Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.

The differential effect of emotional loneliness and social loneliness on late-life depression.

OBJECTIVES: Loneliness adversely affects the prognosis, treatment, and remission of late-life depression. However, no clear distinction of the cause or definition of loneliness was imposed in existing literatures, resulting in mixed findings of the effect of loneliness to late-life depression (LLD). The aim of this study was to explore the association between different facets of loneliness and risk factors of LLD, specifically, if age of onset in LLD possess a different clinical profile in the clinical group. METHOD: 101 Chinese patients with depression and 81 healthy elderlies aged 60 or above were assessed on loneliness level, depressive symptoms, cognitive symptoms, physical condition, and motivational level. Univariate analyses were applied in exploring group differences in clinical profiles and multivariate regression to determine variables associated with subsets of loneliness. RESULTS: LLD patients reported more emotional loneliness but not social loneliness than healthy controls (p < 0.001). Emotional loneliness was the only significant predictor of suicidal ideation, particularly on patients with early-onset depression, explaining 26.8% of the effect (p < 0.001). Finally, the effect of medical comorbidity on depression severity was mediated by emotional loneliness(Z = 2.159, p = 0.031). CONCLUSION: The current research highlights more attention should be placed on the age of onset and medical comorbidity in elderlies with depression. The distinction between emotional loneliness and social loneliness is better understood in the Asian population, reinforcing the importance of taking cultural influence into account when understanding psychological constructs.

Gene-gene interaction analysis for age at onset of bipolar disorder in a Korean population.

BACKGROUND: Multiple genes might interact to determine the age at onset of bipolar disorder. We investigated gene-gene interactions related to age at onset of bipolar disorder in the Korean population, using genome-wide association study (GWAS) data. METHODS: The study population consisted of 303 patients with bipolar disorder. First, the top 1000 significant single-nucleotide polymorphisms (SNPs) associated with age at onset of bipolar disorder were selected through single SNP analysis by simple linear regression. Subsequently, the QMDR method was used to find gene-gene interactions. RESULTS: The best 10 SNPs from simple regression were located in chromosome 1, 2, 3, 10, 11, 14, 19, and 21. Only five SNPs were found in several genes, such as FOXN3, KIAA1217, OPCML, CAMSAP2, and PTPRS. On QMDR analyses, five pairs of SNPs showed significant interactions with a CVC exceeding 1/5 in a two-locus model. The best interaction was found for the pair of rs60830549 and rs12952733 (CVC = 1/5, P < 1E-07). In three-locus models, four combinations of SNPs showed significant associations with age at onset, with a CVC of >1/5. The best three-locus combination was rs60830549, rs12952733, and rs12952733 (CVC = 2/5, P < 1E-6). The SNPs showing significant interactions were located in the KIAA1217, RBFOX3, SDK2, CYP19A1, NTM, SMYD3, and RBFOX1 genes. CONCLUSIONS: Our analysis confirmed genetic interactions influencing the age of onset for bipolar disorder and identified several potential candidate genes. Further exploration of the functions of these promising genes, which may have multiple roles within the neuronal network, is necessary.

Trends in the characteristics and outcomes of older patients with non-traumatic spinal cord injury treated in inpatient rehabilitation facilities: 2013-2018.

OBJECTIVE: To describe the characteristics and outcomes of older (≥ 65 years of age) patients with a non-traumatic spinal cord injury (NTSCI) treated in inpatient rehabilitation facilities (IRFs) between 2013 and 2018. DESIGN: Observational study. SETTING: IRFs in the United States. PARTICIPANTS: 93,631 IRF Medicare stays for patients with NTSCI. INTERVENTIONS: Not Applicable. MAIN OUTCOME MEASURES: Length of stay, self-care and mobility function, discharge destination. RESULTS: Between 2013 and 2018, the number of older (≥ 65 years of age) Medicare patients with a NTSCI treated in IRFs increased about 22.1 percent, from 14,149 to 17,275. In addition to the increase, patients' sociodemographic characteristics shifted to have a slightly higher percentage of patients aged 65-74 years, a slightly higher percentage of males, and slightly fewer patients who identified as Hispanic. There was also a trend of more patients in the higher acuity case-mix groups and comorbidities tiers, but the median length of stay remained 12 days across all years. The percent of patients discharged home or to a community-based setting varied from 73.7 to 75.2 without a trend, although discharge self-care and mobility function increased slightly across the years. CONCLUSIONS: Between 2013 and 2018, the number of Medicare patients with NTSCI treated in IRFs increased by more than 22 percent. While patient complexity increased, the median length of stay remained 12 days across the years. Discharge self-care and mobility function increased slightly, and the percent of patients discharged home ranged from 73.7 to 75.2 across the years.

