Age At Onset Research Articles

Clinicodemographic and Genetic Modifier Correlation in an X-Linked Dystonia-Parkinsonism Cohort from Mindanao.

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.

Genetic architecture of a single cohort of 230 Indian Parkinson's Disease patients

IntroductionIndian Parkinson's Disease (PD) patients are severely underrepresented in terms of genetic studies and little is known about the frequency of variants and their impact on motor and nonmotor symptoms (NMS). MethodsThis retrospective cross-sectional study was conducted in PD patients undergoing treatment at a tertiary care hospital from India. Patients were advised genetic testing if they had (i) age at onset (AAO) of motor symptoms at or before 50 years (EOPD), (ii) positive family history of PD, parkinsonism or dystonia. All patients underwent whole exome sequencing and potentially pathogenic variants were identified. ResultsClinical and genetic data were available for 230 (163 males, 70.4 %) patients. Thirty-five pathogenic and likely pathogenic variants in various PD genes were identified in 47 patients resulting in a yield of 20.4 %. In the remaining, 82 patients had either variants of uncertain significance or had variants in genes not associated with parkinsonism and 101 patients did not have any non-benign variants. Patients with genetically mediated PD had a lower AAO and statistically greater frequency of dystonia (36.2 %), postural instability (29.8 %) and mood disorder (29.8 %) and a higher Hoehn and Yahr score (2.9). Among the 47 patients, 11 patients had PARK-PRKN, six patients had PARK-PLA2G6, and 22 patients had PARK-GBA1. ConclusionAround one-fifth of early-onset PD can have an underlying monogenetic cause. PARK-GBA1, PARK-PRKN and PARK-PLA2G6 are the commoner causes of genetically mediated PD in India. Patients with genetic cause had an earlier age at onset, and more frequent dystonia, postural instability and dyskinesia.

Association between exposure to antidepressants and stimulants and age at onset of mania or psychosis: A retrospective population-based cohort study

This study investigated the impact of prior antidepressant and stimulant exposure on the age at onset (AAO) of first episode mania (FEM) or psychosis (FEP). Patients with FEP and FEM born after 1985 in Olmsted County, Minnesota, were identified using the Rochester Epidemiology Project. Duration and peak dose of antidepressant and stimulant exposure were quantified by review of the electronic health record. Peak doses were converted to defined daily dose (DDD), and cumulative exposure was calculated as DDD multiplied by treatment duration. Linear models were used to assess relationships between AAO with any exposures, and cumulative antidepressant and stimulant exposures. A total of 190 FEM/FEP patients (mean AAO=20.8 ± 3.7 years) were included. There was no significant difference in AAO with vs. without exposure to antidepressants or stimulants. Cumulative antidepressant exposure correlated with a later AAO in overall sample (r = 0.28, p < 0.001), and in FEP (r = 0.33, p < 0.001). No significant correlation emerged between cumulative stimulant exposure and AAO. Multivariable modeling confirmed that cumulative antidepressant exposure (Estimate=2.42, 95 %CI=1.66–3.18, p < 0.001), but not cumulative stimulant exposure (Estimate=-0.04, 95 %CI=-1.10–1.02, p = 0.94), was associated with later AAO. Antidepressant and stimulant exposures were not associated with earlier AAO. However, cumulative antidepressant exposure was associated with later AAO. Limitations include retrospective design and relatively small sample size. Our findings may inform adolescent treatment recommendations when assessing risk for psychotropic-related adverse events. Further risk modeling investigations of antidepressants and stimulants with larger sample sizes are needed to explore the role of antidepressant and stimulant exposure in the trajectory leading to FEM/FEP.

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset.

Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke. Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10-5 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Causal associations of physical activity and leisure sedentary behaviors with age at onset of Huntington's disease: A mendelian randomization study

BackgroundHuntington's disease (HD) is a neurodegenerative disorder for which effective therapies are currently lacking. Studies suggest that increasing physical activity (PA) and reducing leisure sedentary behavior (LSB) mitigate the progression of HD, but their causal relationship with the age at onset (AAO) of HD remains uncertain. To investigate this, we conducted the Two-sample Mendelian Randomization (MR). MethodsExposure were retrieved from the UK BioBank's (UKB) Genome-Wide Association Study (GWAS). PA included accelerometer-based average PA, vigorous PA, self-reported moderate-to-vigorous PA (MVPA), and light do-it-yourself activity. LSB included television (TV) time, computer time, and driving time. Outcome came from the GWAS of the GEM-HD Consortium. We applied several MR methods such as inverse variance weighted (IVW), MR-Egger regression, weighted median (WM) for sensitivity analysis. ResultsIncreases in light PA (β = 8.53 years, 95 % CI = 10.64 to 44.09, P = 0.001) and accelerometer-based vigorous PA (β = 5.18, 95 % CI = 0.92 to 9.43, P = 0.017) delayed AAO of HD, while longer TV time was associated with earlier AAO of HD (β = −2.88 years, 95 % CI = −4.99 to −0.77, P = 0.007). However, other PA and LSB phenotypes did not significantly affect AAO of HD. ConclusionThe study revealed a unidirectional causality between PA, LSB and the AAO of HD. Increasing PA and reducing TV time delay HD onset. Therefore, we recommend increasing physical activity and reducing sedentary behavior to delay the occurrence of motor symptoms for premanifest HD individuals.

Caffeine Consumption and Interaction with ADORA2A, CYP1A2 and NOS1 Variants Do Not Influence Age at Onset of Machado-Joseph Disease.

The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.

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

The objective of this study was 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. We included data from 4367 patients with idiopathic PD, 159 patients with GBA1-PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO (β = − 1.07, p = 6 × 10–7) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p = 0.0001), 44% (p < 2 × 10–16), and 55% (p < 2 × 10–16), compared to no use. An additive effect of aspirin (β = 7.62, p = 9 × 10–7) and PGS (β = − 1.58, p = 0.0149) was found for AAO without an interaction (p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1-PD (p > 0.05). 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.

Adaptive and Innate Immunity Are Key Drivers of Age at Onset of Multiple Sclerosis.

Multiple sclerosis (MS) age at onset (AAO) is a clinical predictor of long-term disease outcomes, independent of disease duration. Little is known about the genetic and biological mechanisms underlying age of first symptoms. We conducted a genome-wide association study (GWAS) to investigate associations between individual genetic variation and the MS AAO phenotype. The study population was comprised participants with MS in 6 clinical trials: ADVANCE (N = 655; relapsing-remitting [RR] MS), ASCEND (N = 555; secondary-progressive [SP] MS), DECIDE (N = 1,017; RRMS), OPERA1 (N = 581; RRMS), OPERA2 (N = 577; RRMS), and ORATORIO (N = 529; primary-progressive [PP] MS). Altogether, 3,905 persons with MS of European ancestry were analyzed. GWAS were conducted for MS AAO in each trial using linear additive models controlling for sex and 10 principal components. Resultant summary statistics across the 6 trials were then meta-analyzed, for a total of 8.3 × 10-6 single nucleotide polymorphisms (SNPs) across all trials after quality control and filtering for heterogeneity. Gene-based tests of associations, pathway enrichment analyses, and Mendelian randomization analyses for select exposures were also performed. Four lead SNPs within 2 loci were identified (p < 5 × 10-8), including a) 3 SNPs in the major histocompatibility complex and their effects were independent of HLA-DRB1*15:01 and b) a LOC105375167 variant on chromosome 7. At the gene level, the top association was HLA-C (p = 1.2 × 10-7), which plays an important role in antiviral immunity. Functional annotation revealed the enrichment of pathways related to T-cell receptor signaling, autoimmunity, and the complement cascade. Mendelian randomization analyses suggested a link between both earlier age at puberty and shorter telomere length and earlier AAO, while there was no evidence for a role for either body mass index or vitamin D levels. Two genetic loci associated with MS AAO were identified, and functional annotation demonstrated an enrichment of genes involved in adaptive and complement immunity. There was also evidence supporting a link with age at puberty and telomere length. The findings suggest that AAO in MS is multifactorial, and the factors driving onset of symptoms overlap with those influencing MS risk.

Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease

The pathological huntingtin (HTT) trinucleotide repeat underlying Huntington disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated with altered AaO and progression, with many found in DNA mismatch repair (MMR)-associated genes. We examine whether lowering expression of these genes affects the rate of repeat expansion in human exvivo models using HD iPSCs and HD iPSC-derived striatal medium spiny neuron-enriched cultures. We have generated a stable CRISPR interference HD iPSC line in which we can specifically and efficiently lower gene expression from a donor carrying over 125 CAG repeats. Lowering expression of each member of the MMR complexes MutS (MSH2, MSH3, and MSH6), MutL (MLH1, PMS1, PMS2, and MLH3), and LIG1 resulted in characteristic MMR deficiencies. Reduced MSH2, MSH3, and MLH1 slowed repeat expansion to the largest degree, while lowering either PMS1, PMS2, or MLH3 slowed it to a lesser degree. These effects were recapitulated in iPSC-derived striatal cultures where MutL factor expression was lowered. CRISPRi-mediated lowering of key MMR factor expression to levels feasibly achievable by current therapeutic approaches was able to effectively slow the expansion of the HTT CAG tract. We highlight members of the MutL family as potential targets to slow pathogenic repeat expansion with the aim to delay onset and progression of HD and potentially other repeat expansion disorders exhibiting somatic instability.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

Risk factors associated with age at onset of Parkinson’s disease in the UK Biobank

Substantial evidence shown that the age at onset (AAO) of Parkinson’s disease (PD) is a major determinant of clinical heterogeneity. However, the mechanisms underlying heterogeneity in the AAO remain unclear. To investigate the risk factors with the AAO of PD, a total of 3156 patients with PD from the UK Biobank were included in this study. We evaluated the effects of polygenic risk scores (PRS), nongenetic risk factors, and their interaction on the AAO using Mann–Whitney U tests and regression analyses. We further identified the genes interacting with nongenetic risk factors for the AAO using genome-wide environment interaction studies. We newly found physical activity (P < 0.0001) was positively associated with AAO and excessive daytime sleepiness (P < 0.0001) was negatively associated with AAO, and reproduced the positive associations of smoking and non-steroidal anti-inflammatory drug intake and the negative association of family history with AAO. In the dose-dependent analyses, smoking duration (P = 1.95 × 10−6), coffee consumption (P = 0.0150), and tea consumption (P = 0.0008) were positively associated with AAO. Individuals with higher PRS had younger AAO (P = 3.91 × 10−5). In addition, we observed a significant interaction between the PRS and smoking for AAO (P = 0.0316). Specifically, several genes, including ANGPT1 (P = 7.17 × 10−7) and PLEKHA6 (P = 4.87 × 10−6), may influence the positive relationship between smoking and AAO. Our data suggests that genetic and nongenetic risk factors are associated with the AAO of PD and that there is an interaction between the two.

Multimodal analysis of disease onset in Alzheimer’s disease using Connectome, Molecular, and genetics data

Alzheimer’s disease (AD) and its related age at onset (AAO) are highly heterogeneous, due to the inherent complexity of the disease. They are affected by multiple factors, such as neuroimaging and genetic predisposition. Multimodal integration of various data types is necessary; however, it has been nontrivial due to the high dimensionality of each modality. We aimed to identify multimodal biomarkers of AAO in AD using an extended version of sparse canonical correlation analysis, in which we integrated two imaging modalities, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), and genetic data in the form of single-nucleotide polymorphisms (SNPs) obtained from the Alzheimer’s disease neuroimaging initiative database. These three modalities cover low-to-high-level complementary information and offer multiscale insights into the AAO. We identified multivariate markers of AAO in AD using fMRI, PET, and SNP. Furthermore, the markers identified were largely consistent with those reported in the existing literature. In particular, our serial mediation analysis suggests that genetic variants influence the AAO in AD by indirectly affecting brain connectivity by mediation of amyloid-beta protein accumulation, supporting a plausible path in existing research. Our approach provides comprehensive biomarkers related to AAO in AD and offers novel multimodal insights into AD.

