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MRI brain comparison and measurements in control person and person with Huntington's Disease. Anatomical landmarks of the basal ganglia (putamen in blue and caudate in red) are shown on the normal T1 axial MRI (left), with measurement markers of atrophy (CC: inter-caudate distance; FH: frontal horn distance of lateral ventricles; IT: inner table of skull). In contrast, severe caudate and frontal-predominant global atrophy are demonstrated in an MRI of Huntington's Disease (right). MRI for Figure 2 is created by the authors with adapted measurements from Ho et al. 14
Source publication
Objectives:
Huntington's disease (HD) is a profoundly incapacitating, and ultimately fatal, neurodegenerative disease. HD is presently incurable, so the current goal is to allow affected individuals to live as well as possible with the illness, to maximise functional independence and quality of life for the person with HD, their carers and family...
Context in source publication
Context 1
... or corticostriatal MRI atrophy (particularly caudate and putamen) have been implicated as a useful marker for disease progression. 12 Clinically, measuring inter-caudate distance against the inner aspect of the skull, or the frontal span of the lateral ventricle, are useful methods for identifying caudate atrophy (see Figure 2). Significant cerebral cortical grey and white matter loss in patients with HD is also common, particularly in frontal zones. ...
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Background
Disease-modifying treatments for Huntington’s disease (HD) are entering clinical trials: there is a pressing need for objective outcome measures of disease progression. Our previous work showed an association between 2 novel, objective cognitive tasks and apathy - a core feature of disease progression in HD.
Objective
Evaluate the longi...
Citations
... Symptom presentation begins mid-life in a prodromal phase, often with the onset of subclinical cognitive difficulties, and behavioural and psychiatric symptoms, followed by subtle motor symptoms. The presence of unequivocal motor dysfunction is a hallmark requirement for the clinical motor diagnosis of manifest HD. 1 Currently, this clinical motor diagnosis is provided by a neurologist, following completion of the Unified Huntington's Disease Rating Scale (UHDRS), and indicates that the rater has ≥99% confidence that observed motor abnormalities are unequivocal signs of disease. 2 While the separation of participants into 'premanifest' and 'manifest' HD categories is useful for clinical purposes, utilisation of these groupings is too simplified for the purpose of effecting research into progression across the full HD disease spectrum. ...
... First, we have restricted the examination of neuropsychiatric function to anxiety and depression symptoms to limit participant burden. We prioritized the examination of anxiety and depression symptoms due to their prevalence in HD [74] and evidence of the benefits of CCT to these symptoms in other populations [12]. Nonetheless, other neuropsychiatric symptoms such as apathy are also prevalent in HD and may interact with the effects of CCT or mediate the effects on cognition. ...
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 )
... The resulting mutant protein accumulation causes neurodegeneration that results in movement disorders, cognitive decline, and behavioral or psychiatric symptoms (1). Although the clinical diagnosis of HD has been traditionally defined by the development of movement disorders (e.g., chorea), patients usually experience psychiatric problems years before the onset of motor symptoms (2,3). One of the most common psychiatric disorders in HD is depression, which can affect up to three-quarters of individuals with HD (4,5). ...
Depression is a common psychiatric disorder among individuals with Huntington's disease (HD). Depression in HD and major depressive disorder appear to have different pathophysiological mechanisms. Despite the unique pathophysiology, the treatment of depression in HD is based on data from the treatment of major depressive disorder in the general population. The objective of this systematic review was to conduct a comprehensive evaluation of the available evidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies on the treatment of depression in HD were identified by searching MEDLINE, Embase, and PsycInfo. The initial search yielded 2,771 records, 41 of which were ultimately included. There were 19 case reports, seven case series, three cross-sectional studies, one qualitative study, nine nonrandomized studies, and two randomized trials among the included studies. The most common assessment tools were the Hospital Anxiety and Depression Scale (N=8), the Beck Depression Inventory (N=6), and the Hamilton Depression Rating Scale (N=6). Only 59% of the included studies assessed depressive symptoms with a scoring system. The pharmacological options for the treatment of depression included antidepressants and antipsychotics. Nonpharmacological approaches were multidisciplinary rehabilitation, psychotherapy, and neurostimulation. Limited evidence on the treatment of depression in HD was available, and this literature consisted mainly of case reports and case series. This systematic review highlights the knowledge gap and the pressing need for HD-specific research to determine the efficacy of treatment approaches for depression in HD.