Whole-exome sequencing in a Chinese sample provides preliminary evidence for the link between rare/low-frequency immune-related variants and early-onset schizophrenia.

Rare and low-frequency variants contribute to schizophrenia (SCZ), and may influence its age-at-onset (AAO). We examined the association of rare or low-frequency deleterious coding variants in Chinese patients with SCZ. We collected DNA samples in 197 patients with SCZ spectrum disorder and 82 healthy controls (HC), and performed exome sequencing. The AAO variable was ascertained in the majority of SCZ participants for identify the early-onset (EOS, AAO<=18) and adult-onset (AOS, AAO>18) subgroups. We examined the overall association of rare/low-frequency, damaging variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels using Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was conducted. Resampling was used to obtain empirical p-values and to control for family-wise error rate (FWER). In binary-trait association tests, we identified 5 potential candidate risk genes and 10 gene ontology biological processes (GOBP) terms, among which PADI2 reached FWER-adjusted significance. In quantitative rare-variant association tests, we found marginally significant correlations of AAO with alterations in 4 candidate risk genes, and 5 GOBP pathways. Together, the biological and functional profiles of these genes and gene sets supported the involvement of perturbations of neural systems in SCZ, and altered immune functions in EOS.

Clinical and Genetic Characteristics Associated With Survival Outcome in Late-Onset Huntington's Disease in South Korea.

BACKGROUND AND PURPOSE: The onset of Huntington's disease (HD) usually occurs before the age of 50 years, and the median survival time from onset is 15 years. We investigated survival in patients with late-onset HD (LoHD) (age at onset ≥60 years) and the associations of the number of mutant CAG repeats and age at onset (AAO) with survival in patients with HD. METHODS: Patients with genetically confirmed HD at six referral centers in South Korea between 2000 and 2020 were analyzed retrospectively. Baseline demographic, clinical, and genetic characteristics and the survival status as at December 2020 were collected. RESULTS: Eighty-seven patients were included, comprising 26 with LoHD (AAO=68.77±5.91 years, mean±standard deviation; 40.54±1.53 mutant CAG repeats) and 61 with common-onset HD (CoHD) (AAO=44.12±8.61 years, 44.72±4.27 mutant CAG repeats). The ages at death were 77.78±7.46 and 53.72±10.86 years in patients with LoHD and CoHD, respectively (p<0.001). The estimated survival time was 15.21±2.49 years for all HD patients, and 10.74±1.95 and 16.15±2.82 years in patients with LoHD and CoHD, respectively. More mutant CAG repeats and higher AAO were associated with shorter survival (hazard ratio [HR]=1.05, 95% confidence interval [CI]=1.01-1.09, p=0.019; and HR=1.17, 95% CI=1.03-1.31, p=0.013; respectively) for all HD patients. The LoHD group showed no significant factors associated with survival after disease onset, whereas the number of mutant CAG repeats had a significant effect (HR=1.12, 95% CI=1.01-1.23, p=0.034) in the CoHD group. CONCLUSIONS: Survival after disease onset was shorter in patients with LoHD than in those with CoHD. More mutant CAG repeats and higher AAO were associated with shorter survival in patients with HD.

Time to Diagnosis and Its Predictors in Syndromes Associated With Frontotemporal Lobar Degeneration.

OBJECTIVES: Frontotemporal Lobar Degeneration (FTLD) causes a heterogeneous group of neurodegenerative disorders with a wide range of clinical features. This might delay time to diagnosis. The aim of the present study is to establish time to diagnosis and its predictors in patients with FTLD-associated syndromes. DESIGN: Retrospective study. SETTING: Tertiary referral center. PARTICIPANTS: A total of 1029 patients with FTLD-associated syndromes (age: 68 [61-73] years, females: 46%) from 1999 to 2023 were included in the present study. MEASUREMENTS: Time to diagnosis was operationalized as the time between symptom onset and the diagnosis of a FTLD-associated syndrome. The associations between time to diagnosis and possible predictors (demographic and clinical variables) were investigated through univariate and multivariate linear models. RESULTS: Median time to diagnosis was 2 [1-3] years. We observed that younger age at onset (ß = -0.03, p <0.001), having worked as a professional rather than as a blue (ß = 0.52, p = 0.024) or a white (ß = 0.46, p = 0.050) collar, and having progressive supranuclear palsy (p <0.05) or the semantic variant of primary progressive aphasia (p <0.05) phenotypes were significantly associated with increased time to diagnosis. No significant changes of time to diagnosis have been observed over 20 years. CONCLUSIONS: The identification of predictors of time to diagnosis might improve current diagnostic algorithms, resulting in a timely initiation of symptomatic treatments, early involvement in clinical trials, and more adequate public health policies for patients and their families.