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

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. 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. 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. 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.

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

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

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. 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. The mean AAO of hypertension was 42.7years. 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]. 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.

Diagnosis in an early‐onset dementia clinic in the period 2016‐2021 and impact of COVID‐19 pandemic

AbstractBackgroundThe diagnosis of early‐onset neurodegenerative dementias (&lt;65 years) can represent a challenge due to their lower frequency respect to late‐onset dementias and atypical forms of presentation. Cognitive impairment has emerged as a frequent complaint after COVID‐19 infection.MethodWe retrospectively reviewed (2016‐2021) the demographic and clinical data of the new referrals at our early onset dementia clinic (Hospital Clínic Barcelona). We used Fisher’s Exact test and ANOVA in Stata/IC 16.1 to analyze differences between patients visited in 2021, 2020 and the period 2016‐2019.ResultWe evaluated 296 patients in 2021, 104 in 2020 and 98 patients/year in 2016‐2019. In 2021, patients had an age at onset (AAO) of 50.1 years, lower than 2020 (53.4) and the period 2016‐2019 (53.0) (p&lt;0.05). The percentage of women in 2021 (69.6%) was higher than 2020 (57.7) and 2016‐2019 (56.0) (p&lt;0.05). Diagnostic delay was lower in 2021 (2.1 years) than 2020 (3.3) and 2016‐2019 (3.0) (p&lt;0.05). No differences were found in Minimental (MMSE) scores (Table 1).In the period 2016‐2021, the number of neurodegenerative diseases (ND) remained steady, the number of subjective cognitive decline (SCD) decreased and the number of non neurodegenerative causes (NNC) experienced a large increase (Table 1), representing 77.7% of visits in 2021.We did not find differences in the type of ND diagnosis in each period (Figure 1A). ND subgroups did not show differences in AAO, sex or MMSE. In 2021, NND presented lower AAO, higher percentage of women, lower diagnostic delay (Figure 1B) and higher MMSE scores than previous years. No differences were found in the SCD group.Cognitive impairment after Covid‐19 accounted for 16.7% of NND in 2020 (n = 8, AAO 50.6 (11.8), 62.5% female, MMSE 26.8(2.3)) and 66.6% of NND in 2021 (n = 153, AAO 49,0 (10.0), 80.1% female, MMSE 27.8 (2.6)).ConclusionIn 2021 we visited approximately three times more patients than in 2016‐2020, among which we observed an increase in NND, mainly patients with cognitive impairment after Covid‐19. On contrast, we found a similar number of ND diagnosis and reduction in SCD.

Plasma biomarkers as prognostic markers in Alzheimer’s disease: Influence of age at onset

