CAG Repeat Length Research Articles

Brain structural abnormalities in the preclinical stage of Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3): evaluation by MRI morphometry, diffusion tensor imaging and neurite orientation dispersion and density imaging.

To investigate whether neurite orientation dispersion and density imaging (NODDI) could provide the added value for detecting brain microstructural alterations in the preclinical stage of Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) compared with MRI morphometry and diffusion tensor imaging (DTI). Twenty preclinical MJD/SCA3 patients and 21 healthy controls were enrolled. Three b values DWI and 3D T1-weighted images were acquired at 3.0T. Tract-based spatial statistics (TBSS) approach was used to investigate the white matter (WM) alterations in the DTI metrics and NODDI metrics. Gray matter-based spatial statistics (GBSS) approach was used to investigate the grey matter (GM) alterations in the NODDI metrics. Voxel-based morphometry (VBM) approach was performed on the 3D T1-weighted images. The relationship between the cytosine-adenine-guanine (CAG) repeat length and brain microstructural alterations of preclinical MJD/SCA3 was identified. Compared with healthy controls, the preclinical MJD/SCA3 patients showed decreased FA and NDI as well as increased MD, AD, and RD in the WM of cerebellum and brainstem (corrected P < 0.05), and decreased NDI in the GM of cerebellar vermis (corrected P < 0.05). The CAG repeat length in preclinical MJD/SCA3 patients was negatively correlated with the reduced FA and NDI of the infratentorial WM and the reduced NDI of the cerebellum, and positively with the increased MD and RD of the infratentorial WM. NOODI can provide novel quantitative microstructural changes in MJD/SCA3 carriers, expanding our understanding of the gray and white matter (axons and dendrites) degeneration in this frequent ataxia syndrome.

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Size Matters: The CAG Repeat Length of the Androgen Receptor Gene, Testosterone, and Male Adolescent Depression Severity.

There is a distinct increase in the prevalence of depression with the onset of puberty. The role of peripubertal testosterone levels in boys in this context is insufficiently understood and may be modulated by a functional polymorphism of the androgen receptor gene (AR), a variable number of CAG repeats. Moreover, there is preliminary evidence that the relationship between testosterone, CAG repeat length, and the severity of depressive symptoms may differ between subclinical and overt depression, but this has neither been studied in a clinical sample of adolescents with depression nor compared between subclinical and overt depression in an adequately powered study. To investigate the relationship between free testosterone, CAG repeat length of the AR, depression status (subclinical vs. overt), and the severity of depressive symptoms, 118 boys treated as in- or daycare patients at a single psychiatric hospital were studied. Of these, 73 boys had at least mild depressive symptoms according to the Beck Depression Inventory-II (BDI-II > 13). Higher-order moderation analysis in the multiple regression framework revealed a constant relationship between free testosterone and depression severity irrespective of the number of CAG repeats in adolescents with a BDI-II score ≤ 13. In adolescents with a BDI-II score > 13, however, there was a significant negative relationship between free testosterone and BDI-II score in patients with <19 CAG repeats and a significant positive relationship regarding free testosterone and BDI-II score in those with more than 28 CAG repeats, even when considering important covariates. These results suggest that the effects of testosterone on mood in male adolescents with depression depend on the genetic make-up of the AR as well as on depression status. This complex relationship should be considered by future studies addressing mental health issues against an endocrine background and may, moreover, contribute to tailored treatment concepts in psychiatric medicine, especially in adults.

Juvenile-Onset Huntington Disease Pathophysiology and Neurodevelopment: A Review.

ABSTRACTHuntington disease is an autosomal dominant inherited brain disorder that typically becomes manifest in adulthood. Juvenile‐onset Huntington disease refers to approximately 5% of patients with symptom onset before the age of 21 years. The causal factor is a pathologically expanded CAG repeat in the Huntingtin gene. Age at onset is inversely correlated with CAG repeat length. Juvenile‐onset patients have distinct symptoms and signs with more severe pathology of involved brain structures in comparison with disease onset in adulthood. The aim of this review is to compare clinical and pathological features in juvenile‐ and adult‐onset Huntington disease and to explore which processes potentially contribute to the observed differences. A specific focus is placed on molecular mechanisms of mutant huntingtin in early neurodevelopment and the interaction of a neurodegenerative disease and postnatal brain maturation. The importance of a better understanding of pathophysiological differences between juvenile‐ and adult‐onset Huntington disease lies in development and implementation of new therapeutic strategies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Polymorphisms of androgens-related genes and idiopathic male infertility in Turkish men.

