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INTRODUCTION: Pathogenesis in a subgroup of sarcopenic patients seems to be based on a reduced number of motor neurons. This study aimed at investigating the overlap between sarcopenia and neurodegeneration, as reflected by a low number of motor neurons in patients with Parkinsonian syndromes (PS). METHODS: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size (MUSIX) of motor units (MUs) in patients with idiopathic Parkinson disease (iPD, n = 53), patients with atypical Parkinsonian syndrome (aPS, n = 21), and a control group (n = 30). Mean age of participants was 70.3 years and 54.1% were female. Skeletal muscle mass by bioelectrical impedance analysis, hand-grip strength and gait speed were measured. Based on these assessments, sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People. RESULTS: Sarcopenia criteria were met by 10 patients with PS (13.5%). The study group had significantly lower MUNIX values than the control group (109 [SD ±39.1] vs. 129 [SD ±45.1]; p = 0.020) even after adjustment for age and sex. Three of the 5 sarcopenic iPD patients (75%) had pathological low MUNIX values (<80). DISCUSSION/CONCLUSION: Sarcopenia is a frequent comorbidity in PS. The pathologically low MUNIX values found in 75% of our sarcopenic iPD patients provides further support for the existence of a neurodegenerative overlap syndrome with a reduced number of MUs potentially leading to sarcopenia. This finding warrants further evaluation.
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Neuronas Motoras/patología , Trastornos Parkinsonianos/fisiopatología , Sarcopenia/fisiopatología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Alemania , Fuerza de la Mano , Humanos , Masculino , Músculo Esquelético , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/complicaciones , Sarcopenia/complicaciones , Velocidad al CaminarRESUMEN
Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs∗17), in KMT2B, encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B-one de novo nonsense mutation (c.1633C>T [p.Arg545∗]), one de novo essential splice-site mutation (c.7050-2A>G [p.Phe2321Serfs∗93]), and one inherited nonsense mutation (c.2428C>T [p.Gln810∗]) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C>T (p.Gln810∗) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B. Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis.
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Trastornos Distónicos/genética , Haploinsuficiencia/genética , N-Metiltransferasa de Histona-Lisina/genética , Lisina/metabolismo , Adolescente , Adulto , Edad de Inicio , Secuencia de Bases , Niño , Femenino , Humanos , Masculino , Linaje , Adulto JovenRESUMEN
Axial deformities such as camptocormia or Pisa syndrome in people with Parkinson's disease (PwP) are poorly understood. The scarcity of information may result from the shortage of reliable and responsive evaluation instruments. We evaluated the body height loss (BHL) as a new measure for PwP with axial deformities. 50 PwP with axial deformity defined by an UPDRS item 28 value of at least 2 were included in this mono-center study. We measured body height while lying supine and after 1 min of standing, providing a percentage value of BHL, and compared this measure to other clinical variables. BHL depended on the Hoehn and Yahr clinical stage and correlated with clinical scales for function and mobility, but not with timely measures of the axial disorder such as age at diagnosis or duration of disease. ANOVA showed that only lumbar flexion explained the variability of BHL (F = 21.0, p < 0.0001), but not kyphosis (F = 0.4, p = 0.74) or lateroflexion (F = 0.6, p = 0.6). Re-test reliability of BHL was good with к = 0.76 (p < 0.0001). BHL resulted from the lumbar spine and the hip joint and not from the thoracic spine or lateroflexion. This observation conforms to the concept of upper-type and lower-type camptocormia with only the latter leading to a BHL. The assessment of the BHL is shown to be a well defined, easy to perform, and reliable measure for the clinical evaluation of lower-type camptocormia.
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Estatura , Atrofia Muscular Espinal/etiología , Enfermedad de Parkinson/fisiopatología , Curvaturas de la Columna Vertebral/etiología , Anciano , Femenino , Articulación de la Cadera/fisiopatología , Humanos , Región Lumbosacra/fisiopatología , Masculino , Atrofia Muscular Espinal/fisiopatología , Curvaturas de la Columna Vertebral/fisiopatología , Posición de Pie , Posición SupinaRESUMEN
BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.
