis that LOBD might represent a similar clinical phenotype as classic EOBD with respect to core BD symptomatology, functionality, and comorbid physical conditions. Large-scale global collaboration to improve our understanding of BD across the lifespan is needed. [ABSTRACT FROM AUTHOR]

Background: Research findings on factors associated with onset‐age (OA) with bipolar (BD) and major depressive disorders (MDD) have been inconsistent, but often indicate greater morbidity following early OA. Methods: We considered factors associated with OA in 1033 carefully evaluated, systematically followed mood disorder subjects with DSM‐5 BD (n = 505) or MDD (n = 528), comparing rates of descriptive and clinical characteristics following early (age <18), intermediate (18–40), or later onset (≥40 years), as well as regressing selected measures versus OA. Exposure time (years ill) was matched among these subgroups. Results: As hypothesized, many features were associated with early OA: familial psychiatric illness, including BD, greater maternal age, early sexual abuse, nondepressive first episodes, co‐occurring ADHD, suicide attempts and violent suicidal behavior, abuse of alcohol or drugs, smoking, and unemployment. Other features increased consistently with later OA: %‐time‐depressed (in BD and MDD, women and men), as well as depressions/year and intake ratings of depression, educational levels, co‐occurring medical disorders, rates of marriage and number of children. Conclusions: OA averaged 7.5 years earlier in BD versus MDD (30.7 vs. 38.2). Some OA‐associated measures may reflect maturation. Associations with family history and suicidal risk with earlier OA were expected; increases of time‐depressed in both BD and MDD with later OA were not. We conclude that associations of OA with later morbidity are complex and not unidirectional but may be clinically useful. [ABSTRACT FROM AUTHOR]

Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD‐affection status. Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD‐affected and ‐unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival‐type analysis of the AD risk supported modulating roles of multiple group‐specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune‐related biological processes, for example, B cell function. Discussion: These findings suggest involvement of local and inter‐chromosomal modulators of the effects of the APOE alleles on the AD risk. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a highly age‐related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time‐to‐event framework, has recently been successfully applied in other age‐related disorders. Objectives: We aimed to develop and validate a polygenic hazard score model in sporadic PD. Methods: Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single‐study sample of 360 patients and 160 controls. Results: A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49–4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. Conclusions: We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease‐modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective: The main purpose of this study was to evaluate the association between age at onset and social support in outpatients with bipolar disorder who were in the recovery phase. We also investigated the association between age at onset and disability. Methods: A total of 180 bipolar disorder I outpatients, of whom 50 had early onset with age at onset ≤18 years old, 108 had middle onset with age at onset between 19 and 39 years old, and 22 had late onset with age at onset ≥40 years old, were assessed with the Medical Outcomes Study Social Support Scale and Sheehan Disability Scale. Results: The early onset group had lower tangible social support, longer length of illness, more childless participants, lower income and more suicide attempters than the late onset group. Conclusions: Early onset seems to have inferior outcomes in tangible social support than late onset, but this trend should be considered as a starting point for future studies. [ABSTRACT FROM AUTHOR]