Androgens, testosterone and dihydrotestosterone (DHT) are endocrine regulators of spermatogenesis and act via androgen receptor (AR). The aim of this study was to investigate the association(s) of AR (CAG repeat length), SRD5A2 (rs523349, V89L) and TNF-α (rs1800629, -308G/A) polymorphisms with idiopathic male infertility in Turkish men. This case-control study consisted of 312 men with idiopathic infertility and 113 fertile men. Polyacrylamide gel electrophoresis (PAGE) or PCR-restriction fragment length polymorphism methods were used for genotyping. The mean AR CAG repeat length was significantly longer in infertile men than in fertile men (p=0.015). However, there was no significant association between the SRD5A2 genotypes (VV, VL and LL) and the risk of infertility (p=0.516). The genotype frequency and allele distribution of TNF-α -308G/A polymorphism (GG, GA, AA genotypes and G, A alleles) were not associated with male infertility (p=0.779 and p=0.743 respectively). AR CAG repeat expansion might be one of the risk factors for idiopathic male infertility in Turkish men. Further studies investigating the association of male infertility with AR CAG, V89L and -308G/A polymorphisms are warranted to understand the possible associations among them.

CAG repeat polymorphism in androgen receptor and infertility: A case-control study.

BackgroundAndrogens play a role in the development of male phenotype and spermatogenesis during puberty, the function of which is regulated by the androgen receptor (AR) gene. There is a polymorphism site in exon 1 of the gene encoding this receptor that can have different frequencies of CAG trinucleotide repeats and leads to the formation of polyglutamine chains of different lengths in the N-terminal domain of the AR protein and reduced sperm production by affecting spermatogenesis.Objective To investigate whether the cause of a group of unexplained infertilities could be the increased frequency of CAG repeats in the AR gene of patients with oligozoospermia and azoospermia.Materials and MethodsIn this case-control study, 84 men including 42 with unexplained infertility As a case group and 42 fertile men as a control group were selected. The frequency of CAG repeats was determined by the polymerase chain reaction method and then the difference in the frequency of these repeats was determined based on the difference in band size on the agarose gel.ResultsThe mean CAG repeat length in the azoospermia and oligozoospermia group was 17.5 0.63 and in the fertile group it was 16.11 0.75 (p = 0.46). In addition, most men (88.1% in the case group and 71.41% in the control group) had 13-23 repeats.Conclusion No significant correlation was found between CAG repeat length and the risk of male factor infertility in an ethnically defined population of Iranian men. The role of regulatory factors and epigenetic changes should be taken into account too.

The MID1 Protein: A Promising Therapeutic Target in Huntington's Disease.

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. We imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download.

Multimodal Imaging and Visual Evoked Potentials Reveal Key Structural and Functional Features That Distinguish Symptomatic From Presymptomatic Huntington's Disease Brain.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric abnormalities. Currently, matched analyses of structural and functional differences in the brain from the same study cohort and, specifically, in HD patients from an ethnically diverse Indian population are lacking. Such findings aid in identifying noninvasive and sensitive imaging biomarkers. The aim of the study was to understand the structural and functional differences between HD and control brain, and presymptomatic and symptomatic HD brain in the Indian population. Seventeen HD (11 symptomatic HD [S-HD] and six presymptomatic HD [P-HD], with comparable CAG repeats), and 12 healthy controls were examined. Macrostructural (volume), microstructural (diffusivity), and functional (neurochemical levels and glucose metabolism) imaging of the brain was done along with the determination of visual latencies. HD brain showed increased intercaudate distance; significant subcortical volumetric loss; reduced fractional anisotropy; increased mean, axial, and radial diffusivity; lower levels of total N-acetyl aspartate; elevated total choline levels; and reduced glucose metabolism compared with control brain. Interestingly, compared with P-HD, S-HD patients demonstrated a strong inverse correlation between age at onset and CAG repeat length, and prolonged P100 latency. In addition, caudate and putamen in S-HD brain showed significant volumetric loss and increased diffusivity compared with P-HD brain. HD brain showed distinct macrostructural, microstructural, and functional differences compared with control brain in the Indian population. Interestingly, patients with S-HD had a significant volumetric loss, increased diffusivity, altered neurochemical profile, and delayed P100 latency compared with P-HD patients. Examining these alterations clinically could aid in monitoring the progression of HD.

