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X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.
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Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Aprendizaje Automático , Dispositivos Electrónicos Vestibles , Humanos , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Masculino , Adulto , Persona de Mediana Edad , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/diagnóstico , Índice de Severidad de la Enfermedad , Femenino , MarchaRESUMEN
X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.
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OBJECTIVE: To characterize the evolution of swallowing and voice in patients with X-linked dystonia parkinsonism (XDP). STUDY DESIGN: Retrospective case series. METHODS: Retrospective review of 59 patients with XDP from January 2016 to January 2018. All patients underwent complete examinations and quality of life (QOL) surveys (Swallowing Quality of Life questionnaire [SWAL-QOL], Voice-Related Quality of Life [V-RQOL], and Voice Handicap Index [VHI]), and functional endoscopic examination of swallowing. We excluded patients with incomplete records or patients lost to follow-up. Univariate analysis was used to compare 2016 to 2018 Penetration-Aspiration Scale (PAS), SWAL-QOL, V-RQOL, and VHI scores. RESULTS: Ten patients met the inclusion criteria. Nine patients had oromandibular dystonia. Voice-related measures significantly worsened with an increase in mean VHI from 81 to 109.9 (P = 0.026) and decrease in mean V-RQOL from 58 to 28 (P = 0.013). Vocal strain also significantly worsened 0.4 to 1.4 (P = 0.001). Mean PAS scores increased from 4.2 to 5.1 (P = 0.068) and mean SWAL-QOL decreased from 50.4 to 43.5 (P = 0.157). In the SWAL-QOL, the mean Eating Duration score worsened from 0.9 to 0.4 (P = 0.052) and Mental Health score declined from 10.1 to 6.1 (P = 0.077). CONCLUSIONS: Both vocal strain and voice-related QOL measures considerably worsened over the 2-year interval in our limited group of XDP patients with no significant change in PAS scores or swallowing QOL. The findings demonstrated that the pace of disease affecting voice symptoms was different from swallowing symptoms in our study group and that changes in communication ability may be a more sensitive marker for disease progression than swallowing dysfunction.
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Distonía , Trastornos Parkinsonianos , Voz , Humanos , Calidad de Vida/psicología , Estudios Retrospectivos , Distonía/diagnóstico , Encuestas y CuestionariosRESUMEN
X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington's disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.
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Distonía , Trastornos Distónicos , Enfermedad de Huntington , Trastornos Parkinsonianos , Adulto , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X , Humanos , Enfermedad de Huntington/genética , Masculino , Trastornos Parkinsonianos/genética , RetroelementosRESUMEN
INTRODUCTION: X-linked Dystonia-Parkinsonism (XDP) is a progressive, disabling disease characterized by the devastating impairment of bulbar function, including speech and swallowing. Despite these detrimental impacts, bulbar impairments in this population are not well characterized. OBJECTIVES: To identify impairments in the bulbar system measured by oromotor performance in individuals with XDP relative to healthy controls. Secondarily, to detect diagnostic bulbar markers that are sensitive and specific to the initial years of XDP. METHODS: This case-control study included 25 healthy controls and 30 participants with XDP, divided into two subgroups based on the median of their disease length. Multiple clinical and instrumental oromotor tasks and measures were used to evaluate bulbar motor function. RESULTS: Differences were found between both the subgroups with XDP and healthy controls on almost all measures, including maximum performance tasks such as tongue strength, alternating motion rate (AMR), and sequential motion rate (SMR) (p < 0.05). Differences were found between the XDP subgroups and the control group for the percentage of pause time during the speech, a rating of speech severity, and a swallowing task (ps < 0.05). Scores on self-reported questionnaires, tongue strength, the number of repetitions produced during an AMR, percent pause, and speech severity demonstrated good sensitivity and specificity to differentiate the initial years of XDP onset from healthy controls. CONCLUSIONS: Our findings revealed impairments across bulbar functions in participants within the first 7 years of the XDP onset. Highly sensitive and specific bulbar impairment measures were detected in instrumental and self-reported measures that are fundamental for monitoring disease.