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Distonía/genética , Exoma/genética , Mutación/genética , Adenilil Ciclasas/genética , Adulto , Anoctaminas , Proteínas Reguladoras de la Apoptosis/genética , Canales de Cloruro/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Salud de la Familia , Femenino , Estudios de Seguimiento , GTP Ciclohidrolasa/genética , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Chaperonas Moleculares/genética , Proteínas Nucleares/genética , Adulto JovenRESUMEN
Parkinson's disease is the second most common neurodegenerative illness after Alzheimer's disease. In its advanced stages, it is characterized by various special symptoms. In addition to non-motor signs, motor complications are most prominent and most often can only be inadequately improved with pulsatile oral therapies. However, with the aid of continuous dopaminergic stimulation, improvements can be achieved even in advanced stages of the disease. This will not only alleviate motor and non-motor symptoms, but will also lead to a better quality of life. In this context, continuous subcutaneous apomorphine administration by means of a pump has been well established. Its benefits, indications, limitations and practical implementation will be thoroughly described in the expert recommendation. Particularly noteworthy is the rather broad therapeutic window of apomorphine pump treatment, which can be optimally utilized by simple drug titration in a rapidly reversible process. This article presents the results of an expert meeting on apomorphine therapy which took place on July 6, 2016, in Frankfurt (M), Germany.
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Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/uso terapéutico , Apomorfina/administración & dosificación , Apomorfina/uso terapéutico , Bombas de Infusión Implantables , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Humanos , Calidad de VidaRESUMEN
BACKGROUND: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. OBJECTIVES: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. METHODS: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. CONCLUSIONS: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.
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Inhibidores de la Liberación de Acetilcolina/farmacología , Toxinas Botulínicas Tipo A/farmacología , Evaluación de Resultado en la Atención de Salud/métodos , Tortícolis/tratamiento farmacológico , Inhibidores de la Liberación de Acetilcolina/administración & dosificación , Inhibidores de la Liberación de Acetilcolina/efectos adversos , Adulto , Toxinas Botulínicas Tipo A/administración & dosificación , Toxinas Botulínicas Tipo A/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics. RESULTS: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls. CONCLUSIONS: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.
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Antiparkinsonianos/farmacología , Compuestos de Azabiciclo/farmacología , Dopaminérgicos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/tratamiento farmacológico , Piridinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Anciano , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/efectos adversos , Método Doble Ciego , Discinesia Inducida por Medicamentos/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Piridinas/efectos adversosRESUMEN
This study examines entrainment of speech timing and rhythm with a model speaker in healthy persons and individuals with Parkinson's. We asked whether participants coordinate their speech initiation and rhythm with the model speaker, and whether the regularity of metrical structure of sentences influences this behaviour. Ten native German speakers with hypokinetic dysarthria following Parkinson's and 10 healthy controls heard a sentence ('prime') and subsequently read aloud another sentence ('target'). Speech material comprised 32 metrically regular and irregular sentences, respectively. Turn-taking delays and alignment of speech rhythm were measured using speech wave analyses. Results showed that healthy participants initiated speech more closely in rhythm with the model speaker than patients. Metrically regular prime sentences induced anticipatory responses relative to metrically irregular primes. Entrainment of speech rhythm was greater in metrically regular targets, especially in individuals with Parkinson's. We conclude that individuals with Parkinson's may exploit metrically regular cues in speech.
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Percepción Auditiva , Enfermedad de Parkinson/fisiopatología , Acústica del Lenguaje , Anciano , Señales (Psicología) , Disartria/terapia , Femenino , Alemania , Humanos , Lenguaje , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/terapiaRESUMEN
Continuous jejunal levodopa infusion is an increasingly used therapy option in patients with Parkinson's disease who experience severe fluctuations from oral levodopa. In a number of recent reports polyneuropathy in patients receiving jejunal levodopa infusion was referenced to cobalamin (vitamin B12) deficiency. We describe one of three cases from our hospital with severe subacute polyneuropathy that developed during jejunal levodopa infusion, and occurred despite vitamin substitution therapy and normal vitamin B12 and holotranscobalamin serum levels.
