late onset
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2022 ◽  
pp. 108705472110664
Lucy Riglin ◽  
Robyn E. Wootton ◽  
Lucy A. Livingston ◽  
Jessica Agnew-Blais ◽  
Louise Arseneault ◽  

Objective: We investigated whether “late-onset” ADHD that emerges in adolescence/adulthood is similar in risk factor profile to: (1) child-onset ADHD, but emerges later because of scaffolding/compensation from childhood resources; and (2) depression, because it typically onsets in adolescence/adulthood and shows symptom and genetic overlaps with ADHD. Methods: We examined associations between late-onset ADHD and ADHD risk factors, cognitive tasks, childhood resources and depression risk factors in a population-based cohort followed-up to age 25 years ( N=4224–9764). Results: Parent-rated late-onset ADHD was like child-onset persistent ADHD in associations with ADHD polygenic risk scores and cognitive task performance, although self-rated late-onset ADHD was not. Late-onset ADHD was associated with higher levels of childhood resources than child-onset ADHD and did not show strong evidence of association with depression risk factors. Conclusions: Late-onset ADHD shares characteristics with child-onset ADHD when parent-rated, but differences for self-reports require investigation. Childhood resources may delay the onset of ADHD.

2022 ◽  
pp. jrheum.210755
Karoline Walscheid ◽  
Kai Rothaus ◽  
Martina Niewerth ◽  
Jens Klotsche ◽  
Kirsten Minden ◽  

Objective Data on uveitis in juvenile psoriatic arthritis (JPsA), a category of juvenile idiopathic arthritis (JIA), are scarce. We describe prevalence and risk factors for JPsA-associated uveitis (JPsA-U). Methods Cross-sectional data from the National Pediatric Rheumatological Database (from 2002 to 2014) were used to characterize JPsA-U and assess risk factors for uveitis development. Results Uveitis developed in 6.6% of 1862 JPsA patients. JPsA-U patients were more frequently female (73.0 vs 62.9%, p=0.031), ANA positive (60.3 vs 37.0%, p<0.001), younger at JPsA onset (5.3 ± 4.1 vs 9.3 ± 4.4 years, p<0.001), and received DMARD (disease modifying antirheumatic drug) treatment significantly more frequently than JPsA patients without uveitis. On multivariable analysis of a subgroup of 655 patients, mean cJADAS during study documentation was significantly associated with uveitis development. Children with early onset of JPsA were significantly more frequently ANA positive (48.4% vs 35.7% for those younger than 5 years at JPsA onset versus those aged 5 years and older, p<0.001), less often affected by skin disease (55.3% vs 61.0%, p=0.032), but more frequently by uveitis (17.3% vs 3.8%, p<0.001), and required DMARD treatment more frequently (52.9% vs 43.8%, p<0.001). Conclusion The characteristics of JPsA patients developing uveitis are similar to those of patients with uveitis in other JIA categories, such as oligoarticular JIA. Especially those children with early onset of JPsA seem to be at a higher risk for ocular involvement. Our data support the notion of a major clinical difference between those patients with early versus late onset of JPsA.

2022 ◽  
Linda Zhang ◽  
Miguel Calero ◽  
Miguel Medina ◽  
Bryan Strange

The APOE ϵ4 allele is the primary genetic risk factor for late onset Alzheimer's disease (AD). A cardinal problem in determining APOE ϵ4's effect on cognition and brain structure in older individuals is dissociating prodromal changes — linked to increased AD risk — from potential phenotypic differences. To address this, we used cognitive and neuroimaging data from a large cohort of cognitively normal 69-86 year-olds with up to 8 yearly follow-ups to investigate cross-sectional and longitudinal differences between APOE ϵ3/ϵ3 homozygotes and ϵ3/ϵ4 heterozygotes. Although we found a significant age-by-genotype interaction in right hippocampal volume, once our analyses were conditionalised by future diagnosis to account for prodromal mild cognitive impairment (MCI) and AD, this effect was no longer observed. Likewise, longitudinally, rate of hippocampal atrophy was determined not by genotype, but by future diagnosis. Thus, we provide direct evidence in support of the prodromal hypothesis of APOE ϵ4 on brain structure.

2022 ◽  
Vol 12 ◽  
Tannaz Moeini Shad ◽  
Reza Yazdani ◽  
Parisa Amirifar ◽  
Samaneh Delavari ◽  
Marzieh Heidarzadeh Arani ◽  

Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.

Kaustubh Mohite ◽  
Karthik Vijay Nair ◽  
Anilkumar Sapare ◽  
Venkatraman Bhat ◽  
Anju Shukla ◽  

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

2022 ◽  
Dmitry V Zaretsky ◽  
Maria V Zaretskaia ◽  
Yaroslav I Molkov

Amyloid plaques are the main signature of Alzheimer's disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.

2022 ◽  
A. Kemal Topaloglu ◽  
Enver Simsek ◽  
Matthew A. Kocher ◽  
Jamala Mammadova ◽  
Ece Bober ◽  

Abstract Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate (ARC) nucleus of the hypothalamus constitute the GnRH (Gonadotrophin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix (bHLH) family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism (IHH) cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2’s critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

2022 ◽  
Micaela E Consens ◽  
Yuxiao Chen ◽  
Vilas Menon ◽  
Yanling Wang ◽  
Julie A Schneider ◽  

Background: Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, it remains unclear which neuronal subtypes are most vulnerable to degeneration and contribute most to cognitive decline. Methods: We analyzed postmortem bulk brain RNA-sequencing (RNAseq) data collected from three studies of aging and AD comprising six neocortical regions (704 individuals; 1037 samples). We estimated relative cell type proportions from each brain sample using neuronal subclass-specific marker genes derived from ultra-high depth single-nucleus RNAseq data (snRNAseq). We associated cell type proportions with AD across all samples using mixed-effects mega-analyses. Bulk tissue analyses were complemented by analyses of three AD snRNAseq datasets using the same cell type definitions and diagnostic criteria (51 individuals). Lastly, we identified cell subtype associations with specific neuropathologies, cognitive decline, and residual cognition. Results: In our mega-analyses, we identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β=-0.48, pbonf=8.98x10-9) and intra-telencephalic (IT) excitatory neurons (β=-0.45, pbonf =4.32x10-7). snRNAseq-based cell type proportion analyses especially supported the association of SST neurons. Analyses of cell type proportions with specific AD-related phenotypes in ROS/MAP consistently implicated fewer SST neurons with greater brain-wide postmortem tau and beta amyloid (β=-0.155, pFDR=3.1x10-4) deposition, as well as more severe cognitive decline prior to death (β=0.309, pFDR=3.9x10-6). Greater IT neuron proportions were associated strongly with improved cognition (β=0.173, pFDR=8.3x10-5) and residual cognition (β=0.175, pFDR=1.2x10-5), but not canonical AD neuropathology. Conclusions: Proportionally fewer SST and IT neurons were significantly associated with AD diagnosis across multiple studies and cortical regions. These findings support seminal work implicating somatostatin and pyramidal neurons in the pathogenesis of AD and improves our current understanding of neuronal vulnerability in AD.

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