Background: Age at onset (AAO) is an essential feature of Parkinson's disease (PD) and can help predict disease progression and mortality. Identification of genetic variants influencing AAO of PD could lead to a better understanding of the disease's biological mechanism and provide clinical guidance. However, genetic determinants for AAO of PD remain mostly unknown, especially in the Asian population.Objectives: To identify genetic determinants for AAO of PD in the Asian population.Methods: We performed a genome-wide association meta-analysis on AAO of PD in 5166 Chinese patients with PD (Ndiscovery  = 3628, Nreplication  = 1538). We then conducted a further cross-ethnic meta-analysis using our results and summary statistics for the AAO of PD from the European population.Results: The total heritability of AAO of PD was around 0.10 ~ 0.14, similar to that (~0.11) estimated in populations of European ancestry. One novel significant intergenic locus rs9783733 (NDN; PWRN4) was identified (P = 3.14E-09, beta = 2.30, SE = 0.39). Remarkably, this variant could delay AAO of PD by ~2.43 years, with a more considerable effect on males (~3.18 years) than females (~1.45 years). The variant was suggestively significant in the cross-ethnic meta-analysis and suggested a positive selection in the East Asian population. Additionally, cross-ethnic meta-analysis identified a significant locus rs356203 in SNCA (P = 2.35E-11, beta = -0.71, SE = 0.01).Conclusions: These findings improve the current understanding of the genetic etiology of AAO of PD in different ethnic groups, and provide a new target for further research on PD pathogenesis and potential therapeutic options. © 2021 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: Bipolar disorder (BD) is a chronic mental health disorder with significant morbidity and mortality. Age at onset (AAO) may be a key variable in delineating more homogeneous subgroups of BD patients. However, no known research has systematically assessed how BD age‐at‐onset subgroups should be defined. Methods: We systematically searched the following databases: Cochrane Central Register of Controlled Trials, PsycINFO, MEDLINE, Embase, CINAHL, Scopus, Proquest Dissertations and Theses, Google Scholar and BIOSIS Previews. Original quantitative English language studies investigating AAO in BD were sought. Results: A total of 9454 unique publications were identified. Twenty‐one of these were included in data analysis (n = 22981 BD participants). Fourteen of these studies (67%, n = 13626 participants) found a trimodal AAO distribution: early‐onset (µ = 17.3, σ = 1.19, 45% of sample), mid‐onset (µ = 26.0, σ= 1.72, 35%), and late‐onset (µ = 41.9, σ= 6.16, 20%). Five studies (24%, n = 1422 participants) described a bimodal AAO distribution: early‐onset (µ = 24.3, σ = 6.57, 66% of sample) and late‐onset (µ = 46.3, σ = 14.15, 34%). Two studies investigated cohort effects on BD AAO and found that when the sample was not split by cohort, a trimodal AAO was the winning model, but when separated by cohort a bimodal distribution fit the data better. Conclusions: We propose that the field conceptualises bipolar disorder age‐at‐onset subgroups as referring broadly to life stages. Demarcating BD AAO groups can inform treatment and provide a framework for future research to continue to investigate potential mechanisms of disease onset. [ABSTRACT FROM AUTHOR]

Objectives: The effect of environmental and lifestyle factors on patients with LRRK2 (leucine‐rich repeat kinase 2) p.Gly2019Ser (LRRK2+/PD+) compared to idiopathic PD (iPD) has yet to be thoroughly investigated. Methods: In a homogeneous Tunisian Arab Berber population, we recruited 200 idiopathic PD and 199 LRRK2 p.Gly2019Ser mutation carriers, of whom 142 had PD (LRRK2+/PD+) and 57 were unaffected (LRRK2+/PD−). Case report form (CRF) questionnaires (motor and non‐motor symptoms) including the Geoparkinson Questionnaire were used to assess environmental and lifestyle factors. Results: In LRRK2+/PD+, tobacco use was significantly associated with a later median age at onset (AAO). The median AAO was 60 years (interquartile range = 52–67.25) for tobacco users, compared to 52 years (interquartile range = 45.25–61) for non‐users (P = 0.0042 at adjusted α = 0.025). Additionally, we observed an independent but additive effect of black tea consumption and tobacco use. Conclusions: Our data suggest that tobacco and black tea have a protective effect on age at onset in LRRK2+/PD+. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objectives: Large‐scale studies on phenotypic differences between bipolar disorder type I (BDI) and type II (BDII) are scarce. Methods: Individuals with BDI (N = 4806) and BDII (N = 3960) were compared with respect to clinical features, illness course, comorbid conditions, suicidality, and socioeconomic factors using data from the Swedish national quality assurance register for bipolar disorders (BipoläR). Results: BDII had higher rate of depressive episodes and more frequent suicide attempts than BDI. Furthermore, the BDII group were younger at first sign of mental illness and showed higher prevalence of psychiatric comorbidity but were more likely to have completed higher education and to be self‐sustaining than the BDI group. BDII more frequently received psychotherapy, antidepressants, and lamotrigine. BDI patients had higher rate of hospitalizations and elated episodes, higher BMI, and higher rate of endocrine, nutritional, and metabolic diseases. BDI were more likely to receive mood stabilizers, antipsychotic drugs, electroconvulsive therapy, and psychoeducation. Conclusions: These results demonstrate clear differences between BDI and II and counter the notion that BDII is a milder form of BDI, but rather a more complex condition with regard to clinical course and comorbidity. [ABSTRACT FROM AUTHOR]