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Tronco Encefálico/fisiopatología , Trastornos de Deglución , Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Trastornos del Habla , Adulto , Anciano , Estudios de Casos y Controles , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Trastornos Distónicos/complicaciones , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/fisiopatología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Habla/diagnóstico , Trastornos del Habla/etiología , Trastornos del Habla/fisiopatologíaRESUMEN
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10-8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
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Trastornos Distónicos/genética , Genes Modificadores , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Sitios Genéticos , Penetrancia , Adulto , Edad de Inicio , Anciano , Alelos , Estudios de Casos y Controles , Reparación de la Incompatibilidad de ADN , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores Protectores , Adulto JovenRESUMEN
BACKGROUND: X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript. OBJECTIVES: The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism. METHODS: RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array. RESULTS: In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79. CONCLUSIONS: TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedades Genéticas Ligadas al Cromosoma X , Factores Asociados con la Proteína de Unión a TATA , Adulto , Biomarcadores , Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Histona Acetiltransferasas/genética , Humanos , Filamentos Intermedios , Masculino , Factores Asociados con la Proteína de Unión a TATA/genética , Factor de Transcripción TFIID/genéticaRESUMEN
BACKGROUND: X-linked dystonia parkinsonism (XDP) is a rare disorder characterized by adult-onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism. Gait impairment is common. METHODS: Case series of 4 XDP patients with a unique gait disorder. RESULTS: The patients displayed a characteristic gait disorder with combined dystonic and parkinsonian gait features, with phasic knee bending. Of these patients, all had parkinsonism and three-quarters had prominent dystonic features, but 1 had predominant parkinsonism and subtle dystonic features. CONCLUSION: Although XDP is a classic form of dystonia parkinsonism, some cases can mimic idiopathic Parkinson's disease. We describe a gait disorder which appears unique to XDP, involving phasic dystonic knee bending superimposed on parkinsonian shuffling, and may help clinically differentiate one of our parkinsonian-predominant patients from more-common forms of parkinsonism. The gait is distinct from other complex dystonic disorders with gait involvement.
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OBJECTIVES: To systematically characterize and describe voice and swallowing manifestations in patients with X-linked dystonia parkinsonism (XDP) and correlate with quality-of-life (QOL) measures. METHODS: Thirty-four patients with XDP with communication and swallowing difficulties underwent neurological examination, head and neck examination, nasopharyngoscopy, QOL surveys (Swallowing Quality of Life questionnaire [SWAL-QOL] and Voice Handicap Index [VHI]), and functional endoscopic evaluation of swallowing (FEES) to assess the extent of dysfunction. RESULTS: All patients showed high rates of lingual, oromandibular, and laryngeal dysfunction, as well as severe QOL changes in swallowing and communication ability. The most common head and neck manifestations of dystonic symptoms were difficulty coordinating the mouth and tongue (79%), uncontrollable tongue thrusting (53%), and jaw opening (35%). Laryngeal symptoms including vocal strain (adductor voice breaks) or stridor (32%), as well as velopharyngeal insufficiency (20%), were also identified. Of the patients with laryngeal symptoms, 18% had respiratory dystonia. Swallowing assessments showed significant abnormalities in oral bolus control and oropharyngeal dysphagia. FEES examinations showed that 87.5% of the study group had penetration or aspiration. QOL scores showed an average VHI of 94.4 (severe dysfunction), and SWAL-QOL showed an average of 37.7 (severe dysfunction). CONCLUSION: Swallowing and voice impairment in XDP is not well characterized and presents a more distinctive phenomenology than other neurological disorders, with a unique set of challenges for treatment. This is the first study to systematically evaluate laryngeal and pharyngeal dysfunction in XDP patients and correlate with QOL measures. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:171-177, 2020.
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Trastornos de Deglución/etiología , Trastornos Distónicos/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Calidad de Vida , Trastornos de la Voz/etiología , Correlación de Datos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.