... The fatal autosomal-dominant inherited Huntington's Disease (HD) is accompanied by manifold motor, cognitive, behavioral-psychiatric, and functional impairments [1][2][3]. To objectify psychiatric symptoms and disease-specific functional impairments, various research approaches have been followed to gain insights into underlying genetic and pathophysiological changes [4][5][6][7][8]. The distinct cause of disease with a cytosine-adenineguanin (CAG)-trinucleotide expansion on chromosome 4 in the Huntingtin gene (HTT) results in misfolded Huntingtin proteins. ...
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.
... The typical diagnosis of Huntington disease is marked by the presence of choreiform movements in middle age, accompanied by an array of dysexecutive neurocognitive and behavioral symptoms. 1 Although these clinical manifestations are commonly attributed to the frontostriatum, longitudinal studies have revealed widespread brain and cognitive changes that predate the motor onset, and that are not frontostriatally mediated. 2,3 In particular, a significant body of work has implicated hippocampal involvement in HD. 4 Many facets of hippocampal dysfunction are commonly observed in early HD. ...
Introduction:
While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.
Methods:
We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months.
Results:
Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group.
Conclusions:
Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.
... Importantly, presymptomatic HD gene carriers have a higher prevalence of depression, which can appear up to ten years before motor symptoms [68]. In addition to having a significant negative influence on the patient's quality of life and autonomy, psychiatric symptoms may also have a major detrimental impact on family members and other caregivers, and can lead to functional impairment [69]. These psychological aspects, rather than the mobility disorder, are thought to be the most devastating to HD patients, and frequently lead to hospitalization and are the best predictors of the requirement for residential care [70]. ...
Huntington’s disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients’ quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable.
... Huntington's disease is a degenerative disease that usually manifests itself in middle age and presents motor, cognitive and psychiatric symptoms. It occurs due to the gradual atrophy of the striatum, in particular by the specific loss of spinous neurons in the striatum, causing stress on the dopaminergic receptors and resulting in the progression of the disease [94]. ...
Background
Neurological disorders are composed of several diseases that affect the central and peripheral nervous system; among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects.
Introduction
The search for new treatments has led to the investigation of multi-target drugs.
Method
This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, cerebral ischemia, and Parkinson's disease.
Result
As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity.
Conclusion
It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.
... However, owing to the low prevalence of HD in Asia and underestimated patients, only a few systematic clinical studies on the Chinese HD population are available. The reported prevalence of psychiatric symptoms and disorders varies considerably due to diverse study populations at different stages of HD and the use of different assessment methods with varying definitions of psychiatric phenomena [17][18][19][20]. Our previous study with the limited number of patients (58 subjects) did not include non-motor symptoms analysis [21] and another study focused on genetic features and the majority of their patients were from southeastern China [22]. ...
Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. There is a paucity of comprehensive clinical analysis in Chinese HD patients due to the low prevalence of HD in Asia. We aimed to comprehensively describe the motor, neuropsychiatric symptoms, and functional assessment in patients with HD from China. A total of 205 HD patients were assessed by the Unified Huntington’s Disease Rating Scale (UHDRS), the short version of Problem-Behavior Assessment (PBA-s), Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI). Multivariate logistic regression analysis was used to explore the independent variables correlated with neuropsychiatric subscales. The mean age of motor symptom onset was 41.8 ± 10.0 years old with a diagnostic delay of 4.3 ± 3.8 years and a median CAG repeats of 44. The patients with a positive family history had a younger onset and larger CAG expansion than the patients without a family history (p < 0.05). There was a significant increase in total motor score across disease stages (p < 0.0001). Depression (51%) was the most common neuropsychiatric symptom at all stages, whereas moderate to severe apathy commonly occurred in advanced HD stages. We found lower functional capacity and higher HAMD were independently correlated with irritability; higher HAMD and higher BDI were independently correlated with affect; male sex and higher HAMD were independently correlated with apathy. In summary, comprehensive clinical profile analysis of Chinese HD patients showed not only chorea-like movement, but psychiatric symptoms were outstanding problems and need to be detected early. Our study provides the basis to guide clinical practice, especially in practical diagnostic and management processes.
