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BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.
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Exenatida , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedad de Parkinson , Humanos , Método Doble Ciego , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Resultado del Tratamiento , Exenatida/análogos & derivados , Exenatida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéuticoRESUMEN
Background and Objectives: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP). Methods: Patients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point). Results: The efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%). Discussion: In this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment. Trial Registration Information: ClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016. Classification of Evidence: This Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.
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BACKGROUND: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. METHODS: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. FINDINGS: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. INTERPRETATION: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. FUNDING: AbbVie.
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Discinesias , Enfermedad de Parkinson , Humanos , Carbidopa/efectos adversos , Levodopa/efectos adversos , Antiparkinsonianos/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Celulitis (Flemón)/inducido químicamente , Celulitis (Flemón)/tratamiento farmacológico , Agonistas de Dopamina , Discinesias/tratamiento farmacológicoRESUMEN
BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.
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Demencia , Enfermedad de Parkinson , Humanos , Resultado del Tratamiento , Estreñimiento , Defecación , Método Doble CiegoRESUMEN
BACKGROUND: Feedback from wearable biosensors may help assess motor function in Parkinson's disease (PD) patients and titrate medication. Kinesia 360 continuously monitors motor symptoms via wrist and ankle sensors. METHODS: PD0049 was a 12-week pilot study to investigate whether using Kinesia 360â¯at home could improve motor symptom management in PD patients starting transdermal dopamine agonist rotigotine. Adults with PD and insufficiently controlled motor symptoms (prescribed rotigotine) were randomized 1:1 to Control Group (CG) or Experimental Group (EG) before starting rotigotine. Motor symptoms were assessed in all patients at baseline and Week 12 (W12) using Unified PD Rating Scale (UPDRS) III and Kinesia ONE, which measures standardized motor tasks via a sensor on the index finger. Between baseline and W12, EG used Kinesia 360â¯at home; clinicians used the data to supplement standard care in adjusting rotigotine dosage. RESULTS: At W12, least squares mean improvements in UPDRS II (-2.1 vs 0.5, pâ¯=â¯0.004) and UPDRS III (-5.3 vs -1.0, p = 0.134) were clinically meaningfully greater, and mean rotigotine dosage higher (4.8 vs 3.9 mg/24 h) in EG (n = 19) vs CG (n = 20). Mean rotigotine dosage increase (+2.8 vs + 1.9 mg/24 h) and mean number of dosage changes (2.8 vs 1.8) during the study were higher in EG vs CG. Tolerability and retention rates were similar. CONCLUSION: Continuous, objective, motor symptom monitoring using a wearable biosensor as an adjunct to standard care may enhance clinical decision-making, and may improve outcomes in PD patients starting rotigotine.
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Actigrafía , Toma de Decisiones Clínicas , Agonistas de Dopamina/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Dispositivos Electrónicos Vestibles , Actigrafía/instrumentación , Actigrafía/métodos , Anciano , Femenino , Humanos , Masculino , Proyectos Piloto , Parche TransdérmicoRESUMEN
BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG, designated in the United States as carbidopa-levodopa enteral suspension, CLES) was approved in the United States in 2015 for the treatment of refractory motor fluctuations in individuals with Parkinson disease (PD). Many neurologists in the United States have not had personal experience with implementation and management of the unique delivery system for this treatment. METHODS AND FINDINGS: This educational review was developed to provide practitioners with an understanding of LCIG use from the clinician's point of view. Practical recommendations for the use of LCIG from the early planning stages through long-term patient management were compiled from the published literature, regulatory guidance, and clinical experience. Among the topics reviewed were: assembling a multidisciplinary treatment team, identifying treatment candidates, patient/care partner education, procedural considerations, post-procedural care, LCIG initiation and titration, troubleshooting issues, and ongoing monitoring. For most of these steps, a considerable amount of individualization is possible, which allows clinicians to tailor protocols based on the needs of their teams, the healthcare system, and the patient and care partner. Although clinical practices are heterogeneous, themes of early planning, ongoing education, and a team-based approach to management are universal. CONCLUSIONS: By using established protocols and insights gleaned from experienced practitioners, clinicians who are unfamiliar with LCIG can more feasibly incorporate this treatment option into their armamentarium for treating PD motor fluctuations.
