RESUMEN
AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Hipocampo/patología , Enfermedad por Cuerpos de Lewy/patología , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Corteza Entorrinal/metabolismo , Femenino , Humanos , Masculino , Enfermedad de Parkinson/patología , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Disparities of Parkinson's disease (PD) care have not been assessed. METHODS: We examined the medical records of 309 (83%) non-Hispanic White and 65 (17%) non-White Los Angeles veterans with PD from 1998 to 2004 to determine if care quality as measured by 10 PD indicators different by race/ethnicity. RESULTS: In multivariate modeling, adherence to indicators was higher among non-Hispanic Whites (71% vs. 65%, risk ratio 1.15, 95% CI [1.07-1.32]) compared to non-Whites. Differences in adherence by race/ethnicity were greatest for depression treatment (p<0.05). CONCLUSIONS: We detected disparities in quality of PD care, particularly in depression treatment. Future research should determine causes for these so that interventions can be designed to reduce such disparities.
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Enfermedad de Parkinson/etnología , Enfermedad de Parkinson/terapia , Calidad de la Atención de Salud , Veteranos , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Asiático , Estudios de Cohortes , Hispánicos o Latinos , Humanos , Indígenas Norteamericanos , Masculino , Persona de Mediana Edad , Indicadores de Calidad de la Atención de Salud , Estudios Retrospectivos , Población BlancaRESUMEN
As predictive testing for Parkinson's disease (PD) becomes available, it will be important to understand in whom such testing will be used. To address this issue, we conducted a mail survey of 138 first-degree relatives of PD patients. In the absence of treatment, 60% reported that they would either "definitely" or "probably" be interested in predictive testing. In the setting of a clinical trial, this number increased to 71% (p=0.04) and when neuroprotective therapy is available, interest increased to 90% (p<0.001). Interest in predictive testing for PD is moderate in the absence of effective therapy, and goes up significantly when both clinical trial participation and neuroprotective therapy are offered.
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Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Análisis de Varianza , Correo Electrónico/estadística & datos numéricos , Familia , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
INTRODUCTION: Objective, portable measures of motor function for out-of-office assessments are needed in Parkinson's Disease (PD). This study had 3 objectives. First, to examine change in objective motor measurements in PD (as assessed with the Objective PD Measurement (OPDM) system). Second, to correlate objective measures with clinical features and putative PD cerebrospinal fluid (CSF) and dopaminergic imaging biomarkers. Third, to assess participant compliance with and perceptions of serial in-home motor assessments. METHODS: De novo PD subjects participating in this pilot study of the Parkinson Progression Markers Initiative (PPMI) completed OPDM assessments at home weekly for 3 months and in the clinic at baseline and 3-, 6-, and 12-months. Tasks included (i)digitography (ii)a repetitive hand tapping task and (iii)timed pegboard task. A global objective motor score (OMS) was derived from the latter three. MDS-UPDRS-III score was obtained at each time point, and CSF and dopamine transporter (DAT) SPECT at baseline. RESULTS: 27 participants, mean age 62.6 years, 19 male were included. A mean of 10.5 in-home assessments were completed. There was no significant change in in-home OMS over 12 weeks (p = 0.48). There was strong correlation between mean baseline OMS and MDS-UPDRS-III scores (spearman's rho = 0.60, p=<0.0001). Baseline OMS predicted 6-month MDS-UPDRS-III (ß = 0.80, p = 0.0002) but not change in MDS-UPDRS-III score, DAT SPECT, or putative CSF biomarkers. CONCLUSIONS: This study suggests that administration of in-home motor tasks as part of a large multi-center study is feasible and scores derived from these assessments may serve as surrogates of in-person clinician-assessed motor score.
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Mano/fisiopatología , Movimiento/fisiología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Desempeño Psicomotor/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Físico , Índice de Severidad de la EnfermedadRESUMEN
The detection of respiratory muscle weakness in ALS is necessary to plan initiation of noninvasive positive pressure ventilation and begin discussion of advanced directives. The authors measured the erect seated and supine forced vital capacity (FVC) in 38 patients with ALS and 15 controls. The supine FVC is significantly lower and the erect--supine FVC difference is significantly greater in patients with complaints of dyspnea, orthopnea, and daytime fatigue.
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Esclerosis Amiotrófica Lateral/fisiopatología , Postura/fisiología , Trastornos Respiratorios/fisiopatología , Capacidad Vital/fisiología , Adulto , Femenino , Humanos , MasculinoRESUMEN
A 57-year-old awake man developed central neurogenic hyperventilation associated with a pontine mass. Serum pH reached as high as 7.72 with serum carbon dioxide of 6 torr. Examination of CSF during overbreathing showed that CSF pH was markedly alkaline. Pathologic study showed a well-differentiated pontine astrocytoma. The combination of alkaline CSF and an infiltrating pontine lesion supports a structural, rather than chemical, mechanism for central hyperventilation.