... Neuropsychiatric symptoms like depression, anxiety, and apathy are common features of HD and they normally manifest prior to motoric deficits [51,71]. Similarly, cognitive decline is a key hallmark of HD that may precede the onset of motor symptoms in HD patients [71]. Thus, we evaluated the behavior of zQ175 Δneo mice compared to their WT littermates. ...
... Neuropsychiatric symptoms like depression, anxiety, and apathy are common features of HD and they normally manifest prior to motoric deficits [51,71]. Similarly, cognitive decline is a key hallmark of HD that may precede the onset of motor symptoms in HD patients [71]. ...
... Neuropsychiatric symptoms like depression, anxiety, and apathy are common features of HD and they normally manifest prior to motoric deficits [51,71]. Similarly, cognitive decline is a key hallmark of HD that may precede the onset of motor symptoms in HD patients [71]. Thus, we evaluated the behavior of zQ175 ∆neo mice compared to their WT littermates. ...
Huntington's disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms, (ii) knowledge of the possible HD target space and general data awareness, (iii) detailed characterizations of available disease models, (iv) better suitable models, and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomy-cin resistance cassette was excised from zQ175 mice, generating a new line: zQ175 Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15-57 weeks of age. Specifically, zQ175 Δneo mice showed early astrogliosis from 15 weeks; growth retardation , body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks, and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget da-taset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.
... Los síntomas psiquiátricos tienen gran impacto para los pacientes ya que disminuyen la autonomía, aumentan el deterioro cognitivo y afectan la calidad de vida y funcionalidad del paciente, y para la familia generando mayor sobrecarga en el cuidado 42,43 . ...
Resumen
Introducción
La enfermedad de Huntington (EH) es un trastorno neurodegenerativo y hereditario. A partir del diagnóstico predictivo se han descrito características clínicas incipientes en la fase prodrómica, y varios estudios han reportado aumento de síntomas psiquiátricos en portadores de la mutación causante de la EH, sin síntomas motores, en esta fase.
Objetivo Identificar malestar psicológico en portadores de la mutación causante de la EH sin síntomas motores, mediante el Symptom Checklist 90 (SCL-90), y correlacionar con la carga y cercanía de la enfermedad.
Método
Una muestra de 175 participantes de un Programa de Diagnóstico Predictivo de EH (PDP-EH) se dividió en portadores PEH (39,4%) y no portadores NPEH (61,6%) de la mutación causante de EH. Mediante fórmulas matemáticas se obtuvo la carga de enfermedad y cercanía a la etapa manifiesta en el grupo PEH y se correlacionó con los resultados del inventario SCL-90-R.
Resultados
Al comparar los resultados obtenidos en el SCL-90-R de los PEH y NPEH, la diferencia se observa en el índice de malestar por síntomas positivos, donde los portadores obtienen mayor puntuación promedio. Las correlaciones entre carga de enfermedad y síntomas psicológicos se dan en los dominios: obsesiones y compulsiones, sensibilidad interpersonal, hostilidad, índice de severidad global e índice de malestar somático positivo. Se observa una correlación baja entre la carga de enfermedad y las puntuaciones obtenidas en el malestar psicológico.
Conclusiones
En general encontramos que el grupo PEH obtiene un puntaje mayor en las dimensiones evaluadas con el SCL-90, muestran relación con la carga y diferencias por la cercanía de la enfermedad. Puntajes mayores en las dimensiones del SCL-90-R en portadores del gen para la EH pueden sugerir un hallazgo temprano de la sintomatología psicológica en la enfermedad.