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PURPOSE OF REVIEW: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). RECENT FINDINGS: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. SUMMARY: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.
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Lewy pathology occurs in 8-17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
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Demencia/patología , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/patología , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Estudios Retrospectivos , alfa-Sinucleína/aislamiento & purificaciónRESUMEN
OBJECTIVE: To explore whether associations of potential risk factors for incidental Lewy body disease (iLBD) are similar to those for Parkinson disease (PD). DESIGN: Brain autopsy study (1988-2004) of subjects without evidence of neurodegenerative disease or tremor who were evaluated by at least 1 physician within 1 year of death. Researchers analyzed incidental Lewy pathology blinded to clinical abstraction. SETTING: Olmsted County, Minnesota. Subjects Residents of Olmsted County and the immediate vicinity aged older than 60 years. MAIN OUTCOME MEASURES: Whether risk factors previously associated with PD in Olmsted County are also associated with iLBD. RESULTS: Of 235 subjects, 34 had iLBD (14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the 2 sets of odds ratio (OR) estimates, with 11 of 16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for physician occupation and caffeine intake, the ORs for iLBD were in the same direction and statistically significant, whereas for education, head injury, and number of children, they were in the same direction but not significant; they were in the opposite direction but not statistically significant for depression and anxiety. Incidental Lewy body disease was not associated with various end-of-life conditions or causes of death, though these patients were slightly older and more likely cachectic. CONCLUSIONS: Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of iLBD could represent preclinical PD, arrested PD, or a partial syndrome due to a lesser burden of causative factors. Incidental Lewy body disease is not explained by nonspecific end-of-life brain insults.
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Encéfalo/patología , Enfermedad por Cuerpos de Lewy/epidemiología , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/patología , Adolescente , Adulto , Anciano , Autopsia , Encéfalo/fisiopatología , Causalidad , Niño , Preescolar , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Humanos , Lactante , Enfermedad por Cuerpos de Lewy/fisiopatología , Masculino , Registros Médicos , Persona de Mediana Edad , Minnesota/epidemiología , Oportunidad Relativa , Enfermedad de Parkinson/fisiopatología , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Non-motor manifestations of Parkinson disease (PD) are common and some may actually antedate motor dysfunction. Extrapyramidal signs in PD are tightly linked to striatonigral dopaminergic denervation associated with neuronal loss and Lewy bodies in the residual neurons of the substantia nigra. Lewy bodies composed of abnormal alpha-synuclein are the histologic hallmark of PD, and their presence beyond midbrain dopaminergic neurons is considered to be the pathologic substrate of many, if not all, of the non-motor manifestations of PD. We review the pathologic correlates of autonomic dysfunction (cardiac and gastrointestinal), hyposmia, depression, rapid eye movement behavior disorder and dementia in PD For each non-motor clinical feature there is strong evidence to suggest a role for alpha-synuclein pathology, lending further support for the notion that PD is a multisystem alpha-synucleinopathy.