Early-onset obsessive-compulsive disorder: Sociodemographic and clinical characterization of a large outpatient cohort.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a prevalent and disabling condition characterized by a wide variety of phenotypic expressions. Several studies have reinforced the hypothesis of OCD heterogeneity by proposing subtypes based on predominant symptomatology, course, and comorbidities. Early-onset OCD (EO) could be considered a neurodevelopmental subtype of OCD, with evidence of distinct neurocircuits supporting disease progression. To deepen the heterogeneous nature of the disorder, we analyzed sociodemographic and clinical differences between the EO and late-onset (LO) subtypes in a large outpatient cohort. METHODS: Two hundred and eighty-four patients diagnosed with OCD were consecutively recruited from the OCD Tertiary Clinic at Luigi Sacco University Hospital in Milan. Sociodemographic and clinical variables were analyzed for the entire sample and compared between the two subgroups (EO, age <18 years [n = 117,41.2 %]; LO: late-onset, age ≥18 years [n = 167, 58.8 %]). RESULTS: The EO group showed a higher frequency of male gender (65 % vs 42.5 %, p < .001), and a higher prevalence of Tic and Tourette disorders (9.4 % vs 0 %, p < .001) compared to the LO group. Additionally, in the EO subgroup, a longer duration of untreated illness was observed (9.01 ± 9.88 vs 4.81 ± 7.12; p < .001), along with a lower presence of insight (13.8 % vs. 7.5 %, p < .05). CONCLUSIONS: The early-onset OCD subtype highlights a more severe clinical profile compared to the LO group. Exploring distinct manifestations and developmental trajectories of OCD can contribute to a better definition of homogeneous subtypes, useful for defining targeted therapeutic strategies for treatment.

Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson's disease.

We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and L-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and L-serine, as well as the other glutamate N-methyl-D-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine and other NMDAR-related amino acids between PD and HC. However, we found that D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of D-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of D-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum D-serine and D-/Total serine may represent a valuable biochemical signature of PD.

Comparing the effects of GBA variants and onset age on clinical features and progression in Parkinson's disease.

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.

Age at cardiovascular disease onset, dementia risk, and the role of lifestyle factors.

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.

Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.

Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.

Early-onset alcohol, tobacco, and illicit drug use with age at onset of hypertension: a survival analysis.

PURPOSE: To examine the associations of age when first substance use and early-onset substance use before age 18 with age at onset (AAO) of hypertension. METHODS: This study included 19,270 individuals with AAO of hypertension from the 2015-2019 National Survey on Drug Use and Health. Age when first use of 10 substance use variables included alcohol, daily cigarettes, cigars, smokeless tobacco, marijuana, cocaine, hallucinogens, lysergic acid diethylamide (LSD), inhalants, and methamphetamine use. The outcome was AAO of hypertension and variable cluster analysis was used to classify the exposures and outcome. Substance use status was classified into three categories: early-onset substance use (first used substance before age 18), late-onset substance use (first used substance after age 18), and never used. RESULTS: The mean AAO of hypertension was 42.7 years. Age when first use of 10 substance use variables had significant correlations with AAO of hypertension (all p values < 0.001). Individuals with early-onset alcohol, cigars, smokeless tobacco, marijuana, hallucinogens, inhalants, cocaine, LSD, and methamphetamine use revealed significantly earlier onset of hypertension than those never used. Compared with never used substances, the Cox regression model showed that early-onset alcohol, smokeless tobacco, marijuana, inhalants, and methamphetamine use had an increased risk of AAO of hypertension [hazard ratio (HR) (95%CI) = 1.22 (1.13, 1.31), 1.36 (1.24, 1.49), 1.85 (1.75, 1.95), 1.41 (1.30, 1.52), and 1.27 (1.07,1.50), respectively]. CONCLUSION: These findings suggest that intervention strategies or programs focusing on preventing early-onset substance use before age 18 may delay the onset of adult hypertension.

