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1.
Sci Rep ; 12(1): 12081, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840753

RESUMO

Digital health technologies enable remote and therefore frequent measurement of motor signs, potentially providing reliable and valid estimates of motor sign severity and progression in Parkinson's disease (PD). The Roche PD Mobile Application v2 was developed to measure bradykinesia, bradyphrenia and speech, tremor, gait and balance. It comprises 10 smartphone active tests (with ½ tests administered daily), as well as daily passive monitoring via a smartphone and smartwatch. It was studied in 316 early-stage PD participants who performed daily active tests at home then carried a smartphone and wore a smartwatch throughout the day for passive monitoring (study NCT03100149). Here, we report baseline data. Adherence was excellent (96.29%). All pre-specified sensor features exhibited good-to-excellent test-retest reliability (median intraclass correlation coefficient = 0.9), and correlated with corresponding Movement Disorder Society-Unified Parkinson's Disease Rating Scale items (rho: 0.12-0.71). These findings demonstrate the preliminary reliability and validity of remote at-home quantification of motor sign severity with the Roche PD Mobile Application v2 in individuals with early PD.


Assuntos
Aplicativos Móveis , Doença de Parkinson , Tecnologia de Sensoriamento Remoto , Humanos , Doença de Parkinson/fisiopatologia , Reprodutibilidade dos Testes , Smartphone , Tremor/fisiopatologia
2.
Dev Med Child Neurol ; 64(1): 125-134, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34275143

RESUMO

AIM: To further identify and broaden the phenotypic characteristics and genotype spectrum of the dehydrodolichol diphosphate synthase (DHDDS) gene. METHOD: Pathogenic variants of DHDDS were identified by whole-exome sequencing; clinical data of 10 patients (six males, four females; age range 2-14y; mean age 5y 9mo, SD 3y 3mo) were collected and analysed. RESULTS: All patients had seizures, and myoclonic seizures could be seen in eight patients, with myoclonic status epilepticus in three. The interictal electroencephalogram (EEG) in four patients at seizure onset showed generalized slow waves, slow wave mixed spikes, and spike and waves. Tremor, ataxia, and hypertonia was observed in six, five, and three patients respectively. The results of short-latency somatosensory evoked potential in two patients were normal, and the symptom of tremor was captured on EEG without time-locked discharges in one patient, suggesting that the tremor in both patients was a motor impairment rather than myoclonic seizures. Global developmental delay occurred in all patients, among whom nine showed severe intellectual disability and one moderate. Five DHDDS variants were identified, three of which have not been reported previously. INTERPRETATION: Myoclonic seizure is the most common seizure type in heterozygous DHDDS variants, while myoclonic status epilepticus can also occur. The pattern of interictal EEG discharges is characterized by slow waves rather than spike and waves, and generalized discharges was prominent.


Assuntos
Alquil e Aril Transferases/genética , Epilepsias Mioclônicas/genética , Convulsões/genética , Estado Epiléptico/genética , Tremor/genética , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/fisiopatologia , Potenciais Somatossensoriais Evocados/genética , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Convulsões/fisiopatologia , Estado Epiléptico/fisiopatologia , Tremor/fisiopatologia , Sequenciamento Completo do Exoma
3.
CNS Neurosci Ther ; 28(2): 218-225, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34758102

RESUMO

INTRODUCTION: Parkinson's (PD) is a common degenerative disease of the central nervous system. It affects more than 6 million individuals worldwide. The typical clinical manifestations include static tremor, slow movement, and unstable posture. However, the correlation between head tremor and the severity of PD remains unclear. METHODS: In the current study, 18 patients and 18 healthy subjects were recruited to undergo a phonation test. Noldus facereader 7.0 software was used to analyze the range of head trembling between the two groups. RESULTS: The data revealed that patients with PD had significant differences in the x-, y-, and z-axis of head movement with respect to the specific pronunciation syllables compared with the normal group. Moreover, the head movement of the patients with PD was positively correlated with the severity of the disease in the single, double, and multiple syllable tests. In the phonetic test, the head displacement of patients with PD was significantly greater than that of healthy individuals, and the displacement range was positively correlated with the severity of the disease. CONCLUSION: These pieces of evidence suggested that the measurement of head displacement assists the early diagnosis and severity of the disease.