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Astrocitoma/complicaciones , Neoplasias Encefálicas/complicaciones , Hiperventilación/etiología , Puente , Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Líquido Cefalorraquídeo/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Hiperventilación/líquido cefalorraquídeo , Ácido Láctico/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , VigiliaRESUMEN
BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.
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Acetamidas/efectos adversos , Acetamidas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Cooperación del Paciente , Receptores de GlutamatoRESUMEN
UNLABELLED: [99mTc]TRODAT-1 is a radiolabeled tropane that binds dopamine transporters. The primary goal of this study was to determine whether its regional cerebral distribution could differentiate between patients with Parkinson's disease and healthy human volunteers. METHODS: The sample consisted of 42 patients with Parkinson's disease, 23 age-matched controls, and 38 healthy adults younger than 40 y old. SPECT scans of the brain were acquired on a triple-head gamma camera 3-4 h after the intravenous injection of 740 MBq (20 mCi) [99mTc]TRODAT-1. Mean counts per pixel were measured manually in subregions of the basal ganglia and normalized to the mean background counts to give specific uptake values ([SUVs] approximately k3/k4). Patient and control groups were also compared with automated statistical parametric mapping techniques. Logistic discriminant analyses were performed to determine the optimum uptake values for differentiating patients from age-matched controls. RESULTS: Quantitative image analysis showed that the group mean SUVs in patients were less than the mean values in controls for all regions (all Ps < 0.000001). There was overlap in the caudate as well as in the anterior-most portion of the putamen, but not in the posterior putamen, even when the asymptomatic sides of 5 patients with clinically defined hemi-Parkinson's disease were factored in. CONCLUSION: The findings indicate that Parkinson's disease can be detected with [99mTc]TRODAT by simply inspecting the images for uptake in the posterior putamen. Appropriate asymmetries seem to be visible with quantification in patients with clinically defined hemi-Parkinson's disease, even though changes in the putamen contralateral to the clinically unaffected side in these patients appear to precede the development of symptoms.
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Encéfalo/diagnóstico por imagen , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Compuestos de Organotecnecio , Enfermedad de Parkinson/diagnóstico por imagen , Tropanos , Adulto , Anciano , Encéfalo/metabolismo , Estudios de Casos y Controles , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Compuestos de Organotecnecio/farmacocinética , Enfermedad de Parkinson/metabolismo , Cintigrafía , Radiofármacos/farmacocinética , Tropanos/farmacocinéticaRESUMEN
Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations.
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Inhibidores de Catecol O-Metiltransferasa , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Benzofenonas/farmacología , Benzofenonas/uso terapéutico , Catecoles/farmacología , Catecoles/uso terapéutico , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Nitrilos , Nitrofenoles , Ensayos Clínicos Controlados Aleatorios como Asunto , Selegilina/farmacología , Selegilina/uso terapéutico , TolcaponaRESUMEN
We evaluated the diagnostic accuracy of SPECT imaging using [(99m)Tc]TRODAT-1 (TRODAT), a relatively inexpensive technetium-labeled dopamine transporter ligand, in distinguishing 29 patients with early PD from 38 healthy volunteers. Mean TRODAT uptake values were significantly decreased in the caudate (p=0.0097) and anterior and posterior putamen (p < 0.0001) of PD patients compared to controls. Using the posterior putamen as the main region of interest resulted in the greatest accuracy (sensitivity 0.79, specificity 0.92). These findings show that TRODAT imaging can accurately differentiate early PD patients from controls and has the potential to improve the diagnosis of patients with early signs of PD.
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Compuestos de Organotecnecio , Enfermedad de Parkinson/diagnóstico por imagen , Radiofármacos , Tomografía Computarizada de Emisión de Fotón Único/normas , Tropanos , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Genetic and epidemiological studies are critical to understanding the etiology of Parkinson's Disease (PD), and may lead to rational treatments for the disease. This article reviews the clinical features, epidemiology and genetics of PD, with emphasis on insights from recent genetic and epidemiological studies.
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Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Humanos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/economía , Estudios en Gemelos como AsuntoRESUMEN
OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.
