RESUMO
The learning ability of 12 patients with Parkinson's disease (PD) was studied using a verbal paired-associate learning task, and was compared with that of ten patients with Alzheimer's Disease (AD) and 12 controls (NC). Overall, the PD patients performed significantly better than the AD patients but significantly worse than the NC subjects. Their performance was not related to their overall level of cognitive functioning as measured by the Mattis' Dementia Rating Scale, but was unequally distributed suggesting that the PD population actually consisted of more than one subgroup. A low error group performed like controls, while a high error group had a learning impairment comparable to that of AD patients. It is concluded that PD patients may have three patterns of neuropsychologic performance: some are unimpaired, some have "focal" abnormalities, and some have a generalized impairment of cognitive function.
Assuntos
Envelhecimento/psicologia , Doença de Alzheimer/psicologia , Aprendizagem/fisiologia , Doença de Parkinson/psicologia , Idoso , Cognição/fisiologia , Feminino , Humanos , Masculino , Aprendizagem por Associação de Pares/fisiologiaRESUMO
We previously reported markedly reduced (-76%) dopamine (DA) levels in the putamen of seven patients with spinocerebellar ataxia type 1 (SCA1) who had no evidence of nigral cell loss or parkinsonism. To determine whether the DA reduction was accompanied by loss of DA nerve terminals, we measured levels of the DA transporter ([3H]WIN, 35,428 binding; DA transporter protein) and the vesicular monoamine transporter ([3H]DTBZ binding) in the putamen of these patients. As compared with the controls (n = 14), mean putamen concentrations of [3H]WIN 35,428 binding (-45%), dopamine transporter protein (-61%), and [3H]DTBZ binding (-48%) were significantly reduced in this SCA1 subgroup. We conclude that the degeneration in nigrostriatal DA neurons begins at the nerve ending in SCA1.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Terminações Nervosas/metabolismo , Proteínas do Tecido Nervoso , Degenerações Espinocerebelares/metabolismo , Degenerações Espinocerebelares/patologia , Substância Negra/patologia , Adulto , Biomarcadores , Cadáver , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/metabolismo , Humanos , Pessoa de Meia-Idade , Putamen/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/metabolismoRESUMO
We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.
Assuntos
Aminas Biogênicas/metabolismo , Corpo Estriado/metabolismo , Genes Dominantes , Neurotransmissores/metabolismo , Atrofias Olivopontocerebelares/genética , Dopamina/metabolismo , Humanos , Atrofias Olivopontocerebelares/metabolismo , Atrofias Olivopontocerebelares/patologia , Substância Negra/patologiaRESUMO
To determine whether the cognitive status of patients with dominantly inherited spinocerebellar ataxia (DSCA) might be related to neurologic severity, we administered a comprehensive neuropsychological test battery to 43 patients with DSCA, ranging in ataxia severity from mild to end-stage. As compared with the controls, the mildly ataxic patients scored normally or close to normal as a group on all of the neuropsychological tests. In contrast, approximately one-half of the moderately and all of the severely ataxic patients showed poor performance, independent of age, Hamilton Rating Scale for Depression score, or education, on the Wisconsin Card Sorting Test, suggesting impaired executive system function. In addition, a subgroup of these patients had a neuropsychological profile suggestive of mild generalized cognitive impairment. We conclude that DSCA is not a homogeneous group of disorders with respect to cognitive status and that the neurologic severity of the disorder is a major factor. Impaired executive system function could be explained by damage to olivopontocerebellar system control over cerebral cortical function or to damage to other neuronal systems (especially cholinergic) that degenerate in parallel with the olivopontocerebellar system.