Assuntos
Movimentos da Cabeça/fisiologia , Doença de Parkinson/fisiopatologia , Tremor/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Gravidade do Paciente , Tremor/diagnóstico , Tremor/etiologia
5.
J Neurosci ; 41(47): 9844-9858, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34702744

RESUMO

Tremor, a common and often primary symptom of Parkinson's disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from 10 patients (9 male, 1 female) performing a naturalistic visual-motor task. From this task, we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.SIGNIFICANCE STATEMENT Tremor is a common symptom of Parkinson's disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this article, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinson's tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.


Assuntos
Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Córtex Sensório-Motor/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Tremor/fisiopatologia , Idoso , Eletrocorticografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Tremor/etiologia
6.
Genes (Basel) ; 12(10)2021 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-34681027

RESUMO

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5' UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54-200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.


Assuntos
Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Insuficiência Ovariana Primária/genética , Tremor/genética , Aneuploidia , Ataxia/fisiopatologia , Expansão das Repetições de DNA/genética , Replicação do DNA/genética , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Instabilidade Genômica/genética , Humanos , Insuficiência Ovariana Primária/fisiopatologia , Tremor/fisiopatologia , Expansão das Repetições de Trinucleotídeos/genética
7.
Neurorehabil Neural Repair ; 35(11): 1020-1029, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34551639

RESUMO

Background. Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for selected Parkinson's disease (PD) patients. Gait characteristics are often altered after surgery, but quantitative therapeutic effects are poorly described. Objective. The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait 6 months postoperatively in patients with PD and compare the outcomes with preoperative baseline and to asymptomatic controls without PD. Methods. A convenience sample of thirty-two patients with PD (19 with postural instability and gait disorder (PIGD) type and 13 with tremor dominant disease) and 51 asymptomatic controls participated. Parkinson patients were tested prior to the surgery in both OFF and ON medication states, and 6-months postoperatively in the ON stimulation condition. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I to IV and medication were compared to preoperative conditions. Asymmetry ratios, phase coordination index, and walking speed were assessed. Results. MDS-UPDRS I to IV at 6 months improved significantly, and levodopa equivalent daily dosages significantly decreased. STN-DBS increased step time asymmetry (hedges' g effect sizes [95% confidence interval] between pre- and post-surgery: .27 [-.13, .73]) and phase coordination index (.29 [-.08, .67]). These effects were higher in the PIGD subgroup than the tremor dominant (step time asymmetry: .38 [-.06, .90] vs .09 [-.83, 1.0] and phase coordination index: .39 [-.04, .84] vs .13 [-.76, .96]). Conclusions. This study provides objective evidence of how STN-DBS increases asymmetry and dyscoordination of gait in patients with PD and suggests motor subtypes-associated differences in the treatment response.


Assuntos
Estimulação Encefálica Profunda , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/terapia , Doença de Parkinson/terapia , Equilíbrio Postural , Desempenho Psicomotor , Núcleo Subtalâmico , Tremor/terapia , Idoso , Feminino , Seguimentos , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/classificação , Doença de Parkinson/complicações , Equilíbrio Postural/fisiologia , Desempenho Psicomotor/fisiologia , Tremor/etiologia , Tremor/fisiopatologia
8.
JCI Insight ; 6(19)2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34437302

RESUMO

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.


Assuntos
Proteínas de Transporte/genética , Hipotonia Muscular/genética , Debilidade Muscular/genética , Músculo Esquelético/fisiopatologia , Doenças Musculares/genética , Sarcômeros/genética , Tremor/genética , Animais , Feminino , Técnicas de Introdução de Genes , Heterozigoto , Masculino , Camundongos , Hipotonia Muscular/fisiopatologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/fisiopatologia , Mutação de Sentido Incorreto , Pletismografia Total , Músculos Respiratórios/fisiopatologia , Sarcômeros/metabolismo , Sarcômeros/fisiologia , Sarcômeros/ultraestrutura , Tremor/fisiopatologia
9.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445074

RESUMO

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult "gain-of-function" syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.


