This review provides a comprehensive framework for the diagnostic approach and management of Huntington's disease (HD) tailored to the Korean population. Key topics include genetic counseling, predictive testing, and reproductive options like preimplantation genetic testing. Strategies for assessing disease progression in premanifest HD through laboratory investigations, biofluid, and imaging biomarkers are highlighted. Special considerations for juvenile and late-onset HD, along with associated comorbidities like diabetes mellitus, hypertension, and cardiovascular abnormalities, are discussed. The guide emphasizes personalized symptom management, including pharmacotherapy, physical therapy, and nutritional support, while exploring emerging disease-modifying treatments. A multidisciplinary care model is advocated to improve outcomes for HD patients and caregivers in Korea.

Mild cognitive impairment (MCI) has been recognized as a possible precursor to Alzheimer's disease (AD). Recent research focusing on connected speech has uncovered various features strongly correlated with MCI due to AD and related dementias. Despite these advancements, the impact of early cognitive decline on articulatory precision has not been thoroughly investigated.

This study introduced the phoneme log-likelihood ratio (PLLR) to assess the articulatory precision of speakers across different cognitive status levels and compared its effectiveness to existing well-studied acoustic features.

The study utilized speech recordings from a picture description task, which included data from 324 cognitively unimpaired participants with low amyloid-β burden (CU, Aβ(- )), 47 cognitively unimpaired participants with high amyloid-β burden (CU, Aβ(+ )), 69 participants with MCI, and 20 participants with dementia. Nine acoustic features were extracted from the speech recordings, covering three categories: speech fluency, speech pace, and articulatory precision. Welch's t -test and Hedge's g were adopted to assess their discriminative ability.

A reduction in speech fluency and pace was observed among participants in the MCI and dementia groups. The PLLR shows large effect sizes in distinguishing between cognitively unimpaired participants with low Aβ burden and those diagnosed with MCI or dementia. Additionally, the test-retest reliability experiment indicated moderate repeatability of the features under study.

The study reveals PLLR as a sensitive indicator capable of detecting subtle articulatory variations across groups, while also providing further support for the association between reduced articulatory precision and early cognitive decline.

Mild cognitive impairment (MCI) has been described as a transitional state between normal aging and dementia, which can be both identified and tracked over time from qualitative and/or quantitative perspectives. Each definition of MCI involves some subjective cognitive complaint, some level of objective cognitive impairment, and generally intact daily functioning. Progression to dementia is common on follow-up in MCI, but stability and reversion to normal cognition can also occur. Quantitative methods might allow health care providers to evaluate and follow the subtle declines in MCI, as well as examine possible benefits of interventions with this at-risk condition.

Synaptic dysfunction is an early pathogenic event leading to cognitive decline in Huntington's disease (HD). We previously reported that the active ADAM10 level is increased in the HD cortex and striatum, causing excessive proteolysis of the synaptic cell adhesion protein N-Cadherin. Conversely, ADAM10 inhibition is neuroprotective and prevents cognitive decline in HD mice. Although the breakdown of cortico-striatal connection has been historically linked to cognitive deterioration in HD, dendritic spine loss and long-term potentiation (LTP) defects identified in the HD hippocampus are also thought to contribute to the cognitive symptoms of the disease. The aim of this study is to investigate the contribution of ADAM10 to spine pathology and LTP defects of the HD hippocampus. We provide evidence that active ADAM10 is increased in the hippocampus of two mouse models of HD, leading to extensive proteolysis of N-Cadherin, which has a widely recognized role in spine morphology and synaptic plasticity. Importantly, the conditional heterozygous deletion of ADAM10 in the forebrain of HD mice resulted in the recovery of spine loss and ultrastructural synaptic defects in CA1 pyramidal neurons. Meanwhile, normalization of the active ADAM10 level increased the pool of synaptic BDNF protein and activated ERK neuroprotective signaling in the HD hippocampus. We also show that the ADAM10 inhibitor GI254023X restored LTP defects and increased the density of mushroom spines enriched with GluA1-AMPA receptors in HD hippocampal neurons. Notably, we report that administration of the TrkB antagonist ANA12 to HD hippocampal neurons reduced the beneficial effect of GI254023X, indicating that the BDNF receptor TrkB contributes to mediate the neuroprotective activity exerted by ADAM10 inhibition in HD. Collectively, these findings indicate that ADAM10 inhibition coupled with TrkB signaling represents an efficacious strategy to prevent hippocampal synaptic plasticity defects and cognitive dysfunction in HD.