Assuntos
Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos , Degenerações Espinocerebelares/psicologia , Adulto , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degenerações Espinocerebelares/complicações , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/fisiopatologiaRESUMO
Beas-Zarate and coworkers (Eur. J. Pharmacol., 198 (1991) 7-14) recently reported markedly reduced concentration of presynaptic serotonin neurotransmitter markers in cerebellum of rodents which had suffered destruction of the inferior olivary-cerebellar (climbing fibre) projections by the neurotoxin 3-acetylpyridine; these experimental animal data suggested that serotonin might be one of the neurotransmitters released by climbing fibres. We measured the concentration of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with dominantly-inherited olivopontocerebellar atrophy (OPCA) who all had near-total degeneration of the inferior olivary climbing fibres. As compared with the controls, mean concentration of serotonin in cerebellar cortex of the OPCA patients was normal whereas 5-HIAA levels (+79%, P less than 0.02) and 'turnover' ratio 5-HIAA/serotonin (+148%, P less than 0.05), on average, were significantly elevated. These data do not support the notion that serotonin is a predominant neurotransmitter of the human climbing fibre. However, the markedly elevated serotonin turnover ratio suggests the possibility of increased serotonergic neuronal activity, which might alter, and perhaps improve, the functioning of the preserved cerebellar cortical neurones in OPCA.
Assuntos
Córtex Cerebelar/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Atrofias Olivopontocerebelares/metabolismo , Serotonina/metabolismo , Adulto , Genes Dominantes , Humanos , Atrofias Olivopontocerebelares/genéticaRESUMO
We report two patients with dyskinesia responding to antidepressants. The first is a 70-year-old man with depression, Parkinsonism and neuroleptic-induced tardive dyskinesia who presented with hysterical mutism. After recovery from the mutism, he was started on desipramine for depression. One week later the dyskinesia improved markedly. The second patient is a 61-year-old man with Parkinson's disease, dementia, depression and L-dopa-induced oro-lingual-facial dyskinesias. He was taking levodopa, trihexyphenydil and bromocriptine. The depression was treated first with desipramine and later with trazodone. The dyskinesia improved significantly on both drugs. The response of the dyskinesias to antidepressant medication may be due to the fact that antidepressants decrease beta-adrenoreceptor sensitivity and density which in turn may result in a diminished release of dopamine since beta-adrenoceptors mediate the noradrenaline-stimulated release of dopamine.
Assuntos
Antidepressivos/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Idoso , Transtorno Depressivo/tratamento farmacológico , Desipramina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/tratamento farmacológico , Trazodona/uso terapêuticoRESUMO
In order to characterize more completely the nature of the frontal lobe-type cognitive changes in patients with dominantly inherited olivopontocerebellar atrophy (OPCA) we administered two tasks sensitive to frontal system dysfunction, delayed alternation (DA) and delayed response (DR), to 12 patients from one OPCA family. Affected members from this family have previously been shown to have a marked and widespread cerebral (including frontal) cortical cholinergic reduction as severe as that observed in Alzheimer's disease. Performance on DA, but not on DR, was significantly impaired in the OPCA patients compared to that in the controls. We suggest that the DA deficits in OPCA could be a consequence of a loss of cholinergic innervation to orbitofrontal or possibly temporal cortical areas and/or damage to the integrity of the cerebello-frontal neuronal connections.
