Huntington's disease: from molecular pathogenesis to clinical treatment

Ross, Christopher A.; Tabrizi, Sarah J.

doi:10.1016/s1474-4422(10)70245-3

Cited by 1,404 publications

(1,203 citation statements)

References 161 publications

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“…Htt is also believed to play a role in vesicle transport and in regulating gene transcription and RNA trafficking (Cattaneo et al, 2005;Finkbeiner, 2011;Ross and Tabrizi, 2011;Zuccato et al, 2010). Therefore, HD involves both loss-of-function of the normal Htt that impairs its fundamental role in neuronal cells, and predominantly gain-of-function by the mutant Htt proteins that form amyloid-like inclusions ).…”

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Ii431 Huntington's Diseasementioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Huntington's disease (HD) is a monogenic, neurodegenerative disorder, characterized by motor, cognitive, and neuropsychiatric disturbance 2. As it is both autosomal dominant and fully penetrant, HD gene carriers can be identified many years prior to clinical onset, enabling neurodegenerative brain changes to be tracked from the earliest stages.…”

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confidence: 99%

In vivo characterization of white matter pathology in premanifest huntington's disease

Zhang

Gregory

Scahill

et al. 2018

Annals of Neurology

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ObjectiveHuntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early premanifest stages (pre‐HD). However, although DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite orientation dispersion and density imaging (NODDI) is a novel magnetic resonance imaging (MRI) technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre‐HD using NODDI.MethodsDiffusion‐weighted MRI data that support DTI and NODDI were acquired from 38 pre‐HD and 45 control participants. Using whole‐brain and region‐of‐interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole‐brain changes in DTI metrics were also examined.ResultsThe pre‐HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre‐HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia.InterpretationOur findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre‐HD, coupled with altered local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se. Ann Neurol 2018;84:497–504

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“…It is characterized by progressively worsening motor and nonmotor deficits including cognitive abnormalities (which over time lead to dementia), neuropsychiatric symptoms,5 weight loss,6 and sleep and circadian disturbances (for a review see Videnovic et al7). Although pathogenic pathways are beginning to be unraveled offering targets for treatment,8 the precise pathophysiological mechanisms of HD are poorly understood 9. Previously we have shown that sleep disturbances are present in early manifest disease,10 and several studies on transgenic animal models of HD have shown that sleep progressively worsens as the disease develops11, 12, 13, 14 dependently on age and gene dosage 15.…”

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Sleep deficits but no metabolic deficits in premanifest Huntington's disease

Lázár

Panin

Goodman

et al. 2015

Annals of Neurology

104

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ObjectiveHuntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage.MethodsWe performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age‐ and sex‐matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x‐ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain.ResultsCompared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4–7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations.InterpretationThe results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology. Ann Neurol 2015;78:630–648

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Huntington's disease: from molecular pathogenesis to clinical treatment

Cited by 1,404 publications

References 161 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

In vivo characterization of white matter pathology in premanifest huntington's disease

Sleep deficits but no metabolic deficits in premanifest Huntington's disease

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