RESUMEN
BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.
Asunto(s)
Estado de Salud , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de Vida , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Planificación de Atención al Paciente , PronósticoRESUMEN
Parkinson's disease (PD) is associated with mitochondrial dysfunction, specifically a deficiency of complex I of the electron transport chain. Most, although not all, studies indicate that this deficiency is limited to brain regions with neurodegeneration. The current studies tested for deficiencies in other mitochondrial components in PD brain in a neuropathologically unaffected region where the abnormality cannot be attributed to secondary effects of neurodegeneration. The activity of a key (and arguably rate-limiting) tricarboxylic acid cycle enzyme, the alpha-ketoglutarate dehydrogenase complex (KGDHC), was measured in the cerebellum of patients with PD. Activity in 19 PD brains was 50.5% of that in 18 controls matched for age, sex, post-mortem interval, and method of preservation (P<0.0019). The protein subunits of KGDHC were present in normal amounts in PD brains, indicating a relatively discrete abnormality in the enzyme. The activities of another mitochondrial enzyme, glutamate dehydrogenase (GDH), were normal in PD brains. These results demonstrate that specific reductions in KGDHC occur even in pathologically unaffected areas in PD, where the decline is unlikely to be a non-specific result of neurodegeneration. Reductions in the activity of this enzyme, if widespread in the brain, may predispose vulnerable regions to further damage.
Asunto(s)
Encéfalo/metabolismo , Ciclo del Ácido Cítrico , Trastornos Parkinsonianos/metabolismo , Adolescente , Adulto , Cadáver , Causas de Muerte , Niño , Femenino , Glutamato Deshidrogenasa/metabolismo , Humanos , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Complejos Multienzimáticos/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Valores de ReferenciaRESUMEN
To clarify the role of neuronal complex 1 activity in idiopathic Parkinson's disease (IPD), expression of mitochondrial mRNA encoding the ND1 subunit of mitochondrial complex I was examined by semiquantitative in situ hybridization histochemistry in melanized neurons of human substantia nigra in IPD cases and control subjects. Expression of mRNA encoding the glycolytic enzyme, aldolase C, was also examined in substantia nigra and other neurons of the midbrain and brain stem. ND1 mRNA expression was strong in melanized substantia nigra neurons but undetectable in nigral glia. Levels of expression in nigral neurons were higher than in neurons of the red nucleus or cranial nerve nuclei, but similar values were obtained in pontine neurons. ND1 mRNA expression was reduced by about 25% in melanized neurons in IPD. There was no relationship between ND1 expression per cell and disease duration or L-DOPA dosage in the IPD group. No change in ND1 expression was observed in pontine neurons in IPD, and ND1 expression in the locus ceruleus was also unchanged. Melanized nigral neurons expressed lower levels of aldolase C mRNA than other midbrain or brain stem populations in both control and IPD material. These findings suggest that dopamine neurons are more strongly dependent on mitochondrial energy metabolism and oxidative phosphorylation than other brain stem populations. Because mitochondrial complex I activity is significantly reduced in IPD, intrinsically low expression of glycolytic enzymes, together with disease-related reduction in complex I activity, may be a contributory factor predisposing nigral neurons
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Fructosa-Bifosfato Aldolasa/metabolismo , Neuronas/enzimología , Enfermedad de Parkinson/enzimología , ARN Mensajero/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/enzimología , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana EdadRESUMEN
Neuronal injury has been consistently found in A10 midbrain dopamine neurons in Parkinson's disease (PD). To assess changes in neurotransmitter-related gene transcription, in these neurons in PD, tyrosine hydroxylase (TH) mRNA expression was examined in the ventral tegmental area (VTA) of seven PD cases and seven control subjects, using in situ hybridization histochemistry (ISHH). In controls, TH mRNA expression was found in both melanised and non-melanised neurons in the VTA. Neither population expressed dopamine beta-hydroxylase (DBH). Of the melanised neurons, 99% were TH mRNA positive. The level of the TH mRNA signal (expressed as grain density per cell) was similar in the two populations (melanised: 0.129+/-0.004 (mean+/-S.E.M.), n=142 vs. non-melanised: 0.138+/-0.006, n=89, P>0.05, Student's t-Test). In PD cases there was no significant change in TH mRNA expression in melanised neurons (0.138+/-0.003, n=196), and the proportion of positively labeled melanised neurons was 98%. However, non-melanised neurons showed significantly higher TH mRNA (0.163+/-0.006, n=87) than non-melanised neurons in control subjects (P<0.005) and melanised neurons in the PD cases (P<0.0005). This up-regulation of TH mRNA expression in non-melanised neurons may suggest the existence of a compensatory mechanism at presynaptic level.
