RESUMO
PURPOSE: The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies. METHODS: A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented. RESULTS: MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology. CONCLUSION: This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , alfa-Sinucleína/genética , Proteínas tau/genética , Idoso de 80 Anos ou mais , Encéfalo/patologia , Feminino , Haplótipos , Humanos , Corpos de Lewy/patologia , Masculino , Tamanho do Órgão , Doença de Parkinson/genética , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND/AIMS: Hallucinations have been linked to a constellation of cognitive deficits in Parkinson's disease (PD), but it is not known whether multi-modal hallucinations are associated with greater neuropsychological dysfunction. METHODS: 152 idiopathic PD patients were categorized based on the presence or absence of hallucinations and then were further subdivided into visual-only (VHonly; n = 35) or multi-modal (VHplus; n = 12) hallucination groups. All participants underwent detailed neuropsychological assessment. RESULTS: Participants with hallucinations performed more poorly on select neuropsychological measures and exhibited more mood symptoms. There were no differences between VHonly and VHplus groups. CONCLUSIONS: PD patients with multi-modal hallucinations are not at greater risk for neuropsychological impairment than those with single-modal hallucinations.
Assuntos
Transtornos Cognitivos/complicações , Transtornos Cognitivos/psicologia , Cognição/fisiologia , Alucinações/complicações , Alucinações/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Afeto/fisiologia , Idoso , Antiparkinsonianos/uso terapêutico , Atenção/fisiologia , Transtornos Cognitivos/epidemiologia , Estimulação Encefálica Profunda , Emoções/fisiologia , Função Executiva/fisiologia , Feminino , Alucinações/epidemiologia , Humanos , Testes de Inteligência , Idioma , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/epidemiologia , Doença de Parkinson/terapia , Escalas de Graduação Psiquiátrica , Risco , Percepção Espacial/fisiologiaRESUMO
While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38)), survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48)), and PD age at onset (R(2) = 0.68, p = 1.68 x 10(-51)). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.
Assuntos
Axônios/fisiologia , Predisposição Genética para Doença , Genômica , Doença de Parkinson/genética , Estudos de Casos e Controles , Humanos , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Genetic variation in fibroblast growth factor 20 (FGF20) has been associated with risk of Parkinson's disease (PD). Functional evidence suggested the T allele of one SNP, rs12720208 C/T, altered PD risk by increasing FGF20 and alpha-synuclein protein levels. Herein we report our association study of FGF20 and PD risk in four patient-control series (total: 1,262 patients and 1,881 controls), and measurements of FGF20 and alpha-synuclein protein levels in brain samples (nine patients). We found no evidence of association between FGF20 variability and PD risk, and no relationship between the rs12720208 genotype, FGF20 and alpha-synuclein protein levels.
Assuntos
Fatores de Crescimento de Fibroblastos/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Peripheral neuropathy is a well recognized toxicity of taxanes, usually resulting to dose modification and changes in the treatment plan. Taxanes produce a symmetric, axonal predominantly sensory distal neuropathy with less prominent motor involvement. A "dying back" process starting from distal nerve endings followed by effects on Schwann cells, neuronal body or axonal transport changes and a disturbed cytoplasmatic flow in the affected neurons is the most widely accepted mechanism of taxanes neurotoxicity. The incidence of taxanes-induced peripheral neuropathy is related to causal factors, such as single dose per course and cumulative dose and risk factors including treatment schedule, prior or concomitant administration of platinum compounds or vinca alcaloids, age and pre-existing peripheral neuropathy of other causes. The most reliable method to assess taxanes neurotoxicity is by clinical examination combined with electrophysiological evaluation. There is currently no effective symptomatic treatment for paclitaxel-associated pain, myalgias and arthralgias. Tricyclic antidepressants and anticonvulsants have been used as symptomatic treatment of neurotoxicity with some measure of success. Therefore, new approaches for prophylaxis against taxanes-induced peripheral neuropathy are needed. Several neuroprotective agents including, thiols, neurotrophic factors, and antioxidants hold promise for their ability to prevent neurotoxicity resulting from taxanes exposure. However, further confirmatory trials are warranted on this important clinical topic. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of taxanes-induced peripheral neuropathy. We also highlight areas of future research.
Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Taxoides/efeitos adversos , Antineoplásicos/uso terapêutico , Humanos , Incidência , Neoplasias/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Doenças do Sistema Nervoso Periférico/terapia , Fatores de Risco , Taxoides/uso terapêuticoRESUMO
BACKGROUND: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings. METHODS: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons. RESULTS AND DISCUSSION: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles. CONCLUSION: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.