Huntington's disease (HD) causes progressive cognitive decline, with no available treatments. Computerized cognitive training (CCT) has shown efficacy in other populations, but its effects in HD are largely unknown. This pilot study will explore the effects and neural mechanisms of CCT in HD. The intervention group participants will complete 12 weeks of multidomain CCT. Control group participants will receive lifestyle education and access to CCT after the study. The primary outcome is change in processing speed. Secondary outcomes include - change in other cognitive domains, functional brain network connectivity (derived from MRI) and psychosocial function. Feasibility outcomes include rates of recruitment, adherence and retention. This study may provide insights into the effects of CCT in HD and guide future trials.Clinical Trial Registration: ACTRN12622000908730 (ClinicalTrials.gov).

Although Huntington's disease (HD) has classically been viewed as an autosomal-dominant inherited neurodegenerative motor disorder, cognitive and/or behavioral changes are predominant and often an early manifestation of disease. About 40% of individuals in the presymptomatic period of HD meet the criteria for mild cognitive impairment, later progressing to dementia. The heterogenous spectrum of cognitive decline is characterized by deficits across multiple domains, particularly executive dysfunctions, but the underlying pathogenic mechanisms are still poorly understood. Investigating the pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. Multimodal imaging revealed circuit-wide gray and white matter degenerative processes in several key brain regions, affecting prefronto-striatal/cortico-basal ganglia circuits and many other functional brain networks. Studies in transgenic animal models indicated early synaptic dysfunction, deficient neurotrophic transport and other molecular changes contributing to neuronal death. Synaptopathy within the cerebral cortex, striatum and hippocampus may be particularly important in mediating cognitive and neuropsychiatric manifestations of HD, although many other neuronal systems are involved. The interaction of mutant huntingtin protein (mHTT) with tau and its implication for cognitive impairment in HD is a matter of discussion. Further neuroimaging and neuropathological studies are warranted to better elucidate early pathophysiological mechanisms and to develop validated biomarkers to detect patients' cognitive status during the early stages of the condition significantly to implement effective preventing or management strategies.

Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase.

To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset).

A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance.

Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms.

Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.

Huntington's disease (HD) is a neurodegenerative disorder involving psychiatric, cognitive and motor deficits, as well as peripheral symptoms, including gastrointestinal dysfunction. The R6/1 HD mouse model expresses a mutant human huntingtin transgene and has been shown to provide an accurate disease model. Recent evidence of gut microbiome disruption was shown in preclinical and clinical HD. Therefore, we aimed to assess the potential role of gut microbial modulation in the treatment of HD. The R6/1 HD mice and wild-type littermate controls were randomised to receive diets containing different amounts of fibre: high-fibre (10 % fibre), control (5 % fibre), or zero-fibre (0 % fibre), from 6 to 20 weeks of age. We characterized the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal function and gut morphological changes. Faeces were collected for gut microbiome profiling using 16S rRNA sequencing, at 14 and 20 weeks of age. When compared to the control diet, high-fibre diet improved the performance of HD mice in behavioral tests of cognitive and affective function, as well as the gastrointestinal function of both HD and wild-type mice. While the diets changed the beta diversity of wild-type mice, no statistical significance was observed at 14 or 20 weeks of age within the HD mice. Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC) models were performed to evaluate microbiota composition, which identified differences, including a decreased relative abundance of the phyla Actinobacteriota, Campylobacterota and Proteobacteria and an increased relative abundance of the families Bacteroidaceae, Oscillospiraceae and Ruminococcaceae in HD mice when compared to wild-type mice after receiving high-fibre diet. PICRUSt2 revealed that high-fibre diet also decreased potentially pathogenic functional pathways in HD. In conclusion, high-fibre intake was effective in enhancing gastrointestinal function, cognition and affective behaviors in HD mice. These findings indicate that dietary fibre interventions may have therapeutic potential in Huntington's disease to delay clinical onset, and have implications for related disorders exhibiting dysfunction of the gut-brain axis.

To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations).

Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables.

Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency.

This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted.

Cognitive impairment has been widely accepted as a disease progression measure prior to the onset of Huntington's disease. We propose a sophisticated measurement error correction method that can handle potentially correlated measurement errors in longitudinally collected exposures and multiple outcomes. The asymptotic theory for the proposed method is developed. A simulation study is conducted to demonstrate the satisfactory performance of the proposed two-stage fitting method and shows that the independent working correlation structure outperforms other alternatives. We conduct a comprehensive longitudinal analysis to assess how brain striatal atrophy affects impairment in various cognitive domains for Huntington's disease.

Huntington's disease is an autosomal dominant neurodegenerative disease caused by the repetition of cytosine, adenine, and guanine trinucleotides on the short arm of chromosome 4p16.3 within the Huntingtin gene. In this study, we aim to examine and map the existing evidence on the use of innovations in the rehabilitation of Huntington's disease. A scoping review was conducted on innovative rehabilitative treatments performed on patients with Huntington's disease. A search was performed on PubMed, Embase, Web of Science, and Cochrane databases to screen references of included studies and review articles for additional citations. Of an initial 1117 articles, only 20 met the search criteria. These findings showed that available evidence is still limited and that studies generally had small sample sizes and a high risk of bias. Regarding cognitive rehabilitation, it has emerged that VR- and PC-based methods as well as NIBS techniques are feasible and may have promising effects in individuals with Huntington's disease. On the other hand, scarce evidence was found for cognitive and motor training that might have a slight impact on overall cognitive function in individuals with Huntington's disease. Data show that further investigation is needed to explore the effects of innovative rehabilitation tools on cognition, especially considering that cognitive and psychiatric symptoms can precede the onset of motor symptoms by many years.

The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD-consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non-motor diagnostic criteria for HD.

To provide (1) a recommended clinical approach toward non-motor diagnostic criteria in persons with HD and facilitation of accurate diagnosis; (2) recommended practices for medical treatment providers to screen and longitudinally monitor non-motor signs of HD.

The Huntington Study Group re-established the Neuropsychology Working Group, then recruited a multi-disciplinary group of neuropsychologists, neurologists, and psychiatrists to conduct an unstructured literature review and discuss expert opinions on practice, to facilitate an informal consensus opinion to accomplish the objectives.

The opinion and an example protocol for medical treatment providers to screen, monitor, and triage non-motor signs and symptoms of Huntington's disease is provided.

Clinical diagnosis of non-motor HD is empirically justified and clinically important. Screening and triage by non-neuropsychologist clinicians can aid in detecting and monitoring non-motor Huntington's disease manifestation. The Neuropsychology Working Group consensus advances good clinical practice, clinical research, and quality of life. A companion position paper presenting the details of our consensus opinion regarding evidence-based guidelines for neuropsychological practice is forthcoming.

Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment.

We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another.

The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories.

The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains.

A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation.

Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p < .05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p < .05) in diverse cognitive domains.

Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains.

To find sensitive neurophysiological correlates of non-motor symptoms in Huntington's disease (HD), which are essential for the development and assessment of novel treatments.

We used resting state EEG to examine differences in oscillatory activity (analysing the isolated periodic as well as the complete EEG signal) and functional connectivity in 22 late premanifest and early stage people with HD and 20 neurotypical controls. We then assessed the correlations between these neurophysiological markers and clinical measures of apathy and processing speed.

Significantly lower theta and greater delta resting state power was seen in the HD group, as well as significantly greater delta connectivity. There was a significant positive correlation between theta power and processing speed, however there were no associations between the neurophysiological and apathy measures.

We speculate that these changes in oscillatory power and connectivity reflect ongoing, frontally concentrated degenerative and compensatory processes associated with HD.

Our findings support the potential utility of quantitative EEG as a proximate marker of processing speed, but not apathy in HD.

Cognitive decline in Huntington's disease (HD) begins early in the disease course, however the reported prevalence and severity of cognitive impairment varies based on diagnostic approach. A Movement Disorders Society Task Force recently endorsed the use of standardized DSM-5-based criteria to diagnose neurocognitive disorder (NCD) in Huntington's disease.

To determine the prevalence and severity of cognitive impairment across different stages of HD by applying NCD criteria (mild and major) to participant data from the Enroll-HD database.

Enroll-HD participants were triaged into either premanifest (preHD), manifest or control groups. PreHD was further dichotomized into preHD near or preHD far based on predicted time to diagnosis using the scaled CAG-age product score (CAPs). Embedded cognitive performance and functional independence measures were used to determine prevalence of NCD (mild and major) for all groups.

Prevalence of NCD-mild was 25.2%-38.4% for manifest HD, 22.8%-47.3% for preHD near, 11.5%-25.1% for preHD far, and 8.8%-19.1% for controls. Prevalence of NCD-major was 21.1%-57.7% for manifest HD, 0.5%-16.3% for preHD near, 0.0%-4.5% for preHD far, and 0.0%-3.0% for controls.

The prevalence of NCD in HD is elevated in preHD and demonstrates a sharp rise prior to diagnosis. In manifest HD, the vast majority of participants meet criteria for NCD. These findings are important for optimizing clinical care and/or anticipating the need for supportive services.

Cognitive impairment is the core precursor to dementia and other cognitive disorders. Current hypotheses suggest that they share a common pathological basis, such as inflammation, restricted neurogenesis, neuroendocrine disorders, and the destruction of neurovascular units. Fibroblast growth factors (FGFs) are cell growth factors that play essential roles in various pathophysiological processes via paracrine or autocrine pathways. This system consists of FGFs and their receptors (FGFRs), which may hold tremendous potential to become a new biological marker in the diagnosis of dementia and other cognitive disorders, and serve as a potential target for drug development against dementia and cognitive function impairment. Here, we review the available evidence detailing the relevant pathways mediated by multiple FGFs and FGFRs, and recent studies examining their role in the pathogenesis and treatment of cognitive disorders and dementia.

Cognitive decline has been reported in premanifest and manifest Huntington's disease but reliable biomarkers are lacking. Inner retinal layer thickness seems to be a good biomarker of cognition in other neurodegenerative diseases.

To explore the relationship between optical coherence tomography-derived metrics and global cognition in Huntington's Disease.

Thirty-six patients with Huntington's disease (16 premanifest and 20 manifest) and 36 controls matched by age, sex, smoking status, and hypertension status underwent macular volumetric and peripapillary optical coherence tomography scans. Disease duration, motor status, global cognition and CAG repeats were recorded in patients. Group differences in imaging parameters and their association with clinical outcomes were analyzed using linear mixed-effect models.

Premanifest and manifest Huntington's disease patients presented thinner retinal external limiting membrane-Bruch's membrane complex, and manifest patients had thinner temporal peripapillary retinal nerve fiber layer compared to controls. In manifest Huntington's disease, macular thickness was significantly associated with MoCA scores, inner nuclear layer showing the largest regression coefficients. This relationship was consistent after adjusting for age, sex, and education and p-value correction with False Discovery Rate. None of the retinal variables were related to Unified Huntington's Disease Rating Scale score, disease duration, or disease burden. Premanifest patients did not show a significant association between OCT-derived parameters and clinical outcomes in corrected models.

In line with other neurodegenerative diseases, OCT is a potential biomarker of cognitive status in manifest HD. Future prospective studies are needed to evaluate OCT as a potential surrogate marker of cognitive decline in HD.

Cognitive impairment is prevalent in Huntington's disease (HD), with no treatments currently available. While cognition-oriented treatments and physical exercise have shown efficacy in improving cognition in other populations, they have not been systematically reviewed in HD. This systematic review aims to examine the effects of cognitive and exercise interventions on cognition in HD, along with effects on psychosocial function, functional independence, and neuroimaging outcomes. Seventeen studies (three cognitive, seven exercise, seven combining cognitive and physical exercise) were included. While there was generally low certainty of evidence, interventions that included cognitive training appeared to have larger effect sizes on cognition, while physical exercise (alone or combined with cognitive rehabilitation or stimulation) showed negligible effect sizes. On the other hand, combined interventions had larger effects on psychosocial function. Finally, effects on functional independence appeared negligible following exercise and combined interventions, and effects on neuroimaging outcomes were inconclusive. Larger studies should seek to confirm the benefits of cognitive and physical interventions, and further explore changes in functional independence and neural outcomes.

Longitudinal data clustering is challenging because the grouping has to account for the similarity of individual trajectories in the presence of sparse and irregular times of observation. This paper puts forward a hierarchical agglomerative clustering method based on a dissimilarity metric that quantifies the cost of merging two distinct groups of curves, which are depicted by B-splines for the repeatedly measured data. Extensive simulations show that the proposed method has superior performance in determining the number of clusters, classifying individuals into the correct clusters, and in computational efficiency. Importantly, the method is not only suitable for clustering multivariate longitudinal data with sparse and irregular measurements but also for intensely measured functional data. Towards this end, we provide an R package for the implementation of such analyses. To illustrate the use of the proposed clustering method, two large clinical data sets from real-world clinical studies are analyzed.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington's disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington's disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington's disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington's disease and their effect on brain structure.

To investigate if executive and social cognitive dysfunction was associated with apathy in a large cohort of Huntington's disease gene expansion carriers.

Eighty premanifest and motor-manifest Huntington's disease gene expansion carriers (Mini-Mental State Examination score ≥ 24 and Montreal Cognitive Assessment score ≥ 19) and thirty-two controls were examined with the Lille Apathy Rating Scale (LARS), a tailored and quantitative measure of apathy, and a comprehensive cognitive battery on executive functions and social cognition (emotion recognition, theory of mind and sarcasm detection), as well as general correlates like demographic variables, and neuropsychiatric and cognitive screening tests.

The motor-manifest Huntington's disease gene expansion carriers had significantly different scores on most measures of social cognition and executive functions, compared to premanifest and control participants. Apathy was significantly correlated with most executive test scores, but the Emotion Hexagon was the only social cognitive test score significantly correlated with apathy. We found that the motor score and the depression score were the only significant predictors of the apathy score, when the social cognitive and executive tests with the strongest association with the global LARS score were entered into a multiple stepwise regression model. No cognitive test score could significantly predict apathy. The model explained 21 % of the total variance.

Despite being significantly correlated with apathy neuropsychological variables did not have a significant impact on apathy when variables as depression and motor symptoms were taken into account. Apathy should be considered an independent symptom of Huntington's disease that requires specific examination.

In this manuscript we propose a spline-based sieve nonparametric maximum likelihood estimation method for joint distribution function with bivariate interval-censored data. We study the asymptotic behavior of the proposed estimator by proving the consistency and deriving the rate of convergence. Based on the sieve estimate of the joint distribution, we also develop an efficient nonparametric test for making inference about the dependence between two interval-censored event times and establish its asymptotic normality. We conduct simulation studies to examine the finite sample performance of the proposed methodology. Finally we apply the method to assess the association between two subtypes of mild cognitive impairment (MCI): amnestic MCI and non-amnestic MCI, for Huntington disease (HD) using data from a 12-year observational cohort study on premanifest HD individuals, PREDICT-HD.

Huntington's disease (HD) is a dramatic neurodegenerative disorder encompassing severe motor symptoms coupled to significant cognitive and social cognition deficits. However, it is not clear whether and how patients' neuropsychological profile changes between the prodromal and the manifest stages of the condition. The aim of the present in-depth review is to consider cognitive and social cognition impairment in HD patients by differentiating deficits arising before diagnosis from those evident from the manifest phase onwards.

Electronic databases were searched between January 1st , 2010 and December 31st , 2020 by using multiple combinations of keywords related to the investigation of neuropsychological profile in HD for preliminary search, and by defining strict selection criteria for studies to be included.

Forty-two studies were included. Evidence suggests that the neuropsychological profile in HD reflects a complex pathological spectrum of deficits. It includes impairment in the realms of executive functions, memory, attention, information processing, and social cognition. Interestingly, patients' profiles differ significantly between the manifest and the prodromal stages of their condition, not only in quantitative terms but also from a qualitative point of view.

Researchers and clinicians should thus include in clinical routine timely and specific neuropsychological assessments in order to monitor patients' cognitive status as time goes by, with the ultimate goal to implement effective clinical management strategies.

The neuropsychological profile in HD encompasses a complex pathological spectrum of deficits. Patients' profiles differ significantly between the manifest and the prodromal stages of their condition. Clinicians should include in everyday practice a timely and specific neuropsychological assessment. Detecting patients' cognitive status during the early stages of the condition already can contribute significantly to implement effective clinical management strategies.

Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.

Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase.

To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset).

A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance.

Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms.

Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.

Alzheimer's disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington's disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

Social health is an important concern in persons with Huntington's disease (HD); however, there is little literature examining this construct in this population.

While cross-sectional data supports the clinical utility of two Neuro-QoL social health measures in persons with HD, data is still needed to establish their longitudinal validity.

Participants (N = 358) completed baseline and at least one follow-up (12- and 24-month) assessment that included the completion of Neuro-QoL Social Health computer adaptive tests (CATs) and short forms (for Ability to Participate in Social Roles and Activities [SRA] and Satisfaction with SRA). Test-retest reliability was examined using intra class correlations, and one-way ANOVAs with Bonferroni post-hoc contrasts were used to determine whether there were group differences among premanifest, early- and late-stage HD participants on the Social health measures. In addition, standardized response means were used to examine longitudinal responsiveness, and mixed or general linear models were used to examine change over time (relative to self-reported change on an associated anchor item about social health and clinician-rated change based on Total Functional Capacity scores from the UHDRS).

Test-retest reliability of the measures was excellent (ICCs ranged from 0.82 to 0.87 across the different measures) and persons with greater disease burden reported more problems with social health than those at earlier stages in the disease process (all p < 0.0001). Responsiveness was supported for all measures except the Ability to Participate in SRA CAT; participants who had self-reported or clinician-rated declines in health generally had 12- and 24-month declines on the Neuro-QoL measures.

Findings indicate that these measures may be useful for studies attempting to assess change in social health over time.

Neurofilament light chain (NfL) is an emerging biomarker of neural degeneration. NfL is an integral component of axons and is released into the bloodstream and cerebrospinal fluid during neurodegeneration; hence it can be used to monitor disease progression. Given that several neurological disorders are accompanied by cognitive decline, recent literature has investigated the relationship between NfL levels and cognition. The objective of this scoping review was to determine whether a consistent relationship between NfL and cognition exists in the context of variable degrees of neurodegeneration present across several neurological disorders. Four electronic databases were searched for relevant articles and 160 articles were initially identified. After article screening, 37 studies met the final inclusion criteria. Studies were then qualitatively synthesized to determine the relationship between NfL and cognition across a variety of neurological disorders. The large majority of studies found that NfL levels are inversely correlated with cognition, such that higher NfL levels are associated with poorer cognition. This relationship was not universal, however, and this discrepancy was speculated to be due to the nature of the neurological disorder, individual differences between participants, or methodological inconsistencies. Further study is required, and associated recommendations were proposed for the design of future investigations.

Cognitive impairment is a distinguishing feature of many neurodegenerative diseases. The intra-dimensional (ID) extra-dimensional (ED) attentional set shift task is part of a clinical battery of tests used to evaluate executive function in Huntington's and Alzheimer's disease patients. The IDED task, however, has not translated well to pre-clinical rodent models of neurological disease.

The ability to perform executive tasks coupled with a long lifespan makes sheep (Ovis aries) an ideal species for modelling cognitive decline in progressive neurodegenerative conditions. We describe the methodology for testing the performance of sheep in the IDED task using a semi-automated system in which visual stimuli are presented as coloured letters on computer screens.

During each stage of IDED testing, all sheep (n = 12) learned successfully to discriminate between different colours and letters. Sheep were quick to learn the rules of acquisition at each stage. They required significantly more trials to reach criterion (p < 0.05) and made more errors (p < 0.05) following stimulus reversal, with the exception of the ED shift (p > 0.05).

Previous research shows that sheep can perform IDED set shifting in a walk-through maze using solid objects with two changeable dimensions (colour and shape) as the stimuli. Presenting the stimuli on computer screens provides better validity, greater task flexibility and higher throughput than the walk-through maze.

All sheep completed each stage of the task, with a range of abilities expected in an outbred population. The IDED task described is ideally suited as a quantifiable and clinically translatable measure of executive function in sheep.

The majority of persons with Huntington disease (HD) experience mental health symptoms. Patient-reported outcome (PRO) measures are capable of capturing unobservable behaviors and feelings relating to mental health. The current study aimed to test the reliability and responsiveness to self-reported and clinician-rated change over time of Neuro-QoL and PROMIS mental health PROs over the course of a 24-month period.

At baseline, 12-months, and 24-months, 362 participants with premanifest or manifest HD completed the Neuro-QoL Depression computer adaptive test (CAT), PROMIS Depression short form (SF), Neuro-QoL Anxiety CAT, PROMIS Anxiety SF, PROMIS Anger CAT and SF, Neuro-QoL Emotional/Behavioral Dyscontrol CAT and SF, Neuro-QoL Positive Affect and Well-Being CAT and SF, and Neuro-QoL Stigma CAT and SF. Participants completed several clinician-administered measures at each time point, as well as several global ratings of change at 12- and 24-months. Reliability (test-retest reliability and measurement error) and responsiveness (using standardized response means and general linear models) were assessed.

Test-retest reliability and measurement error were excellent for all PROs (all ICC ≥ .90 for test-retest reliability and all SEM percentages ≤ 6.82%). In addition, 12- and 24-month responsiveness were generally supported for the Neuro-QoL and PROMIS mental health PROs; findings relative to clinician-rated anchors of change (e.g., SRMs for the group with declines ranged from .38 to .91 for 24-month change and .09 to .45, with the majority above .25 for 12-month change) were generally more robust than those relative to self-reported anchors of change (e.g., SRMs for the group with declines ranged from .02 to .75, with the majority above .39 for 24-month change and .09 to .45, with the majority above .16 for 12-month change).

The Neuro-QoL and PROMIS mental health PROs demonstrated strong psychometric reliability, as well as responsiveness to self-reported and clinician-rated change over time in people with HD.

The clinical diagnosis of Parkinson's disease (PD) based on motor signs is often preceded by several non-motor symptoms that can indicate early prodromal neurodegenerative processes. Such prodromal symptoms can aid the early detection of PD, but their specificity for prodromal PD in comparison to prodromes of other movement disorders is still largely unclear. We here aim to give a first insight into the published evidence of prodromal non-motor symptoms in PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease (HD), progressive supranuclear palsy (PSP) and spinocerebellar ataxia (SCA). REM-sleep behavior disorder (RBD) and autonomic dysfunction have been observed in the prodromes of PD, MSA, DLB and SCA. Depression and cognitive decline have been reported for prodromal PD, DLB, HD, SCA, and PSP. Olfactory loss has only been described in prodromal PD/DLB. However, estimating the specificity of prodromal non-motor symptoms in PD is so far complicated by scarce prospective evidence and study limitations. Information on marker specificity is a prerequisite for an accurate early (differential) diagnosis of prodromal diseases, as well as specific recruitment for targeted neuroprotective interventions. We here would like to raise awareness of these issues and encourage further prospective research of prodromal non-motor symptoms in neurodegenerative movement disorders and other diseases.

Huntington's disease (HD) is an extraordinary disorder that usually strikes when individuals are in the prime of their lives, as was the case for the influential 20th century musician Woody Guthrie. HD demonstrates the exceptionally fine line between life and death in such 'genetic diseases', as the only difference between those who suffer horribly and die slowly of this disease is often just a handful of extra tandem repeats (beyond the normal polymorphic range) in a genome that constitutes over 3 billion paired nucleotides of DNA. Furthermore, HD presents as a complex and heterogenous combination of psychiatric, cognitive and motor symptoms, so can appear as an unholy trinity of 'three disorders in one'. The autosomal dominant nature of the disorder is also extremely challenging for affected families, as a 'flip of a coin' dictates which children inherit the mutation from their affected parent, and the gene-negative family members bear the burden of caring for the other half of the family that is affected. In this review, we will focus on one of the earliest, and most devastating, symptoms associated with HD, depression, which has been reported to affect approximately half of gene-positive HD family members. We will discuss the pathogenesis of HD, and depressive symptoms in particular, including molecular and cellular mechanisms, and potential genetic and environmental modifiers. This expanding understanding of HD pathogenesis may not only lead to novel therapeutic options for HD families, but may also provide insights into depression in the wider population, which has the greatest burden of disease of any disorder and an enormous unmet need for new therapies.

To determine the frequency and relative importance of symptoms experienced by adults with Huntington disease (HD) and to identify factors associated with a higher disease burden.

We performed 40 qualitative interviews (n = 20 with HD, n = 20 caregivers) and analyzed 2,082 quotes regarding the symptomatic burden of HD. We subsequently performed a cross-sectional study with 389 participants (n = 156 with HD [60 of whom were prodromal], n = 233 caregivers) to assess the prevalence and relative importance (scale 0-4) of 216 symptoms and 15 symptomatic themes in HD. Cross-correlation analysis was performed based on sex, disease duration, age, number of CAG repeats, disease burden, Total Functional Capacity score, employment status, disease status, and ambulatory status.

The symptomatic themes with the highest prevalence in HD were emotional issues (83.0%), fatigue (82.5%), and difficulty thinking (77.0%). The symptomatic themes with the highest relative importance to participants were difficulty thinking (1.91), impaired sleep or daytime sleepiness (1.90), and emotional issues (1.81). High Total Functional Capacity scores, being employed, and having prodromal HD were associated with a lower prevalence of symptomatic themes. Despite reporting no clinical features of the disease, prodromal individuals demonstrated high rates of emotional issues (71.2%) and fatigue (69.5%). There was concordance between the prevalence of symptoms reported by manifest individuals and caregivers.

Many symptomatic themes affect the lives of those with HD. These themes have a variable level of importance to the HD population and are identified both by those with HD and by their caregivers.

Cognitive impairment is an essential feature of Huntington's disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking.

We aimed to explore the utility of the Parkinson's disease-Cognitive Rating Scale (PD-CRS) for the screening of global cognition in HD.

A multicenter cohort of 132 HD patients at different disease stages and 33 matched healthy controls were classified as having preserved cognition, mild cognitive impairment (HD-MCI) or dementia (HD-Dem) according to the Clinical Dementia Rating and Functional Independence Score. The PD-CRS and the Mini-Mental State Examination were administered. Receiver operating characteristic curve analysis was used to determine optimal cutoffs to differentiate patients according to their cognitive status.

A PD-CRS cutoff score ≤ 81/82 was optimal to detect HD-MCI (sensitivity = 93%; specificity = 80%; area under the curve (AUC) = 0.940), and ≤ 63/64 was optimal to detect HD-Dem (sensitivity = 90%; specificity = 87%; AUC = 0.933). MMSE scores failed to show robust psychometric properties in this context.

The PD-CRS is a valid and reliable instrument to assess global cognition in HD in routine clinical care and clinical trials.

Learning and memory impairment manifests years before the onset of motor impairments in Huntington's disease (HD). Oxytocin (OXT), as a neurohypophyseal neuropeptide has a key role in both learning and memory. Hence, we investigated possible protective effect of OXT on instrumental fear conditioning memory impairment by 3-Nitropropionic acid (3-NP) induced HD, considering sex and prenatal stress effects. Pregnant Wistar rats were exposed to restraint stress for 45 min three times a day, from the gestational day 8 to parturition. 3-NP was injected intraperitoneally (20 mg/kg) for 5-7 days after OXT (10 μg/μl. icv) injection in the male and female offspring rats respectively. One day after the last 3-NP injection, the rotarod and passive avoidance task were conducted. As the key molecular determinants in metabolism and memory processes, we measured the activity of acetylcholinesterase (AChE) and the amount of receptor interacting protein3 (RIP3) in the hippocampus, prefrontal cortex, striatum and amygdala using spectrophotometry and western blotting respectively. Besides, the activity of glutamate dehydrogenase was measured (GDH) as a chain between metabolism and memory formation. The results indicated that OXT improved learning and memory impairment caused by 3-NP or prenatal stress in both sexes. It was along with a significant decrease in the level of RIP3, AChE and GDH activities. However, in the presence of prenatal stress, the OXT could improve 3-NP induced learning and memory impairments just in female rats. So it could be suggested as an effective neurotherapeutic agent in diseases such as HD, but its sex and context dependency should be considered carefully.

Individuals with Huntington disease (HD) experience progressive cognitive decline that may appear years before motor manifestations of the disease. These declines have a profound effect on health-related quality of life (HRQOL) over the disease course, and thus it is important that self-report measures of cognitive function are validated for use in longitudinal studies.

359 individuals with premanifest or manifest HD completed baseline and at least one follow-up (12- and 24-month) assessment. Neuro-QoL™ Cognitive Function was administered at each time-point. Participants completed a self-reported global rating of cognitive change, as well as performance-based cognitive changes (using the Symbol Digit Modalities Test). Standardized response means (SRMs) and general linear models evaluated whether Neuro-QoL™ Cognitive Function was responsive to change over time with respect to self-reported and performance-based anchors. Test-retest reliability and known-group validity were also examined.

Responsiveness was supported by effect sizes that were small in magnitude, but in the expected direction relative to self-reported and performance-based change. General linear models generally supported 12- and 24-month responsiveness relative to self-reported cognitive change and 12-month responsiveness relative to performance-based change. Test-retest reliability was excellent, and the measure exhibited known-group validity.

Longitudinal analyses generally indicate that the Neuro-QoL™ Cognitive Function measure is sensitive to change over time in individuals with HD. Neuro-QoL Cognitive Function changes reflect self-reported cognitive change at 12 and 24 months and performance-based change at 12 months. This measure may be useful in clinical trials or longitudinal observation studies.

Huntington's disease (HD) is a neurological disorder that causes severe motor symptoms that adversely impact health-related quality of life. Patient-reported physical function outcome measures in HD have shown cross-sectional evidence of validity, but responsiveness has not yet been assessed.

This study evaluates the responsiveness of the Huntington Disease Health-Related Quality of Life (HDQLIFE) and the Quality of Life in Neurological Disorders (Neuro-QoL) physical function measures in persons with HD.

A total of 347 participants completed baseline and at least 1 follow-up (12-month and 24-month) measure (HDQLIFE Chorea, HDQLIFE Swallowing Difficulties, HDQLIFE Speech Difficulties, Neuro-QoL Upper Extremity Function, and/or Neuro-QoL Lower Extremity Function). Of the participants that completed the baseline assessment, 338 (90.9%) completed the 12-month assessment, and 293 (78.8%) completed the 24-month assessment. Standardized response means and general linear models evaluated whether the physical function measures were responsive to self-reported and clinician-rated change over time.

Small to moderate effect sizes for the standardized response means supported 12-month and 24-month responsiveness of the HDQLIFE and Neuro-QoL measures for those with either self-reported or clinician-rated declines in function. General linear models supported 12-month and 24-month responsiveness for all HRQOL measures relative to self-reported declines in health, but generally only 24-month responsiveness was supported relative to clinician-rated declines in function.

Longitudinal analyses indicate that the HDQLIFE and the Neuro-QoL physical function measures are sensitive to change over time in individuals with HD. Thus, these scales exhibit evidence of responsiveness and may be useful outcome measures in future clinical trials. © 2019 International Parkinson and Movement Disorder Society.