RESUMEN
AIMS: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). METHODS: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. RESULTS: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. CONCLUSIONS: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
Asunto(s)
Degeneración Lobar Frontotemporal/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , beta Carioferinas/metabolismo , Adulto , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The purpose of this study was to investigate the neuropathological substrates underlying in vivo hippocampal atrophy on magnetic resonance imaging (MRI) in autopsy confirmed neurodegenerative dementia cases. METHODS: Thirty-one neuropathologically verified cases (23 with Lewy body dementia (LBD) and eight with Alzheimer's disease (AD)) were included who had undergone an MRI scan close to death (mean 1.5 years). Manual volumetric measurements were undertaken for the hippocampus, entorhinal cortex and amygdala on MRI, along with quantitative neuropathological analysis of plaque, tangle and Lewy body pathology in the same regions. The relationship between neuropathology and MRI volumes was assessed using correlations and linear regression. RESULTS: Hippocampal and amygdala volumes were significantly smaller in cases with AD than with LBD, but there was no difference in entorhinal cortex volume. Analysing all cases together, a significant positive correlation was observed between normalised hippocampal volume and percent area of Lewy bodies in the hippocampus (r=0.449, p=0.017) but not with tangles (r=0.059, p=0.766) or plaques (r=-0.361, p=0.119). There were no other significant correlations between regional MRI volume and measures of neuropathology. Regression analysis showed that overall diagnosis of AD rather than burden of individual pathological changes was the most significant predictor of hippocampal volume loss in autopsy confirmed cases. CONCLUSION: Our results suggest that (i) hippocampal and amygdala but not entorhinal cortex, volumes differ between AD and LBD and (ii) factors other than current markers of neurodegenerative pathological change are responsible for atrophy of medial temporal lobe structures in AD and LBD.
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Demencia/patología , Anciano , Anciano de 80 o más Años , Atrofia/diagnóstico , Atrofia/etiología , Autopsia , Femenino , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Análisis de RegresiónRESUMEN
OBJECTIVE: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.
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Dopamina/metabolismo , Predisposición Genética a la Enfermedad , Neuronas/metabolismo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Piridoxal Quinasa/genética , Sustancia Negra/patología , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Inglaterra , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Genotipo , Alemania , Humanos , Italia , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Enfermedad de Parkinson/patología , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.
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Enfermedad de Alzheimer/diagnóstico , Demencia Vascular/diagnóstico , Enfermedad por Cuerpos de Lewy/diagnóstico , Lóbulo Temporal/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Atrofia/diagnóstico , Atrofia/etiología , Demencia Vascular/complicaciones , Demencia Vascular/patología , Diagnóstico Diferencial , Femenino , Hipocampo/patología , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/patología , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Demencia Vascular/líquido cefalorraquídeo , Demencia Vascular/diagnóstico , alfa-Sinucleína/líquido cefalorraquídeo , gamma-Sinucleína/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Diagnóstico Diferencial , Femenino , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunohistoquímica , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Masculino , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadAsunto(s)
Infecciones por Citomegalovirus/diagnóstico , Degeneración Lobar Frontotemporal/diagnóstico , Encéfalo/metabolismo , Encéfalo/patología , Infecciones por Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/patología , Diagnóstico Diferencial , Femenino , Degeneración Lobar Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Humanos , Filamentos Intermedios/metabolismo , Persona de Mediana Edad , Proteína FUS de Unión a ARN/metabolismoRESUMEN
Light microscopic, and scanning and transmission electron microscopic studies of the nodes of Ranvier of the distal peripheral nerves of mice with muscular dystrophy (dy/dy) are reported. Extensive widening of the nodes, retraction of Schwann cell cytoplasm and myelin, paranodal thinning of the myelin sheaths, and loss of nodal gap substance were observed. There was no loss of myelinated fibers. The changes at the nodes of Ranvier probably explain the slowed maximum conduction velocity observed in dystrophic peripheral nerves.
