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BACKGROUND: Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses. To test this hypothesis, pituitary glands were removed from 18 horses: four untreated PPID-affected horses, four aged and four young horses without signs of PPID, and six PPID-affected horses that had been treated with pergolide at 2 µg/kg orally once daily for 6 months. DA concentrations and TH expression levels in PI tissues were determined by high performance liquid chromatography with electrochemical detection and Western blot analyses, respectively. RESULTS: DA and TH levels were lowest in PI collected from untreated PPID-affected horses while levels in the pergolide treated horses were similar to those of aged horses without signs of PPID. CONCLUSIONS: These findings provide evidence of restoration of DA and TH levels following treatment with pergolide. Equine PPID is a potential animal model of dopaminergic neurodegeneration, which could provide insight into human neurodegenerative diseases.
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Agonistas de Dopamina/uso terapéutico , Dopamina/metabolismo , Enfermedades de los Caballos/tratamiento farmacológico , Pergolida/uso terapéutico , Enfermedades de la Hipófisis/veterinaria , Tirosina 3-Monooxigenasa/metabolismo , Envejecimiento , Animales , Caballos , Enfermedades de la Hipófisis/tratamiento farmacológico , Adenohipófisis Porción Intermedia/efectos de los fármacos , Adenohipófisis Porción Intermedia/patologíaRESUMEN
The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
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Edición/normas , Proyectos de Investigación/normas , Animales , Edición/tendencias , Distribución Aleatoria , Tamaño de la Muestra , Estadística como AsuntoRESUMEN
Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
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Enfermedades de los Ganglios Basales/genética , Calcinosis/genética , Mutación , Enfermedades Neurodegenerativas/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Adulto , Anciano , Secuencia de Aminoácidos , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Estudios RetrospectivosRESUMEN
Parkinson's disease (PD) is heterogenous in its presentation, progression and response to therapies. Genetic polymorphisms may account for some of this variability. Several single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor gene BDNF have been associated with differing clinical outcomes from different dopaminergic replacement strategies, and one of these, the rs6265 SNP, has been associated with a milder clinical phenotype in the unmedicated, early-stage of PD. We examined if other BDNF SNPs with potential pharmacogenetic effects also are associated with different rates of disease progression. The Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study was analyzed retrospectively. DNA samples (n = 217) were genotyped for the BDNF rs908867, rs11030094, rs10501087, rs1157659, and rs1491850 SNPs, and the primary endpoint was time to initiate symptomatic pharmacotherapy. Genotypes were compared using the Cox proportional hazard ratio (HR) with baseline age, sex, site, time since PD diagnosis and rs6265 genotype as covariates. The primary endpoint was associated with a delay with three SNPs: rs10501087 [HR (95% Confidence Interval) = 28.3 (3.6-223.1, p = 0.002) and 7.6 (1.9-29.8, p = 0.004) for T/T and T/C subjects, respectively, vs. C/C subjects], rs1491850 [HR = 3.3 (1.3-8.4, p = 0.04) and 2.8 (1.3-6.4, p = 0.03) for T/T and T/C subjects, respectively, vs. C/C subjects] and rs11030094 [HR = 2.5 (1.1-5.6, p = 0.03) and 2.0 (1.3-6.4, p = 0.03) for A/A and A/G subjects, respectively, vs. G/G subjects]. From the primary endpoint, specific rs10501087, rs1491850, and rs11030094 SNP genotypes are associated with a slower rate of PD progression in the unmedicated state. A prospective clinical trial examining many BDNF SNPs is warranted.
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Chronic hyperglycaemia is detrimental to pancreatic beta-cells by causing impaired insulin secretion and diminished beta-cell function through glucotoxicity. Understanding the mechanisms underlying beta-cell survival is crucial for the prevention of beta-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic beta-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5'-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic beta-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic beta-cells. Greater knowledge of the molecular mechanisms linking autophagy and beta-cell survival may unveil novel therapeutic targets needed to preserve beta-cell function.
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Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Animales , Apoptosis , Caspasa 3/metabolismo , Proliferación Celular , Supervivencia Celular , Lisosomas/metabolismo , Masculino , Potenciales de la Membrana , Membranas Mitocondriales/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient's clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.
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Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.