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Cuerpos de Lewy/patología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , alfa-Sinucleína/metabolismo , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Ansiedad/patología , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Enfermedades del Sistema Nervioso Autónomo/patología , Demencia/etiología , Demencia/metabolismo , Demencia/patología , Depresión/etiología , Depresión/metabolismo , Depresión/patología , Humanos , Trastorno de la Conducta del Sueño REM/etiología , Trastorno de la Conducta del Sueño REM/metabolismo , Trastorno de la Conducta del Sueño REM/patologíaRESUMEN
BACKGROUND: The significance of Lewy bodies detected at autopsy in the brains of clinically normal individuals is uncertain but may represent preclinical Parkinson disease (PD). OBJECTIVE: To determine whether diminished striatal dopaminergic innervation and nigral cell loss are present in incidental Lewy body disease (iLBD), as one might expect if it is a forerunner of PD. DESIGN: Case-control study. SETTING: Medical records and archival brain tissue were obtained from a tertiary medical center for further study. PARTICIPANTS: Brains from clinically healthy individuals older than 60 years with alpha-synuclein-immunoreactive Lewy bodies (iLBD; n = 12) were compared with those from clinically healthy individuals with no alpha-synuclein pathologic findings (n = 31) and patients with PD (n = 25). MAIN OUTCOME MEASURES: Striatal dopaminergic integrity assessed in sections of putamen by immunofluorescence for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2), neuronal loss score in the substantia nigra, and distribution of Lewy bodies according to PD stage. RESULTS: Among the participants with iLBD, decreased striatal dopaminergic immunoreactivity was documented for both TH (33%) and VMAT2 (42%), compared with the pathologically normal subjects; as expected, the reductions were even greater in PD (73% decrease for TH and 96% decrease for VMAT2). Substantia nigra neuronal loss inversely correlated with both striatal TH (r = -0.84) and VMAT2 (r = -0.77). In addition, PD stage inversely correlated with both striatal VMAT2 (r = -0.85) and TH (r = -0.85). CONCLUSIONS: The results indicate that iLBD has nigrostriatal pathological features that are intermediate between those in pathologically normal persons and those with PD. The findings suggest that iLBD probably represents presymptomatic PD, rather than nonspecific, age-related alpha-synuclein pathological changes.
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Hallazgos Incidentales , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = -0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = -0.61, P < 0.001), and disease duration (r = -0.63, P < 0.001). Immunohistochemistry for alpha-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of alpha-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity.
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Corazón/inervación , Degeneración Nerviosa/patología , Enfermedad de Parkinson/patología , Sistema Nervioso Simpático/patología , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Humanos , Hipotensión Ortostática/diagnóstico , Hipotensión Ortostática/patología , Cuerpos de Lewy/patología , Masculino , Fibras Nerviosas/patología , Neuritas/patología , Enfermedad de Parkinson/diagnóstico , Pericardio/inervación , Pericardio/patología , Médula Espinal/patología , Tirosina 3-Monooxigenasa/análisis , alfa-Sinucleína/análisisRESUMEN
Lewy bodies, the histologic hallmark of Parkinson's disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.
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Enfermedad por Cuerpos de Lewy/epidemiología , Enfermedad por Cuerpos de Lewy/etiología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Anciano , Anciano de 80 o más Años , Tronco Encefálico/patología , Muerte Celular , Distribución de Chi-Cuadrado , Femenino , Humanos , Incidencia , Enfermedad por Cuerpos de Lewy/patología , Masculino , Miocardio/metabolismo , Enfermedad de Parkinson/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Unusual compulsive behaviors (weighing, card and video game playing, fishing, gardening, intense interest in established hobbies, locking and unlocking doors, repetitive dressing and undressing) occurred in relation to dopamine agonist therapy (six patients) and levodopa therapy (one patient) in seven patients with parkinsonism (seven Parkinson's disease, one multiple system atrophy). These behaviors occurred in tandem with pathological gambling, hypersexuality, compulsive eating, compulsive shopping or punding in six of the seven cases. Obsessive thoughts were present in one patient, with no prior history of obsessive-compulsive disorder. The simultaneous occurrence of these phenomenologically distinct behaviors in this group of patients suggests that a broad spectrum of psychopathology may occur in this context and should be monitored for in routine neurological practice.
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Conducta Compulsiva/inducido químicamente , Agonistas de Dopamina/efectos adversos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
OBJECTIVE: To define the molecular etiology of early-onset parkinsonism and peripheral neuropathy. METHODS: Two sisters had early-onset parkinsonism (dystonic toe curling, action tremor, masked face, bradykinesia, stooped posture, and rigidity), together with clinical and electrophysiological signs of sensorimotor axonal peripheral neuropathy. RESULTS: No mutations were found in the genes for parkin or PINK1. Muscle biopsies showed ragged-red and cytochrome c oxidase-negative fibers, and biochemistry showed decreased activities of respiratory chain complexes containing mitochondrial DNA-encoded subunits. Multiple mitochondrial DNA deletions were seen by long polymerase chain reaction, and sequencing of the POLG gene showed that the patients were compound heterozygous for two patogenic mutations. INTERPRETATION: POLG mutations can cause early-onset parkinsonism in the absence of progressive external ophthalmoplegia.
