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.

Findings on Age at Onset of Cancer in Diabetic and Non-diabetic Populations.

Background Diabetes mellitus and cancer are two associated chronic diseases. Despite being a widely researched topic, the underlying mechanisms of this association remain unclear. One of the poorly explored topics regarding diabetes and cancer is the relation between the age of cancer onset and diabetes mellitus status; therefore, this research exposes the difference in the age of cancer diagnosis in both groups. Methods We conducted a retrospective study by reviewing the clinical files on a secondary care hospital's database. Files from first-time consultations of patients over 18 diagnosed using a histopathological report were included. The present study aimed to determine whether there is a difference in age at the onset of cancer in diabetic and non-diabetic individuals. Moreover, we calculated the average BMI at the onset for both populations. Results Our study included 8,741 patients; 1,551 (17.8%) were diabetic, and 7,190 (82.2%) were non-diabetic. From 28 types of cancer, 27 showed a difference in the age at the onset of cancer when diabetic and non-diabetic subjects were compared. This difference is significant as it suggests a potential link between diabetes and cancer, which could have implications for early detection and prevention strategies. Out of the 27 types, 17 showed statistical significance with p-values ranging from 0.048 to <0.0001 considering a 95% CI. Among those, the most significant types of cancer were breast, cervical, lung, ovarian, rectal, thyroid, and sarcoma, reporting p-values <0.0001. The mean age at onset of cancer in diabetic and non-diabetic populations was 62.7 years (SD ± 3.9) and 55.3 years (SD ± 7.9), respectively, showing a difference of 7.4 years in both groups. The BMI was statistically significant in patients with breast (p = 0.006), endometrial (p = 0.007), head and neck (p=0.014), and thyroid (p = 0.022) cancer types. Conclusion  The data offer a critical view of the relationship between cancer and diabetes. Since virtually no one has produced a similar report, there is a broad field for researching the causal factors implicated in the pathway of diabetic and non-diabetic individuals who develop cancer. Research regarding metformin, diabetic neuropathy, and other possible causes must be addressed to determine whether they are involved in this process.

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.

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.

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.

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.

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.

Neighborhood-Level Predictors of Age-at-First-Diagnosis of Psychotic Disorders: A Swedish Register-Based Cohort Study.

The relationship between neighborhood-level factors and the incidence of psychotic disorders is well established. However, it is unclear whether neighborhood characteristics are also associated with age-at-first-diagnosis of these disorders. We used linked Swedish register data to identify a cohort of persons first diagnosed with an ICD-10 non-affective or affective psychotic disorder (F20-33) between 1997 and 2016. Using multilevel mixed-effect linear modelling, we investigated whether neighborhood deprivation and population density at birth were associated with age-at-first diagnosis of a psychotic disorder. Our final cohort included 13,440 individuals, with a median age-at-first-diagnosis of 21.8 years for women (interquartile range [IQR]: 19.0-25.5) and 22.9 years for men (IQR: 20.1-26.1; P < .0001). In an unadjusted model, we found no evidence of an association between neighborhood deprivation and age-at-first-diagnosis of psychotic disorder (P = .07). However, after multivariable adjustment, age-at-first-diagnosis increased by .13 years (95% CI: .05 to .21; P = .002) for a one standard deviation increase in neighborhood deprivation. This was equivalent to a later diagnosis of 47 days (95% CI: 18 to 77). We found no evidence of a different relationship for non-affective versus affective psychoses [LRT χ 2(1) = .14; P = .71]. Population density was not associated with age-at-first-diagnosis in unadjusted (P = .81) or adjusted (P = .85) models. Later age-at-first-diagnosis for individuals born in more deprived neighborhoods suggests structural barriers in accessing equitable psychiatric care.