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Antiparkinsonianos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/genética , Variación Genética/genética , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Diagnóstico Precoz , Femenino , Humanos , Estudios Longitudinales , Masculino , Enfermedad de Parkinson/diagnóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Novel therapeutic approaches using stem cell transplantation to treat neurodegenerative diseases have yielded promising results. However, survival of stem cells after transplantation has been very poor in animal models, and considerable efforts have been directed at increasing the viability of engrafted stem cells. Therefore, understanding the mechanisms that regulate survival and death of neural stem cells is critical to the development of stem cell-based therapies. Hippocampal neural (HCN) stem cells derived from the adult rat brain undergo cell death following insulin withdrawal, which is associated with downregulation of antiapoptotic Bcl-2 family members. To understand the type of cell death in HCN cells following insulin withdrawal, apoptosis markers were assessed. Of note, DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the dramatically increased formation of autophagic vacuoles with cytoplasmic contents. Staurosporine induced robust activation of caspase-3 and nucleosomal DNA fragmentation, suggesting that the machinery of apoptosis is intact in HCN cells despite the apparent absence of apoptosis following insulin withdrawal. Autophagic cell death was suppressed by knockdown of autophagy-related gene 7, whereas promotion of autophagy by rapamycin increased cell death. Taken together, these data demonstrate that HCN cells undergo a caspase-independent, autophagic cell death following insulin withdrawal. Understanding the mechanisms governing autophagy of adult neural stem cells may provide novel strategies to improve the survival rate of transplanted stem cells for treatment of neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.
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Células Madre Adultas/citología , Autofagia , Hipocampo/citología , Insulina/deficiencia , Neuronas/citología , Células Madre/citología , Animales , Apoptosis , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Inmunohistoquímica , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Nestina , Neuronas/ultraestructura , Ratas , Células Madre/ultraestructura , Vacuolas/ultraestructura , Proteína bcl-X/metabolismoRESUMEN
OBJECTIVE: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine. METHODS: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex. RESULTS: Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = -0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = -0.44; p = 0.006). No significant associations were observed in men. CONCLUSIONS: Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine. CLINICALTRIALSGOV IDENTIFIER: NCT00833690. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.
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Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Caracteres Sexuales , Ácido Úrico/sangre , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Inosina/uso terapéutico , Masculino , Pruebas de Estado Mental y Demencia , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.
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Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Sustancia Negra/efectos de los fármacos , Sulfonas/farmacología , Sulfonas/uso terapéutico , Animales , Axones/metabolismo , Western Blotting , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa 5 , Purinas/farmacología , Purinas/uso terapéutico , Citrato de Sildenafil , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Dopamine (DA) neurons comprising the A11 diencephalospinal system represent the major source of DA innervation to the spinal cord. These neurons project axons throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. Loss of DA-mediated sensorimotor function in the lumbar segment of spinal cord is implicated in the etiology of Restless Legs Syndrome (RLS), which is more prevalent in females as compared with males. The purpose of the present study was to compare the density (DA concentrations) and catabolic activity (3,4-dihydroxyphenylacetic acid; DOPAC) of A11 DA neurons innervating the lumbar spinal cord of male and female C57/BL6 mice, and to determine if there is a sexual difference in the regulation of these neurons by D2 autoreceptor-mediated mechanisms. DA concentrations in the lumbar spinal cord were higher in males, suggesting a greater A11 DA innervation as compared with females, whereas there was no sexual difference in the activity (DOPAC/DA ratio) of these DA neurons under basal conditions. Blockade of D2 receptors with raclopride caused a significant increase in the DOPAC/DA ratio in the striatum and nucleus accumbens in both males and females, but had no effect in the spinal cord. Blockade of neuronal impulse flow and DA release with gamma-butyrolactone (GBL) increased DA concentrations in the spinal cord, but this increase was not prevented by pretreatment with the D2 agonist quinelorane. These results are consistent with the conclusion that A11 diencephalospinal DA neurons in both males and females lack presynaptic synthesis modulating D2 autoreceptors.
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Diencéfalo/citología , Dopamina/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D2/fisiología , Caracteres Sexuales , Ácido 3,4-Dihidroxifenilacético/metabolismo , 4-Butirolactona/farmacología , Análisis de Varianza , Animales , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Interacciones Farmacológicas , Electroquímica/métodos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Quinolinas/farmacología , Racloprida/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
INTRODUCTION: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD. METHODS: A retrospective analysis was conducted using data collected in the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study. DNA samples (nâ¯=â¯217) were genotyped for the Bdnf rs6265 variant, and the primary endpoint was time to initiate levodopa. The Parkinson's Progression Markers Initiative (PPMI) was used for validation (nâ¯=â¯383). RESULTS: The primary endpoint of time to initiate levodopa was associated with a delay in subjects with two copies of the rs6265 minor (Met66) allele (HR: 4.9; 95% CI: 1.3-18.8). Secondary endpoints were not different among genotypes. PPMI subjects with two Met66 alleles demonstrated significantly lower total and part III Movement Disorder Society - United Parkinson's Disease Rating Scale (MDS-UPDRS) scores at baseline, as well as more tremor-related symptoms, but not a delay in initiation of maintenance pharmacotherapy. CONCLUSIONS: Data from two distinct, unmedicated, early-stage PD cohorts suggest that carrying two copies of the rs6265 Met66 allele (â¼4% of the population) is associated with less severity in motor symptoms and potentially a slower rate of progression.
