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BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. OBJECTIVE: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. METHODS: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. RESULTS: During the 3-month period, the costs were 20,573 (France), 19,959 (Germany), 18,319 (the Netherlands), 25,649 (Sweden), and 12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. CONCLUSION: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Trastornos Parkinsonianos/epidemiología , Trastornos Parkinsonianos/terapia , Europa (Continente)/epidemiología , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/terapia , AlemaniaRESUMEN
Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.
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Enfermedad de Parkinson/genética , Proteína Desglicasa DJ-1/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Análisis Mutacional de ADN , Femenino , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
BACKGROUND: Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA. METHODS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18). RESULTS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA. CONCLUSION: Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiples Sistemas , Receptor de Serotonina 5-HT1A , Encéfalo/diagnóstico por imagen , Humanos , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Método Doble Ciego , Fluoxetina/uso terapéutico , Humanos , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Calidad de Vida , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
OBJECTIVE: Asleep deep brain stimulation (DBS) for Parkinson's disease (PD) is being performed more frequently; however, motor outcomes and safety of asleep DBS have never been assessed in a prospective randomized trial. METHODS: We conducted a prospective, randomized, noncomparative trial to assess the motor outcomes of asleep DBS. Leads were implanted in the subthalamic nucleus (STN) according to probabilistic stereotactic coordinates with a surgical robot under O-arm© imaging guidance under either general anesthesia without microelectrode recordings (MER) (20 patients, asleep group) or local anesthesia with MER and clinical testing (9 patients, awake group). RESULTS: The mean motor improvement rates on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-3) between OFF and ON stimulation without medication were 52.3% (95% CI: 45.4-59.2%) in the asleep group and 47.0% (95% CI: 23.8-70.2%) in the awake group, 6 months after surgery. Except for a subcutaneous hematoma, we did not observe any complications related to the surgery. Three patients (33%) in the awake group and 8 in the asleep group (40%) had at least one side effect potentially linked with neurostimulation. CONCLUSIONS: Owing to its randomized design, our study supports the hypothesis that motor outcomes after asleep STN-DBS in PD may be noninferior to the standard awake procedure.
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Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Cirugía Asistida por Computador , Humanos , Imagenología Tridimensional , Enfermedad de Parkinson/terapia , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , VigiliaRESUMEN
INTRODUCTION: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. METHODS: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. RESULTS: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. DISCUSSION: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.
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Enfermedad de Alzheimer , Instituciones de Atención Ambulatoria , Atrofia/patología , Encéfalo/patología , Trastornos de la Memoria , Anciano , Enfermedad de Alzheimer/clasificación , Enfermedad de Alzheimer/patología , Estudios de Cohortes , Femenino , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/clasificaciónRESUMEN
Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of a large prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival.
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Atrofia de Múltiples Sistemas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Francia , Humanos , Hipotensión Ortostática/complicaciones , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/complicaciones , Pronóstico , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
We describe excessive buccal saliva (EBS) prevalence in patients with Parkinson's Disease (PD) and controls of the COPARK study, its changes between "ON" and OFF" conditions and over time, its impact on Health-related Quality of life (HRQoL), and factors associated with this condition. We studied 671 ambulatory PD patients and 177 age/sex-matched controls. We defined "sialorrhea" as UPDRS item #6 (salivation) = 1 or 2; and "drooling" as item #6 = 3 or 4. SCOPA-Aut drooling score (item #2) was also available in a subset (45%) of the cohort. HRQoL was assessed by the PDQ-39 and SF-36 scales. Twenty-four months' follow-up data were available in 401/671 patients. EBS as assessed by UPDRS was present in 38% of PD patients in the "ON" condition ("Sialorrhea": 35%; "drooling": 3%). There were also more PD patients reporting "drooling" than controls according to the SCOPA-Aut (49% vs 19%, p < 0.01). UPDRS salivation score was worse in the "OFF" vs "ON" condition in PD patients with motor fluctuations (0.90 ± 0.94 vs 0.54 ± 0.79, p < 0.01). UPDRS salivation score worsened after ~ 24 months of follow-up (0.47 ± 0.70 vs 0.64 ± 0.81, p < 0.01). Worse PDQ-39 scores were observed in PD patients with EBS in bivariate but not in multivariate analyses. EBS was directly related to PD duration and severity, male gender, dysphagia, hypomimia, and autonomic dysfunction (logistic regression). EBS was more frequent in PD patients than controls, worsened in the "OFF" condition and after ~ 24 months of follow-up, moderately affected HRQoL, and was correlated with indices of bradykinesia, dysphagia, and autonomic dysfunction.