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Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Carbidopa/administración & dosificación , Carbidopa/efectos adversos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Polineuropatías/inducido químicamente , Anciano , Combinación de Medicamentos , Humanos , Infusiones Parenterales , Yeyuno , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Polineuropatías/tratamiento farmacológico , Polineuropatías/fisiopatología , Vitamina B 12/administración & dosificación , Vitamina B 12/sangreRESUMEN
OBJECTIVE: To investigate the efficacy of a two-week programme of repetitive exercise with cueing and movement strategies upon freezing of gait in people with Parkinson's disease. DESIGN: Randomized cross-over trial. SETTING: Specialist clinic for Parkinson's disease. SUBJECTS: A total of 22 patients with Parkinson's disease and freezing while other symptoms had favorably responded to dopaminergic treatment. INTERVENTION: Patients were randomized into a four-week cross-over trial, and received either treatment (Group 1) or no treatment (Group 2) during Period 1, and switched during Period 2. Treatment consisted of a two-week programme during which the patients exercised cueing, and movement strategies together with a physiotherapist. MAIN MEASURE: The primary outcome measure was a freezing score assessed from blinded and random ratings of video recordings. The secondary outcome measure was a patient-reported freezing questionnaire. Mean differences between the treatment periods (treatment arms) were evaluated for treatment (period) effects. Sums of treatment periods were evaluated for carry-over effects. RESULTS: The programme led to a significant treatment effect in the freezing score of 3.0 improvement (95% confidence interval 0.9-5.0; p < 0.01). No carry-over or period effects were detected. The questionnaire revealed a period effect, so groups were compared after Period 1, where a significant difference was found (15.0 vs. 11.7; p < 0.05). CONCLUSIONS: The two-week physiotherapy programme reduced the severity of freezing in patients with Parkinson's disease.
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Terapia por Ejercicio/métodos , Trastornos Neurológicos de la Marcha/rehabilitación , Enfermedad de Parkinson/rehabilitación , Anciano , Estudios Cruzados , Señales (Psicología) , Femenino , Trastornos Neurológicos de la Marcha/etiología , Alemania , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pacientes Ambulatorios , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la EnfermedadRESUMEN
Background: The multimodal complex treatment for Parkinson's disease (MCT) provides inpatient care by a multi-disciplinary team for people with Parkinson's disease (PwP) in Germany. Objectives: We conducted a 5-year real-world mono-center cohort study to describe the effectiveness of MCT in the full cohort and various subgroups and outcome predictors. Methods: We collected an anonymized dataset between Jan 2015 and Dec 2019, involving N = 1773. The self-reported MDS-UPDRS part II was used as primary outcome, and clinical routine data for explanatory variables. PwP were categorized as responders or non-responders according to a response of at least 3 points 4 weeks after discharge. Results: N = 591 complete data records were available for statistical analyses. The full group improved by -2.4 points on the MDS-UPDRS II (P = <0.0001). 47.7% (n = 282) and 52.3% (n = 309) were coded as responders and non-responders, respectively. A clinically meaningful response was positively associated to age (χ2 = 11.07, P = 0.018), as well as baseline-severity of the MDS-UPDRS II (χ2 = 6.05, P = 0.048) and negatively associated to the presence of psychiatric disorder (χ2 = 3.9, P = 0.048) and cognitive dysfunction (χ2 = 7.29, P = 0.007). Logistic regression showed that baseline severity of the MDS-UPDRS II predicted therapy success. PwP with moderate baseline-severity had an about 2fold chance (OR 2.08; 95% CI 1.20-3.61; P = 0.009) and with severe an about 6fold chance (OR 5.92; 95% CI 2.76-12.68; P < 0.0001) to benefit clinically meaningful. Discussion: In a naturalistic setting of a specialized Parkinson's center, MCT improved ADL disability of PwP at least 4 weeks after discharge. Moderately and severely impaired patients were more likely to achieve clinically meaningful responses.