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Factor Neurotrófico Derivado del Encéfalo/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Índice de Severidad de la Enfermedad , Anciano , Antiparkinsonianos/efectos adversos , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Factores de TiempoRESUMEN
Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show alpha-synuclein (alpha-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP+/MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of alpha-Syn was absolutely mandatory to observe MPP+/MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing alpha-Syn or in alpha-Syn-/- mice. MPP+/MPTP also induced a significant accumulation of alpha-Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP+ lead to differential alterations in p-Tau and alpha-Syn levels in a cytoskeleton-bound, vs. a soluble, cytoskeleton-free fraction, inducing their coimmunoprecipitation in the cytoskeleton-free fraction and neuronal soma. Subchronic MPTP exposure increased sarkosyl-insoluble p-Tau in striatum of WT but not alpha-Syn-/- mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly alpha-Syn-dependent, increased formation of PHF-1-reactive Tau, suggesting convergent overlapping pathways in the genesis of clinically divergent diseases such as AD and PD.
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Intoxicación por MPTP/fisiopatología , alfa-Sinucleína/genética , Proteínas tau/metabolismo , Animales , Línea Celular , Clonación Molecular , Modelos Animales de Enfermedad , Humanos , Intoxicación por MPTP/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Transfección , alfa-Sinucleína/deficiencia , alfa-Sinucleína/metabolismoRESUMEN
Parkinson disease (PD) is prevalent in elderly individuals and is characterized by selective degeneration of nigrostriatal dopamine (NSDA) neurons. Interestingly, not all dopamine (DA) neurons are affected equally by PD and aging, particularly mesolimbic (ML) DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA) neurons and astrocyte DA metabolism. There were no differences in phenotypic markers of DA synthesis, reuptake or metabolism in NSDA or MLDA neurons in aged mice, but MLDA neurons displayed lower DA stores. Astrocyte metabolism of DA to 3-methoxytyramine (3-MT) in the striatum was decreased in aged mice, but was maintained in the nucleus accumbens. Despite diminished DA vesicular storage capacity in MLDA neurons, susceptibility to acute neurotoxicant exposure was similar in young and aged mice. These results reveal an age- and neurotoxicant-induced impairment of DA metabolic activity in astrocytes surrounding susceptible NSDA neurons as opposed to maintenance of DA metabolism in astrocytes surrounding resistant MLDA neurons, and suggest a possible therapeutic target for PD.
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BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SDâ=â1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SEâ=â0.002, pâ=â0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (pâ<â0.001), Ambulatory Capacity (pâ<â0.001), and the Rankin (pâ=â0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.
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Progresión de la Enfermedad , Inhibidores de la Monoaminooxidasa/farmacología , Evaluación de Resultado en la Atención de Salud/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Anciano , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/administración & dosificación , Factores de TiempoRESUMEN
The management of advancing Parkinson's disease (PD) is a daunting task, complicated by dynamic medication responses, side effects, and treatment-refractory symptoms in an aging patient population. The motor and nonmotor complications of advancing PD are reviewed, and practical treatment strategies are provided. Careful assessment in the context of the known natural history of advancing PD and rational treatment choices can create significant improvement in the lives of patients who have advancing PD.
