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2.
Chem Biol Interact ; 315: 108907, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31778667

RESUMO

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG140 knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age. OBJECTIVE: This study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG140 KI mouse model of HD after motor symptoms have emerged. METHODS: CAG140 KI mice at 13-15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD+/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod. RESULTS: Exercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase. CONCLUSIONS: These changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.


Assuntos
Comportamento Animal/fisiologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Atividade Motora/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Teste de Esforço/métodos , Feminino , Doença de Huntington/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Ácidos Tricarboxílicos/metabolismo
3.
BMC Neurol ; 19(1): 316, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818276

RESUMO

BACKGROUND: Huntington's disease (HD) is a progressive, neurological disorder that results in both cognitive and physical impairments. These impairments affect an individual's gait and, as the disease progresses, it significantly alters one's stability. Previous research found that changes in stride time patterns can help delineate between healthy and pathological gait. Autoregressive (AR) modeling is a statistical technique that models the underlying temporal patterns in data. Here the AR models assessed differences in gait stride time pattern stability between the controls and individuals with HD. Differences in stride time pattern stability were determined based on the AR model coefficients and their placement on a stationarity triangle that provides a visual representation of how the patterns mean, variance and autocorrelation change with time. Thus, individuals who exhibit similar stride time pattern stability will reside in the same region of the stationarity triangle. It was hypothesized that individuals with HD would exhibit a more altered stride time pattern stability than the controls based on the AR model coefficients and their location in the stationarity triangle. METHODS: Sixteen control and twenty individuals with HD performed a five-minute walking protocol. Time series' were constructed from consecutive stride times extracted during the protocol and a second order AR model was fit to the stride time series data. A two-sample t-test was performed on the stride time pattern data to identify differences between the control and HD groups. RESULTS: The individuals with HD exhibited significantly altered stride time pattern stability than the controls based on their AR model coefficients (AR1 p < 0.001; AR2 p < 0.001). CONCLUSIONS: The AR coefficients successfully delineated between the controls and individuals with HD. Individuals with HD resided closer to and within the oscillatory region of the stationarity triangle, which could be reflective of the oscillatory neuronal activity commonly observed in this population. The ability to quantitatively and visually detect differences in stride time behavior highlights the potential of this approach for identifying gait impairment in individuals with HD.


Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Marcha/fisiologia , Doença de Huntington/fisiopatologia , Modelos Estatísticos , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Caminhada/fisiologia , Adulto Jovem
4.
Neurology ; 93(22): e2042-e2052, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31662494

RESUMO

OBJECTIVE: Dysarthric speech of persons with Huntington disease (HD) is typically described as hyperkinetic; however, studies suggest that dysarthria can vary and resemble patterns in other neurologic conditions. To test the hypothesis that distinct motor speech subgroups can be identified within a larger cohort of patients with HD, we performed a cluster analysis on speech perceptual characteristics of patient audio recordings. METHODS: Audio recordings of 48 patients with mild to moderate dysarthria due to HD were presented to 6 trained raters. Raters provided scores for various speech features (e.g., voice, articulation, prosody) of audio recordings using the classic Mayo Clinic dysarthria rating scale. Scores were submitted to an unsupervised k-means cluster analysis to determine the most salient speech features of subgroups based on motor speech patterns. RESULTS: Four unique subgroups emerged from the cohort of patients with HD. Subgroup 1 was characterized by an abnormally fast speaking rate among other unique speech features, whereas subgroups 2 and 3 were defined by an abnormally slow speaking rate. Salient speech features for subgroup 2 overlapped with subgroup 3; however, the severity of dysarthria differed. Subgroup 4 was characterized by mild deviations of speech features with typical speech rate. Length of CAG repeats, Unified Huntington's Disease Rating Scale total motor score, and percent intelligibility were significantly different for pairwise comparisons of subgroups. CONCLUSION: This study supports the existence of distinct presentations of dysarthria in patients with HD, which may be due to divergent pathologic processes. The findings are discussed in relation to previous literature and clinical implications.


Assuntos
Disartria/fisiopatologia , Doença de Huntington/fisiopatologia , Acústica da Fala , Adulto , Idoso , Análise por Conglomerados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fala
5.
Adv Exp Med Biol ; 1175: 355-381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583595

RESUMO

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease that results in motor, cognitive and psychiatric dysfunction. It is caused by a polyglutamine repeat expansion mutation in the widely expressed HTT protein. The clinical manifestations of HD have been largely attributed to the neurodegeneration of specific neuronal cell types in the brain. However, it has become clear that other cell types, including astrocytes, play important roles in the pathogenesis of HD. The mutant HTT (mHTT) protein is present in neuronal and non-neuronal cell types throughout the nervous system. Studies designed to understand the contribution of mHTT expression in non-neuronal cell types to HD pathogenesis has lagged considerably behind those focused on neurons. However, the role of astrocytes in HD has received more attention over the last 5-10 years. In this chapter we present an overview of HD and our current understanding of astrocytic involvement in this disease. We describe the neuropathological features of HD and provide evidence of morphological and molecular changes in mHTT expressing astrocytes. We review data from animal models and HD patients that implicate mHTT expressing astrocytes to the progression of HD.