Effect of CAG repeats on the age at onset of patients with spinocerebellar ataxia type 2 in China.

Spinocerebellar ataxia type 2 (SCA2) is one of the most common autosomal dominant ataxias in the world. Several reports revealed that CAG repeats in some polyQ-containing genes may affect the age at onset (AAO) of patients with SCA2, however, little studies were conducted among Chinese patients with SCA2. Thus, the aim of this study is to evaluate the effect of CAG repeats on the AAO of patients with SCA2 in China. A total of 119 patients with SCA2 were enrolled and were divided into 2 groups according to their major phenotype: 17 patients from 9 families with Parkinson's syndrome were grouped as the Parkinson's disease-SCA2 (PD-SAC2); 91 patients from 66 SCA2 families and 11 sporadic SCA2 patients were grouped as the ataxia-SCA2 (A-SCA2). Blood samples were obtained from the subjects, and the CAG repeat length in ATXN2 and other (CAG)n-containing genes was screened using fluorescent PCR. The Spearman's rank correlation between the CAG repeat length in (CAG)n-containing genes and AAO was analyzed. Regression analysis was performed to investigate whether the CAG repeat length could explain the variant of AAO. A t-test was used to compare the difference of CAG repeat length in (CAG)n-containing genes between the PD-SAC2 and A-SCA2 groups. The CAG repeat length in the longer allele of ATXN2 was negatively correlated with AAO of SCA2 (R=-0.251, P<0.05), and the CAG repeat length could explain 41.7% of the variation of AAO. AAO negatively correlated with the CAG repeat length in the shorter allele of ATXN7 (R=-0.251, P=0.006) or in the longer allele of TBP gene (R=-0.197, P=0.034). A tendency of delay in the AAO was also observed in patients with SCA2 carrying the CAG repeat within the ATXN3, CACNA1A, ATXN7, TBP, and RAI1. In addition, we found that the CAG repeat length in ATXN7 and ATXN2 between the A-SCA2 and the PD-SCA2 groups was significantly different (both P<0.05). The CAG repeat in ATXN2 is a major genetic factor for the AAO of patients with SCA2 in China. The CAG repeat length in ATXN3, CACNA1A, ATXN7, TBP, and RAI1 genes might be a potential factor associated with the AAO of SCA2. The CAG repeat in ATXN7 might be a potential factor affecting the Parkinson's syndrome in SCA2.

Androgen receptor polymorphism, testosterone levels, and prognosis in patients with acute myocardial infarction.

AimsLow testosterone has been associated with cardiovascular disease in men but with contradictory findings. Testosterone bind to the androgen receptor and polymorphisms of the receptor gene such as CAG repeat length may affect transcriptional activity, possibly mitigating testosterone effects. The aims were to study the CAG repeat length and testosterone levels at four time points following a myocardial infarction (MI) and to analyse possible relationships between CAG repeat length and cardiovascular prognosis.Methods and resultsMale patients admitted for acute MI (n = 122) from the Glucose in Acute Myocardial Infarction study were included. Blood samples were drawn at four time points (day after admission, at discharge, and at 3 and 12 months post-infarction) for assessment of testosterone levels. Patients were followed for a median of 11.6 years. Cox regression analyses were performed for CAG repeat length by one unit increment and by > vs. ≤median for cardiovascular events and all-cause mortality. Median CAG repeat length was 20. There was no difference in testosterone levels at each time point when dividing the cohort into ≤ vs. >CAG repeat median (=20). There was no association between CAG repeat length either as a continuous or categorical variable in unadjusted and age-adjusted Cox analyses for cardiovascular events. While CAG >20 was associated with all-cause mortality in unadjusted analyses (hazard ratio 2.19, 95% confidence interval 1.13–4.22; P = 0.02), it did not remain significant following adjustment for age.ConclusionCAG repeat length was not associated with testosterone levels or prognosis in men with acute MI.