Asunto(s)
Distrofia Muscular Animal/patología , Nódulos de Ranvier/ultraestructura , Animales , Ratones , Nervios Periféricos/ultraestructura , Células de Schwann/ultraestructuraRESUMEN
BACKGROUND: Cognitive impairment is common in depression, but underlying mechanisms remain unknown. We examined whether increases in Alzheimer-type or vascular pathology are associated with cognitive impairments in elderly depressed subjects. METHODS: Eleven subjects who had died during a well-documented episode of DSM-IV major depression were included. Neuropathologic assessments, blind to group membership, included standardized assessment of neuritic plaques, neurofibrillary tangles, and Lewy Bodies in frontal, temporal, parietal, and occipital cortices. Braak staging of Alzheimer pathology was also performed. Cerebral microvascular disease was scored according to a previously validated scale, and a score for cerebral and systemic atheroma of large and medium sized arteries was obtained. RESULTS: No subject had Lewy bodies. Plaque and tangle counts for all subjects were well within published norms for age-matched control subjects. There were no significant differences in plaque or tangle counts between subjects who were cognitively impaired (n = 5) and those who were nonimpaired (n = 6) during their depressive illness. Similarly, neither total microvascular pathology nor deep frontal microvascular pathology differed between the two groups. CONCLUSIONS: Our results indicate that the liability for some patients to develop cognitive impairment during a depressive episode is not related to an increase in Alzheimer-type or vascular neuropathologic change. This indicates that other mechanisms must underlie both the cognitive impairment associated with depression and the observation that depression is a risk factor for dementia.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Arterias Cerebrales/patología , Trastornos del Conocimiento/patología , Trastorno Depresivo/patología , Anciano , Capilares/patología , Circulación Cerebrovascular/fisiología , Trastornos del Conocimiento/etiología , Trastorno Depresivo/complicaciones , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , MasculinoRESUMEN
Histochemistry and immunocytochemistry using an antibody to adult rat slow-type myosin demonstrated that about 10% of the fibers in the mouse extensor digitorum longus and semimembranosus muscles contain slow myosin during the first month after birth. In adult animals, these muscles have only 0-08% slow myosin-containing fibers. These results demonstrate a developmentally linked disappearance of an adult-type myosin, and show that the adult phenotype of muscle fibers is not necessarily determined before birth as previously suggested.
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Desarrollo de Músculos , Miosinas/análisis , Animales , Anticuerpos/inmunología , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Endogámicos , Distrofia Muscular Animal/patología , Miosinas/inmunología , FenotipoRESUMEN
OBJECTIVE: To determine the validity of a clinical diagnosis of probable or possible dementia with Lewy bodies (DLB) made using International Consensus criteria. BACKGROUND: Validation studies based on retrospective chart reviews of autopsy-confirmed cases have suggested that diagnostic specificity for DLB is acceptable but case detection rates as low as 0.22 have been suggested. METHODS: We evaluated the first 50 cases reaching neuropathologic autopsy in a cohort to which Consensus clinical diagnostic criteria for DLB, National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD, and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria for vascular dementia (VaD) had been prospectively applied. RESULTS: Twenty-six clinical diagnoses of DLB, 19 of AD, and 5 of VaD were made. At autopsy, 29 DLB cases, 15 AD, 5 VaD, and 1 progressive supranuclear palsy were identified. The sensitivity and specificity of a clinical diagnosis of probable DLB in this sample were 0.83 and 0.95. Of the five cases receiving a false-negative diagnosis of DLB, significant fluctuation was present in four but visual hallucinations and spontaneous motor features of parkinsonism were generally absent. Thirty-one percent of the DLB cases had additional vascular pathology and in two cases this contributed to a misdiagnosis of VaD. No correlations were found between the distribution of Lewy bodies and clinical features. CONCLUSION: The Consensus criteria for DLB performed as well in this prospective study as those for AD and VaD, with a diagnostic sensitivity substantially higher than that reported by previous retrospective studies. DLB occurs in the absence of extrapyramidal features and in the presence of comorbid cerebrovascular disease. Fluctuation is an important diagnostic indicator, reliable measures of which need to be developed further.