Assuntos
Alucinações/epidemiologia , Doença de Parkinson/epidemiologia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Estudos de Coortes , Comorbidade , Feminino , Florida/epidemiologia , Alucinações/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Parkinson's disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model.
Assuntos
Cardiopatias/diagnóstico , Cardiopatias/etiologia , Doença de Parkinson/complicações , Disautonomias Primárias/diagnóstico , Disautonomias Primárias/etiologia , 3-Iodobenzilguanidina , Humanos , Anidridos Ftálicos , Tomografia por Emissão de Pósitrons/métodosRESUMO
Acquired chronic hepatocerebral degeneration is a central nervous system disorder secondary to several conditions related to hepatic dysfunction. Clinical features of acquired chronic hepatocerebral degeneration include a hyperkinetic extrapyramidal syndrome, neuropsychiatric symptoms, or both. We present for the first time a pediatric case of acquired chronic hepatocerebral degeneration secondary to endstage biliary disease. The pediatric phenotype of acquired chronic hepatocerebral degeneration is presented, and the differential diagnosis in regard to Wilson's disease and management alternatives are discussed.
Assuntos
Doenças dos Gânglios da Base/fisiopatologia , Encefalopatia Hepática/fisiopatologia , Falência Hepática/fisiopatologia , Transtornos Neurocognitivos/fisiopatologia , Adolescente , Atrofia/etiologia , Atrofia/patologia , Atrofia/fisiopatologia , Doenças dos Gânglios da Base/etiologia , Doenças dos Gânglios da Base/patologia , Sistema Biliar/patologia , Sistema Biliar/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/fisiopatologia , Doença Crônica , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Evolução Fatal , Feminino , Globo Pálido/metabolismo , Globo Pálido/patologia , Globo Pálido/fisiopatologia , Encefalopatia Hepática/etiologia , Degeneração Hepatolenticular/diagnóstico , Humanos , Fígado/patologia , Fígado/fisiopatologia , Falência Hepática/complicações , Imageamento por Ressonância Magnética , Manganês/metabolismo , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/patologia , Falha de Tratamento , Vitaminas/uso terapêuticoRESUMO
BACKGROUND: Anterocollis (AC) is a form of cervical dystonia (CD) that produces patterned, repetitive muscle contractions that result in neck flexion. It has been mainly described in the context of parkinsonian movement disorders including Parkinson's disease and multiple system atrophy. MATERIAL/METHODS: We performed a review of consecutive AC patients seen in our Movement Disorders Clinic over a 15-year period. The diagnosis of AC was based on degree of abnormal neck anteroflexion. RESULTS: Out of 399 CD patients 27 (6.8%) had features of AC. AC was more prevalent in women (67.3%). It was associated with neuroleptic exposure, PD and a family history of movement/neurological disorder. No definite cases with MSA and AC were described in our cohort. Botulinum toxin injections and tetrabenazine produced clinical improvement. CONCLUSIONS: The demographic and phenotypic features and treatment outcomes of AC in our cohort were somewhat different from other types of CD.
Assuntos
Toxinas Botulínicas/uso terapêutico , Torcicolo/tratamento farmacológico , Torcicolo/fisiopatologia , Idoso , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Torcicolo/diagnóstico , Resultado do TratamentoRESUMO
Retrocollis (RC) is a form of cervical dystonia (CD) that produces patterned, repetitive muscle contractions that result in neck extension. We performed a review of consecutive CD patients seen in our Division over a 15-year period. Out of 399 CD patients, 59 (14.8%) had features of RC. Pain was very frequently reported among patients ( approximately 80%). RC was frequently associated with neuroleptic exposure (20.3%) and a history of head/neck trauma (23.7%). Of patients injected with botulinum toxin type A, 24.5% reported excellent, 32.1% moderate, 16.9% mild and 24.5% no response to injections. Oral antidystonic medications had limited contribution to symptom relief.