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Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Genoma Humano , Transcriptoma/genética , Empalme Alternativo/genética , Elementos Alu/genética , Secuencia de Bases , Sistemas CRISPR-Cas/genética , Estudios de Cohortes , Familia , Femenino , Sitios Genéticos , Haplotipos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Intrones/genética , Masculino , Repeticiones de Minisatélite/genética , Modelos Genéticos , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Elementos de Nucleótido Esparcido Corto , Factores Asociados con la Proteína de Unión a TATA/genética , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/genética , Factor de Transcripción TFIID/metabolismoRESUMEN
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1 This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.
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Expansión de las Repeticiones de ADN , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Histona Acetiltransferasas/genética , Retroelementos , Elementos de Nucleótido Esparcido Corto , Factores Asociados con la Proteína de Unión a TATA/genética , Factor de Transcripción TFIID/genética , Orden Génico , Estudios de Asociación Genética , Sitios Genéticos , Humanos , Masculino , Modelos Biológicos , Linaje , Fenotipo , Regiones Promotoras Genéticas , Activación TranscripcionalRESUMEN
X-linked dystonia-parkinsonism(XDP) is a neurodegenerative disorder endemic to the Philippines. A rating scale was developed by the authors under the guidance of the Movement Disorder Society of the Philippines (MDSP) to assess XDP severity and progression, functional impact, and response to treatment in future clinical trials. Our main objective was to validate our new scale, the XDP-MDSP scale. The initial validation process included pragmatic testing to XDP patients followed by a modified Delphi procedure with an international advisory panel of dystonia, parkinsonism and scale development experts. Pearson correlation was used to assess construct validity of our new scale versus the assess construct validity of our new scale versus standard dystonia, parkinsonism, non-motor and functional scales; and also to assess divergent validity against behavioral and cognitive scales. The 37-item XDP-MDSP scale has five parts: I-dystonia, II-parkinsonism, III-non-motor features, IV-ADL, and V-global impression. After initial validation, the scale was administered to 204 XDP patients. Inter-domain correlation for the first four parts was acceptable. The correlation between these domains and the global rating was slightly lower. Correlations between Parts I, II, III, and IV versus standard dystonia, parkinsonism, non-motor and functional scales were acceptable with values ranging from 0.323 to 0.428. For divergent validity, a significant correlation was seen with behavioral scales. No significant correlation was noted with the cognitive scale. The proposed XDP-MDSP scale is internally valid but the global rating subscale may need to be modified or eliminated. While there is convergent validity, divergent validation was successful only on cognitive and not behavioral scales. The frequent co-occurrence of anxiety and depression, and its effect on the motor and functional state, may explain this finding.
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INTRODUCTION: X-linked recessive dystonia-parkinsonism (XDP, DYT3) is highly prevalent in the Philippines and manifests with varying phenotype. We sought to evaluate the significance of transcranial brain sonography as a biomarker for parkinsonism-predominant phenotype. METHODS: 90 Filipino participants were enrolled into a cross-sectional study: 39 patients with XDP, 21 asymptomatic first-degree relatives of XDP patients, and 30 healthy control subjects. Echogenicity of the substantia nigra and the lenticular nuclei was digitally quantified. Brain sonography data were compared with video-based clinical assessment, genetic status and pedigree charts. RESULTS: The majority of patients had hyperechogenicity of the substantia nigra (79%) and/or the lenticular nuclei (81%). Disease duration correlated with echointensity of lenticular nuclei (Pearson test, r = 0.55, p = 0.029) but not substantia nigra (p = 0.31). Abnormal substantia-nigra hyperechogenicity was more frequent in patients with prominent parkinsonism (100%) compared to those without (68%; χ2 test, p = 0.035). The grading of substantia-nigra echogenicity (normal/increased) in patients was in all cases identical to that in their respective asymptomatic relatives. All patients with "familial" substantia-nigra normoechogenicity presented with a phenotype of predominant dystonia and only mild parkinsonism. In turn, "familial" substantia-nigra hyperechogenicity indicated a phenotype with moderate to severe parkinsonism (sensitivity, 100%; specificity, 67%; Fisher test, p = 0.021). CONCLUSION: Findings imply early alteration of the substantia nigra in XDP mutation carriers prone to develop parkinsonism. Thus, substantia-nigra hyperechogenicity may be regarded as a preclinical risk marker of parkinsonism-predominant XDP. Furthermore, this biomarker is clustered in some families suggesting the existence of one or more genetic co-factors influencing the phenotype of the disease.