Asunto(s)
Enfermedad por Cuerpos de Lewy/patología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Conferencias de Consenso como Asunto , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
We investigated the prognostic significance of a new method of mitotic figure quantitation, 'mitotic percentage index' (MPI), tumour S phase fraction (SPF) and DNA ploidy measured by flow cytometry, and various clinical prognostic factors including age, sex, tumour stage, degree of surgical resection, radiotherapy dose and adjuvant chemotherapy in 70 cases of childhood medulloblastoma diagnosed between 1968 and 1996. In univariate analysis, MPI (P < 0.0001), posterior fossa radiotherapy dose (P = 0.003), tumour stage (P = 0.014), craniospinal radiotherapy dose (P = 0.019), year of diagnosis (P = 0.024) and SPF (P = 0.048) were significantly related to survival. In multivariate analysis, including tumour c-erbB-2 oncogene product expression, only MPI (P < 0.0001), craniospinal radiotherapy dose (P = 0.003) and tumour stage (P = 0.035) retained independent prognostic significance, while age achieved significance (P = 0.039). A close relationship was observed between MPI and SPF (coeff = 0.8, P < 0.0001) and MPI and the percentage of tumour cells expressing the c-erbB-2 oncogene product (coeff = 0.416, P < 0.0001). This study has identified MPI as a new independent prognostic factor for childhood medulloblastoma. Its close relationship with tumour SPF confirms it as an accurate measure of tumour proliferation and its close relationship to expression of the c-erbB-2 oncogene supports a role for this growth factor receptor in the deregulation of normal mitogenic signal transduction in this malignancy.
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Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Índice Mitótico , Fase S , Adolescente , Neoplasias Cerebelosas/química , Neoplasias Cerebelosas/genética , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Lactante , Masculino , Meduloblastoma/química , Meduloblastoma/genética , Ploidias , Pronóstico , Receptor ErbB-2/análisis , Análisis de SupervivenciaRESUMEN
Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.
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Azetidinas/farmacocinética , Encefalopatías/metabolismo , Receptores Nicotínicos/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Análisis de Varianza , Autorradiografía/métodos , Sitios de Unión , Estudios de Casos y Controles , Demencia Vascular/metabolismo , Femenino , Humanos , Técnicas In Vitro , Isótopos de Yodo/farmacocinética , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , Enfermedad de Parkinson/metabolismo , Radioquímica/métodos , Distribución TisularRESUMEN
PURPOSE: P53 gene mutations are the common genetic changes encountered in human cancers, and there is extensive evidence that the P53 status may determine tumor response to therapy. This study was carried out to investigate whether there is any correlation between accumulation (overexpression) of P53 protein and poor prognosis in patients with head and neck carcinomas treated with radical radiotherapy. METHODS AND MATERIALS: Seventy-nine patients with head and neck carcinomas who were diagnosed and treated in 1989-90 with curative radiotherapy were studied retrospectively. Paraffin sections from archival material were studied using immunohistochemical staining (IHC) with mouse monoclonal antibodies (D0-7) to human P53 protein. Univariate and multivariate analysis of loco-regional tumor control and patient survival were performed on possible prognostic factors. RESULTS: Forty-two (53%) patients showed positive IHC staining in their tumors. Fifty-three percent of the laryngeal, 64% of the oropharyngeal, and 43% of the oral cavity carcinomas showed P53 overexpression. All tumor specimens with vascular, lymphatic, and/or sarcolemmal invasion showed P53 overexpression. The proportion of tumor-stained nuclei was higher in the poorly differentiated than in the well and moderately differentiated tumors (p < 0.05), but there was no correlation with the patient overall or disease-free 5-year actuarial survival. There was no difference in the 5-year actuarial survival and disease-free survival between patients with P53 immunostaining in their tumors and those with no immunostaining (59% vs. 65% and 57% vs. 51%, respectively). The TNM tumor stage was the most significant prognostic factor with 5-year actuarial survival of 87% for early and 14% for late stages (p << 0.0001). There was a significant correlation between immunostaining and history of smoking (p = 0.02). CONCLUSION: The data demonstrate that the P53 accumulation as detected by immunohistochemical staining in a group of head and neck carcinomas was not predictive of patient's poor survival or disease-free survival. Multivariate statistical analysis showed that the TNM tumor stage was the only significant prognostic factor. There was a significant association between P53 accumulation and smoking.