Assuntos
Astrócitos/citologia , Doença de Huntington/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Neurônios
6.
Neurochem Res ; 44(9): 2031-2043, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410709

RESUMO

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Doença de Parkinson/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Animais , Humanos , Neurônios/fisiologia , Biogênese de Organelas
7.
Curr Opin Ophthalmol ; 30(6): 443-448, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31449085

RESUMO

PURPOSE OF REVIEW: Impaired eye movements are frequently seen in ophthalmic and neurologic clinical practice, especially in individuals with movement disorders. Identification of the abnormal movement can aid initial diagnosis and improve understanding of the underlying disease pathophysiology. The present article reviews the ocular motor manifestations and recent research on them in common movement disorders. RECENT FINDINGS: Ocular motor manifestations and their pathophysiologic correlates are being defined. In particular, study of eye movements can help clarify the changing clinicopathologic spectrum of atypical parkinsonian disorders. The pathophysiology and natural history of blepharospasm are being elucidated. Recent research focuses on high-resolution imaging and other technological advances to improve the sensitivity of the ocular motility exam. Eye movements are being studied as biomarkers for diagnosis and progression in clinical care and trials. SUMMARY: The current review summarizes ocular motor manifestations in common movement disorders, and presents recent research investigating their cause and treatment.


Assuntos
Blefarospasmo/diagnóstico , Doença de Huntington/diagnóstico , Doença de Niemann-Pick Tipo C/diagnóstico , Transtornos da Motilidade Ocular/diagnóstico , Doença de Parkinson/diagnóstico , Ataxias Espinocerebelares/diagnóstico , Blefarospasmo/fisiopatologia , Movimentos Oculares/fisiologia , Humanos , Doença de Huntington/fisiopatologia , Doença de Niemann-Pick Tipo C/fisiopatologia , Transtornos da Motilidade Ocular/fisiopatologia , Doença de Parkinson/fisiopatologia , Ataxias Espinocerebelares/fisiopatologia
8.
Yale J Biol Med ; 92(2): 291-303, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249490

RESUMO

Huntington's disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Doença de Huntington/fisiopatologia , Disautonomias Primárias/fisiopatologia , Animais , Humanos , Hipotálamo Anterior/fisiopatologia , Modelos Biológicos , Doenças Neurodegenerativas/fisiopatologia , Fatores de Tempo
9.
Biofactors ; 45(5): 666-689, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185140

RESUMO

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcumina/farmacologia , Demência/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Disponibilidade Biológica , Curcuma/química , Curcumina/isolamento & purificação , Demência/metabolismo , Demência/fisiopatologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/fisiopatologia , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/fisiopatologia , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatologia , Fármacos Neuroprotetores/isolamento & purificação , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Patentes como Assunto , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Priônicas/fisiopatologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia
10.
Cells ; 8(6)2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208073

RESUMO

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy.


Assuntos
Dopamina/metabolismo , Doença de Huntington/fisiopatologia , Doença de Huntington/terapia , Inflamação/patologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Transmissão Sináptica , Administração Intranasal , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Rastreamento de Células , Ritmo Circadiano , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Regulação da Expressão Gênica , Humanos , Doença de Huntington/genética , Inflamação/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Atividade Motora , Fatores de Crescimento Neural/metabolismo , Sono , Análise de Sobrevida , Tirosina 3-Mono-Oxigenase/metabolismo
11.
Mol Neurobiol ; 56(10): 6873-6882, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30937636

RESUMO

White matter (WM) abnormalities are a well-established feature of Huntington disease (HD), although their nature is not fully understood. Here, we asked whether remyelination as a measure of WM plasticity is impaired in a model of HD. Using the cuprizone assay, we examined demyelination and remyelination responses in YAC128 HD mice. Treatment with 0.2% cuprizone (CPZ) for 6 weeks resulted in significant reduction in mature (GSTπ-positive) oligodendrocyte counts and FluoroMyelin staining in the corpus callosum, leading to similar demyelination states in YAC128 and wild-type (WT) mice. Six weeks following cessation of CPZ, we observed robust remyelination in WT mice as indicated by an increase in mature oligodendrocyte counts and FluoroMyelin staining. In contrast, YAC128 mice exhibited an impaired remyelination response. The increase in mature oligodendrocyte counts in YAC128 HD mice following CPZ cessation was lower than that of WT. Furthermore, there was no increase in FluoroMyelin staining compared to the demyelinated state in YAC128 mice. We confirmed these findings using electron microscopy where the CPZ-induced reduction in myelinated axons was reversed following CPZ cessation in WT but not YAC128 mice. Our findings demonstrate that remyelination is impaired in YAC128 mice and suggest that WM plasticity may be compromised in HD.


