Cytosine-adenine-guanine Repeat Research Articles

Sleep Fragmentation Despite Intact Rest-Activity Patterns in Premanifest Huntington's disease: An Actigraphy Study

ObjectiveSleep research in Huntington’s disease (HD) has primarily focused on manifest HD, with significantly less attention given to premanifest HD (Pre-HD). Therefore, we investigated sleep and rest-activity patterns in people with Pre-HD versus healthy controls (HC). MethodsWe conducted a cross-sectional study including 36 Pre-HD and 48 HC participants. Pre-HD participants were stratified into three groups according to their proximity to estimated diagnosis, using a cytosine-adenine-guanine (CAG) and current age-based predictive model: NEAR (<9 years to diagnosis), MID (9-15 years to diagnosis) and FAR (>15 years to diagnosis). Sleep and rest-activity patterns were assessed using wrist-worn actigraphy, a sleep diary, and sleep questionnaires. ResultsNEAR and MID groups experienced higher fragmentation index than HC and FAR groups. NEAR and MID groups also exhibited greater WASO than the FAR group. NEAR and MID groups showed lower intra-daily variability (IV) than HC and FAR groups, with the NEAR group also being more active in the most active 10 hours (M10). Groups did not differ on subjective sleep measures, inter-daily stability (IS), sleep regularity index, relative amplitude, or amount of activity in the least active five hours (L5). Considering all Pre-HD participants, fewer years to diagnosis, higher CAG-age-product (CAP) scores (a measure of cumulative exposure to the HD-causing gene mutation) and larger CAG repeat lengths correlated with higher WASO, fragmentation index, L5, IS, and lower sleep efficiency and IV. Higher CAP score correlated with higher M10. ConclusionsDespite intact rest-activity patterns and similar subjective sleep quality to HC, greater sleep fragmentation is a prominent and early feature in Pre-HD. Therefore, reducing sleep fragmentation may be a potential target for sleep intervention in HD. Longitudinal studies using larger samples are needed to assess sleep across the disease spectrum and its impact on clinical outcomes, like cognition.

Poly ADP-ribose signaling is dysregulated in Huntington disease

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.

Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.

Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure-function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure-function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins' dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders.

Molecular genetic analysis of cytosine-adenine-guanine repeats in huntingtin gene

Background: Huntington’s disease (HD) is a dominantly transmitted progressive neurodegenerative disorder due to abnormal expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. Materials and Methods: The study involved a total of 35 HD patients identified through clinical evaluations. CAG repeats expansion analysis was conducted using polymerase chain reaction (PCR) to confirm positive cases. Results: Employing CAG flacking PCR in 35 cases, 19 tested positive, predominantly displaying CAG repeats in the range of 40–50. Noteworthy cases include a 5-month-old patient with 44 CAG repeats and an 80-year-old patient with 46 CAG repeats. Conclusion: The identification of the genetic defect in HD permits direct genetic testing to comprehend the complexities of HD in India, aiming for effective approaches in diagnosis, treatment, and prevention.

Investigating Holistic Natural Strategies for The Management of Huntington's Disease