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Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/terapia , Antiparkinsonianos/efectos adversos , Progresión de la Enfermedad , Humanos , Levodopa/efectos adversos , Procedimientos Neuroquirúrgicos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Resultado del TratamientoRESUMEN
Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury (Behrouz et al., 2007; Benskey et al., 2012). The recovery of the TIDA neurons is dependent on de novo protein synthesis and positively correlated with an increase in parkin mRNA and protein expression (Benskey et al., 2012, 2015). Inhibition of parkin upregulation renders TIDA neurons susceptible to degeneration following MPTP exposure. In addition to parkin, other potentially protective proteins are likely to be differentially regulated in TIDA and NSDA neurons following neurotoxicant exposure. The regulation of potential transcription factors for parkin and other neuroprotective pathway genes are of interest since they may provide novel targets for PD disease modifying therapies. As such, we sought to determine if there are time-dependent differences in the expression of AP-1 transcription factors c-Fos, c-Jun, FosB, ΔFosB and JunD in TIDA and NSDA neurons of mice following acute MPTP exposure. We observed that both FosB and ΔFosB expression increase in brain regions containing TIDA, but not NSDA neurons. Furthermore, the nuclear and long-term expression of ΔFosB is consistent with its role as a transcription factor that may influence parkin transcription, which may underlie the unique ability of TIDA neurons to recovery from an injury that leads NSDA neurons to degeneration.
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The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy. Baseline data from 1616 out of the 1741 participants were evaluated using univariable and multivariable logistic or generalized logit regression analyses for available factors associated with the choice of dopaminergic therapy. The dopaminergic therapy choice was determined as: (i) therapy that subjects recalled taking 180days before the study; (ii) therapy at baseline; and (iii) the longest duration of therapy reported by participants. Younger age, higher education level, longer length of time since PD diagnosis and use of an adjunctive, non-dopaminergic or monoamine oxidase inhibitor medication were associated with more frequent use of dopamine agonist compared to levodopa or combination therapy.
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Antiparkinsonianos/uso terapéutico , Conducta de Elección , Dopaminérgicos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Aceptación de la Atención de Salud/estadística & datos numéricos , Factores de Edad , Anciano , Canadá/epidemiología , Escolaridad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/uso terapéutico , Análisis Multivariante , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
The spleen is a visceral organ that contracts during hypoxia to expel erythrocytes and immune cells into the circulation. Spleen contraction is under the control of noradrenergic sympathetic innervation. The activity of noradrenergic neurons terminating in the spleen capsule is regulated by α2-adrenergic receptors (AR). Interactions between endogenous cannabinoid signaling and noradrenergic signaling in other organ systems suggest endocannabinoids might also regulate spleen contraction. Spleens from mice congenitally lacking both CB1 and CB2 cannabinoid receptors (Cnr1 -/- /Cnr2 -/- mice) were used to explore the role of endocannabinoids in spleen contraction. Spleen contraction in response to exogenous norepinephrine (NE) was found to be significantly lower in Cnr1 -/- /Cnr2 -/- mouse spleens, likely due to decreased expression of capsular α1AR. The majority of splenic Cnr1 mRNA expression is by cells of the spleen capsule, suggestive of post-synaptic CB1 receptor signaling. Thus, these studies demonstrate a role for CB1 and/or CB2 in noradrenergic splenic contraction.
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Neuronas Adrenérgicas/metabolismo , Receptor Cannabinoide CB1/deficiencia , Receptor Cannabinoide CB2/deficiencia , Bazo/inervación , Bazo/metabolismo , Neuronas Adrenérgicas/efectos de los fármacos , Animales , Femenino , Contracción Isométrica/efectos de los fármacos , Contracción Isométrica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Norepinefrina/farmacología , Técnicas de Cultivo de Órganos , Bazo/efectos de los fármacosRESUMEN
A pathological hallmark of Parkinson׳s disease (PD) is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, which underlies the motor symptoms of PD. While there is severe loss of midbrain NSDA neurons, tuberoinfundibular (TI) DA neurons in the mediobasal hypothalamus (MBH) remain intact. In the present study, confocal microscopic analysis revealed that mitochondrial content and numbers of mitophagosomes were lower in NSDA neuronal cell bodies in the substantia nigra pars compacta (SNpc) compared to TIDA neuronal cell bodies in the arcuate nucleus (ARC) of C57BL/6J male mice. Mitochondrial respiration, mass, membrane potential and morphology were determined using bioenergetic, flow cytometric and transmission electron microscopic analyses of synaptosomes isolated from discrete brain regions containing axon terminals of NSDA and TIDA neurons. Maximum and spare respiratory capacities, and mitochondrial mass were lower in synaptosomal mitochondria derived from the striatum (ST) as compared with the MBH, which correlated with lower numbers of mitochondria per synaptosome in these brain regions. In contrast, there was no regional difference in mitochondrial basal, maximum or spare respirations following inhibition of Complex I activity with rotenone. These results reveal that higher numbers of viable mitochondria are correlated with more extensive autophagic mitochondrial quality maintenance in TIDA neurons as compared with NSDA neurons.