CAG Repeat Length Research Articles

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.

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.

Background:Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.Objective:The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.Methods:We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels.Results:The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume.Conclusion:Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3.

Androgen receptor polymorphism, mental rotation, and spatial visualization in men

Circulating levels of testosterone (T) have been hypothesized to influence spatial cognition in adult men, but empirical support for this idea is mixed. Many of testosterone’s effects are mediated by the classic nuclear androgen receptor (AR), which contains a polymorphic glutamine repeat (CAG repeat sequence) that varies significantly across individual men and confers differences in receptor function and therefore individual responsivity to T. We genotyped the AR CAG repeat length in 146 healthy adult men who also performed cognitive tests of mental rotation and spatial visualization. Circulating T concentrations were measured in saliva. CAG repeat length was found to be a significant predictor of spatial scores on tests of visualization but not mental rotation. A weaker AR was associated with lower visualization scores. In contrast, T itself, but not CAG repeat length predicted scores on two mental rotation tests. These results support the view that T action in the brain modestly influences spatial cognition in healthy men, but suggest that T’s effects on mental rotation might not be AR-dependent and instead occur through an alternative mechanism.

HTT CAG Repeat Length Variation in Huntington Disease (HD) Patients: Experience from a US Reference Laboratory (2376)

HTT CAG Repeat Length Variation in Huntington Disease (HD) Patients: Experience from a US Reference Laboratory (2376)

Longitudinal Evaluation of the Effect of Tricyclic Antidepressants and Neuroleptics on the Course of Huntington's Disease-Data from a Real World Cohort.

Background: Reducing the progress of neurodegeneration is a key goal in Huntington´s disease (HD). A previously performed systematic screening for medications with neuroprotective features identified tricyclic antidepressants and neuroleptics as neuroprotective and mitochondrioprotective agents. Here, we analyzed the characteristics of disease manifestation, progression and potential beneficial effects in HD patients treated with afore-mentioned medications compared to un- and otherwise treated motor-manifest patients in a large real-world cohort over two years. Methods: We analyzed cross-sectional data of the largest cohort worldwide of motor-manifest HD patients using the ENROLL-HD database, including demographic, moleculargenetic, clinical-motoric, cognitive and functional data. Longitudinal data of up to two years were obtained to analyze potential effects on disease progression between groups with different medications used. Data were analyzed using repeated ANOVA-analyses while controlling for the co-variates age and CAG-repeat length. Results: We identified n = 7397 motor-manifest HD patients using no or different medication (HD-ctrl) and subgroups treated with clomipramine (n = 56), clozapine (n = 66), chlorpromazine (n = 17), doxepine (n = 34) and desi-, imi- or trimipramine (n = 19). Demographic parameters, disease onset and CAP-score did not differ. Total motor scores (TMS) at baseline were higher in patients treated with clozapine (p < 0.001), chlorpromazine and clomipramine (p < 0.05) compared to HD-ctrl with higher sub scores for bradykinesia (all p < 0.01) and dystonia in clozapine treated patients (p < 0.001). Functional and cognitive capacities were worse in medication groups in comparison to HD-ctrl at baseline (p < 0.001). Repeated measures analysis of variance documented no differences regarding motoric, functional and cognitive disease progressions between groups. Conclusions: We identified group differences, potentially caused by side effects or potential selection bias in terms of bradykinetic motoric symptoms, more dystonia and lower functional and cognitive performance in some treatment groups at baseline, which were not entirely explained because of underlying fundamental characteristics. Disease progression regarding clinical, functional and cognitive outcomes over two years was not affected by any of the treatment groups compared to HD-ctrl. Our data do not support our hypothesis of a potential neuroprotective effect of these drugs on disease progression.