Assuntos
Fatores de Risco , Torcicolo , Resultado do Tratamento , Adulto , Toxinas Botulínicas Tipo A/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/uso terapêutico , Estudos Retrospectivos , Estatísticas não Paramétricas , Torcicolo/classificação , Torcicolo/tratamento farmacológico , Torcicolo/epidemiologiaRESUMO
BACKGROUND AND PURPOSE: Myoclonus-dystonia (MD) is a rare movement disorder characterized by myoclonic jerks, dystonia and a variety of psychiatric symptoms. Neuroimaging and electrophysiologic studies have not been able to detect any specific central nervous system abnormality. We report for the first time a well-characterized case with MD and abnormal brain perfusion imaging using single photon emission computed tomography (SPECT) with (99m)Tc-ethyl cysteinate dimer (ECD). A review of the literature on the phenotypic and pathogenetic considerations for MD is also presented. METHODS: To better define the functional regional central nervous system involvement in MD, we conducted a brain perfusion SPECT with (99m)Tc-ECD in a patient diagnosed with typical disease. RESULTS: Analysis of the SPECT data revealed significantly reduced regional cerebral blood flow (rCBF) in both temporal lobes (left > right and medial > lateral). Reduced rCBF was also observed in both frontal lobes and the right caudate nucleus. CONCLUSIONS: Our findings of reduced frontotemporal and striatal rCBF in the absence of other neuroimaging and electrophysiologic findings correlate well with the clinical manifestations in our patient and suggest possible functional/metabolic involvement of these areas in the etiopathogenesis of MD.
Assuntos
Corpo Estriado/diagnóstico por imagem , Distonia/diagnóstico por imagem , Lobo Frontal/diagnóstico por imagem , Mioclonia/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagem , Adulto , Corpo Estriado/patologia , Cisteína/análogos & derivados , Análise Mutacional de DNA , Distonia/genética , Distonia/patologia , Lobo Frontal/patologia , Humanos , Masculino , Mioclonia/genética , Mioclonia/patologia , Compostos de Organotecnécio , Sarcoglicanas/genética , Lobo Temporal/patologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, especially the G2019S mutation, have been identified as a common cause of Parkinson's disease in southern European and other Mediterranean populations (Iberians, Ashkenazi Jews and North African Arabs). Owing to the geographic and historic vicinity of Greece with areas of high prevalence of LRRK2 mutations we studied the frequency of the G2019S mutation in a well characterized cohort of familial and sporadic Parkinson's disease patients of Greek origin from mainland Greece. The prevalence of the LRRK2 R1441C mutation and the G2385R Asian polymorphism was also determined. We identified no patients with any of the studied mutations/polymorphisms. Very low prevalence of the LRRK2 G2019S mutation has been reported in other southern European populations. LRRK2 mutations appear to be limited in certain populations and differing ancestry and founder effects may explain the reported variability. Accurate estimations of the frequency and penetrance of different LRRK2 mutations are essential for correct and cost-efficient use of genetic testing and proper genetic counseling of patients with Parkinson's disease.
Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Doença de Parkinson/genética , Polimorfismo Genético/genética , Proteínas Serina-Treonina Quinases/genética , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Efeito Fundador , Frequência do Gene , Marcadores Genéticos/genética , Testes Genéticos , Grécia/epidemiologia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/metabolismo , Penetrância , PrevalênciaRESUMO
The naturally occurring, non-essential amino acid beta-N-methylamino-L-alanine (BMAA) has been recently found in high concentrations in brain tissues of patients with tauopathies such as the Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS/PDC) in the South Pacific island of Guam and in a small number of Caucasian, North American patients with sporadic Alzheimer's disease. BMAA is produced by cyanobacteria that are present in all conceivable aquatic and/or terrestrial ecosystems and may be accumulated in living tissues in free and protein-bound forms through the process of biomagnification. Although its role in human degenerative disease is highly debated, there is mounting evidence in support of the neurotoxic properties of BMAA that may be mediated via mechanisms involving among others the regulation of glutamate. Glutamate-related excitotoxicity is among the most prominent factors in the etiopathogenesis of human neurodegenerative diseases. Due to the wide geographical distribution of cyanobacteria and the possible implications of BMAA neurotoxic properties in public health more research towards this direction is warranted.
Assuntos
Diamino Aminoácidos/toxicidade , Doenças Neurodegenerativas/induzido quimicamente , Toxinas de Cianobactérias , Dieta , Guam/epidemiologia , Humanos , Doença dos Neurônios Motores/epidemiologia , Degeneração Neural/induzido quimicamente , Neurotoxinas/toxicidade , Transtornos Parkinsonianos/epidemiologiaRESUMO
Overlaps in clinical, pathological and molecular features of Parkinson's disease (PD), dementing and motor tauopathies have prompted association studies in search of common genetic risk factors that may predispose or modify this spectrum of disorders. To explore possible phenotypic implications, we studied common tau and ApoE gene polymorphisms, associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and PD, in a clinically and pathologically characterized cohort of PD patients and aged control subjects. Our results reveal a novel association between PD-related hallucinations and H1H1 genotype. We also report an association between PDD and the presence of the ApoE epsilon4 allele. Better determination of subsets of PD patients based upon the presence of specific phenotypic features may improve the accuracy of association studies.