Assuntos
Ataxia/patologia , Síndrome do Cromossomo X Frágil/patologia , Insuficiência Ovariana Primária/patologia , Tremor/patologia , Adulto , Animais , Ataxia/genética , Ataxia/fisiopatologia , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/fisiopatologia , Tremor/genética , Tremor/fisiopatologia , Expansão das Repetições de Trinucleotídeos
10.
Neurobiol Dis ; 158: 105465, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364975

RESUMO

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases.


Assuntos
Doença de Pelizaeus-Merzbacher/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Gliose , Macaca mulatta , Masculino , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Mutação de Sentido Incorreto , Proteína Proteolipídica de Mielina , Bainha de Mielina/patologia , Tremor/genética , Tremor/fisiopatologia , Substância Branca
11.
J Parkinsons Dis ; 11(4): 1507-1535, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34250950

RESUMO

Despite clinical evidence of poor oral health and hygiene in Parkinson's disease (PD) patients, the mouth is often overlooked by both patients and the medical community, who generally focus on motor or psychiatric disorders considered more burdensome. Yet, oral health is in a two-way relationship with overall health-a weakened status triggering a decline in the quality of life. Here, we aim at giving a comprehensive overview of oral health disorders in PD, while identifying their etiologies and consequences. The physical (abnormal posture, muscle tone, tremor, and dyskinesia), behavioral (cognitive and neuropsychiatric disorders), and iatrogenic patterns associated with PD have an overall detrimental effect on patients' oral health, putting them at risk for other disorders (infections, aspiration, pain, malnutrition), reducing their quality of life and increasing their isolation (anxiety, depression, communication issues). Interdisciplinary cooperation for prevention, management and follow-up strategies need to be implemented at an early stage to maintain and improve patients' overall comfort and condition. Recommendations for practice, including (non-)pharmacological management strategies are discussed, with an emphasis on the neurologists' role. Of interest, the oral cavity may become a valuable tool for diagnosis and prognosis in the near future (biomarkers). This overlooked but critical issue requires further attention and interdisciplinary research.


Assuntos
Doença de Parkinson , Ansiedade/psicologia , Humanos , Saúde Bucal , Doença de Parkinson/complicações , Qualidade de Vida , Tremor/fisiopatologia
12.
Parkinsonism Relat Disord ; 89: 1-3, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34175496

RESUMO

DNAJC6 mutation causes two types of phenotypes: slowly progressive parkinsonism with levodopa response and rapidly progressive parkinsonism with additional manifestations like intellectual disability, epilepsy etc. We report a new phenotype wherein an adolescent girl developed blepharospasm followed by jaw opening, lingual and cervical dystonia followed by tremors of limbs (rest and action) with rigidity, bradykinesia. The dystonia-parkinsonism phenotype has not been described. She had novel homozygous missense mutation in DNAJC6 gene.


Assuntos
Distonia/fisiopatologia , Proteínas de Choque Térmico HSP40/genética , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , Tremor/fisiopatologia , Adolescente , Blefarospasmo/etiologia , Blefarospasmo/fisiopatologia , Distonia/etiologia , Feminino , Humanos , Hipocinesia/etiologia , Hipocinesia/fisiopatologia , Arcada Osseodentária/fisiopatologia , Mutação de Sentido Incorreto , Pescoço/fisiopatologia , Transtornos Parkinsonianos/complicações , Fenótipo , Língua/fisiopatologia , Tremor/etiologia
13.
Brain ; 144(11): 3436-3450, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34145898