Cognitive impairment and associations with structural brain networks, endocrine status, and risk genotypes in newly orchiectomized testicular cancer patients

A higher incidence of cognitive impairment (CI) has previously been reported among orchiectomized testicular cancer patients (TCPs), but little is known about the underlying pathophysiology. The present study assessed CI in newly orchiectomized TCPs and explored the structural brain networks, endocrine status, and selected genotypes. Forty TCPs and 22 healthy controls (HCs) underwent neuropsychological testing and magnetic resonance imaging, and provided a blood sample. CI was defined as a z-score ≤ -2 on one neuropsychological test or ≤ -1.5 on two neuropsychological tests, and structural brain networks were investigated using graph theory. Associations of cognitive performance with brain networks, endocrine status (including testosterone levels and androgen receptor CAG repeat length), and genotypes (APOE, BDNF, COMT) were explored. Compared with HCs, TCPs performed poorer on 6 out of 15 neuropsychological tests, of which three tests remained statistically significant when adjusted for relevant between-group differences (p< 0.05). TCPs also demonstrated more CI than HCs (65% vs. 36%;p = 0.04). While global brain network analysis revealed no between-group differences, regional analysis indicated differences in node degree and betweenness centrality in several regions (p < 0.05), which was inconsistently associated with cognitive performance. In TCPs, CAG repeat length was positively correlated with delayed memory performance (r = 0.36;p = 0.02). A COMT group × genotype interaction effect was found for overall cognitive performance in TCPs, with risk carriers performing worse (p = 0.01). No effects were found for APOE, BDNF, or testosterone levels. In conclusion, our results support previous findings of a high incidence of CI in newly orchiectomized TCPs and provide novel insights into possible mechanisms.

A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington's Disease.

Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington’s disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington’s disease, influencing the choice of biomarkers and the recruitment of participants.

SCA2 in the Indian population: Unified haplotype and variable phenotypic patterns in a large case series

BackgroundSpinocerebellar ataxia-2 is one of the most prevalent SCA type across the world and one of the commonest in India. We aimed to characterize SCA2 patients both clinically and genetically (ATXN2-CAG repeats and its haplotypic background). MethodsA total of 436 SCA2 patients were recruited consecutively comprising individuals of multiple ethnicities and two large multigenerational families. A detailed clinical evaluation and genetic analysis for CAG repeat length estimation and two marker based haplotype analysis [rs695871 and rs695872 located 177 bp and 106 bp upstream of CAG sequence in Exon 1 of ATXN2] was performed. ResultsGeneralized limb ataxia and slow saccades were prevalent features in majority of our patients, while hyporeflexia and extrapyramidal features were less commonly observed manifestations. Slow ocular saccades, upper limb ataxia and tremor showed significant associations with age of onset, CAG repeat length and disease duration. We observed a 100% association of C-C haplotype with the expanded ATXN2 repeats. ConclusionThis study represents the largest study of SCA2 Indian patients that highlights the clinico-genetic manifestations and haplotype analysis. A significant proportion of patients have not shown the characteristic slow saccades and hyporeflexia thus indicating the influences of other factors in modulation of the disease which warrants further investigations. The observation of CC haplotype in all our SCA2 patients indicates a common origin across all Indian sub populations and that also indicate a common global founder event in the past.

Variants in Genes of Calpain System as Modifiers of Spinocerebellar Ataxia Type 3 Phenotype

Calpain-mediated proteolysis has been proposed to modulate the pathogenesis of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), a disorder due to a CAG repeat expansion (CAGexp) at ATXN3. We aimedto investigate if single-nucleotide polymorphisms (SNPs) at calpain gene CAPN2 and at calpastatin gene CAST modulate the age at onset (AO) and disease progression in SCA3/MJD. A total of 287 SCA3/MJD symptomatic subjects (151 families) were included. AO was analyzed and controlled by the CAG repeat length of expanded allele and family. Candidate polymorphisms were chosen based on the literature and on a priori criteria. The CAG repeat length and SNPs were genotyped according to standard methods. AO of carriers of AA and AG + GGrs1559085 genotypes in CAST and with the median value of 75 repeats at the expanded allele were 34.23 (33.07-35.38) and 36.42years (34.50-38.34), respectively (p = 0.049, mixed model treating the expanded CAG repeat size as fixed effect and family as random effect). Carriers of haplotype Crs27852/Grs1559085 had mean AO of 37.23 (12.76) and 33.42years (12.20) (p = 0.047, Student's t test). Our data suggest an association between allele Grs1559085 and haplotype Crs27852/Grs1559085 at CAST and variations in the AO of SCA3/MJD subjects, independent from the effects of the CAGexp and family. The present results support the potential role of calpain cleavage pathway over modulation of SCA3/MJD phenotype.