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INTRODUCTION: Parkinson's disease (PD) represents the fastest growing neurodegenerative disease with an increasing prevalence worldwide. It is characterised by complex motor and non-motor symptoms that lead to considerable disability. Specialised physiotherapy has been shown to benefit patients with PD. The Parkinson Netzwerk Therapie (PaNTher) was created to improve access to specialised physiotherapy tailored to care priorities of PD patients. This study aims to evaluate the effectiveness, acceptability and needs of the PaNTher network by neurologists and physiotherapists involved in the network in outpatient care. METHODS AND ANALYSIS: This is a mixed-method, prospective, pragmatic non-randomised cohort study of parallel groups, with data collection taking place in Bavaria, Germany, between 2020 and 2024. Patients with PD insured by the Allgemeine Ortskrankenkasse Bayern (AOK Bayern) living in Bavaria will be recruited for study participation by network partners. Patients in the intervention group must reside in Munich or the surrounding area to ensure provision of specialised physiotherapy in close proximity to their place of residence. Controls receive care as usual. Six and 12 months after baseline, all patients receive a follow-up questionnaire. Mixed-effect regression models will be used to examine changes in impairment of activities of daily living and quality of life of patients with PD enrolled in the programme over time compared with usual care. Qualitative interviews will investigate the implementation processes and acceptability of the PaNTher network among neurologists and physiotherapists. The study is expected to show that the PaNTher network with an integrative care approach will improve the quality and effectiveness of the management and treatment of patients with PD. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee at the medical faculty of the Ludwig-Maximilians-University Munich (20-318). Results will be published in scientific, peer-reviewed journals and presented at national and international conferences.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/diagnóstico , Calidad de Vida , Actividades Cotidianas , Estudios de Cohortes , Estudios Prospectivos , Atención Ambulatoria , Estudios Observacionales como AsuntoRESUMEN
The prevalence of Parkinson's disease (PD) will double by 2030. PD is no longer regarded as a single disease entity. Monogenetic forms may appear clinically identical to sporadic PD. The corona pandemic has caused a deterioration in a great proportion of patients due to concerns of accessing medical care. During this time, teleconsultations emerged as a helpful service for many PD patients as they can reliably administer parts of the neurological examination remotely. New studies address the ongoing controversy about whether the use of levodopa should be delayed. The conclusion is that physicians should not be afraid of using levodopa to treat patients early in the course of PD. Furthermore, the role of dopamine agonists is changing. Besides their known high rates of edema, somnolence and hallucinations dopamine agonists are associated with the development of impulse control disorders in approx. half of the treated patients. During the last 10 years, only two new substances (safinamide, opicapone) have come onto the market in Germany, both with the indication as add on therapy to levodopa in patients with fluctuations. The use of deep brain stimulation and drug pumps in patients with levodopa effect fluctuations is growing, because at this point in the course of the disease, patients also accept invasive therapies that can prolong and optimize independence. Patients who need levodopa more than 5 times a day and who have severe, disturbing OFF phases (>â2 hours a day) despite optimal non-levodopa-based treatment can consider these options. PD stage and symptom-focused, guideline-based physiotherapy has a positive effect on the course of the disease, everyday performance and quality of life and reduces the risk of falling. Multidisciplinary networks are proving effective in reducing falls and hospital admissions.
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Levodopa , Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Agonistas de Dopamina/efectos adversos , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Calidad de VidaRESUMEN
BACKGROUND: Spoken language is constantly undergoing change: Speakers within and across social and regional groups influence each other's speech, leading to the emergence and drifts of accents in a language. These processes are driven by mutual unintentional imitation of the phonetic details of others' speech in conversational interactions, suggesting that continuous auditory-motor adaptation takes place in interactive language use and plasticity of auditory-motor representations of speech persists across the lifespan. The brain mechanisms underlying this large-scale social-linguistic behavior are still poorly understood. RESEARCH AIM: To investigate the role of cerebellar and basal ganglia dysfunctions in unintended adaptation to the speech rhythm and articulation rate of a second speaker. METHODS: Twelve patients with spinocerebellar ataxia type 6 (SCA6), 15 patients with Parkinson's disease (PD), and 27 neurologically healthy controls (CTRL) participated in two interactive speech tasks, i.e., sentence repetition and "turn-taking" (i.e., dyadic interaction with sentences produced by a model speaker). Production of scripted sentences was used as a control task. Two types of sentence rhythm were distinguished, i.e., regular and irregular, and model speech rate was manipulated in 12 steps between 2.9 and 4.0 syllables per second. Acoustic analyses of the participants' utterances were performed to determine the extent to which participants adapted their speech rate and rhythm to the model. RESULTS: Neurologically healthy speakers showed significant adaptation of rate in all conditions, and of rhythm in the repetition task and partly also the turn-taking task. Patients with PD showed a stronger propensity to adapt than the controls. In contrast, the patients with cerebellar degeneration were largely insensitive to the model speaker's rate and rhythm. Contrary to expectations, sentences with an irregular speech rhythm exerted a stronger adaptive attraction than regular sentences in the two patient groups. CONCLUSIONS: Cerebellar degeneration inhibits the propensity to covertly adapt to others' speech. Striatal dysfunction in Parkinson's disease spares or even promotes the tendency to accommodate to other speakers' speech rate and rhythm.