RESUMO

A characteristic and intriguing feature of functional neurological disorder is that symptoms typically manifest with attention and improve or disappear with distraction. Attentional phenomena are therefore likely to be important in functional neurological disorder, but exactly how this manifests is unknown. The aim of the study was to establish whether in functional tremor the attentional focus is misdirected, and whether this misdirection is detrimental to the movement, or rather reflects a beneficial compensatory strategy. Patients with a functional action tremor, between the ages of 21-75, were compared to two age and gender matched control groups: healthy control participants and patients with an organic action tremor. The groups included between 17 and 28 participants. First, we compared the natural attentional focus on different aspects of a reaching movement (target, ongoing visual feedback, proprioceptive-motor aspect). This revealed that the attentional focus in the functional tremor group, in contrast to both control groups, was directed to ongoing visual feedback from the movement. Next, we established that all groups were able to shift their attentional focus to different aspects of the reaching movement when instructed. Subsequently, the impact of attentional focus on the ongoing visual feedback on movement performance was evaluated under several conditions: the reaching movement was performed with direct, or indirect visual feedback, without any visual feedback, under three different instruction conditions (as accurately as possible/very slowly/very quickly) and finally as a preparatory movement that was supposedly of no importance. Low trajectory length and low movement duration were taken as measures of good motor performance. For all three groups, motor performance deteriorated with attention to indirect visual feedback, to accuracy and when instructed to move slowly. It improved without visual feedback and when instructed to move fast. Motor performance improved, in participants with functional tremor only, when the movement was performed as a preparatory movement without any apparent importance. In addition to providing experimental evidence for improvement with distraction, we found that the normal allocation of attention during aimed movement is altered in functional tremor. Attention is disproportionately directed towards the ongoing visual feedback from the moving hand. This altered attentional focus may be partly responsible for the tremor, since it also worsens motor performance in healthy control participants and patients with an organic action tremor. It may have its detrimental impact through interference with automatic movement processes, due to a maladaptive shift from lower- to higher-level motor control circuitry.


Assuntos
Atenção/fisiologia , Transtorno Conversivo/fisiopatologia , Desempenho Psicomotor/fisiologia , Tremor/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Brain Dev ; 43(8): 863-866, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34090716

RESUMO

BACKGROUND: Joubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable. CASE REPORT: We report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year. CONCLUSION: Irritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.


Assuntos
Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Pré-Escolar , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/patologia , Feminino , Movimentos da Cabeça/fisiologia , Humanos , Humor Irritável/fisiologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Retina/diagnóstico por imagem , Retina/patologia , Tremor/etiologia , Tremor/fisiopatologia
15.
Parkinsonism Relat Disord ; 87: 137-141, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34091375

RESUMO

BACKGROUND: Depression is more frequently associated with akinetic-rigid/postural instability gait difficulty subtypes of Parkinson's disease than with tremor-dominant subtype. OBJECTIVES: The aim of the study is to investigate the frequency of exposure to antidepressant drugs, as proxy of depression, before motor onset according to Parkinson's disease subtypes. METHOD: Based on a historical cohort design, the exposure to antidepressant drugs before Parkinson's disease motor onset was obtained from the drug prescription database and assessed in the resident population of the Local Healthcare Trust of Bologna (443,117 subjects older than 35 years). Diagnosis of Parkinson's disease and subtype (tremor dominant, non-tremor dominant) at onset were recorded by neurologists and obtained from the "ParkLink Bologna" record linkage system. Exposure to antidepressants was compared both to the general population and between the two subtypes. RESULTS: From 2006 to 2018, 198 patients had a tremor dominant subtype at onset whereas 450 did not. Comparison with the general population for antidepressant exposure showed an adjusted hazard ratio of 0.86 (95% CI 0.44-1.70) for the tremor dominant subtype and 1.66 (1.16-2.39) for the non-tremor dominant subtype. Comparison of non-tremor dominant with tremor dominant subtypes showed an adjusted odds ratio of 1.86 (1.05-3.95) for antidepressant exposure. CONCLUSIONS: In our study, non-tremor dominant Parkinson's disease at onset was significantly associated with exposure to antidepressants in comparison to the general population and in comparison with the tremor dominant subtype. These results support the hypothesis of different biological substrates for different Parkinson's disease subtypes even before motor onset.