Pediatric Type 1 Diabetes: Is Age at Onset a Determining Factor in Advanced Hybrid Closed-Loop Insulin Therapy?

BACKGROUND: The integration of continuous glucose monitoring systems with insulin infusion pumps has shown improved glycemic control, with improvements in hyperglycemia, hypoglycemia, Hb1Ac, and greater autonomy in daily life. These have been most studied in adults and there are currently not many articles published in the pediatric population that establish their correlation with age of debut. METHODS: Prospective, single-study. A total of 28 patients (mean age 12 ± 2.43 years, 57% male, duration of diabetes 7.84 ± 2.46 years) were included and divided into two groups according to age at T1D onset (≤4 years and >4 years). Follow-up for 3 months, with glucometric variables extracted at different cut-off points after the start of the closed-loop (baseline, 1 month, 3 months). RESULTS: Significant improvement was evidenced at 1 month and 3 months after closed-loop system implantation, with better glycemic control in the older age group at baseline at TIR (74.06% ± 6.37% vs. 80.33% ± 7.49% at 1 month, p < 0.003; 71.87% ± 6.58% vs. 78.75% ± 5.94% at 3 months, p < 0.009), TAR1 (18.25% ± 4.54% vs. 14.33% ± 5.74% at 1 month, p < 0.006; 19.87% ± 5.15% vs. 14.67% ± 4. 36% at 3 months, p < 0.009) and TAR2 (4.75% ± 2.67% vs. 2.75% ± 1.96% at 1 month, p = 0.0307; 5.40% ± 2.85% vs. 3% ± 2.45% at 3 months, p < 0.027). CONCLUSIONS: the use of automated systems such as the MiniMedTM780G system brings glucometric results closer to those recommended by consensus, especially in age at T1D onset >4 years. However, the management in pediatrics continues to be a challenge even after the implementation of these systems, especially in terms of hyperglycemia and glycemic variability.

Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. METHODS: To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant. RESULTS: The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO. CONCLUSIONS: Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.

Prevalence of early and late onset of chronic diseases and multimorbidity and its association with physical, mental and functional health among older Indian adults.

BACKGROUND: Identifying people with early and late onset of chronic conditions might help target the subpopulations that are more vulnerable to negative mental, physical and functional health outcomes. The current study aimed to examine the association of early and late onset of chronic single and multiple morbidities with self-perceived physical and mental health, functional limitations and physical inactivity among older Indian adults. METHODS: Cross-sectional study was conducted using data from the Longitudinal Ageing Study in India (LASI) Wave 1 (2017-2018). The total sample size for the present study was 31,386 older adults age 60 years or older. Multivariable binary logistic regression analysis was used to establish the association between the outcomes (poor perceived physical/mental health, functional difficulty and physical inactivity) and explanatory variables (early [ = < 50 years of age] and late [> 50 years]) onset of chronic illnesses such as hypertension, diabetes, heart attack, heart disease, stroke, cancer, lung disease, arthritis, osteoporosis and psychiatric disease). RESULTS: Overall, 24.21% of the sample population had poor self-perceived physical health, whereas 8.67% of participants had poor self-perceived mental health. The prevalence of difficulty in ADL, difficulty in IADL, and physical inactivity was 23.77%, 48.36%, and 68.9%, respectively. Odds of poor perceived mental health were higher for the respondents with early as well as late onset of hypertension, stroke, and arthritis; while individuals with late onset of diabetes, and heart disease had higher odds of poor perceived mental health than those without chronic disease. Individuals with early onset of single morbidity were more likely to report ADL difficulty (adjusted odds ratio [AOR]: 1.33, confidence interval [CI]: 1.06-1.67); while those with late onset of single (AOR: 1.34, CI: 1.17-1.53) and multimorbidity (AOR: 1.91, CI: 1.63-2.24) were more likely to report ADL difficulty compared with individuals without morbidity. Individuals with early as well as late-onset of multimorbidity had more than two times higher odds of reporting poor physical health, poor mental health and IADL difficulty compared with individuals without chronic disease. CONCLUSIONS: The present study revealed that early and/or late onset of chronic single and/or multiple morbidities significantly predicted poor self-perceived physical and mental health, functional limitations and physical inactivity among older Indian adults. The findings further suggest that late onset of chronic diseases such as cancer and stroke and multi-morbidity had stronger associations with physical inactivity that may help identify high risk groups for screening and support.