Asunto(s)
Encéfalo/enzimología , Regulación Enzimológica de la Expresión Génica , Neuronas/enzimología , Enfermedad de Parkinson/genética , Transcripción Genética , Tirosina 3-Monooxigenasa/genética , Área Tegmental Ventral/enzimología , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/uso terapéutico , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Neuronas/clasificación , Especificidad de Órganos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/enzimología , ARN Mensajero/genética , Valores de ReferenciaRESUMEN
BACKGROUND: Infants born very preterm (<33 weeks) are at increased risk of neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can be predicted by neonatal ultrasonography, but little is known of their later function. We investigated the effect of very preterm birth on brain structure and neurocognitive and behavioural functioning in adolescence. METHODS: A cohort of 105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic scans at University College Hospital, London, and were prospectively examined at 1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and 21 age-matched full-term controls underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images were assessed by two neuroradiologists unaware of ultrasonographic findings or case or control status. FINDINGS: Of the 72 cases, 40 had unequivocally abnormal MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter were especially common in cases. More brain lesions were identified by MRI than by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. INTERPRETATION: Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.
Asunto(s)
Encefalopatías/etiología , Encéfalo/patología , Trastornos del Conocimiento/etiología , Recien Nacido Prematuro , Adolescente , Desarrollo Infantil , Discapacidades del Desarrollo/etiología , Estudios de Seguimiento , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Pruebas NeuropsicológicasRESUMEN
A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.
Asunto(s)
Enfermedades del Sistema Nervioso Central/diagnóstico , Sarcoidosis/diagnóstico , Corticoesteroides/uso terapéutico , Adulto , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Ciclosporina/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Sarcoidosis/complicaciones , Sarcoidosis/tratamiento farmacológico , Tomografía Computarizada por Rayos X/métodosRESUMEN
The contribution of the dopamine-synthetic capacity of nigral neuronal subregions to their vulnerability to degeneration in idiopathic Parkinson's disease (IPD) was explored using semiquantitative in situ hybridization to study expression of mRNA encoding the rate-limiting dopamine synthetic enzyme, tyrosine hydroxylase (TH). Expression of mRNA, the structural protein, beta-tubulin, and the glycolytic enzyme, fructose-1,6, biphosphate aldolase (aldolase C) was studied in parallel in individual neurons of the substantia nigra pars compacta (SNc) in matched groups of IPD and control subjects. TH mRNA expression was found to be heterogeneously expressed in nigral neurons in control and IPD subjects. There was no significant difference in mean values for TH mRNA expression between control and IPD cases and none between nigral subregions, either in control subjects or in established IPD subjects in this study, but there was evidence for a selective upregulation of TH mRNA expression in non-melanized neurons in IPD. There was no relationship between TH mRNA expression disease duration or L-dopa dosage in the IPD group. Mean TH mRNA values for two additional 40-year-old control subjects fell within the range of values of the aged-control group. Aldolase C and beta-tubulin expression did not differ between control and IPD groups or between nigral subregions. These findings suggest that regulation of dopamine synthesis at the level of the cell body does not play a part in determining the pattern of nigral cell vulnerability in IPD. The heterogeneous pattern of TH synthesis was not age-dependent and may be of physiological significance in nigral function. There was no evidence for compensatory upregulation of TH synthesis in surviving melanized neurons in IPD but non-melanized neurons may be involved in this process. Surviving nigral neurons in IPD appear to retain the capacity for normal aldolase C and beta-tubulin peptide synthesis. Long-term L-dopa treatment does not appear to compromise normal function of nigral dopaminergic neurons.