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Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Trastornos Parkinsonianos , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/fisiopatología , Ultrasonografía , Adulto , Estudios de Casos y Controles , Progresión de la Enfermedad , Trastornos Distónicos/complicaciones , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/genética , Filipinas , Grabación de Cinta de VideoRESUMEN
OBJECTIVE: This study aims to investigate the influence of deep brain stimulation (DBS) on caregiver burden and quality of life in Parkinson's disease. METHODS: A cross-sectional retrospective study utilizing the National Parkinson Foundation Quality Improvement Initiative clinical study was conducted. A group of 275 patients who had undergone DBS for Parkinson's disease were extracted from 2916 subjects who were included in this data base. The data were compared to an age, sex, and disease severity matched control group. A secondary analysis was then performed on two more control groups that were matched to account for presence or absence of motor fluctuations. The multidimensional caregiver strain index and Parkinson's disease quality-of-life questionnaire 39 summary index were compared. RESULTS: The multidimensional caregiver strain index did not differ between the DBS group (16.9 ± 11.8) and a matched non-DBS group (16.1 ± 17.6, p = 0.618). The quality-of-life index was, however, significantly better in the DBS group (28.9 ± 15.6) than in the non-DBS group (32.3 ± 17.6, p = 0.034). A secondary analysis revealed that the total caregiver strain score was lower in the no motor fluctuation control group than the other two groups (p < 0.05). Regression analysis revealed significant relationships between the quality-of-life index and caregiver strain index total scores (p < 0.001), between caregiver strain index total score and age at surgery (p = 0.027), and also between the interval since surgery (p = 0.048). CONCLUSIONS: Although there were several limitations to this study, DBS seems to improve quality of life without significantly increasing caregiver burden.
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Cuidadores/psicología , Costo de Enfermedad , Estimulación Encefálica Profunda/psicología , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/terapia , Calidad de Vida/psicología , Anciano , Estudios Transversales , Estimulación Encefálica Profunda/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVES: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities. METHODS: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson's disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the unified Parkinson's disease rating scale (UPDRS) part IV (items 32-34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case-control study. RESULTS: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131). CONCLUSIONS: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects.
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Estimulación Encefálica Profunda , Discinesias/terapia , Globo Pálido/cirugía , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/cirugía , Anciano , Estudios de Casos y Controles , Estimulación Encefálica Profunda/métodos , Discinesias/etiología , Femenino , Globo Pálido/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Estudios Retrospectivos , Núcleo Subtalámico/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVES: Transcranial sonography of the substantia nigra for diagnosing premotor stages of Parkinson disease has been attracting increasing interest. Standard reference values defining an abnormal increased echogenic size (hyperechogenicity) of the substantia nigra have been established in several populations using high-end stationary ultrasound systems. It is unknown whether a portable ultrasound system can be appropriately used and how the Filipino population would compare with the well-studied white population. METHODS: We prospectively studied substantia nigra echogenic sizes and third ventricle widths in 71 healthy adult German participants and 30 age- and sex-matched Filipino participants using both a well-established stationary ultrasound system (in the German cohort) and a recently distributed portable ultrasound system (in both ethnic cohorts). RESULTS: Mean substantia nigra echogenic sizes, cutoff values defining abnormal hyperechogenicity, and intra-rater reliability were similar with both systems and in both ethnic cohorts studied. The Filipino and German participants did not differ with respect to the frequency of insufficient insonation conditions (each 3%) and substantia nigra hyperechogenicity (10% versus 9%; P = .80). However, third ventricle widths were smaller in the Filipino than the German participants (mean ± SD, 1.6 ± 1.1 versus 2.4 ± 1.0 mm; P = .004). CONCLUSIONS: The frequency of substantia nigra hyperechogenicity appears to be homogeneous in white and Asian populations. Screening for this feature may well be performed with a present-day portable ultrasound system.