Cognitive impairment in spinocerebellar ataxia type 12

IntroductionCognitive impairment has now been recognised to be present in patients with several of spinocerebellar ataxias (SCAs). Cognitive impairment in patients with spinocerebellar ataxia type 12 has not been evaluated. ObjectiveTo evaluate the cognitive impairment in patients diagnosed with spinocerebellar ataxia type 12 (SCA12). MethodsWe conducted a cross sectional study and enrolled 30 (20 male and 10 female) genetically confirmed SCA12 patients and 30 healthy, age, gender and education matched individuals as controls. Cognitive domains were tested using a battery of validated neurocognitive tests. ResultMean age of patients was 51.6 ± 8.0 years and mean disease duration was 5.3 ± 3.0 years. Mean International Cooperative Ataxia Rating Scale (ICARS) score was 29.8 ± 12.5. SCA 12 patients scored significantly lower than controls in executive function and new learning ability. Other tested cognitive domains were also affected but did not reach statistical significance. Age, age at onset, severity of ataxia, disease duration and CAG repeat length did not correlate with cognitive impairment. ConclusionCognitive impairment is a part of the spectrum of SCA12 and is characterized by dysfunction in executive function and new learning ability even early in the course of disease.

Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.

Association of CAG Repeat Length in the Huntington Gene With Cognitive Performance in Young Adults.

To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington disease (HD), we performed a cross-sectional analysis of the Enroll-HD database. We analyzed data from young, developing adults (≤30 years of age) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene expansion (CAG ≥36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, and a total motor score of <10 and had to be >28.6 years from their predicted motor onset. We performed regression analyses to investigate the nonlinear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level. There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference test scores. There were significant negative relationships between CAG repeat length and scores on Parts A and B of the Trails Making Test (p < 0.05), indicating that longer CAG repeat lengths were associated with better performance. An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathologic CAG ranges were associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development. This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.

Age-Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin.

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040.

Abnormal eye movements in spinocerebellar ataxia type 3

BackgroundAbnormal eye movements are common in spinocerebellar ataxias Type 3 (SCA3). We conducted the research to explore the frequency of abnormal eye movements in Chinese patients with SCA3, to compare the demographic and clinical characteristics between SCA3 patients with and without each type of abnormal eye movement, and to explore the correlation between abnormal eye movements and the severity of ataxia.MethodsSeventy-four patients with SCA3 were enrolled in this cross-sectional study. Six types of abnormal eye movements including impaired smooth pursuit, increased square-wave jerks (SWJ), gaze-evoked nystagmus (GEN), slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy were evaluated by experienced neurologists. The severity of ataxia was evaluated by Scale for the Assessment and Rating of Ataxia (SARA).ResultsThe prevalence of impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy in Chinese SCA3 patients was 28.4, 13.5, 78.4, 41.9, 23.0, and 5.4%, respectively. SCA3 patients with GEN had higher scores of International Cooperative Ataxia Rating Scale (ICARS-IV) and total ICARS, and longer length of CAG repeat than patients without GEN. SCA3 patients with slowing of saccades had a longer disease duration, higher scores of ICARS-I, ICARS-II, total ICARS and SARA than patients without slowing of saccades. SCA3 patients with saccadic hypo/hypermetria had higher scores of ICARS-III, ICARS-IV, and SARA than patients without saccadic hypo/hypermetria. The demographic and clinical characteristics did not differ significantly between SCA3 patients with and without impaired smooth pursuit, increased SWJ, or supranuclear gaze palsy. Multivariate linear regression showed that the number of abnormal eye movements (0–6), disease duration, Hamilton Depression Rating Scale-24 (HDRS-24) score, and CAG repeat length were positively correlated with SARA score, whereas Montreal Cognitive Assessment (MoCA) score was negatively correlated with SARA score in SCA3.ConclusionsAn increased number of abnormal eye movement types correlated with the severity of ataxia in SCA3.

Mood alterations in mouse models of Spinocerebellar Ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.

Redox Imbalance Associates with Clinical Worsening in Spinocerebellar Ataxia Type 2.