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Enfermedad de Parkinson , Ataxias Espinocerebelosas , Humanos , Habla , Fonética , Ganglios Basales , Medición de la Producción del HablaRESUMEN
INTRODUCTION: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. METHODS: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. RESULTS: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. CONCLUSIONS: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
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Variaciones en el Número de Copia de ADN , Distonía/genética , Trastornos Distónicos/genética , Secuenciación del Exoma , Adulto , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Distonía/diagnóstico , Trastornos Distónicos/diagnóstico , Femenino , Humanos , MasculinoRESUMEN
Festination and freezing of gait (FOG) are sudden episodic inabilities to initiate or sustain locomotion mostly experienced during the later stages of Parkinson's disease (PD) or other higher-level gait disorders. The aim of this study was to develop a clinical rating instrument for short-interval rating of festination and FOG. Foot movements of 33 patients were video taped and rated during 12 episodes in a standardized course on a four-level interval scale according to severity. Motor blocks were provoked in four situations and by three levels of dual-tasking (tasks). Addition of the item scores produced a FOG score. The assessment requires less than 15 min. The inter-rater and re-test reliability of the FOG score is high (Kendall kappa = 0.85-0.92, P < 0.0001). Variability of the item scale due to situations and tasks can be attributed to unidimensional group factors (Cronbach's alpha 0.84 and 0.94). Group comparisons and a logistic regression model show significant effects for both situations and tasks on the item scale (Friedman test: "situation": P < 0.0001, "task": P < 0.0001). Six patients with PD have significantly different scores during mobile (practical ON; 6.2 +/- 3.9) and immobile (practical OFF; 15.8 +/- 4.6) medication states (P < 0.05). The FOG score correlates with the 10 m number of steps (rho = 0.58; P = 0.001) and with the self-evaluation of FOG (rho = 0.51; P < 0.01). Our results encourage the further use of the FOG score to evaluate festination and FOG.
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Evaluación de la Discapacidad , Reacción Cataléptica de Congelación/fisiología , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/etiología , Trastornos Parkinsonianos/complicaciones , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
The clock drawing test (CDT) is a widely used dementia screening instrument that assesses executive and visuospatial abilities; studies in patients with Alzheimer's disease (AD) suggest frontoposterior networks to be involved in clock drawing. Clock drawing errors are also often observed in dementia with Lewy bodies (DLB), but the functional neuroanatomical substrate of impaired clock drawing has not been firmly established in this disorder. The present study was designed to provide initial evidence for brain metabolic alterations associated with CDT performance in DLB. Twenty-one patients with DLB were enrolled. CDT ratings were correlated with the regional cerebral metabolic rate of glucose (rCMRglc) measured by (18)F-fluoro-2-deoxy-glucose positron emission tomography ((18)F-FDG PET) in the statistical parametric mapping software package SPM5, controlling for overall cognitive impairment as measured by the Mini-Mental-State Examination (MMSE) score. There was a significant negative association between test scores and rCMRglc in a left-hemispheric posterofrontal network including the temporoparietal and dorsal pre-motor cortices and the precuneus. The present study provides evidence for a direct association between frontoparietal dysfunction and impaired CDT performance in DLB. These findings also suggest that the CDT is an appropriate screening instrument for this disorder and that metabolic dysfunction, and therefore disease severity, is mirrored by performance on the test.