Huntington's disease (HD), a multifaceted neurological disorder, presents a complex clinical scenario. An autosomal dominant neurodegenerative ailment called Huntington's disease is brought on by increase in number of CAG (Cytosine-Adenine-Guanine) repeats, which causes the creation of a mutant Huntingtin protein (mHTT) resulting in neuronal death and mental disabilities in human beings. End signs and symptoms can include significant weight loss, difficulty swallowing or breathing, recurrent aspiration pneumonia, declined health and uncontrolled pain. The excessive production of ROS (Reactive Oxygen Species) in nervous tissues is considered a significant risk factor in most of the neurological diseases including HD. Transcriptional regulation, immunological system, and mitochondrial function are all disrupted by mHTT. Although natural products have shown promise in ameliorating symptoms, it is important to note that no singular "phytoconstituent" has been definitively linked to its therapeutic intervention. Nevertheless, certain naturally occurring compounds have exhibited promising outcomes in preclinical investigations. This article focuses on a few phytoconstituents that are known to have a variety of neuroprotective effects through a wide range of biological activities. By stimulating the Nrf2 (Nuclear factor erythroid 2-related factor) pathway and suppressing NF-κB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells), astaxanthin, berberine, and sulfarophane increase the antioxidant and anti-inflammatory activity, resulting in neuroprotection. Curcumin leads to metal chelating effect and decline in reactive oxygen species which are certainly one among the vital processes to impede and manage the disorders causing neurodegeneration including HD. This affects the upregulation of HSPs (Heat Shock Proteins) which helps in HD management. Naringin reduces level of oxidative stress and inflammation by free radical scavenging, NF-κB stimulates cell survival and prevents apoptosis by upregulating anti-apoptotic genes expression and downregulating proapoptotic genes.

Analysis of HTT CAG repeat expansion among healthy individuals and patients with chorea in Korea

BackgroundAlthough the epidemiology of Huntington's disease (HD) in Korea differs notably from that in Western countries, the genetic disparities between these regions remain unclear. ObjectiveTo investigate the characteristics and clinical significance of cytosine-adenine-guanine (CAG) repeat size associated with HD in the Korean population. MethodsWe analyzed the CAG repeat lengths of the HTT gene in 941 healthy individuals (1,882 alleles) and 954 patients with chorea (1,908 alleles) from two referral hospitals in Korea. We presented normative CAG repeat length data for the Korean population and computed the reduced penetrance (36–39 CAG) and intermediate allele (27–35 CAG) frequencies in the two groups. Furthermore, we investigated the relationship between intermediate alleles and chorea development using logistic regression models in individuals aged ≥55 years. ResultsThe mean (±standard deviation) CAG repeat length in healthy individuals was 17.5 ± 2.0, with a reduced penetrance allele frequency of 0.05 % (1/1882) and intermediate allele frequency of 0.69 % (13/1882). We identified 213 patients with genetically confirmed HD whose CAG repeat length ranged from 39 to 140, with a mean of 45.2 ± 7.9 in the longer allele. Compared with normal CAG repeat alleles, intermediate CAG repeat alleles were significantly related to a higher risk of developing chorea (age of onset range, 63–84 years) in individuals aged ≥55 years. ConclusionsThis study provides insights into the specific characteristics of CAG repeat lengths in the HTT gene in the Korean population. The reduced penetrance and intermediate allele frequencies in the Korean general population seem to be lower than those reported in Western populations. The presence of intermediate alleles may increase the risk of chorea in the Korean elderly population, which requires further large-scale investigations.

The association of cytosine-adenine-guanine repeat polymorphism in the androgen receptor gene with nodulocystic acne in Egyptian patients

Background: The role of androgens in acne pathophysiology has been supported by long-standing clinical and experimental observations. Methods: Genotyping for the androgen receptor gene was performed by PCR-based fragment length analysis, aiming to investigate cytosine-adenine-guanine (CAG) repeat polymorphism in Egyptian nodulocystic acne patients to clarify its relevance to the pathogenesis. Detailed frequency of CAG repeats number in patients and control groups, in 25 males and 25 females and Comparison of CAG repeat number regarding demographic and clinical characteristics was performed. Results: It was found that females had a higher frequency of longer CAG repeats compared to males, while in control group there was an even distribution of CAG number repeats in both females and males. Male and female acne patients had significantly lower number of CAG repeats compared to controls with statistically significant difference (p≤0.05). Comparison of CAG repeat number regarding demographic and clinical characteristics revealed no significant correlation or association with patients’ age, duration of acne, onset or course of the disease. Conclusions: These findings support the hypothesis that CAG repeats number affects AR activity, therefore, acne development and severity. Moreover, analysis of CAG repeats number in acne patients can be of considerable importance in the treatment strategy, indicating the role of antiandrogen therapy in acne patients.