Background Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease presenting with redox imbalance. However, the nature and implications of redox imbalance in SCA2 physiopathology have not been fully understood. Objective The objective of this study is to assess the redox imbalance and its association with disease severity in SCA2 mutation carriers. Methods A case-control study was conducted involving molecularly confirmed SCA2 patients, presymptomatic individuals, and healthy controls. Several antioxidant parameters were assessed, including serum thiol concentration and the superoxide dismutase, catalase, and glutathione S-transferase enzymatic activities. Also, several prooxidant parameters were evaluated, including thiobarbituric acid-reactive species and protein carbonyl concentrations. Damage, protective, and OXY scores were computed. Clinical correlates were established. Results Significant differences were found between comparison groups for redox markers, including protein carbonyl concentration (F = 3.30; p = 0.041), glutathione S-transferase activity (F = 4.88; p = 0.009), and damage (F = 3.20; p = 0.045), protection (F = 12.75; p < 0.001), and OXY (F = 7.29; p = 0.001) scores. Protein carbonyl concentration was positively correlated with CAG repeat length (r = 0.27; p = 0.022), while both protein carbonyl concentration (r = −0.27; p = 0.018) and OXY score (r = −0.25; p = 0.013) were inversely correlated to the disease duration. Increasing levels of antioxidants and decreasing levels of prooxidant parameters were associated with clinical worsening. Conclusions There is a disruption of redox balance in SCA2 mutation carriers which depends on the disease stage. Besides, redox changes associate with markers of disease severity, suggesting a link between disruption of redox balance and SCA2 physiopathology.

Genetic profile and clinical characteristics of Chinese patients with spinocerebellar ataxia type 2: A multicenter experience over 10years.

Spinocerebellar ataxia type 2 (SCA2) is the second most common type of spinocerebellar ataxia in China. However, data on the clinical and genetic features of Chinese SCA2 patients are scarce. This study aims to provide a comprehensive description of in the Chinese SCA2 cohort. A total of 135 patients with SCA2 from 92 families and 104 unrelated normal controls were recruited from three medical centers between 2008 and 2020. Sanger sequencing and TA cloning were used to determine the CAG repeat length and intrinsic structure. The clinical data of patients with SCA2, including electromyography, magnetic resonance imaging, positron-emission tomography, and clinical scale scores, were recorded. The mean±SD age at onset of SCA2 patients was 32.6±11.9years and the corresponding CAG repeat length was 42.1±3.6. CAG repeat length accounted for 64% of the age-at-onset variance. We observed that patients had a significantly lower proportion of (CAG)8 CAA(CAG)4 CAA(CAG)8 within normal alleles than normal controls (48.8% vs. 64.9%; p=0.003), while the distribution of the proportion of (CAG)13 CAA (CAG)8 was the opposite. Peripheral neuropathy was frequent, occurring in 75.9% of the patients. Parkinsonism was relatively common, with a frequency of 11.8%. Two patients with parkinsonism had a significantly more severe reduction in dopamine transporter levels in the bilateral striatum than the one patient with pure ataxia. An infant-onset case of SCA2 with more than 180 CAG repeats was characterized by global development delay, hypotonia and hearing impairment. This study describes the genetic profile and clinical characteristics of the largest SCA2 cohort to date in the Chinese population and analyzes inter-population differences. Many aspects of this study population were different from other populations with SCA2.

Incidence of Huntington disease in a northeastern Spanish region: a 13-year retrospective study at tertiary care centre