Assuntos
Apolipoproteínas E/genética , Encéfalo/metabolismo , Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Polimorfismo Genético/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/sangue , Apolipoproteína E4/genética , Apolipoproteínas E/sangue , Encéfalo/patologia , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Feminino , Frequência do Gene , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Alucinações/sangue , Alucinações/genética , Alucinações/fisiopatologia , Humanos , Masculino , Doença de Parkinson/sangue , Doença de Parkinson/fisiopatologia , Fenótipo , Valor Preditivo dos Testes , Paralisia Supranuclear Progressiva/sangue , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/fisiopatologia , Proteínas tau/metabolismoRESUMO
Painless arms/moving fingers is a rare variant of the painful limbs/moving extremities syndrome (PLME) characterized by slow involuntary movements of the toes or fingers. Its typical form is associated with limb pain. We report the first case of painless arms/moving fingers and describe its favorable response to botulinum toxin A injections. The presence of dystonic symptoms in our case argues in favor of a possible implication of a dystonic mechanism in at least some cases of PLME.
Assuntos
Toxinas Botulínicas/uso terapêutico , Distonia/complicações , Dedos/fisiopatologia , Transtornos dos Movimentos/tratamento farmacológico , Dor/tratamento farmacológico , Adulto , Feminino , Humanos , Injeções Intramusculares , Dor/complicaçõesRESUMO
Orthostatic hypotension (OH) in Parkinson's disease (PD) patients may be a significant source of morbidity and discomfort. Although peripheral ANS components have been associated with its development, central mechanisms are probably involved. The insular cortex is a central site of autonomic and limbic integration and neuropathologic studies have indicated its involvement in the neurodegenerative process of PD. To this end, we studied the neuropathology of the insular, temporal and parietal cortices in PD patients with and without OH. Our results suggest an association between the severity of PD-related neuropathology in the insular cortex and OH. Further research into the subject is warranted.
Assuntos
Córtex Cerebral/patologia , Hipotensão Ortostática/etiologia , Hipotensão Ortostática/patologia , Corpos de Lewy/patologia , Doença de Parkinson/complicações , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipotensão Ortostática/mortalidade , Masculino , Estatísticas não ParamétricasRESUMO
Multiple system atrophy (MSA) is by nature a 'sporadic' disease with no evidence of familial aggregation observed. However, the alpha-synuclein locus (SNCA) multiplication families have clinically displayed parkinsonism and autonomic dysfunction. The present study did not find any SNCA multiplications in a series of 58 pathologically confirmed MSA cases excluding this event as a common cause of MSA. The question of a genetic component in MSA remains to be answered.
Assuntos
Atrofia de Múltiplos Sistemas/genética , alfa-Sinucleína/genética , Análise Mutacional de DNA , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
BACKGROUND: Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene (LRRK2) that cause parkinsonism. The "common" LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease. OBJECTIVE: To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T. MAIN OUTCOME MEASURES: Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations. RESULTS: Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants. CONCLUSIONS: The underlying disease mechanisms of LRRK2 G2019S-associated parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.
Assuntos
Glicina/genética , Mutação , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Serina/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Modelos MolecularesRESUMO
Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.
Assuntos
Biomarcadores/metabolismo , Regulação da Expressão Gênica , Proteínas Mitocondriais/genética , Doença de Parkinson/genética , Proteína S6 Ribossômica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação Oxidativa , RNA Mensageiro/metabolismo , Proteína S6 Ribossômica/metabolismo , Substância Negra/metabolismoRESUMO
A randomized, controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy (PIPN). Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were randomly assigned to receive either chemotherapy with vitamin E (300 mg twice a day, Group I) or chemotherapy without vitamin E supplementation (Group II). A detailed neurological examination and electrophysiological study was performed during and 3 months after chemotherapy. The severity of PIPN was summarized by means of a modified Peripheral Neuropathy (PNP) score. The incidence of neurotoxicity differed significantly between groups, occurring in 3/16 (18.7%) patients assigned to the vitamin E supplementation group and in 10/16 (62.5%) controls (P=0.03). The relative risk (RR) of developing PIPN was significantly higher in controls than in vitamin E group patients (RR=0.3, 95% confidence interval (CI)=0.1-0.9). Mean PNP scores were 2.25+/-5.1 (range 0-15) for patients in Group I and 11+/-11.63 (range 0-32) for those in Group II (P=0.01). Vitamin E supplementation was well tolerated and showed an excellent safety profile. This study shows that vitamin E effectively and safely protects patients with cancer from the occurrence of paclitaxel-induced peripheral nerve damage. A double-blind, placebo-controlled trial is needed to confirm these results.