Clinical predictors and neural correlates for compromised swallowing safety in Huntington disease.

Dysphagia is one of the most common and important complications in Huntington disease (HD), frequently leading to aspiration pneumonia and mortality. Objective estimates of prevalence using instrumental diagnostics and data on neural correlates of dysphagia in HD are scarce or lacking entirely. Similarly, its correlation with other clinical markers is still not fully known. We aimed at defining clinical risk factors and neural correlates for compromised swallowing safety in HD more precisely. Thirty-four HD subjects (16 female, Shoulson & Fahn Stage I-IV, two premanifest) underwent a full clinical-neurological examination including the cranial nerves, the Unified Huntington's Disease Rating Scale total motor score, and the Mini-Mental State Examination. Fiberoptic endoscopic evaluation of swallowing (FEES) was performed by a trained speech and language therapist. Twenty-sixsubjects additionally underwent a high-resolution anatomical magnetic resonance imaging (MRI) scan (T1, 3-T Siemens Prisma). Moreover, we correlated clinical and atrophy (MRI) measures with swallowing safety levels as judged by the validated Penetration-Aspiration Scale. FEES showed penetration or aspiration in 70.6%. Using partial correlation, no significant correlations were found between swallowing safety and any of the clinical markers after correcting for disease duration and CAG repeat length. Voxel-based morphometry demonstrated atrophy associated with compromised swallowing safety in a network of parietothalamocerebellar areas related to sensorimotor communication, notably excluding striatum. Our results characterise dysphagia in HD as a disorder of communication between sensory and motor networks involved in swallowing. This finding and high rates of silent aspiration argue in favor of instrumental swallowing evaluation early in the disease.

Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes. Previous studies suggested dysregulated molecular networks in a CAG length genotype- and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats. Furthermore, a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats. However, an integrated analysis correlating phenotype features with genotypes (CAG repeat expansions) was not conducted previously. In this study, we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples, together with behavioral features (396 PhenoCube behaviors and 111 NeuroCube behaviors) in Htt CAG-knock-in mice. We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration. The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions, which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain. We also identified 15 chemicals with significant responses for genes with enriched behavioral features, most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry. Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.

Differential Diagnosis of Chorea-HIV Infection Delays Diagnosis of Huntington's Disease by Years.

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

Directly reprogrammed Huntington's disease neural precursor cells generate striatal neurons exhibiting aggregates and impaired neuronal maturation.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Using a highly efficient protocol for direct reprogramming of adult human fibroblasts with chemically modified mRNA, we report the first generation of HD induced neural precursor cells (iNPs) expressing striatal lineage markers that differentiated into DARPP32+ neurons from individuals with adult-onset HD (41-57 CAG). While no transcriptional differences between normal and HD reprogrammed neurons were detected by NanoString nCounter analysis, a subpopulation of HD reprogrammed neurons contained ubiquitinated polyglutamine aggregates. Importantly, reprogrammed HD neurons exhibited impaired neuronal maturation, displaying altered neurite morphology and more depolarized resting membrane potentials. Reduced BDNF protein expression in reprogrammed HD neurons correlated with increased CAG repeat lengths and earlier symptom onset. This model represents a platform for investigating impaired neuronal maturation and screening for neuronal maturation modifiers to treat HD.

Propensity for somatic expansion increases over the course of life in Huntington disease.

Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than the length of the inherited allele. Here, we measured somatic expansion in blood samples collected from the same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue from 15 adults and 7 fetal mutation carriers, to examine somatic expansions at different stages of life. Post-mortem brains, as previously reported, had the greatest expansions, but fetal cortex had virtually none. Somatic instability in blood increased with age, despite blood cells being short-lived compared to neurons, and was driven mostly by CAG repeat length, then by age at sampling and by interaction between these two variables. Expansion rates were higher in symptomatic subjects. These data lend support to a previously proposed computational model of somatic instability-driven disease.