BackgroundDespite the progress in the knowledge of Huntington disease (HD) in recent years, the epidemiology continues uncertain, so the study of incidence becomes relevant. This is important since various factors (type of population, diagnostic criteria, disease-modifying factors, etc.) make these data highly variable. Therefore, the genetic diagnosis of these patients is important, since it unequivocally allows the detection of new cases.MethodsDescriptive retrospective study with 179 individuals. Incidence of HD was calculated from the ratio of number of symptomatic cases newly diagnosed per 100,000 inhabitants per year during the period 2007–2019 in Aragon (Spain).Results50 (27.9%) incident cases of HD (CAG repeat length ≥ 36) were identified from a total of 179 persons studied. The remaining 129/179 (72.1%) were HD negative (CAG repeat length < 36). 29 (58.0%) females and 21 (42.0%) males were confirmed as HD cases. The overall incidence was 0.648 per 100,000 patient-years. 11/50 positive HD cases (22.0%) were identified by performing a predictive test, without clinical symptoms. The minimum number of CAG repeats found was 9 and the most common CAG length among HD negative individuals was 16.ConclusionsOur incidence lied within the range reported for other Caucasian populations. Implementation of new techniques has allowed to determine the exact number of CAG repeats, which is especially important in patients with triplet expansions in an HD intermediate and/or incomplete penetrance allele, both in diagnostic, predictive and prenatal tests.

Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

BackgroundCharacterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. MethodsCapitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. ResultsWe show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. ConclusionsHD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

In vivo microstructural white matter changes in early spinocerebellar ataxia 2.

White matter (WM) integrity of Spinocerebellar ataxia 2 (SCA2) is poorly understood, more so in the early stages of SCA2. In this study, we evaluated the microstructural integrity of the WM tracts with an emphasis on the nature of in vivo pathological involvement in early SCA2. We evaluated the MRI images of 26 genetically proven SCA2 patients with disease duration <5years and 24 age- and gender-matched healthy controls using tract-based spatial statistics (TBSS) to identify the WM tract changes and their clinico-genetic correlates (age at onset, duration of disease, ataxia severity and CAG repeat length) using standard methodology. The mean age at onset and duration of disease were 28.7±8.51years and 3.5±0.69months, respectively. The mean CAG repeat length was 42.5±4.6, and the ataxia severity score was 16.1±4.9. Altered DTI scalars signifying degeneration was present in the bilateral anterior thalamic radiation (ATR), corticospinal tract (CST), inferior fronto-occipital fasciculus (IFOF), superior and inferior longitudinal fasciculus (SLF and ILF), uncinate fasciculus (UF), cingulum, corpus callosum (CC), forceps major and forceps minor (corrected p<.05). DTI scalars representing demyelination was seen in the superior cerebellar peduncle (SCP) and cerebellar WM. There was a significant correlation of SARA score with axial diffusivity of the bilateral cingulum, ATR, CST, forceps minor, IFOF, ILF, SLF and SCP on the right side (corrected p<.05). Extensive WM involvement is present in early SCA2. The DTI scalars indicate degeneration and demyelination and may have clinical implications.

Is There a Relation Between Caregiver Burden and Cognitive Dysfunction in Huntington\u2019s Disease?

Caring for a family member with Huntington’s disease (HD) can be seriously burdensome. Cognitive and neuropsychiatric symptoms that are part of HD can impact the quality of life of caregivers. Therefore, we investigated the relationship between caregiver burden, cognitive impairment and patient characteristics. A retrospective cross-sectional study was performed on 33 adult HD-outpatient-caregiver dyads. We assessed caregiver burden and cognitive functioning of the included patient on the same day with the MCSI and MoCA respectively. For statistical analysis, we performed a network analysis and used descriptive statistics to describe our study sample. Caregivers scored on average 13.5 out of 26 points on the MCSI. The scores on the MoCA of the HD patients varied from 9 to 30 and was on average 22. Our network analysis demonstrated an indirect relationship between cognitive functioning and caregiver burden, in which CAG repeat length and the time since HD has been diagnosed are the primary mediators. We found a negative association between CAG repeat length and cognitive functioning. Furthermore, a relationship was found between higher caregiver burden and psychotropic drug use. We observed an indirect relationship between cognitive functioning and caregiver burden using network analysis. This analysis produces comprehensible results with the variables of interest. This study sheds new light on the components that make up caregiver burden in HD.

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3.

In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design. Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length. On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression. Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2021;89:66-73.