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Enfermedad de Parkinson , Sialorrea , Estudios de Cohortes , Humanos , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Calidad de Vida , Saliva , Índice de Severidad de la Enfermedad , Sialorrea/epidemiología , Sialorrea/etiologíaRESUMEN
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
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Proteínas de la Ataxia Telangiectasia Mutada/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Empalme Alternativo , Ciclo Celular , Línea Celular , Análisis Mutacional de ADN , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Mutación , FenotipoRESUMEN
Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
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Mitofagia/genética , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Proteínas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Animales , Células COS , Estudios de Casos y Controles , Consanguinidad , Femenino , Silenciador del Gen , Heterogeneidad Genética , Células HEK293 , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , Linaje , Fenotipo , Proteínas Quinasas/metabolismo , Proteínas/metabolismo , Reproducibilidad de los Resultados , Turquía , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society.
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Enfermedades del Sistema Nervioso Autónomo/patología , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Humanos , Cuerpos de Lewy/patología , Atrofia de Múltiples Sistemas/fisiopatología , Oligodendroglía/patología , Enfermedad de Parkinson/complicaciones , Trastornos Parkinsonianos/complicacionesRESUMEN
We tested in a translational approach the usefulness of plasma creatine kinase (CK) as an objective biomarker for levodopa-induced dyskinesia (LID). Plasma CK levels were measured in five dyskinetic parkinsonian non-human primates (NHP) and in ten PD patients with LID who participated in a treatment trial with simvastatin. Plasma CK levels were increased in dyskinetic NHP and correlated with LID severity while they were not affected by LID severity in PD patients.
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Antiparkinsonianos/efectos adversos , Creatina Quinasa/sangre , Discinesia Inducida por Medicamentos/sangre , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/fisiopatología , Humanos , Macaca , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la EnfermedadRESUMEN
Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.
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Núcleo Caudado/patología , Estimulación Encefálica Profunda/tendencias , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/terapia , Adulto , Anciano , Femenino , Humanos , Inflamación/patología , Inflamación/terapia , Masculino , Persona de Mediana EdadRESUMEN
Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value.
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Canales de Calcio/genética , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/fisiopatología , Canalopatías/genética , Canalopatías/fisiopatología , Metaloendopeptidasas/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Genes Dominantes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder that is characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. Some symptomatic treatments are available while neuroprotection or disease-modification remain unmet treatment needs. The pathologic hallmark is the accumulation of aggregated alpha-synuclein (α-syn) in oligodendrocytes forming glial cytoplasmic inclusions, which qualifies MSA as synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. Despite progress in our understanding of the pathogenesis of MSA, the origin of α-syn aggregates in oligodendrocytes is still a matter of an ongoing debate. We critically review here studies published in the field over the past 5 years dealing with pathogenesis, genetics, clinical signs, biomarker for improving diagnostic accuracy, and treatment development.
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Atrofia de Múltiples Sistemas , Humanos , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Atrofia de Múltiples Sistemas/etiología , Atrofia de Múltiples Sistemas/metabolismoRESUMEN
BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.
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Dopaminérgicos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Imidazoles/farmacología , Levodopa/efectos adversos , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/tratamiento farmacológico , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Anciano , Método Doble Ciego , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Piridinas/efectos adversosRESUMEN
BACKGROUND: Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia. METHODS: Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken. RESULTS: Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated. CONCLUSION: Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as "delayed-onset Friedreich's ataxia." As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.
Asunto(s)
Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Niño , Electrocardiografía , Femenino , Ataxia de Friedreich/sangre , Ataxia de Friedreich/fisiopatología , Genotipo , Hemoglobina Glucada/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Cooperación Internacional , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Anciano , Catecol O-Metiltransferasa , Dopamina/metabolismo , Método Doble Ciego , Genotipo , Humanos , Levodopa/uso terapéutico , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
BACKGROUND: MSA is a sporadic progressive neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of alpha-synuclein aggregates in the cytoplasm of oligodendrocytes along with neuronal loss and neuroinflammation, as well as blood-brain barrier dysfunction and myelin deterioration. Matrix metalloproteinases are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix, demyelination, and blood-brain barrier permeability. Several lines of evidence indicate a role for these enzymes in various pathological processes, including stroke, multiple sclerosis, Parkinson's, and Alzheimer's disease. METHODS: This study aimed to assess potential alterations of matrix metalloproteinase-1, -2, -3, and -9 expression or activity in MSA postmortem brain tissue. RESULTS: Gelatin zymography revealed increased matrix metalloproteinase-2 activity in the putamen, but not in the frontal cortex, of MSA patients relative to controls. Immunohistochemistry revealed increased number of glial cells positive for matrix metalloproteinase-1, -2, and -3 in the putamen and frontal cortex of MSA patients. Double immunofluorescence revealed that matrix metalloproteinase-2 and -3 were expressed in astrocytes and microglia. Only matrix metalloproteinase-2 colocalized with alpha-synuclein in oligodendroglial cytoplasmic inclusions. CONCLUSION: These results demonstrate widespread alterations of matrix metalloproteinase expression in MSA and a pattern of increased matrix metalloproteinase-2 expression and activity affecting preferentially a brain region severely affected (putamen) over a relatively spared region (frontal cortex). Elevated matrix metalloproteinase expression may thus contribute to the disease process in MSA by promoting blood-brain barrier dysfunction and/or myelin degradation.