Assuntos
Doença de Huntington/fisiopatologia , Remielinização/fisiologia , Animais , Axônios/patologia , Axônios/ultraestrutura , Corpo Caloso/patologia , Corpo Caloso/fisiopatologia , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Humanos , Doença de Huntington/complicações , Doença de Huntington/patologia , Masculino , Camundongos Transgênicos , Neuroglia/metabolismo , Neuroglia/patologia
12.
Elife ; 82019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017573

RESUMO

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.


Assuntos
Corpo Estriado/patologia , Proteína Huntingtina/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Proteínas Mutantes/metabolismo , Neurônios/metabolismo , Canais de Potássio Shal/metabolismo , Animais , Modelos Animais de Doenças , Proteína Huntingtina/genética , Camundongos , Proteínas Mutantes/genética
13.
Neuropharmacology ; 151: 1-12, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940536

RESUMO

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB1 allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB1 PAMs to treat the signs and symptoms of HD.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Indóis/uso terapêutico , Receptor CB1 de Canabinoide/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica/efeitos dos fármacos , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia
14.
J Neurol ; 266(6): 1340-1350, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30834978

RESUMO

BACKGROUND/AIMS: The presence of non-motor symptoms in Huntington's disease (HD) has not been systematically assessed so far. Our objective was to know their prevalence and to compare it with a cohort of patients with Parkinson's disease (PD). MATERIALS AND METHODS: Participants were consecutively recruited from our outpatient clinic. They were assessed through the motor part of the Unified Huntington's Disease Rating Scale, the motor part of the Unified Parkinson's Disease Rating Scale, the total functional capacity scale and the PD non-motor symptoms questionnaire. RESULTS: We enrolled 123 participants: 53 HD, 45 PD and 25 healthy controls (HC). Non-motor symptoms were significantly more prevalent in HD patients than in HC. The most frequent non-motor symptoms in HD, involving more than 50% of patients, were attentional deficits, apathy, dysphagia, memory complaints, depression falls, insomnia and urinary urgency. The total score of non-motor symptoms correlated with disease duration, total functional capacity and disease stage. HD scored significantly higher than PD in 11 items (dysphagia, constipation, bowel incontinence, faecal tenesmus, weight loss, memory, apathy, attention, falls, nightmares, delusions) and in four domains (cognitive, hallucinations and delusions, digestive and cardiovascular). PD did not score significantly higher than HD in any domain. CONCLUSIONS: HD patients have a high prevalence of non-motor symptoms, which is even higher than in PD, and correlates with disease progression.


Assuntos
Apatia/fisiologia , Sintomas Comportamentais/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Transtornos de Deglutição/fisiopatologia , Doença de Huntington/fisiopatologia , Doença de Parkinson/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Transtornos Urinários/fisiopatologia , Adulto , Idoso , Sintomas Comportamentais/etiologia , Disfunção Cognitiva/etiologia , Estudos Transversais , Transtornos de Deglutição/etiologia , Feminino , Humanos , Doença de Huntington/complicações , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Distúrbios do Início e da Manutenção do Sono/etiologia , Transtornos Urinários/etiologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30783551

RESUMO

Background: Huntington's disease (HD) is a rare, progressive neurodegenerative disease. Currently, there is no cure for the disease, but treatment may alleviate HD symptoms. In recent years, several exercise training interventions have been conducted in HD patients. In the current article, we review previous studies investigating targeted exercise training interventions in HD patients. Methods: We performed a literature search using the PubMed, Scopus, Web of Science, and Google Scholar databases on exercise training interventions in HD patients. Six publications fulfilled the criteria and were included in the review. Results: Exercise training resulted in beneficial effects on cardiovascular and mitochondrial function. Training effects on cognition, motor function, and body composition were less congruent, but a positive effect seems likely. Health-related quality of life during the training interventions was stable. Most studies reported no related adverse events in response to training. Discussion: Exercise training seems to be safe and feasible in HD patients. However, current knowledge is mainly based on short, small-scale studies and it cannot be transferred to all HD patients. Therefore, longer-term interventions with larger HD patient cohorts are necessary to draw firm conclusions about the potentially positive effects of exercise training in HD patients.