Asunto(s)
Dopamina/biosíntesis , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/farmacología , Estudios de Casos y Controles , Femenino , Fructosa-Bifosfato Aldolasa/biosíntesis , Fructosa-Bifosfato Aldolasa/efectos de los fármacos , Humanos , Hibridación in Situ , Levodopa/farmacología , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Transcripción Genética/fisiología , Tubulina (Proteína)/biosíntesis , Tubulina (Proteína)/efectos de los fármacos , Tirosina 3-Monooxigenasa/biosíntesis , Tirosina 3-Monooxigenasa/efectos de los fármacosRESUMEN
Expression of nitric oxide synthase (NOS) mRNA in post mortem brain was studied in putamen, globus pallidus and subthalamic nucleus (STN) of neurologically normal control subjects and patients with Parkinson's disease (PD) using in situ hybridization histochemistry. In PD, a significant increase in NOS mRNA expression was observed in the dorsal two-thirds of the STN with respect to the ventral one-third of the STN. A significant increase in NOS mRNA expression per cell in the medial medullary lamina of the globus pallidus was also observed in PD. NOS mRNA expression was significantly reduced in PD putamen. These findings provide evidence of increased activity of STN neurotransmitter systems in PD and demonstrate for the first time in any species that basal ganglia nitric oxide systems can be selectively regulated in response to changes in dopaminergic input.
Asunto(s)
Ganglios Basales/enzimología , Regulación Enzimológica de la Expresión Génica , Óxido Nítrico Sintasa/genética , Enfermedad de Parkinson/metabolismo , Anciano , Anciano de 80 o más Años , Cadáver , Femenino , Humanos , Hibridación in Situ , Masculino , Óxido Nítrico Sintasa de Tipo I , ARN Mensajero/análisisRESUMEN
DNA fragmentation was examined in situ in flash-frozen human postmortem midbrain as a marker for programmed cell death. A large series of cases comprising 16 pathologically confirmed idiopathic Parkinson's disease (IPD) cases, 14 control cases without brain pathology, and a group of 6 patients with other parkinsonian movement disorders were examined using TdT-mediated dUTP-biotin 3' end-labeling histology. Labeling of neurons and glia was seen in the substantia nigra of control and IPD cases and in other movement disorder cases. Labeled nuclei were seen in melanized nigral neurons; apoptotic bodies were also found but were more commonly associated with nigral glia. In the control group, labeling of neurons and glia was strongly associated with poor agonal status, assessed by tissue pH, a marker for antemortem hypoxia. The mean tissue pH of the control group with neuronal labeling was 6.28 (SEM .057), which was significantly different from that of the unlabeled group 6.55 (SEM .055). Mean tissue pH for all cases was 6.38. There was no association of nigral neuronal labeling with poor agonal status in the IPD cases, which showed labeling throughout the range of pH values. However, extranigral labeling, seen in the mesencephalon, red nucleus, superior colliculus, rostral pons, and periaqueductal gray matter, in all three subject groups was associated with tissue pH values of less than 6.3. These findings suggest that DNA fragmentation is influenced by antemortem hypoxia and that apoptosis-like changes seen in the postmortem nigra may parallel those seen in experimental ischemia in the animal brain. The likely influence of perimortem factors on these changes indicates that results from postmortem studies of apoptotic cell death in neurodegenerative disease should be treated with caution and underlines the importance of determining postmortem markers for agonal status in human brain.
Asunto(s)
Apoptosis , Fragmentación del ADN , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Anciano , Anciano de 80 o más Años , Cadáver , Femenino , Humanos , Concentración de Iones de Hidrógeno , Etiquetado Corte-Fin in Situ , Masculino , Trastornos del Movimiento/patologíaRESUMEN
Microglial activation is a prominent feature of affected brain areas in multiple system atrophy. Microglia express proinflammatory peptides, which may be a result of activation of nuclear factor-KB. We investigated the nuclear presence of RelA, the 65 kDa subunit of the NF-KB/RelA family in striatum and brain stem of patients with multiple system atrophy. Affected brain areas of patients with multiple system atrophy showed a marked immunoreactivity for nuclear Rel A p65, which was almost exclusively localized in activated microglia. Interestingly nuclear translocation of Rel A was not detected in striatal tissue of controls and Parkinson disease patients. Thus, NF-kappaB/Rel A complexes may play a role in mediating microglial activation in multiple system atrophy.