Huntington's Disease with Small CAG Repeat Expansions.

Carriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied. To study the phenotype of CAG36-38 repeat carriers. We included 35 patients and premanifest carriers of CAG36-38 repeats. We compared clinical and neuropsychological profiles of 11 CAG36-38 patients with 11 matched CAG40-42 patients. In addition, we analyzed 243 CAG36-38 individuals from the ENROLL study to complete the phenotype description. Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG36-38 and typically CAG40-42 expanded individuals. Chorea as the first symptom was significantly less frequent for CAG36-38 patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG36-38 carriers (P = 0.003). The similar cognitive and different motor profile of CAG36-38 (n = 243) and CAG40-42 (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e-8) and diagnosis happened significantly later in CAG36-38 (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29). We showed that small CAG36-38 expansion carriers had a similar cognitive profile to those with the more common CAG40-42 expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype and clinical phenotype analysis of a Family with Kennedy disease.

To investigate the clinical phenotype-genotype correlations of a family with Kennedy disease (KD) and improve our understanding of the disease. KD was confirmed after clinical phenotypic analyses, laboratory tests, polymerase chain reaction assays for cytosine-adenine-guanine (CAG) repeats, and neuro-electrophysiological tests. The disease was assessed using the KD1234 scale and the spinal and bulbar muscular atrophy functional rating scale. The average age of disease onset was 30.8 ± 2.85 years. Clinically diagnosed members had 48 CAG repeats (≥35 is abnormal) in the androgen receptor gene. The patients exhibited gynecomastia and testicular dysfunction. The lesions mainly involved the medulla oblongata and spinal cord. Progesterone and serum creatine kinase levels were significantly high. Electromyography showed chronic neurogenic damage and abnormal sensory and motor conduction in family members who did not participate in sports, exercise, or physical hobbies. Our study showed that this family had a stable inheritance of CAG repeats, and the genotype was consistent with the clinical phenotype. Gynecomastia was the first symptom, with progressive androgen resistance resulting in testicular atrophy, infertility, and sexual dysfunction. Changes in serum creatine kinase may indicate the progression or relief of symptoms, and rehabilitation may delay the progression of muscle atrophy.

Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index.

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable-similar to those of higher risk of coronary artery disease and type 2 diabetes-and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.

A Comprehensive Bioinformatics Approach to Identify Molecular Signatures and Key Pathways for the Huntington Disease.

Huntington disease (HD) is a degenerative brain disease caused by the expansion of CAG (cytosine-adenine-guanine) repeats, which is inherited as a dominant trait and progressively worsens over time possessing threat. Although HD is monogenetic, the specific pathophysiology and biomarkers are yet unknown specifically, also, complex to diagnose at an early stage, and identification is restricted in accuracy and precision. This study combined bioinformatics analysis and network-based system biology approaches to discover the biomarker, pathways, and drug targets related to molecular mechanism of HD etiology. The gene expression profile data sets GSE64810 and GSE95343 were analyzed to predict the molecular markers in HD where 162 mutual differentially expressed genes (DEGs) were detected. Ten hub genes among them (DUSP1, NKX2-5, GLI1, KLF4, SCNN1B, NPHS1, SGK2, PITX2, S100A4, and MSX1) were identified from protein-protein interaction (PPI) network which were mostly expressed as down-regulated. Following that, transcription factors (TFs)-DEGs interactions (FOXC1, GATA2, etc), TF-microRNA (miRNA) interactions (hsa-miR-340, hsa-miR-34a, etc), protein-drug interactions, and disorders associated with DEGs were predicted. Furthermore, we used gene set enrichment analysis (GSEA) to emphasize relevant gene ontology terms (eg, TF activity, sequence-specific DNA binding) linked to DEGs in HD. Disease interactions revealed the diseases that are linked to HD, and the prospective small drug molecules like cytarabine and arsenite was predicted against HD. This study reveals molecular biomarkers at the RNA and protein levels that may be beneficial to improve the understanding of molecular mechanisms, early diagnosis, as well as prospective pharmacologic targets for designing beneficial HD treatment.

Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood–brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.

Neuropsychiatric Disturbance in Huntington’s Disease: Approach to Management

IntroductionHuntington’s Disease (HD) is an autosomal dominant, neurodegenerative condition with a prevalence of 10.6-13.7 per 100,000, caused by the trinucleotide CAG (cytosine, adenine, guanine) repeat expansion in the HTT gene. HD is characterized by a range of motor, cognitive, and psychiatric symptoms, the latter of which usually manifest prior to the onset of motor or cognitive disturbances. Amongst psychiatric symptoms, changes in personality are most common, followed by depression. Psychosis has a higher prevalence in those with early-onset HD.ObjectivesThis case report aims to demonstrate an apporach to the management of neuropsychiatric disturbances in HD as well as expose the need for development of an evidence-based apprach to treatment.MethodsPubMed was searched for the criteria Huntington’s Disease AND Psychosis, with a secondary search for Management of Psychosis in Huntington’s Disease.ResultsThe patient is a 54-year-old male with no psychiatric history and reported past medical history of Huntington’s Disease, diagnosed one month ago. He was brought to the Psychiatric ED due to agitation and disorganized behavior at home. On admission, he demonstrated disorganized behavior, grandiose delusions, neurocognitive deficits, and reported auditory hallucinations. With the initiation of tetrabenazine and risperidone his psychiatric symptoms improved and he was able to be discharged to a long-term care facility.ConclusionsLiterature is scarce regarding treatment of psychiatric manifestations of HD. We catered our approach towards safe and effective symptoms management in a multidisciplinary manner. Further research is required to reach an evidence-based consensus as well as develop specific guidelines for managing psychiatric conditions related to HD.DisclosureNo significant relationships.

IGF-1 as a Potential Therapy for Spinocerebellar Ataxia Type 3.

Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a downstream mediator of GH, in vivo for SCA3 treatment. IGF-1 (50 mg/kg) or saline, once a week, was intraperitoneally injected to SCA3 84Q transgenic mice harboring a human ATXN3 gene with a pathogenic expanded 84 cytosine–adenine–guanine (CAG) repeat motif at 9 months of age. Compared with the control mice harboring a 15 CAG repeat motif, the SCA3 84Q mice treated with IGF-1 for 9 months exhibited the improvement only in locomotor function and minimized degeneration of the cerebellar cortex as indicated by the survival of more Purkinje cells with a more favorable mitochondrial function along with a decrease in oxidative stress caused by DNA damage. These findings could be attributable to the inhibition of mitochondrial fission, resulting in mitochondrial fusion, and decreased immunofluorescence staining in aggresome formation and ataxin-3 mutant protein levels, possibly through the enhancement of autophagy. The findings of this study show the therapeutic potential effect of IGF-1 injection for SCA3 to prevent the exacerbation of disease progress.

Androgen receptor gene polymorphism and female sexual functionin Egyptian women

BackgroundAndrogen receptor (AR) polymorphism in cytosine–adenine–guanine (CAG) repeat has an effect on the functional capacity of AR in males. However, little researches in this field are available regarding female sexual function.ObjectivesTo investigate the possible link between polymorphism in CAG repeat of AR gene and female sexual function in a sample of Egyptian women.Patients and methodsIn all, 500 married Egyptian women completed a questionnaire regarding sociodemographic, reproductive, and sexual data. AR CAG repeat length was analyzed for those having female sexual dysfunctions using real-time PCR.ResultsThe most sensitive domain to AR CAG repeat length was orgasm domain that showed significant positive correlations with short allele (P = 0.001), long allele (P = 0.015), biallelic mean (P = 0.000), and X-weighted biallelic mean (P = 0.000). Satisfaction domain had significant positive correlations with biallelic mean (P = 0.035) and X-weighted biallelic mean (P = 0.032). However, the pain domain was of significant negative correlations with AR polymorphism of short allele (P = 0.002), biallelic mean (P = 0.013), and X-weighted biallelic mean (P = 0.011).ConclusionsAR polymorphism could represent a nonnegligible aspect in female sexual function. The lower AR CAG repeat polymorphism was of significant impact on female sexual dysfunction affecting mainly female orgasm, followed by pain disorders that finally reflected on her sexual satisfaction.