Assuntos
Terapia por Exercício , Doença de Huntington/terapia , Animais , Exercício/fisiologia , Humanos , Doença de Huntington/fisiopatologia
16.
Neuroscience ; 404: 130-140, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797895

RESUMO

Huntington's disease (HD) is a genetic neurodegenerative disorder of the central nervous system characterized by choreatic movements, behavioral and psychiatric disturbances and cognitive impairments. Deficits in learning and memory are often the first signs of disease onset in both HD patients and mouse models of HD and are in part regulated by the hippocampus. In the R6/2 mouse model of HD, GABAergic transmission can be excitatory in the hippocampus and restoring inhibition can rescue the associated memory deficits. In the present study we determine that hippocampal GABAergic neurotransmission in the R6/2 mouse is disrupted as early as 4 weeks of age and is accompanied by alterations in the expression of key inhibitory proteins. Specifically, spontaneous inhibitory postsynaptic currents were initially increased in frequency at 4 postnatal weeks and subsequently decreased after the mice displayed the typical R6/2 behavioral phenotype at 10 weeks of age. Symptomatic mice also exhibited a change in the probability of GABA release and changes in the basic membrane properties including neuronal excitability and input resistance. These electrophysiological changes in presymptomatic and symptomatic R6/2 mice were further accompanied by alterations in the protein expression level of pre- and postsynaptic inhibitory markers. Taken together, the present findings demonstrate profound alterations in the inhibitory neurotransmission in the hippocampus across the lifespan of the disease, including prior to neuronal degeneration, which suggests that the inhibitory hippocampal synapses may prove useful as a target for future therapeutic design.


Assuntos
Modelos Animais de Doenças , Hipocampo/fisiopatologia , Doença de Huntington/fisiopatologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Inibição Neural/fisiologia , Transmissão Sináptica/fisiologia , Animais , Feminino , Hipocampo/patologia , Proteína Huntingtina/fisiologia , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos
17.
Recent Pat Biotechnol ; 13(3): 187-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747088

RESUMO

BACKGROUND: Protein misfolding is a critical factor in the progression of a large number of neurodegenerative diseases. The incorrectly folded protein is prone to aggregation, leading to aberrant interaction with other cellular proteins, elevated oxidative stress, impaired cellular machinery, finally resulting in cell death. Due to its monogenic origin, Huntington's disease (HD) is a poster child of protein misfolding neurodegenerative disorders. The presence of neuronal inclusions of mutant huntingtin N-terminal fragments, mainly in the cortex and striatum, is a neuropathological hallmark of HD. Inhibition of protein misfolding and aggregation has been attempted using a variety of conventional protein stabilizers. METHODS: This review describes how, in recent times, nucleic acid therapeutics has emerged as a selective tool to downregulate the aberrant transcript and reduce expression of mutant huntingtin, thereby alleviating protein aggregation. Different strategies of use of nucleic acids, including antisense oligonucleotides, short inhibitory RNA sequences and aptamers have been discussed. The following patent databases were consulted: European Patent Office (EPO), the United States Patent and Trademark Office (USPTO), Patent scope Search International and National Patent Collections (WIPO) and Google Patents. RESULTS: Tools such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) are potential therapeutic agents which target the post-transcriptional step, accelerating mRNA degradation and inhibiting the production of the mutant protein. These nucleic acid sequences not only target the elongated CAG triplet repeat translating to an expanded polyglutamine tract in the mutant protein, but have also been used to target single nucleotide polymorphisms associated with the mutant allele. The therapeutic sequences have been investigated in a number of cells and animal models of HD. One antisense sequence, with desirable safety properties, has recently shown downregulation of huntingtin protein in a limited clinical trial. RNA aptamers have also shown promising results in inhibiting protein aggregation in a yeast model of HD. Novel drug delivery techniques have been employed to overcome the blood brain barrier for the use of these therapeutic sequences. CONCLUSION: The selectivity and specificity imparted by nucleic acids, along with novel delivery techniques, make them hopeful candidates for the development of a curative strategy for HD.