Background: An older age at the diagnosis of prostate cancer has been linked to worse prostate cancer-specific survival (PCSS). However, these studies were conducted before the approval of many life-prolonging drugs. This study was aimed at describing outcomes in a contemporary cohort of men diagnosed with de novo metastatic prostate cancer (mPCa) and assessing associations with the age at diagnosis while controlling for known prognostic factors.Methods: The Surveillance, Epidemiology, and End Results registry was used to identify men diagnosed with mPCa from 2004 to 2014. Men were classified by 4 age groups: ≤54, 55 to 64, 65 to 74, and ≥75 years. The median overall survival, PCSS, and restricted mean survival times for any-cause mortality and prostate cancer-specific mortality (PCSM) were calculated. Multivariable and subdistribution hazard ratios for PCSM according to age group and with controlling for race, marital status, and income were estimated.Results: Compared with men aged ≤54 years, men aged ≥75 years experienced a mean PCSS at 5 years that was 6.7 months shorter (95% confidence interval [CI], 5.5-7.8 months). In multivariable analyses, men aged ≥75 years had a 49% increase in the rate of PCSM in comparison with those aged ≤54 years (95% CI, 1.39-1.60). The subdistribution hazard ratio for PCSM between these groups was 1.41 (95% CI, 1.32-1.50).Conclusions: Age was found to be an independent predictor of shorter PCSS in men diagnosed with de novo mPCa even in an era with more effective therapies. Further work is needed to determine the reason for poor outcomes in older men with mPCa. [ABSTRACT FROM AUTHOR]

Background: Functional neurological disorders are generally more common in females than males, but the reason for this gender difference is not well understood. Objectives: In this study, we aim to compare the clinical and demographic features of functional movement disorders (FMDs) between males and females. Methods: We examined clinical data and video‐recordings of patients with FMDs evaluated at the Baylor College of Medicine Movement Disorders Clinic. Results: Of the 196 patients with FMDs, males represented only 30% (n = 59) of the entire cohort. Men had an older age at onset: 40.5 versus 34.1 years (P = 0.026) and an older age at evaluation: 43.8 versus 38.1 years (P = 0.041) compared to women. Functional dystonia was more frequently observed in women: 47.5 versus 20.3% (P < 0.001), but there was a trend for higher frequency of functional gait disorder in men: 44 versus 30% (P = 0.056). Females were particularly over‐represented (73.7%) in children and adolescents; but the genders were equally represented in patients aged ≥50 years. Conclusions: Female patients are over‐represented in FMDs, except in individuals aged ≥50 years. Compared to female patients, males with FMDs present later in life and are less likely to have functional dystonia. [ABSTRACT FROM AUTHOR]

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.Objectives: To perform the largest PD genome-wide association study restricted to a single country.Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Although the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood. Methods: Logistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome‐wide ancestry on AD risk and age at onset. Results: Among the Caribbean Hispanics, individuals with African‐derived ancestry at APOE had 39% lower odds of AD than individuals with European‐derived APOE, after adjusting for APOE genotype, age, and genome‐wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals. Discussion: These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4. [ABSTRACT FROM AUTHOR]