Effect of Ayurvedic interventions as add-on therapy in Huntington's disease: A case report

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder. It is caused due to trinucleotide cytosine-adenine-guanine (CAG) repeat expansion on chromosome 4. The greater the CAG repeat size, the earlier the onset of the disease. It is characterized by motor, cognitive, and psychiatric symptoms. The onset of Juvenile HD occurs before the age of 21 and is rarer compared to adult-onset HD. A 30-year-old female, diagnosed with HD by molecular genetic analysis and magnetic resonance imaging, presented to Ayurveda hospital with chief complaints of abnormal involuntary movements in both the limbs bilaterally, difficulty in walking without support, difficulty in speech, swallowing, episodes of anger outbursts, and hard stools. The Ayurvedic treatment protocol was planned with a course of Nasya (~medication through nasal route), Basti (~medicated enema), and Abhyanga (~therapeutic oleation). Shashtika Shali Pinda Sweda (~sudation by application of poultice with rice), Shiropichu (~therapeutic procedure of placing tampon with oil over head region), and Karnapurana (~filling of ear with medicated liquid) along with internal medications which had Balya (~strength promoting), Brimhana (~restorative measures), Agni balavardhana (~enhancing digestive fire), Rechana (~cleansing), Rasayana (~rejuvenation therapy), and Vatahara (~Vata pacifying) actions were also adopted. By the completion of treatment, improvement was noticed in terms of reduced involuntary movements, better balance while standing, and reduced frequency of falls. Assessment by Abnormal Involuntary Movements Scale showed a reduction from score 30 to 18 after treatment, inferring that Ayurvedic therapies can help in betterment of patients affected with HD.

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.

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.

New Model for Estimation of the Age at Onset in Spinocerebellar Ataxia Type 3.

The aim of this study was to develop an appropriate parametric survival model to predict patient's age at onset (AAO) for spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) populations from mainland China. We compared the efficiency and performance of 6 parametric survival analysis methods (exponential, weibull, log-gaussian, gaussian, log-logistic, and logistic) based on cytosine-adenine-guanine (CAG) repeat length at ATXN3 to predict the probability of AAO in the largest cohort of patients with SCA3/MJD. A set of evaluation criteria, including -2 log-likelihood statistic, Akaike information criterion (AIC), bayesian information criterion (BIC), Nagelkerke R-squared (Nagelkerke R^2), and Cox-Snell residual plot, were used to identify the best model. Among these 6 parametric survival models, the logistic model had the lowest -2 log-likelihood (6,560.12), AIC (6,566.12), and BIC (6,566.14) and the highest value of Nagelkerke R^2 (0.54), with the closest graph to the bisector Cox-Snell residual graph. Therefore, the logistic survival model was the best fit to the studied data. Using the optimal logistic survival model, we indicated the age-specific probability distribution of AAO according to the CAG repeat size and current age. We first demonstrated that the logistic survival model provided the best fit for AAO prediction in patients with SCA3/MJD from mainland China. This optimal model can be valuable in clinical and research. However, the rigorous clinical testing and practice of other independent cohorts are needed for its clinical application. A unified model across multiethnic cohorts is worth further exploration by identifying regional differences and significant modifiers in AAO determination.

FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein aggregation.

FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis, has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent the aggregation of cytosine adenine guanine (CAG)-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here, we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, ubiquitin–proteasome system (UPS) mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead, FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces the accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases.