Search Results (15)

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies. Full article

Background/Objectives: Huntington’s disease (HD) is a neurodegenerative movement disorder associated with significant disability and impairment of Activities of Daily Living (ADLs). The impact of upper limb disability on quality of life (QoL) and its influence on ADLs is not well known yet. The aim of this study was to describe the manipulative dexterity, strength, and manual eye coordination of patients with manifest and premanifest-HD compared to healthy individuals and to analyze its influence on ADLs and QoL. Methods: We performed an observational, cross-sectional study including 71 ambulatory participants (27 manifest-HD patients, 15 premanifest-HD, and 29 controls). We gathered sociodemographic data, as well as clinical data, including cognition (MMSE), HD motor severity (Unified HD rating scale, UHDRS-TMS), QoL (Neuro-QoL), and ADLs (HD-ADL). Hand dexterity and strength in the dominant and non-dominant hand were assessed with the Nine Hole Peg Test, Ten Neurotest, Nut and Bolt Test, dynamometry, and Late-Life FDI. Analysis of covariance (ANCOVA) models were performed to investigate differences in hand function between manifest-HD, premanifest-HD, and controls. Results: Manifest-HD patients had significantly worse performance in manual and finger dexterity, fine-motor coordination, and poorer handgrip strength than premanifest-HD and controls. Premanifest-HD required more time to complete the test than controls. Significant correlations were found between hand variables and Late-Life FDI, Neuro-QoL, HD-ADL, and UHDRS-TMS. Conclusions: HD affects manipulative dexterity and hand function in premanifest and manifest patients. Therefore, to prevent disability and decreased QoL, evaluating the progression of upper limb dysfunction in HD is important to offer the best possible therapeutic interventions. Full article

Background/Objectives: Huntington’s disease (HD) is a fully penetrant neurodegenerative disease with a profound effect on quality of life. In recent years, there has been rapid growth in the description of its pathogenesis and diagnosis. Magnetic resonance spectroscopy (MRS) measurements can aid in the discrimination between premanifest Huntington’s disease (Pre-HD) and healthy control (HC) subjects to establish early supportive and symptomatic management. Our objective was to evaluate metabolic changes using MRS to shed light on its potential as a biomarker through a systematic review. Methods: We followed the PRISMA guidelines, extracting articles from PubMed, Scopus, and the Virtual Health Library. We included patients with pre-HD, HD, and HC subjected to MRS, reporting the concentration of metabolites in at least one brain region. Results: In the putamen, N-acetyl Aspartate (NAA) was significantly decreased in 77.9% and total NAA (tNAA) was decreased in 72.4% of cases; no significant difference was found in 27.5% (n = 19) of cases. Furthermore, when looking into HD vs. pre-HD in the putamen, tNAA and NAA were decreased in 100% of participants. In the caudate nucleus, NAA and creatine were significantly decreased in 100% of HD in comparison to pre-HD participants, whereas tNAA showed a significant decrease in only 50%. Conclusions: MRS can be a relevant tool for the early diagnosis of HD; potential objective biomarkers related to its onset and pathogenesis exist and show differences between controls, pre-HD and HD patients. However, an effort should be made to standardize MRS methodology and reporting in subsequent studies. Full article

Background and objectives: The premanifest phase of Huntington’s disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed using artificial intelligence (AI) software in premanifest HD individuals, focusing on the relationship between CAG triplet expansion and structural biomarkers. Methods: The study included 36 individuals descending from families affected by HD in the Department of Atlántico. Sociodemographic data were collected, followed by peripheral blood sampling to extract genomic DNA for quantifying CAG trinucleotide repeats in the Huntingtin gene. Brain volumes were evaluated using AI software (Entelai/IMEXHS, v4.3.4) based on MRI volumetric images. Correlations between brain volumes and variables such as age, sex, and disease status were determined. All analyses were conducted using SPSS (v. IBM SPSS Statistics 26), with significance set at p < 0.05. Results: The analysis of brain volumes according to CAG repeat expansion shows that individuals with ≥40 repeats evidence significant increases in cerebrospinal fluid (CSF) volume and subcortical structures such as the amygdalae and left caudate nucleus, along with marked reductions in cerebral white matter, the cerebellum, brainstem, and left pallidum. In contrast, those with <40 repeats show minimal or moderate volumetric changes, primarily in white matter and CSF. Conclusions: These findings suggest that CAG expansion selectively impacts key brain regions, potentially influencing the progression of Huntington’s disease, and that AI in neuroimaging could identify structural biomarkers long before clinical symptoms appear. Full article

Background: The Total Functional Capacity (TFC) score is commonly used in Huntington’s disease (HD) research. The classification separates each disease stage (1–5), e.g., as an inclusion criterion or endpoint in clinical trials accepted by the Food and Drug Administration (FDA). In addition to the quantification of age- and CAG-repeat-dependent effects as well as interacting effects of both on the TFC, we aimed to investigate factors influencing the TFC, such as neuropsychiatric, educational, and cognitive disease burden using data from the largest HD observational study to date. In addition, we analyzed data from pre-manifest stages to investigate the influence of the above-mentioned factors on the TFC in that stage. Methods: A moderated regression analysis was conducted to analyze the interaction effects of age and CAG-repeat length on the TFC in HD patients. A simple slope analysis was calculated to illustrate the effects. Depending on TFC results, motor-manifest patients were grouped into five stages. Data from pre-manifest participants were analyzed with regard to years to onset and CAP scores. Results: We identified N = 10,314 participants as manifest HD. A significant part of variance on the TFC was explained by age (R² = 0.029, F (1;10,281) = 308.02, p < 0.001), CAG-repeat length (∆R² = 0.132, ∆F (1;10,280) = 1611.22, p < 0.001), and their interaction (∆R² = 0.049, ∆F (1;10,279) = 634.12, p < 0.001). The model explained altogether 20.9% of the TFC score’s variance (F = 907.60, p < 0.001). Variance of psychiatric and cognitive symptoms significantly differed between stages. Exploratory analysis of median data in pre-manifest participants revealed the highest scores for neuropsychiatric changes between 5 to <20 years from the disease onset. Conclusions: TFC is mainly explained by the neurobiological factors, CAG-repeat length, and age, with subjects having more CAG-repeats showing a faster decline in function. Our study confirms TFC as a robust measure of progression in manifest HD. Full article

Huntington’s disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades. Full article

Introduction: Huntington’s disease (HD) is often on the margin of standard medical practice due to its low prevalence, the lack of causal treatment, and the typically long premanifest window prior to the onset of the symptoms, which contrasts with the long-lasting burden that the disease causes in affected families. Methods: To capture these socio-psychological aspects of HD and map the experiences of affected individuals, persons at risk of HD, and caregivers, we created a questionnaire using a qualitative research approach. The questionnaire containing 16 questions was conducted online for a period of three months through patient associations in Slovakia and their infrastructures. Results: In total, we received 30 responses. The survey results, in particular, indicate insufficient counselling by physicians with explicitly missing information about the possibility of preimplantation genetic diagnostic. There was also a necessity to improve comprehensive social and health care in the later stages of the disease, raise awareness of the disease in the general health community, and provide more information on ongoing clinical trials. Conclusion: The psychosocial effects, as well as the burden, can be mitigated by comprehensive genetic counselling as well as reproductive and financial guidelines and subsequent therapeutic programs to actively support patients, caregivers, children, and adolescents growing up in affected families, preferably with the help of local HD community association. Limitations: We have used online data collection to reach a wider HD community, but at the same time, we are aware that the quality of the data we would obtain through face-to-face interviews would be considerably better. Therefore, future studies need to be conducted to obtain more detailed information. Full article

The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39–51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects. Full article

There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects. Full article

Pain is a minor problem compared with other Huntington Disease (HD) symptoms. Nevertheless, in HD it is poorly recognized and underestimated. So far, no study evaluated the presence of chronic pain in HD. The aim of this pilot study was to evaluate the presence and features of chronic pain in a cohort of HD gene carriers. An observational cross-sectional study was conducted in a cohort of HD gene carriers compared to not gene carriers (n.134 HD subjects, n.74 not gene mutation carriers). A specific pain interview, alongside a neurological, cognitive and behavioural examination, was performed in order to classify the type of pain, subjective intensity. A significant prevalence of “no Pain” in HD was found, which tended to increase with HD progression and a reduced frequency of pain in the last 3 months. A clear difference was found between manifest and premanifest HD in terms of intensity of pain, which did not change significantly with HD progression; however, a tendency emerges to a progressive reduction. No significant group difference was present in analgesic use, type and the site of pain. These findings could support a lower prevalence of chronic pain in manifest HD. Prevalence and intensity of chronic pain seem directly influenced by the process of neurodegeneration rather than by an incorrect cognitive and emotional functioning. Full article

The purpose of this study was to classify Huntington’s disease (HD) stage using support vector machines and measures derived from T1- and diffusion-weighted imaging. The effects of feature selection approach and combination of imaging modalities are assessed. Fourteen premanifest-HD individuals (Pre-HD; on average > 20 years from estimated disease onset), eleven early-manifest HD (Early-HD) patients, and eighteen healthy controls (HC) participated in the study. We compared three feature selection approaches: (i) whole-brain segmented grey matter (GM; voxel-based measure) or fractional anisotropy (FA) values; (ii) GM or FA values from subcortical regions-of-interest (caudate, putamen, pallidum); and (iii) automated selection of GM or FA values with the algorithm Relief-F. We assessed single- and multi-kernel approaches to classify combined GM and FA measures. Significant classifications were achieved between Early-HD and Pre-HD or HC individuals (accuracy: generally, 85% to 95%), and between Pre-HD and controls for the feature FA of the caudate ROI (74% accuracy). The combination of GM and FA measures did not result in higher performances. We demonstrate evidence on the high sensitivity of FA for the classification of the earliest Pre-HD stages, and successful distinction between HD stages. Full article

Background: In addition to the effects on patients suffering from motor-manifest Huntington’s disease (HD), this fatal disease is devasting to people who are at risk, premanifest mutation-carriers, and especially to whole families. There is a huge burden on people in the environment of affected HD patients, and a need for further research to identify at-risk caregivers. The aim of our research was to investigate a large cohort of family members, in comparison with genotype negative and premanifest HD in order to evaluate particular cohorts more closely. Methods: We used the ENROLL-HD global registry study to compare motoric, cognitive, functional, and psychiatric manifestation in family members, premanifest HD, and genotype negative participant as controls. Cross-sectional data were analyzed using ANCOVA-analyses in IBM SPSS Statistics V.28. Results: Of N = 21,116 participants from the global registry study, n = 5174 participants had a premanifest motor-phenotype, n = 2358 were identified as family controls, and n = 2640 with a negative HD genotype. Analysis of variance revealed more motoric, cognitive, and psychiatric impairments in premanifest HD (all p < 0.001). Self-reported psychiatric assessments revealed a significantly higher score for depression in family controls (p < 0.001) when compared to genotype negative (p < 0.001) and premanifest HD patients (p < 0.05). Family controls had significantly less cognitive capacities within the cognitive test battery when compared to genotype negative participants. Conclusions: Within the largest cohort of HD patients and families, several impairments of motoric, functional, cognitive, and psychiatric components can be confirmed in a large cohort of premanifest HD, potentially due to prodromal HD pathology. HD family controls suffered from higher self-reported depression and less cognitive capacities, which were potentially due to loaded or stressful situations. This research aims to sensitize investigators to be aware of caregiver burdens caused by HD and encourage support with socio-medical care and targeted psychological interventions. In particular, further surveys and variables are necessary in order to implement them within the database so as to identify at-risk caregivers. Full article

There has been great progress in Huntington’s disease (HD) research. Yet, effective treatments to halt disease before the onset of disabling symptoms are still unavailable. Scientific breakthroughs require an active and lasting commitment from families. However, they are traditionally less involved and heard in studies. Accordingly, the European Huntington Association (EHA) surveyed individuals at risk (HDRisk) and with premanifest HD (PreHD) to determine which factors affect their willingness to participate in research. Questions assessed research experience and knowledge, information sources, reasons for involvement and noninvolvement, and factors preventing and facilitating participation. The survey included 525 individuals, of which 68.8% never participated in studies and 38.6% reported limited research knowledge. Furthermore, 52% trusted patient organizations to get research information. Reasons for involvement were altruistic and more important than reasons for noninvolvement, which were related to negative emotions. Obstacles included time/financial constraints and invasive procedures, while professional support was seen as a facilitator. PreHD individuals reported less obstacles to research participation than HDRisk individuals. Overall, a high motivation to participate in research was noted, despite limited experience and literacy. This motivation is influenced by subjective and objective factors and, importantly, by HD status. Patient organizations have a key role in fostering motivation through education and support. Full article

Huntington’s disease (HD) is a neurodegenerative dementia with a well recognised genetic cause. Alcohol misuse is a major environmental factor relevant to numerous neurological presentations, including HD. We explored the effects of alcohol intake on clinical features of HD by means of data from the Enroll-HD, which is a global registry study. A retrospective observational study making use of the Enroll-HD periodic dataset up to 2020 (in accordance with the Enroll-HD guidelines, encompassing 16,120 subjects with the HD gene (CAG expansion > 36), was carried out. This included 180 sites in 21 countries. The study looked at the association of alcohol use with the clinical presentation of HD, specifically looking into the age of first symptoms and HD severity. We also describe a specific case with manifest HD, a participant in the Enroll-HD study, whereby the patient’s obsessionality was central to her pattern of high alcohol intake and to her successful avoidance of alcohol thereafter. A record of past problems with high alcohol intake was more common in the group with manifest HD (9.0%, n = 1121) when compared with the pre-manifest carriers of the HD genetic abnormality (2.3%, n = 339). Age at onset of symptoms was not significantly influenced by current alcohol misuse, or past misuse. The severity of clinical impairments in HD was influenced by alcohol. Patients who reported high alcohol intake in the past had a statistically significant increase in motor impairments, by the Unified Huntington’s Disease Rating Scale total motor score (Kruskal–Wallis, post hoc Dunn’s, p < 0.001), and a significantly higher burden of psychiatric symptoms by the Problem Behaviours Assessment score (Kruskal–Wallis, post hoc Dunn’s, p < 0.01) compared with those not reporting high alcohol use. However, the past alcohol group did not have a lower Mini Mental State Examination score (Kruskal–Wallis, post hoc Dunn’s, p > 0.05) The first symptom of HD, as determined by the assessing clinician, was more likely to be psychiatric disturbance in patients currently misusing alcohol or those with prior history of alcohol misuse (55% and 31% respectively) when compared with controls (5%). Individual case experience, such as that presented in this study, shows that HD and alcohol, two major genetic and environmental contributors to neurodegeneration, interact in producing clinical problems. However, the complexities of these interactions are difficult to define, and may require larger studies dedicated to exploring the various factors in this interaction. Full article

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression. Full article