Background: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored.Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO.Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium.Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort.Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown.Objectives: To identify the genetic determinants of PD age at onset.Methods: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset.Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD.Conclusions: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Aim: Age at disease onset has been implicated as an indicator of disease activity and severity in rheumatoid arthritis (RA). This study aimed to investigate how old age at disease onset affects patient treatment and prognosis in early RA. Methods: Data from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. From 2011 to 2015, a total of 2182 patients with RA were enrolled in the cohort; 239 patients were newly diagnosed with RA and were followed up for 2 years. The patients were divided into the following two groups: the young‐onset RA (YORA) which included patients <60 years old (n = 117) and elderly‐onset RA (EORA) which comprised patients ≥60 years old (n = 122). The clinical and laboratory data were compared at baseline, at 1 year, and at 2 years after onset. Results: Disease activity was higher in EORA than in YORA at baseline. Although disease activity was equivalent between EORA and YORA at 1 or 2 years, more EORA patients had bone erosions at baseline and at 2 years. More than 25% of the anti‐citrullinated protein autoantibody (ACPA)‐positive EORA patients without erosions at baseline had bone erosions even if they attained clinical remission at 1 or 2 years, while ~10% of YORA patients had erosions. Conclusion: Bone erosions were more frequently found in EORA. Clinical remission at 1 or 2 years was not enough to protect bone erosions in the ACPA‐positive EORA patients. Optimal treatment strategies preventing radiological damage should be considered for EORA. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results: BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. [ABSTRACT FROM AUTHOR]

Background and purpose: In spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population‐specific models to predict AO. Methods: This was a parametric survival modelling study. Results: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population‐specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population‐specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. Conclusions: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population‐dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins. [ABSTRACT FROM AUTHOR]

Objectives: Little is known about the course of late‐life bipolar disorder (LLBD). First, we studied patients with LLBD retrospectively with regard to age at first mood episode, onset polarity, predominant polarity and episode density and its associations with other clinical variables. Next, we examined prospectively the clinical course and its associated factors. Methods: Data were used from a dynamic cohort (Dutch Older Bipolars [DOBi]) including 101 patients with LLBD (mean age of 68.9 years) at baseline in 2012, with 3‐year follow‐up measurements available for 64 of these patients. Retrospective course was assessed by diagnostic interviews, and at follow‐up polarity and duration for each consecutive episode were noted. Linear and logistic analyses were performed to assess associations between relevant factors and outcome. Results: The mean age at the first episode was 33.0 years. Onset polarity was depression in 44.6% of patients, with a predominant polarity of depression in 47.5%. At 3‐year follow‐up, 37.5% of patients reported at least one mood episode, mainly depression. Life events, somatic illness, use of lithium and other factors were not associated with recurrence during the 3‐year follow‐up. Discussion: A relapse rate of 37.5% in 3 years is high, considering that LLBD patients generally have a longer history of disease and were receiving care and medication. The course of LLBD can provide important information on which clinical factors are associated with recurrence. Further phenotyping may reveal unique predictors for outcome, and both course specifiers and clinical variables should be included. [ABSTRACT FROM AUTHOR]