Assuntos
Antidepressivos/administração & dosagem , Depressão/fisiopatologia , Doença de Parkinson/classificação , Doença de Parkinson/fisiopatologia , Sintomas Prodrômicos , Tremor/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Depressão/tratamento farmacológico , Depressão/epidemiologia , Depressão/etiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Tremor/epidemiologia , Tremor/etiologia
16.
Parkinsonism Relat Disord ; 88: 13-18, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34091412

RESUMO

INTRODUCTION: Tremor-dominant (TD), indeterminate/mixed (ID/M) and postural instability gait difficulty/akinetic-rigid (PIGD/AR) are commonly used subtypes to categorize Parkinson's disease (PD) patients based on their most prominent motor signs. Three different algorithms to determine these motor subtypes are used. Here, we examined if PD subtypes are consistent among algorithms and if subtype stability over time depends on the applied algorithm. METHODS: Using a large longitudinal PD database, we applied 3 published algorithms of PD motor subtype classification in two sets of analyses: 1) cross-sectional analysis in 1185 patients, determining the prevalence of subtypes in 5-year intervals of disease duration; 2) longitudinal analysis of 178 patients, comparing subtypes of individual patients at baseline (within 5 years of diagnosis) and at follow-up ≥ 5 years after baseline. RESULTS: Cross-sectionally, prevalence of subtypes varied widely among the 3 algorithms: 5-32% TD, 9-31% ID/M, and 59-75% PIGD/AR. For all 3 algorithms, cross-sectional analysis showed a marked decline of TD prevalence with disease duration and a corresponding increase in PIGD/AR prevalence, driven by increasing gait/balance scores over time. Longitudinally, only 15-36% of baseline TD patients were still categorized as TD at 6.2 ± 1.0 years of follow-up. In 15-39% of baseline TD patients, the subtype changed to ID/M, and 46-50% changed to PIGD/AR. This shift was observed using all 3 algorithms. CONCLUSION: PD motor subtypes determined by different established algorithms are inconsistent and unstable over time. Lack of subtype fidelity should be considered when interpreting biomarker-subtype correlation and highlights the need for better definition of PD subtypes.


Assuntos
Algoritmos , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Parkinson/classificação , Doença de Parkinson/fisiopatologia , Equilíbrio Postural/fisiologia , Tremor/fisiopatologia , Idoso , Estudos Transversais , Bases de Dados Factuais , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Prevalência , Tremor/etiologia
17.
Hum Mol Genet ; 30(17): 1632-1648, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34077515

RESUMO

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS.


Assuntos
Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Animais , Ataxia/fisiopatologia , Comunicação Celular , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Tremor/fisiopatologia , Expansão das Repetições de Trinucleotídeos
19.
Cell Rep ; 35(3): 109007, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33882305

RESUMO

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.


Assuntos
Globo Pálido/fisiopatologia , Hipercinese/fisiopatologia , Córtex Motor/fisiopatologia , Doença de Parkinson Secundária/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Tremor/fisiopatologia , 4-Aminopiridina/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Globo Pálido/efeitos dos fármacos , Globo Pálido/metabolismo , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Hipercinese/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Córtex Motor/efeitos dos fármacos , Córtex Motor/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Optogenética/métodos , Doença de Parkinson Secundária/metabolismo , Ratos , Ratos Wistar , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Transmissão Sináptica , Tremor/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
20.
Parkinsonism Relat Disord ; 85: 102-108, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33799200

RESUMO

INTRODUCTION: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. METHODS: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI). RESULTS: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. CONCLUSION: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/farmacocinética , Neostriado , Doença de Parkinson , Tremor , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Neostriado/patologia , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Descanso , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/etiologia , Tremor/metabolismo , Tremor/patologia , Tremor/fisiopatologia
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