Assuntos
Aptâmeros de Nucleotídeos/genética , Proteína Huntingtina/antagonistas & inibidores , Doença de Huntington/terapia , Oligonucleotídeos Antissenso/genética , Agregação Patológica de Proteínas/prevenção & controle , RNA Interferente Pequeno/genética , Animais , Aptâmeros de Nucleotídeos/metabolismo , Barreira Hematoencefálica/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Drosophila melanogaster , Sistemas de Liberação de Medicamentos/métodos , Expressão Gênica , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Camundongos , Oligonucleotídeos Antissenso/metabolismo , Patentes como Assunto , Polimorfismo de Nucleotídeo Único , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/fisiopatologia , RNA Interferente Pequeno/metabolismo , Saccharomyces cerevisiae
18.
Ann Neurol ; 85(3): 396-405, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30635944

RESUMO

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioral symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilizes postmortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles. METHODS: Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorized into 2 groups: "motor" or "mood." RESULTS: The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, postmortem delay, CAG repeat in the IT15 gene, or age at death. INTERPRETATION: This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provides novel perspectives interrelating and correlating the variable cerebellar, basal ganglia, and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain. ANN NEUROL 2019;85:396-405.


Assuntos
Cerebelo/patologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Células de Purkinje/patologia , Adulto , Idoso , Autopsia , Encéfalo/patologia , Estudos de Casos e Controles , Contagem de Células , Corpo Estriado/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , Fenótipo
19.
Mov Disord ; 34(2): 274-280, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30644132

RESUMO

BACKGROUND: Disease-modifying clinical trials in persons without symptoms are often limited in methods to assess the impact associated with experimental therapeutics. This study suggests sample enrichment approaches to facilitate preventive trials to delay disease onset in individuals with the dominant gene for Huntington disease. METHODS: Using published onset prediction indexes, we conducted the receiver operating curve analysis for diagnosis within a 3-year clinical trial time frame. We determined optimal cut points on the indexes for participant recruitment and then conducted sample size and power calculations to detect varying effect sizes for treatment efficacy in reducing 3-year rates of disease onset (or diagnosis). RESULTS: Area under the curve for 3 onset prediction indexes all demonstrated excellent value in sample enrichment methodology, with the best-performing index being the multivariate risk score (MRS). CONCLUSIONS: This study showed that conducting an intervention trial in premanifest and prodromal individuals with the gene expansion for Huntington disease is highly feasible using sample enrichment recruitment methods. Ongoing natural history studies are highly likely to indicate additional markers of disease prior to diagnosis. Statistical modeling of identified markers can facilitate participant enrichment to increase the likelihood of detecting a difference between treatment arms in a cost-effective and efficient manner. Such variations may expedite translation of emerging therapies to persons in an earlier phase of the disease. TRIAL REGISTRATION: PREDICT-HD is registered with www.clinicaltrials.gov, number NCT00051324. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Progressão da Doença , Doença de Huntington/fisiopatologia , Doença de Huntington/terapia , Transtornos dos Movimentos/fisiopatologia , Adulto , Feminino , Humanos , Doença de Huntington/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Transtornos dos Movimentos/terapia , Projetos de Pesquisa
20.
Sensors (Basel) ; 19(2)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30634600

RESUMO

This article presents a machine learning methodology for diagnosing Parkinson's disease (PD) based on the use of vertical Ground Reaction Forces (vGRFs) data collected from the gait cycle. A classification engine assigns subjects to healthy or Parkinsonian classes. The diagnosis process involves four steps: data pre-processing, feature extraction and selection, data classification and performance evaluation. The selected features are used as inputs of each classifier. Feature selection is achieved through a wrapper approach established using the random forest algorithm. The proposed methodology uses both supervised classification methods including K-nearest neighbour (K-NN), decision tree (DT), random forest (RF), Naïve Bayes (NB), support vector machine (SVM) and unsupervised classification methods such as K-means and the Gaussian mixture model (GMM). To evaluate the effectiveness of the proposed methodology, an online dataset collected within three different studies is used. This data set includes vGRF measurements collected from eight force sensors placed under each foot of the subjects. Ninety-three patients suffering from Parkinson's disease and 72 healthy subjects participated in the experiments. The obtained performances are compared with respect to various metrics including accuracy, precision, recall and F-measure. The classification performance evaluation is performed using the leave-one-out cross validation. The results demonstrate the ability of the proposed methodology to accurately differentiate between PD subjects and healthy subjects. For the purpose of validation, the proposed methodology is also evaluated with an additional dataset including subjects with neurodegenerative diseases (Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD)). The obtained results show the effectiveness of the proposed methodology to discriminate PD subjects from subjects with other neurodegenerative diseases with a relatively high accuracy.


Assuntos
Marcha/fisiologia , Doença de Parkinson/diagnóstico , Algoritmos , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/fisiopatologia , Teorema de Bayes , Diagnóstico Diferencial , Feminino , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/fisiopatologia , Masculino , Distribuição Normal , Doença de Parkinson/fisiopatologia , Máquina de Vetores de Suporte
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