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Afecto , Limitación de la Movilidad , Servicio Ambulatorio en Hospital , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/psicología , Calidad de Vida/psicología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Servicio Ambulatorio en Hospital/normas , Enfermedad de Parkinson/diagnósticoRESUMEN
BACKGROUND: No recent analysis details Parkinson's Disease (PD) costs or survival for Medicare beneficiaries. This study assesses excess direct costs and survival in Medicare beneficiaries with early and advanced PD. METHODS: Patients with ≥ 2 PD diagnoses (ICD-9-CM: 332.0), ≥ age 65, continuously enrolled in Parts A&B during one-year baseline and study periods were selected from the Medicare 5% sample (N = 3.2 million, 1999-2008). Newly diagnosed patients were defined as having no baseline claims for movement disorder, dementia, Alzheimer's, bipolar disorder, psychosis, falls or related injuries, ambulatory assistance device (walker or wheelchair), or skilled nursing facility. Controls without PD were demographically matched 1:1. Costs to Medicare were compared via Wilcoxon rank-sum tests and inverse probability weighted multivariate regression. Survival was assessed via Cox proportional hazards analysis. RESULTS: Costs in the year post-diagnosis were higher for newly diagnosed patients (N = 9,201, $7423) than controls ($5024), resulting in excess PD-associated costs of $2399 (p < 0.001). Cumulative excess costs were $28,422 from the year prior to index quarter to five years following (p < 0.01). PD patients receiving their first claim for an ambulatory assistance device (N = 11,294) had excess cumulative costs of $50,923 (p < 0.001) over the same period; those receiving their first claim for a skilled nursing facility (N = 10,152) had excess costs of $102,750 (p < 0.001). Hazard rates of mortality were higher among newly diagnosed PD (1.43, p < 0.001), ambulatory assistance device (2.37, p < 0.001) and skilled nursing facility (3.34, p < 0.001) cohorts than in corresponding non-PD groups. CONCLUSIONS: Medicare beneficiaries with PD have substantially and progressively higher costs and mortality compared with controls.
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Costos de la Atención en Salud , Medicare/economía , Enfermedad de Parkinson , Sobrevida , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Enfermedad de Parkinson/economía , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/mortalidad , Estudios Retrospectivos , Estadísticas no Paramétricas , Estados UnidosRESUMEN
OBJECTIVE: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. METHODS: Drawing from larger calibrated item banks, we developed short measures (8-9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. RESULTS: Internal consistency (Cronbach α) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82-0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1-2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. CONCLUSION: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function.
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Estado de Salud , Enfermedades del Sistema Nervioso/psicología , Neurología/instrumentación , Calidad de Vida , Encuestas y Cuestionarios/normas , Anciano , Femenino , Humanos , Internet/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neurología/métodos , Pacientes Ambulatorios/psicología , Reproducibilidad de los Resultados , AutoinformeRESUMEN
OBJECTIVE: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). METHODS: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. RESULTS: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). CONCLUSION: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.
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Disfunción Cognitiva/genética , Análisis Mutacional de ADN , Tamización de Portadores Genéticos , Glucosilceramidasa/genética , Pruebas Neuropsicológicas , Enfermedad de Parkinson/genética , Adulto , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/genética , Disfunción Cognitiva/diagnóstico , Demencia/diagnóstico , Demencia/genética , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/genética , Femenino , Pruebas Genéticas , Genotipo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/genética , Escala del Estado Mental , Persona de Mediana Edad , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/genética , Enfermedad de Parkinson/diagnóstico , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , beta-Glucosidasa/genéticaRESUMEN
BACKGROUND: While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown. OBJECTIVE: To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives. METHODS: We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking. RESULTS: Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001). CONCLUSION: Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.
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Enfermedad de Parkinson/genética , Olfato , Ubiquitina-Proteína Ligasas/genética , Adulto , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/fisiopatologíaRESUMEN
BACKGROUND: Mutations in parkin are a known genetic risk factor for early onset Parkinson's disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. METHODS: We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. RESULTS: Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2-163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0-332.0), depression (score ≥ 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1-657.4), and BDI-II total depression score (ß = 8.4; 95% CI 2.4-11.3) compared to those without parkin mutations. CONCLUSIONS: Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD.
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Depresión/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/psicología , Ubiquitina-Proteína Ligasas/genética , Adulto , Edad de Inicio , Análisis Mutacional de ADN , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Mutación , Pruebas Neuropsicológicas , Fenotipo , Factores de RiesgoRESUMEN
OBJECTIVE: Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. METHODS: A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid ß 1-42 (Aß(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. RESULTS: Lower baseline CSF Aß(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aß(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline. CONCLUSIONS: Reduced CSF Aß(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
Asunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Trastornos del Conocimiento/líquido cefalorraquídeo , Progresión de la Enfermedad , Enfermedad de Parkinson/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/psicología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau). METHODS: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD. RESULTS: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. CONCLUSIONS: Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
Asunto(s)
Biomarcadores/líquido cefalorraquídeo , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Tauopatías/líquido cefalorraquídeo , Hormona Adrenocorticotrópica/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Degeneración Lobar Frontotemporal/complicaciones , Humanos , Interleucina-17/líquido cefalorraquídeo , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estadísticas no Paramétricas , Tauopatías/complicacionesRESUMEN
OBJECTIVES: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. METHODS: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. RESULTS: There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. CONCLUSIONS: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. CLASSIFICATION OF EVIDENCE: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.