Asunto(s)
Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Función Ejecutiva/fisiología , Enfermedad por Cuerpos de Lewy , Percepción Espacial/fisiología , Anciano , Análisis de Varianza , Mapeo Encefálico , Trastornos del Conocimiento/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18 , Lateralidad Funcional , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/patología , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estimulación Luminosa/métodos , Tomografía de Emisión de Positrones/métodosRESUMEN
Afferent feedback from muscles and skin has been suggested to influence our emotions during the control of facial expressions. Recent imaging studies have shown that imitation of facial expressions is associated with activation in limbic regions such as the amygdala. Yet, the physiological interaction between this limbic activation and facial feedback remains unclear. To study if facial feedback effects on limbic brain responses during intentional imitation of facial expressions, we applied botulinum toxin (BTX)-induced denervation of frown muscles in combination with functional magnetic resonance imaging as a reversible lesion model to minimize the occurrence of afferent muscular and cutaneous input. We show that, during imitation of angry facial expressions, reduced feedback due to BTX treatment attenuates activation of the left amygdala and its functional coupling with brain stem regions implicated in autonomic manifestations of emotional states. These findings demonstrate that facial feedback modulates neural activity within central circuitries of emotion during intentional imitation of facial expressions. Given that people tend to mimic the emotional expressions of others, this could provide a potential physiological basis for the social transfer of emotion.
Asunto(s)
Toxinas Botulínicas/toxicidad , Emociones/fisiología , Expresión Facial , Músculos Faciales/fisiología , Retroalimentación Psicológica/fisiología , Red Nerviosa/fisiología , Emociones/efectos de los fármacos , Músculos Faciales/inervación , Femenino , Humanos , Conducta Imitativa/fisiología , Desnervación Muscular/métodos , Red Nerviosa/efectos de los fármacos , Estimulación Luminosa/métodosRESUMEN
BACKGROUND: Freezing of gait is a highly disabling symptom in persons with Parkinson's disease (PwP). Despite its episodic character, freezing can be reliably evaluated using the FOG score. The description of the minimal clinically relevant change is a requirement for a meaningful interpretation of its results. OBJECTIVE: To determine the minimal clinically relevant change of the FOG score. METHODS: We evaluated video recordings of a standardized freezing-evoking gait parkour, i.e., the FOG score just before and 30 minutes after the intake of a regular levodopa dose in a randomized blinded fashion. The minimal clinically relevant response was considered a value of one or more on a 7-step Likert-type response scale [-3; +3] that served as the anchor. The minimal clinically relevant change was determined by ROC analysis. RESULTS: 37 PwP (Hoehn & Yahr stages 2.5-4, 27 male, 10 female) were aged 68.2 years on average (range 45-80). Mean disease duration was 12.9 years (2-29 years). Minimum FOG score was 0 and Maximum FOG score was 29. Mean FOG scores before medication were 10.6, and 11.1 after medication intake, with changes ranging from -14.7 to +16.7. The minimal clinically relevant change (MCRC) for improvement based on expert clinician rating was three scale points with a sensitivity of 0.67 and a specificity of 0.96. CONCLUSIONS: The FOG score is recognized as a useful clinical instrument for the evaluation of freezing in the clinical setting. Knowledge of the MCRC should help to define responses to interventions that are discernible and meaningful to the expert physician and to the patient.
Asunto(s)
Antiparkinsonianos/farmacología , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Levodopa/farmacología , Diferencia Mínima Clínicamente Importante , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Sensibilidad y Especificidad , Método Simple Ciego , Grabación en VideoRESUMEN
Patients with advanced Parkinson's disease regularly experience unstable motor states. Objective and reliable monitoring of these fluctuations is an unmet need. We used deep learning to classify motion data from a single wrist-worn IMU sensor recording in unscripted environments. For validation purposes, patients were accompanied by a movement disorder expert, and their motor state was passively evaluated every minute. We acquired a dataset of 8,661 minutes of IMU data from 30 patients, with annotations about the motor state (OFF,ON, DYSKINETIC) based on MDS-UPDRS global bradykinesia item and the AIMS upper limb dyskinesia item. Using a 1-minute window size as an input for a convolutional neural network trained on data from a subset of patients, we achieved a three-class balanced accuracy of 0.654 on data from previously unseen subjects. This corresponds to detecting the OFF, ON, or DYSKINETIC motor state at a sensitivity/specificity of 0.64/0.89, 0.67/0.67 and 0.64/0.89, respectively. On average, the model outputs were highly correlated with the annotation on a per subject scale (r = 0.83/0.84; p < 0.0001), and sustained so for the highly resolved time windows of 1 minute (r = 0.64/0.70; p < 0.0001). Thus, we demonstrate the feasibility of long-term motor-state detection in a free-living setting with deep learning using motion data from a single IMU.