Abstract: Background: Neurological sequelae occur in 40% of patients with acute encephalopathy (AE). The early prediction of poor outcomes is critical to the initiation of appropriate treatment. The aim of the present study was therefore to elucidate prognostic factors that can be quickly and feasibly evaluated on hospital admission in patients with AE. Methods: We analyzed data from 51 AE patients admitted to Hirakata City Hospital between January 2005 and December 2014. Age at onset, sex, underlying disease, status epilepticus (SE), presence of benzodiazepine‐resistant SE (BZD‐resistant SE), and basic blood serum parameters on admission were evaluated in relation to each patient's outcome. Results: On univariate analysis age at onset, BZD‐resistant SE, and serum aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, and platelet count varied significantly according to outcome. On multivariate analysis age at onset (≤21 months), presence of BZD‐resistant SE, and AST (≥46 IU/L) were identified as independent variables associated with poor outcome. Conclusion: Age at onset, presence of BZD‐resistant SE, and AST are associated with a poor prognosis in AE. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the extent of overlap of the genetic architecture among the sporadic late‐onset Alzheimer's Disease (sLOAD), familial late‐onset AD (fLOAD), sporadic early‐onset AD (sEOAD), and autosomal dominant early‐onset AD (eADAD). Methods: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome‐wide significant loci for LOAD risk. Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10−7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10−7) and sLOAD (OR = 1.40; P = 1.21 × 10−3). The PRS was associated with cerebrospinal fluid ptau181‐Aβ42 on eADAD (P = 4.36 × 10−2). Conclusion: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. [ABSTRACT FROM AUTHOR]

Objective This study aimed to determine whether the rate of clozapine use, an indicator of refractoriness in schizophrenia, is associated with the season of birth and age at onset in patients with schizophrenia based on nationwide data. Methods Patients with schizophrenia ( n = 114 749) who received prescriptions for antipsychotic medication between 2008 and 2014 were retrospectively identified from the Korean National Health Insurance Service database. The study population was divided into three groups based on their age at the onset of schizophrenia (early, middle, and late onset). We assessed differences in the month of birth between patients and the general population. In addition, the cumulative clozapine use was calculated. Results Compared to the late-onset schizophrenia group, the early- and middle-onset groups showed a higher probability of birth during the winter season. In addition, the early-onset group showed the highest cumulative clozapine use rate. In the middle-onset group, the initiation of clozapine use was significantly earlier for patients born in winter compared to those born in summer. Conclusion Our results indicate that the age at onset is an important factor in predicting the prognosis of schizophrenia patients. The season of birth also affects the prognosis, but with less robustness. Specifically, it appears that early disease onset and winter birth might be associated with poor outcomes in Korean patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Aim To determine whether the age at onset of rheumatoid arthritis ( RA) has increased in Japan using a nationwide database (National Database of Rheumatic Diseases by iR-net in Japan, NinJa). Method We analyzed the data of RA patients who had been diagnosed with early RA (disease duration < 2 years) and newly registered in 2003, 2008 or 2013. Results The numbers of patients who developed RA in 2002-2003, 2007-2008, and 2012-2013 were 536, 812 and 1864, respectively. The mean age at RA onset increased significantly from 55.8 years in 2002-2003 and 57.0 years in 2007-2008 to 59.9 years in 2012-2013. The peak age shifted from the 50-59 years age group in 2002-2003 to the 60-69 years age group in 2012-2013. There was no apparent difference in the age at RA onset between male and female RA patients. Notably, in the period 2002-2003, the prevalence of RA was markedly higher in the age group of 50-59 years, which included the first 'baby boomers', than in the age groups of 30-39 and 40-49 years, even with consideration of the variations in the age composition of the general population. Conclusions We have demonstrated that the age at RA onset in Japan has increased significantly over the last decade. This can be attributed to Japan's aging population. In addition, the high prevalence of RA among the first baby boomers suggests that environmental factors might also have contributed to the increase in age at RA onset in Japan. [ABSTRACT FROM AUTHOR]