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Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/etnología , Sistemas de Atención de Punto , Sustancia Negra/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/instrumentación , Adulto , Anciano , Distribución de Chi-Cuadrado , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Filipinas , Estudios Prospectivos , Estadísticas no Paramétricas , Encuestas y CuestionariosRESUMEN
BACKGROUND: Although the diagnosis of Parkinson disease (PD) still relies mainly on the appearance of its classical motor features of resting tremor, rigidity, bradykinesia, and postural instability, nonmotor manifestations in PD are now recognized as an integral component of this multisystem disorder. REVIEW SUMMARY: Nonmotor complications in PD occur commonly. The current understanding of cognitive dysfunction; neuropsychiatric manifestations including psychosis, impulsive control, and compulsive disorders, depression, anxiety and apathy; autonomic complications such as hypotension, erectile dysfunction, and urinary complications; sleep disorders and other nonmotor manifestations are summarized in this review. CONCLUSION: Nonmotor complications often carry a greater impact than motor features in PD. Therefore, heightened awareness and proper recognition of these features are critical in improving a Parkinson patient's quality of life.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/etiología , Trastornos del Conocimiento/etiología , Trastornos Mentales/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , HumanosRESUMEN
OBJECTIVE: Characterize potential risk factors and the relationship of dopamine agonist (DA) withdrawal syndrome (DAWS), dopamine dysregulation syndrome (DDS), and impulse control disorders (ICDs) in Parkinson's disease (PD). METHODS: A retrospective chart review categorized cases into three groups: DAWS, DDS, and ICDs. RESULTS: A total of 1,040 subjects met inclusion criteria. There were 332 subjects with a history of tapering DAs and 26 (7.8%) developed DAWS. Fourteen (1.3%) and 89 (8.6%) met the criteria for both DDS and ICD. Subjects with DAWS, DDS, and ICDs had a higher baseline dose of DA, levodopa, and total dopaminergic medication (p < .05), compared to those without the three conditions. DDS was found to be related to the DAWS group (p < .001). When comparing to the PD population without DDS, younger age at onset of PD (p = .027), presence of DAWS (p < .001), ICDs (p = .003), and punding (p = .042) were all correlated with the DDS group, while male sex (p = .045), younger age at onset of PD (p < .001), presence of DAWS (p < .001), and presence of DDS (p = .001) and punding (p < .001) were related to the ICD group. CONCLUSIONS: There was a strong relationship between DAWS, DDS, and ICD in this large PD cohort. Dopaminergic therapy in a subset of PD patients was strongly associated with addiction-like behavioral issues.
Asunto(s)
Trastornos Disruptivos, del Control de Impulso y de la Conducta/inducido químicamente , Trastornos Disruptivos, del Control de Impulso y de la Conducta/fisiopatología , Agonistas de Dopamina/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Edad de Inicio , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/sangre , Estudios de Cohortes , Comorbilidad , Trastornos Disruptivos, del Control de Impulso y de la Conducta/epidemiología , Agonistas de Dopamina/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatología , Estudios Retrospectivos , Distribución por Sexo , Síndrome de Abstinencia a Sustancias/epidemiología , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
It is now commonly accepted that non-motor symptoms of Parkinson's disease often outweigh and sometimes even antedate the development of motor symptoms of PD. It can prove to be more disabling and more challenging to treat and it clearly impacts quality of life in PD. This article provides a concise review of non-motor features in Parkinson's disease as well as the pathophysiological mechanisms underlying each complication. Currently available management strategies will be outlined as well.