Asunto(s)
Microglía/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , FN-kappa B/fisiología , Anciano , Tronco Encefálico/química , Tronco Encefálico/patología , Núcleo Celular/química , Cuerpo Estriado/química , Cuerpo Estriado/patología , Citoplasma/química , Humanos , Inmunohistoquímica , Antígeno de Macrófago-1/análisis , Microglía/química , Microglía/patología , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , FN-kappa B/análisis , Factor de Transcripción ReIAAsunto(s)
Neocórtex/metabolismo , Enfermedad de Parkinson/metabolismo , Receptores de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/metabolismo , Humanos , Ketanserina/metabolismo , Cinética , Paroxetina/metabolismo , Receptor de Serotonina 5-HT2A , Receptores de Serotonina 5-HT1 , Valores de ReferenciaRESUMEN
Levels of the neurotransmitter somatostatin (SS) have previously been shown to be reduced in the cortex and hippocampus of demented parkinsonian patients and patients with Alzheimer's disease. In situ hybridisation histochemistry (ISHH) was performed with an 35S tail-labelled oligonucleotide DNA probe to human SS mRNA, to examine its expression within the striatum, medial medullary lamina (MML) and reticular thalamic nucleus in Parkinson's disease (PD) and in matched controls. A chronic unilaterally MPTP-lesioned L-DOPA-naive primate model was also examined for comparison of SS mRNA expression with that in human L-DOPA treated PD subjects. Quantitation of SS mRNA expression on emulsion dipped sections revealed a significant increase (82%) in the MML of the globus pallidus in PD (56.5 microm2 of silver grain/cell, n = 9 cases) compared to controls (26.3 microm2/cell, n = 13 cases, p < 0.01, Student's t-test), paralleling the increase previously observed by this group for NOS mRNA. SS mRNA expression was higher in the dorsolateral than ventromedial putamen in controls (p < 0.001; DL: 24.89 +/- SEM 1.35; VM: 17.96 +/- SEM 2.63; n = 14) but this gradient was lost in PD cases (p > 0.05; DL: 22.68 +/- 1.94; VM: 22.17 +/- 2.94; n = 10). These findings suggest specific modification of basal ganglia SS-ergic pathways in PD.
Asunto(s)
Ganglios Basales/metabolismo , Enfermedad de Parkinson/metabolismo , ARN Mensajero/biosíntesis , Somatostatina/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sondas de Oligonucleótidos , Reproducibilidad de los ResultadosRESUMEN
Expression of glutamate decarboxylase-67 messenger RNA was examined in the basal ganglia of normal controls and of cases of Parkinson's disease using in situ hybridization histochemistry in human post mortem material. In controls glutamate decarboxylase-67 messenger RNA expression was detected in all large neurons in both segments of the globus pallidus and in three neuronal subpopulations in the striatum as well as in substantia nigra reticulata neurons and in a small sub-population of subthalamic neurons. In Parkinson's disease, there was a statistically significant decrease of 50.7% in glutamate decarboxylase-67 messenger RNA expression per neuron in the lateral segment of the globus pallidus (controls: mean 72.8 microns2 +/- S.E.M. 8.7 of silver grain/neuron, n = 12; Parkinson's disease: mean 35.9 microns2 +/- S.E.M. 9.7 of silver grain/neuron, n = 9, P = 0.01, Student's t-test). In the medial segment of the globus pallidus, there was a small, but non-significant decrease of glutamate decarboxylase-67 messenger RNA expression in Parkinson's disease (controls: mean 100.6 microns2 +/- S.E.M. 7.2 of silver grain/neuron, n = 11; Parkinson's disease: mean 84.8 microns2 +/- S.E.M. 13.0 of silver grain/neuron, n = 7, P = 0.1, Student's t-test). No significant differences in glutamate decarboxylase-67 messenger RNA were detected in striatal neuronal sub-populations between Parkinson's disease cases and controls. These results are the first direct evidence in humans that there is increased inhibitory drive to the lateral segment of the globus pallidus in Parkinson's disease, as suggested by data from animal models. We therefore provide theoretical support for current experimental neurosurgical approaches to Parkinson's disease.
Asunto(s)
Ganglios Basales/enzimología , Glutamato Descarboxilasa/biosíntesis , Enfermedad de Parkinson/enzimología , ARN Mensajero/biosíntesis , Anciano , Anciano de 80 o más Años , Ganglios Basales/patología , Northern Blotting , Sondas de ADN , Femenino , Globo Pálido/metabolismo , Globo Pálido/patología , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Putamen/metabolismo , Putamen/patología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Núcleos Talámicos/metabolismo , Núcleos Talámicos/patologíaRESUMEN
A simplified and rapid method is described for in situ hybridization (ISHH) studies of human post-mortem brain. Brain tissue was dissected into slices and was flash-frozen at -70 degrees C for storage. ISHH was carried out on 12 microns cryostat sections, post-fixed in 4% paraformaldehyde. The histology of human brain tissue prepared by this technique rivalled that of formalin-fixed, wax-embedded tissue. In ISHH studies, flash-frozen tissue gave superior results to those obtained following long-term fixation of tissue in 10% formalin with subsequent wax-embedding, or short-term prefixation in 4% paraformaldehyde. A systematic evaluation of commonly employed preparative procedures for ISHH was carried out on flash-frozen brain and a simplified protocol, consisting only of fixation and dehydration, was developed as a result of these studies. Specific hybridization of probes to a number of mRNA species was demonstrable in neurons in different brain regions. Using 0.5% glutaraldehyde/4% paraformaldehyde post-fixation, immunohistochemical labelling of TH-positive cortical catecholaminergic neurons and striatal dopaminergic terminals was successfully demonstrated in flash-frozen tissue. The same fixation technique also allowed combination of ISHH and immunohistochemistry for the simultaneous demonstration of tyrosine hydroxylase mRNA and peptide in neurons of human brain stem and cortex. mRNA and peptides in flash-frozen tissue were found to be stable for more than 3 years. ISHH could be readily performed on relatively large brain structures. In addition to permitting excellent ISHH and immunohistochemistry, alone or in combination, flash-freezing allows the maximum versatility of tissue use and does not compromise its study by other neuroscience techniques.