Background An initial diagnosis of Parkinson's disease ( PD) is challenging, especially in patients who have early onset and atypical disease. A genetic etiology for parkinsonism, when established, ends that diagnostic odyssey and may inform prognosis and therapy. The objective of this study was to elucidate the genetic etiology of parkinsonism in patients with early onset disease (age at onset <45 years). Methods Whole-exome sequencing, copy number variability, and short tandem repeat analyses were performed. The analyses were focused on genes previously implicated in parkinsonism and dystonia in patients with early onset parkinsonism. Genotype-phenotype correlations were assessed using regression models. Results The patient cohort was characterized by early onset, slowly progressive parkinsonism with a mean age at onset of 39.2 ± 5.0 years (n = 108). By 10 years of disease duration, the mean Hoehn & Yahr stage was 2.6 ± 0.8, the mean Unified Parkinson's Disease Rating Scale, part III (motor part) score was 24.9 ± 12.1 (n = 83), and 30 patients were cognitively impaired at the last examination (Montreal Cognitive Assessment score ≤ 26). Ten patients with typical early onset PD harbored homozygous or compound heterozygous mutations phosphatase and tensin homolog-induced putative kinase 1 ( PINK1) (n = 4), parkin ( PRKN) (n = 3), or the leucine-rich repeat kinase 2 ( LRRK2) c.6055 G to A transition (n = 3). In addition, 5 patients with more atypical disease were compound heterozygotes for the glucocerebrosidase gene ( GBA) (n = 3) 1 was heterozygous for solute carrier family 2, member 1 ( SLC2A1) and another carried a novel ataxin 2 ( ATXN2) exon 1 duplication. In most patients, the cumulative mutational burden did not appear to contribute to age at onset or progression Conclusion In this clinical series, 15 patients (14%) carried mutations that were linked to monogenic parkinsonism. GBA carriers were most likely to suffer an earlier cognitive demise. Nevertheless, the etiology for most patients with early onset PD remains to be determined. [ABSTRACT FROM AUTHOR]

Objective The primary objective for this study was to assess social cognition in patients with focal epilepsy using a naturalistic task, which accurately models complex real-world social interaction. Methods We conducted an observational study of social cognition in 43 patients with focal epilepsy and in 22 controls. Patients and controls completed The Awareness of Social Inference Test, which measures both basic and advanced social cognition in a realistic video-based format. Patient and controls also completed standard measures of cognitive functioning and measures of depression. Results Compared to controls, we found that patients with epilepsy ( PWEs) had no difficulty identifying positively valenced emotional states (happiness) yet had difficulty identifying most negatively valenced emotional states (anger, fear, and disgust). In addition, PWEs were able to identify sincere exchanges correctly but could not identify sarcastic and insincere exchanges. We found that basic social cognition significantly correlated with standard generalized cognitive measures, whereas advanced social cognition did not. Finally, age at onset had significant impact on social cognition, whereas other epilepsy characteristics did not. Significance PWEs have deficits in social cognition when measured using a naturalistic video-based task. Advanced social cognition may be an independent cognitive domain in PWEs that is not adequately measured using standard psychometric instruments. Problems with social cognition may arise as a consequence of epilepsy during the periods of robust social development in childhood and adolescence. [ABSTRACT FROM AUTHOR]

Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser(UCN). We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555A>G and m.1494C>T, and MT-TS1 m.7445A>G, m.7472insC m.7510T>C and m.7511T>C variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555A>G variant, two others had m.7472insC and one proband had m.7444G>A. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555A>G variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants. [ABSTRACT FROM AUTHOR]

Introduction Individualized estimates of age at detectable amyloid-beta (Aβ) accumulation, distinct from amyloid positivity, allow for analysis of onset age of Aβ accumulation as an outcome measure to understand risk factors. Methods Using longitudinal Pittsburgh compound B (PiB) positron emission tomography data from Baltimore Longitudinal Study of Aging, we estimated the age at which each PiB+ individual began accumulating Aβ. We used survival analysis methods to quantify risk of accumulating Aβ and differences in onset age of Aβ accumulation in relation to APOE ε4 status and sex among 36 APOE ε4 carriers and 83 noncarriers. Results Age at onset of Aβ accumulation for the APOE ε4− and ε4+ groups was 73.1 and 60.7, respectively. APOE ε4 positivity conferred a threefold risk of accumulating Aβ after adjusting for sex and education. Discussion Estimation of onset age of amyloid accumulation may help gauge treatment efficacy in interventions to delay symptom onset in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective It is suggested that age at onset ( AAO) of bipolar I disorder ( BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. Method A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution ( n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview ( n = 250), and a further admixture analysis was undertaken. Results The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. Conclusion The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with first-treatment bipolar I disorder ( BD I). Methods One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ( DSM- IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM- IV was used for DSM- IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative Syndrome Scale correspondingly. Cannabis use within the six last months was recorded. Results After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P < 0.05). Recent use was also associated with more lifetime suicide attempts ( P < 0.01). No group differences were found on symptom levels. Conclusions The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I. [ABSTRACT FROM AUTHOR]