Asunto(s)
ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Enfermedad de Parkinson/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , ADN/genética , ADN Polimerasa gamma , Distonía/fisiopatología , Femenino , Genes Recesivos/genética , Heterocigoto , Humanos , Datos de Secuencia Molecular , Músculo Esquelético/patología , Mutación , Enfermedades Neuromusculares/fisiopatología , Oftalmoplejía Externa Progresiva Crónica/patología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Temblor/fisiopatologíaRESUMEN
BACKGROUND: An atypical form of parkinsonism has been described in patients with chronic liver disease, associated with increased T1 signal in the basal ganglia on magnetic resonance imaging. The magnetic resonance imaging signal changes are characteristic of manganese accumulation, which has been neuropathologically confirmed. Manganese neurotoxicity may result in additional neurologic findings besides parkinsonism. OBJECTIVE: To fully characterize patients with chronic central nervous system symptoms and chronic liver failure associated with basal ganglia T1 hyperintensity. DESIGN: Prospective and retrospective case study. SETTING: Mayo Clinic, Rochester, Minn. PARTICIPANTS: Eight patients referred for neurologic evaluation and studied prospectively, and 7 additional retrospectively identified patients who had been examined by Mayo Clinic neurologists. MAIN OUTCOME MEASURES: Neurologic syndromes identified. RESULTS: Three syndromes were recognized in these 15 patients with liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: (1) isolated parkinsonism, (2) gait ataxia plus other neurologic findings (ataxia-plus), and (3) cognitive impairment with psychiatric features. All but 1 patient had elevated blood manganese levels. Ammonia levels were normal in most, and the neurologic syndromes did not appear to reflect the well-known toxic-metabolic encephalopathy of liver disease. CONCLUSIONS: Chronic liver failure may result in heterogeneous neurologic syndromes that cut across a variety of liver diseases. We selected cases on the basis of evidence of brain manganese accumulation, and this may be a crucial component of these syndromes. Further studies are necessary to explore this issue.
Asunto(s)
Enfermedades de los Ganglios Basales/etiología , Fallo Hepático/etiología , Intoxicación por Manganeso/complicaciones , Adulto , Anciano , Amoníaco/sangre , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Química Encefálica , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Femenino , Ataxia de la Marcha/complicaciones , Ataxia de la Marcha/metabolismo , Ataxia de la Marcha/patología , Humanos , Fallo Hepático/metabolismo , Fallo Hepático/patología , Imagen por Resonancia Magnética/métodos , Masculino , Intoxicación por Manganeso/sangre , Persona de Mediana Edad , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.
Asunto(s)
Antiparkinsonianos/efectos adversos , Agonistas de Dopamina/efectos adversos , Atrofia de Múltiples Sistemas/complicaciones , Enfermedad de Parkinson/complicaciones , Disfunciones Sexuales Psicológicas/inducido químicamente , Adulto , Anciano , Antiparkinsonianos/uso terapéutico , Benzotiazoles , Catecoles/efectos adversos , Catecoles/uso terapéutico , Bases de Datos Factuales , Agonistas de Dopamina/uso terapéutico , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Levodopa/efectos adversos , Levodopa/uso terapéutico , Masculino , Trastornos Mentales/inducido químicamente , Trastornos Mentales/psicología , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Nitrilos , Enfermedad de Parkinson/tratamiento farmacológico , Pramipexol , Tiazoles/efectos adversos , Tiazoles/uso terapéuticoRESUMEN
We report on two cases of sporadic idiopathic Parkinson's disease with motor neuron disease co-occurring in the same individuals. Pathological analysis revealed the presence of Lewy bodies in brainstem nuclei and basal forebrain consistent with Lewy body disease (LBD), as well as motor neuron degeneration and argyrophilic grain disease. We compared our two cases to all previously published pathological cases of combined LBD and motor neuron degeneration.