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson's disease.

Objective: To investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. Methods: We included data from 4375 patients with idiopathic PD, 167 patients with GBA1-PD, and 3091 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The PGS was calculated based on a previously proposed composition of 1805 variants. The association between PGS and lifestyle factors (i.e., coffee, tobacco, and aspirin) on AAO was assessed with linear and Cox proportional hazards models. Results: The PGS showed a negative association with AAO (ß=-1.07, p=6×10-7). The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p=0.0001), 45% (p<2×10-16), and 55% (p<2×10-16), respectively, compared to no use. An additive effect of aspirin (ß=7.61, p=8×10-7) and PGS (ß=-1.63, p=0.0112) was found for AAO without an interaction (p=0.9789) in the linear regressions, and similar effects were seen for tobacco. Aspirin is shown to be a better predictor of AAO (R2=0.1740) compared to coffee and tobacco use (R2=0.0243, R2=0.0295) or the PGS (R2=0.0141). In contrast, no association between aspirin and AAO was found in GBA1-PD (p>0.05). Interpretation: In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect. External validation of our findings is needed.

Genetic insights into the age-specific biological mechanisms governing human ovarian aging.

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data.

Differences in the prevalence and clinical correlates of comorbid suicide attempts in patients with early- and late-onset major depressive disorder.

Objective: There are many studies on differences in the onset age of major depressive disorder (MDD) patients. However, study on differences in clinical correlates of suicide attempts between early- and late-onset MDD patients is limited. The aim of this study was to investigate the differences in the prevalence and clinical correlates of suicide attempts in patients with early- and late-onset MDD in China. Methods: A total of 1718 adult outpatients with MDD were recruited. Demographic and clinical data were collected. The 17-item Hamilton Rating Scale for Depression (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), Positive and Negative Syndrome Scale (PANSS) positive subscale, and Clinical Global Impression-Severity (CGI-S) Scales were used to assess their depressive, anxiety, psychotic symptoms, and the severity of the clinical symptoms, respectively. Results: The prevalence of suicide attempts was higher in late-onset MDD patients (291/1369, 21.3%) than in early-onset MDD patients (55/349, 15.8%) (p = 0.023). However after Bonferroni correction no significant difference was found in the prevalence of suicide attempts in late-onset and late-onset MDD patients (p > 0.05). In both early- and late-onset groups, univariate analysis showed that the following characteristics were significantly associated with suicide attempts: HAMA, HAMD and PANSS positive subscale scores, thyroid stimulating hormone (TSH) levels, blood glucose levels, systolic blood pressure (SBP), and diastolic blood pressure (DBP). In both the early- and late-onset groups, the prevalence rates of severe anxiety disorder and psychotic symptoms were significantly higher in the suicide attempt group than in the non-suicide attempt group. In regression analysis, disease duration, TSH levels and HAMA score were independently associated with suicide attempts in the early-onset group, while TSH levels, HAMA and HAMD score were independently associated with suicide attempts in the late-onset group. Conclusion: This study suggests that suicide attempts are not frequent in early-onset outpatients with MDD compared with late-onset, and some clinical correlates are associated with suicide attempt in early- and late-onset MDD.

Early-onset inherited dystonias versus late-onset idiopathic dystonias: Same or different biological mechanisms?

Dystonia syndromes encompass a heterogeneous group of movement disorders which might be differentiated by several clinical-historical features. Among the latter, age-at-onset is probably the most important in predicting the likelihood both for the symptoms to spread from focal to generalized and for a genetic cause to be found. Accordingly, dystonia syndromes are generally stratified into early-onset and late-onset forms, the former having a greater likelihood of being monogenic disorders and the latter to be possibly multifactorial diseases, despite being currently labeled as idiopathic. Nonetheless, there are several similarities between these two groups of dystonia, including shared pathophysiological and biological mechanisms. Moreover, there is also initial evidence of age-related modifiers of early-onset dystonia syndromes and of critical periods of vulnerability of the sensorimotor network, during which a combination of genetic and non-genetic insults is more likely to produce symptoms. Based on these lines of evidence, we reappraise the double-hit hypothesis of dystonia, which would accommodate both similarities and differences between early-onset and late-onset dystonia in a single framework.