Aims: To investigate the potential effect of six previously reported candidate single nucleotide polymorphisms on age at onset (AAO) among Chinese patients with Machado–Joseph disease (MJD). Methods: Three hundred and twenty-four unrelated molecular-confirmed MJD patients were recruited between January 2006 and December 2014. The screening of candidate polymorphisms was first performed in 173 subjects using the SNaPshot® Multiplex System. The mitochondrial NADH dehydrogenase subunit 3 (MT-ND3) polymorphism 10398A>G (rs2853826) was further verified with Sanger sequencing in additional 151 patients. Results: An inverse correlation was found between expanded CAG repeat length and AAO. The expanded CAG repeat length can explain 63% of AAO variance. The 10398A polymorphism was significantly associated with a 3-year earlier AAO in male patients with MJD (P = 0.001). Stepwise multiple regressions revealed that the 10398A polymorphism could account for nearly 2% of AAO variance in male patients. Conclusion: Six candidate SNPs have been screened in Chinese patients with MJD. A remarkable earlier AAO was noted in male Chinese MJD patients with MT-ND3 gene 10398A polymorphism. [ABSTRACT FROM AUTHOR]

Background Recent genomewide association study meta-analyses have identified 28 loci associated with risk of Parkinson's disease (PD). We sought to investigate whether these genetic risk factors are associated with PD age at onset. Methods Genetic risk scores from these loci were calculated for 6,249 cases. Linear regression tested associations between cumulative genetic risk and PD age at onset. Results Increasing genetic risk scores were associated with earlier age at onset (beta = -0.10, P = 2.92 × 10−8, adjusted r2 = 0.27). Single standard deviation increase in genetic risk score is associated with 37.44 d earlier age at onset. Highest genetic risk was found at 31 to 60 y, onset slightly below average age at onset (AAO). Conclusions Common genetic risk factors have a small but consistent association with AAO in PD. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background The aim of this study was to assess whether recently identified Parkinson's disease (PD) risk genes also influence age at onset in PD. Methods We genotyped 23 single-nucleotide polymorphisms in 1,526 Danish PD patients and performed linear regression analyses with age at onset. The combined impact of PD risk loci on age at onset was assessed by linear regression analyses using a weighted genetic risk score. Results The strongest effects were observed with rs12726330 in GBA (beta = -3.63, P = 2.0 × 10−5) and rs34311866 in TMEM175/GAK (beta = -1.19, P = 4.0 × 10−3), corresponding to a 3.6-y and 1.2-y decrease of age at onset per risk allele, respectively. The weighted genetic risk score yielded significant association with reduced onset age ( P = 3.98 × 10−3), although the variance explained was small (0.6%), and the effect was mostly driven by polymorphisms in GBA and TMEM175/GAK. Conclusions Overall, our study indicates that GBA and TMEM175/GAK significantly alter age at onset in PD. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective In this register-based study of schizophrenia patients aged 65 years or above, mortality and causes of death diagnosed at age of 60+ (very-late-onset schizophrenia-like psychosis, VLOSLP) were studied in comparison with sex- and age-matched general Finnish population. Standardized Mortality Ratios (SMRs) of VLOSLP patients were also compared with those of earlier onset (below 60 years) schizophrenia patients, and hazard of death was calculated between these patient groups. Methods The data was obtained from Finnish nationwide registers and consisted of 918 VLOSLP patients and 6142 earlier onset patients who were at least 65 years on 1 January 1999. The register-based follow-up for mortality covered 10 years between 1999 and 2008. Results Overall SMR was 5.02 (4.61-5.46) in the group of VLOSLP patients and 2.93 (2.83-3.03) in the group of earlier onset patients. In men, SMRs were 8.31 (7.14-9.62; n = 179) and 2.91 (2.75-3.07, n = 1316) and in women 4.21 (3.78-4.66; n = 364) and 2.94 (2.82-3.07, n = 2055). In the VLOSLP group, SMRs were higher in most causes-of-death categories such as accidents, respiratory diseases, dementias, neoplasms and circulatory diseases. However, in direct comparison adjusted for several variables, the difference between these groups was minimal (Hazard Ratio, HR, 1.16 95%CI 1.05-1.27, p = 0.003). Conclusion Patients with VLOSLP, especially men, are at even higher risk of death than schizophrenia patients with earlier onset. Physical comorbidities and accidents in the VLOSLP group mostly explained this result. Targeted clinical interventions with effective collaboration between psychiatry and primary and specialist-level somatic care are crucial to reduce their excess mortality. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a neurodegenerative disorder with a dominant genetic mode of inheritance caused by an expansion of CAG repeats on chromosome 4. Typically, a longer sequence of CAG repeat length is associated with increased risk of experiencing earlier onset of HD. Previous studies of the association between HD onset age and CAG length have favored a logistic model, where the CAG repeat length enters the mean and variance components of the logistic model in a complex exponential-linear form. To relax the parametric assumption of the exponential-linear association to the true HD onset distribution, we propose to leave both mean and variance functions of the CAG repeat length unspecified and perform semiparametric estimation in this context through a local kernel and backfitting procedure. Motivated by including family history of HD information available in the family members of participants in the Cooperative Huntington's Observational Research Trial (COHORT), we develop the methodology in the context of mixture data, where some subjects have a positive probability of being risk free. We also allow censoring on the age at onset of disease and accommodate covariates other than the CAG length. We study the theoretical properties of the proposed estimator and derive its asymptotic distribution. Finally, we apply the proposed methods to the COHORT data to estimate the HD onset distribution using a group of study participants and the disease family history information available on their family members. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background & Aims Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 ( PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence. Methods A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested. Results A higher incidence of alcoholic cirrhosis was observed in individuals with an older (≥24 years) compared with a younger (<24) age at onset of at-risk alcohol consumption ( P-value < 0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis ( P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value < 0.001; 1.53(1.07-2.19), P-value = 0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38). Conclusions Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence. [ABSTRACT FROM AUTHOR]

Aim Heterogeneity of symptoms, course and outcomes in primary psychotic disorders complicates prognosis, treatment and diverse aspects of research. This study aimed to identify interpretable subtypes of first-episode non-affective psychosis based on four early-course features (premorbid academic functioning, premorbid social functioning, duration of the prodrome and age at onset of psychosis). Methods Data from 200 well-characterized patients hospitalized in public-sector inpatient units for first-episode non-affective psychosis were used in latent profile analyses. Derived subtypes were then compared along a number of clinical dimensions using analyses of variance. Results Using four early-course features, three classes were derived. A good premorbid/short prodrome subtype was characterized by a lower severity of positive symptoms, better social/occupational/global functioning, and a shorter duration of untreated psychosis; a poor premorbid/early onset subtype demonstrated greater negative and preoccupation symptoms, as well as greater psychosocial problems; and a long prodrome/late onset subtype was characterized by greater dysphoric symptoms. Conclusions Findings indicate a need for further research with first-episode samples on the utility of subtyping based on early-course (premorbid, prodromal and onset-related) characteristics. Such efforts could enhance the parsing of heterogeneity, thereby advancing clinical practice and research. [ABSTRACT FROM AUTHOR]