Assuntos
Atenção/fisiologia , Dominância Cerebral/genética , Lobo Frontal/fisiopatologia , Genes Dominantes/genética , Rememoração Mental/fisiologia , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/fisiopatologia , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Adulto , Dominância Cerebral/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , LinhagemRESUMO
We measured the levels of aspartate, glutamate, gamma-aminobutyric acid (GABA), and other amino acids in autopsied brain of 6 patients from one family (Pedigree S) with dominantly inherited olivopontocerebellar atrophy. A previous demonstration of reduced aspartate concentration in plasma of affected members of this family suggested the possibility of a generalized disorder of amino acid metabolism affecting the brain. As compared with the control levels, mean levels of aspartate and glutamate were markedly reduced by about 70 and 40%, respectively, in the degenerated cerebellar cortex from the patients. Since the cerebellar aspartate reduction likely exceeds the amount that could be explained by neuronal loss, other factors such as abnormal aspartate metabolism, neurotransmitter turnover, or both are probably involved. Mean aspartate, glutamate, and GABA levels were also reduced by about 10 to 30% in most of the 16 examined extracerebellar brain areas in which no or, at most, mild neuronal cell loss was observed by semiquantitative estimation. Concentrations of taurine, glutamine, and omicron-phosphoethanolamine were normal in all brain areas examined. Our biochemical data provide support to the presence of a generalized, but quantitatively mild, disturbance in amino acid metabolism in patients with olivopontocerebellar atrophy from Pedigree S. The regionally widespread amino acid reductions in the brain, of as yet unknown pathophysiological significance, could be due to a failure of one or more enzymes involved in aspartate and glutamate metabolism.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Aminoácidos/deficiência , Química Encefálica , Cromossomos Humanos Par 6 , Atrofias Olivopontocerebelares/metabolismo , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácido Aspártico/deficiência , Química Encefálica/genética , Etanolaminas/análise , Genes Dominantes , Glutamatos/deficiência , Ácido Glutâmico , Glutamina/análise , Humanos , Pessoa de Meia-Idade , Atrofias Olivopontocerebelares/genética , Taurina/análise , Ácido gama-Aminobutírico/análiseRESUMO
Somatostatin-like immunoreactivity (SLI) was measured in the brains of nine patients with dominantly inherited olivopontocerebellar atrophy (OPCA), who all had a marked deficit of the cholinergic marker choline-acetyltransferase (ChAT) in the cerebral cortex and striatum. Mean concentrations of SLI in OPCA were significantly reduced by 42-58% in parietal and occipital cortices and frontal cortical eye fields, but were normal in other cortical areas, including two subdivisions of the temporal cortex which show marked depletions of both SLI and ChAT in Alzheimer's disease. This dissociation of SLI and ChAT indicates that a cortical cholinergic deficit does not invariably lead to reduction of somatostatin. In the caudate nucleus, the region of OPCA brain having the most severe ChAT deficit (-81%), SLI levels were significantly elevated by 46% and were negatively and significantly correlated with ChAT activities (r = -0.66). The SLI alterations could be due to abnormal somatostatin metabolism or release, or an increased number of somatostatin-containing neurons and could contribute to the brain dysfunction of OPCA.
Assuntos
Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Atrofias Olivopontocerebelares/metabolismo , Somatostatina/metabolismo , Adulto , Colina O-Acetiltransferase/metabolismo , Humanos , Atrofias Olivopontocerebelares/genética , RadioimunoensaioRESUMO
A cerebral cortical cholinergic reduction in dominantly inherited olivopontocerebellar atrophy (OPCA) was recently described. Although the magnitude of the cholinergic reduction was similar to that observed in Alzheimer's disease (AD), none of the OPCA patients was reported to have been demented. We now describe a comprehensive neuropsychological assessment of 11 patients from one of the OPCA pedigrees which we examined biochemically. Detailed neuropsychological testing disclosed previously unrecognized deficits in verbal and nonverbal intelligence, memory, and frontal system function which were positively correlated with the severity of cerebellar ataxia. However, our OPCA patients appeared to be at most only mildly disabled by their cognitive impairment and scored within or close to the normal range on a simple mental status screening examination. This, as well as an absence of any aphasia, apraxia, or agnosia, contrasts with the profile and severity observed in advanced AD dementia, characterized by a similar cortical cholinergic deficit. This finding also suggests that cholinergic reduction may explain only part of the pathophysiology underlying the dementia of AD.
Assuntos
Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos , Atrofias Olivopontocerebelares/fisiopatologia , Sistema Nervoso Parassimpático/fisiopatologia , Degenerações Espinocerebelares/fisiopatologia , Adulto , Doença de Alzheimer/psicologia , Transtornos Cognitivos/psicologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Feminino , Humanos , Testes de Inteligência , Masculino , Atrofias Olivopontocerebelares/psicologia , Desempenho PsicomotorRESUMO
We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.