AbstractBackgroundLittle is known about the influence of age at onset (AAO) on plasma biomarkers and their use as prognostic biomarkers in Alzheimer’s disease (AD).MethodWe selected patients with AD diagnosis with available neuropsychological testing (NPS) at time of diagnosis and two years later, and plasma biomarkers at baseline.NPS battery included Free and Cued Selective Reminding Test (FCSRT), Landscape test (visual memory), Boston Naming Test, Semantic Fluency, BDAE auditory comprehension, Constructional and Ideomotor Praxis, Visual Object and Space Perception (VOSP) Incomplete Letters and Number Location subtests, Trail Making Test (TMT) A and B, Phonemic Fluency, and Digit Span Forward and Backward. NPS scores were compared by AAO: early‐onset AD (EOAD; &lt;65 years) vs. late onset AD (LOAD; &gt;65y).We analyzed plasma biomarkers phosphorilated‐tau181 (p‐tau181), total tau (t‐tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin C‐terminal hydrolase L1 (UCHL‐1) using the Quanterix Simoa p‐tau181 Advantage V2 and Neurology 4‐Plex A assays. Group comparisons and linear regressions adjusted by years of education (YOE) were performed in Stata/IC 16.1.ResultForty‐two participants were included, 23 LOAD and 19 EOAD. Plasma p‐tau181 and GFAP levels were higher in LOAD (Table 1). We did not find differences between LOAD and EOAD in NPS tests at baseline or +2 years (Table 2).Plasma ptau‐181 was associated with progression in MMSE globally, VOSP‐Incomplete letters globally and in EOAD. Plasma NfL were associated to Boston Naming test globally and in EOAD, Semantic fluency test globally, VOSP‐incomplete letters in EOAD, and Free and Total Learning of FCSRT in LOAD. Plasma GFAP was associated to MMSE globally and in EOAD, Free learning of FCSRT in LOAD and VOSP‐Incomplete letters and number location globally. Plasma UCHL‐1 was associated to Semantic fluency test in LOAD (Table 3). Praxis and attention and executive function tests loss were not associated to plasma biomarkers.ConclusionPlasma p‐tau18, NfL, GFAP and UCHL‐1 were associated to pogression in memory, language and visual tests. They were predominantly associated to memory loss in LOAD and language and visual function loss in EOAD. Results need to be interpreted cautiously due to small sample size.

Catalan Early Onset Dementia Network 2021 Report

AbstractBackgroundThe Catalan Early Onset Neurodegenerative Dementia Network is a multicenter project launched in 2020 with the aim of understanding the epidemiology and clinical care of people with early‐onset neurodegenerative dementia and their caregivers.MethodsNeurologists and geriatricians visiting patients with cognitive impairment in Catalonia were invited to prospectively collect demographical and clinical data from patients with age at onset (AAO) less than 65 years visited during the year 2021.ResultWe registered information of 1221 subjects from 14 centers. Mean age was 56,2 years (SD 8.7), 64% were woman. Mean age at symptom onset was 53,9 years (SD 9.1). The most frequent cognitive symptoms at onset were memory impairment (72,9%) and dysexecutive difficulties (21,8%). Mean Mini Mental State Examination (MMSE) score was 26,7 (range 7‐30). Initial clinical diagnose was a non‐neurodegenerative disorder in 81,4% of cases and a neurodegenerative disorder in 17,81%. Genetic counseling accounted for 0,8% of visits. The suspected non‐neurodegenerative and neurodegenerative patients were studied with a neuropsychological test (85,5% vs 86,7%, respectively), magnetic resonance imaging (MRI) (39,9% vs 55,6%), computerized tomography (CT) scan (33,2% vs 34,4%), fluorodeoxyglucose positron emission tomography (FDG‐PET) (6,8% vs 39,0%), amyloid‐PET (3,9% vs 34,4%) and lumbar puncture (7,1%, vs 44,8%). 16,6% of participants had a final diagnose of a neurodegenerative cognitive disorder (10,9% Alzheimer’s disease, 2,3% frontotemporal lobular degeneration, 2,1% MCI of suspected neurodegenerative etiology, 0,58% other neurodegenerative dementias); 83,4% were diagnosed with a non‐degenerative disorder (28,4% subjective cognitive decline (SCD), 25,0% mild cognitive impairment of non‐neurodegenerative etiology, 19,8% cognitive impairment after Covid‐19, 10,2% other dementias). Diagnostic delay was higher for neurodegenerative disorders (17 months: median 12 months (interquartile range (IQR) 19) between AAO and first visit +5 months (IQR 8) between first visit and diagnose) than non‐degenerative disorders (12 months: 9 months (IQR 19,6) + 3 months (IQR 7) respectively).ConclusionOf 1221 patients under 65 years old visited in cognitive disorders units, only 16,6% had a final diagnose of neurodegenerative cognitive disorder. More than a quarter of subjects were diagnosed as SCD and a fifth as cognitive impairment after Covid‐19. In 2021, diagnosis delay was higher in neurodegenerative disorders (median 17 months).