Asunto(s)
Tronco Encefálico/patología , Corteza Cerebral/patología , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Anciano , Anciano de 80 o más Años , Autorradiografía , Femenino , Congelación , Humanos , Masculino , Microtomía , Neuronas/química , Neuronas/enzimología , Sondas de Oligonucleótidos , ARN Mensajero/análisis , Sensibilidad y Especificidad , Fijación del Tejido/normas , Tirosina 3-Monooxigenasa/genéticaRESUMEN
The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.
Asunto(s)
Proteínas Portadoras/genética , Dopamina , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso/genética , Neuropéptidos , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Anciano , Anciano de 80 o más Años , Transporte Biológico , Estudios de Casos y Controles , Recuento de Células , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Expresión Génica , Humanos , Masculino , Valores de Referencia , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
Striatal expression of preproenkephalin and preprotachykinin messenger RNA was studied in normal controls and in patients with Parkinson's disease using in situ hybridization histochemistry. In controls, preproenkephalin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 165 microns 2, accounting for 66% of striatal medium-sized neurons, whereas preprotachykinin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 204 microns 2 (23% larger than those expressing enkephalin, P < 0.05), accounting for 58% of medium-sized striatal neurons. Much lower levels of both preproenkephalin messenger RNA and preprotachykinin messenger RNA were expressed by large neurons in the globus pallidus and substantia nigra reticulata. In addition, preproenkephalin messenger RNA was expressed at low levels by neurons in the subthalamic nucleus. In Parkinson's disease cases, there was a statistically significant increase in preproenkephalin messenger RNA expression in the body of the caudate (109% increase, P < 0.05) and in the intermediolateral putamen (55% increase, P < 0.05) due to an increase in the level of gene expression per neuron rather than an increase in the number of neurons expressing preproenkephalin messenger RNA. Similar increases were observed in other putaminal subregions and in the putamen as a whole, but these did not reach statistical significance. No change in preprotachykinin messenger RNA expression was detected. These findings demonstrate selective up-regulation of a striatal neuropeptide system in Parkinson's disease compatible with increased activity of the "indirect" striatopallidal pathway, which is thought to play a crucial role in the pathophysiology of akinesia and rigidity in this condition.
Asunto(s)
Ganglios Basales/metabolismo , Encefalinas/genética , Enfermedad de Parkinson/genética , Precursores de Proteínas/genética , ARN Mensajero/metabolismo , Taquicininas/genética , Adulto , Anciano , Anciano de 80 o más Años , Autorradiografía , Dopaminérgicos/farmacología , Femenino , Expresión Génica/fisiología , Humanos , Levodopa/farmacología , Masculino , Persona de Mediana Edad , Neostriado/metabolismo , Sensibilidad y EspecificidadRESUMEN
The relationship between pH and mRNA preservation in post-mortem human brain was examined using in situ hybridization histochemistry and Northern hybridization with oligonucleotide probes in a large group of human subjects, including control and neuropathological cases. Tissue pH was found to correlate strongly with preservation of four mRNA species in three brain areas. Tissue with low pH, assumed to result from prolonged terminal hypoxia, contained reduced or absent mRNA, while tissue with higher pH was found to contain quantifiable amounts, the values for pathological brain samples being comparable to those for control material of similar pH. Measurement of tissue pH provides a simple means to screen post-mortem brain for mRNA preservation and is suggested as a means to match material in case-control studies of human neurodegenerative disease.