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Neoplasias Laríngeas/química , Neoplasias Laríngeas/radioterapia , Neoplasias de la Boca/química , Neoplasias de la Boca/radioterapia , Proteínas de Neoplasias/análisis , Proteína p53 Supresora de Tumor/análisis , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hipofaríngeas/química , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/radioterapia , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/radioterapia , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
The human striatum, which receives dopaminergic innervation from the substantia nigra and ventral tegmental area (cell groups A8, A9 and A10), has structural and functional subdivisions both rostrocaudally and dorsoventrally. These relate to motor and non-motor origins of cortical projections and the specific areas of the substantia nigra and ventral tegmental area providing dopaminergic innervation. In the present study, we have evaluated the distribution of a number of dopaminergic parameters in the caudate, putamen and nucleus accumbens at separate coronal levels in a post mortem study in a series of elderly normal individuals aged 55-94 years, with analysis of the effect of post mortem variables. Dopamine D1 receptor density displayed a rostrocaudally declining gradient in the putamen but not in the caudate, such that at levels posterior to the anterior commissure, there was significantly lower D1 binding in the putamen compared to the caudate. The density of dopamine D2 receptors was similar in the putamen and caudate, increasing rostrocaudally. The density of dopamine uptake sites exhibited an increasing rostrocaudal gradient in the caudate, especially ventrally, but not in the putamen, where binding was more constant. The dopamine D3 receptor was concentrated in the ventral striatum, particularly the nucleus accumbens, although there was no evidence of a rostrocaudal gradient. With respect to striosome-matrix compartmentalization, there was no complete segregation, although D1 and D3 receptors were concentrated in striosomes, whereas D2 receptors and uptake sites showed higher density in the matrix. Levels of dopamine were similar in the caudate and putamen, and were significantly elevated at levels including the nucleus accumbens and the anterior commissure. Homovanillic acid and the metabolic index (homovanillic acid/dopamine ratio) were significantly higher in the putamen compared to the caudate, especially at levels from and caudal to the anterior commissure. These distributions of dopamine receptors and metabolic indicators, reflecting the different functional domains of the striatum, are relevant to the interpretation of current in vivo imaging of the dopamine transporter and receptors in neurological and psychiatric disorders. They provide information to assist in the detection of perturbations in expression, in specific diseases, at particular points on rostrocaudal, lateromedial and dorsoventral axes, a level of resolution beyond current neuroimaging capability.
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Proteínas Portadoras/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Anciano , Anciano de 80 o más Años , Autopsia , Núcleo Caudado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Ácido Homovanílico/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Especificidad de Órganos , Cambios Post Mortem , Putamen/metabolismo , Receptores de Dopamina D3RESUMEN
Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily composed of alpha and beta subunits with specific structural, functional and pharmacological properties. In this study we have used immunohistochemistry to investigate the presence of nicotinic acetylcholine receptor subunits in human cerebellum. Tissue was obtained at autopsy from eight adult individuals (aged 36-56 years). Histological sections were prepared from formalin-fixed paraffin-embedded material. alpha 3, alpha 4, alpha 6, alpha 7, beta 2, and beta 4 subunits were present in this brain area associated with both neuronal and non-neuronal cell types. Most Purkinje cells were immunoreactive for all the above subunits, but most strongly for alpha 4 and alpha 7. A proportion of granule cell somata were immunoreactive for all subunits except alpha 3. Punctate immunoreactivity in Purkinje cell and granule cell layers was evident with antibodies against alpha 3, alpha 4, alpha 6, and alpha 7 in parallel with synaptophysin immunoreactivity, suggesting the presence of these subunits on nerve terminals in the human cerebellum. All subunits were present in the dentate nucleus associated with neurones and cell processes. Strong immunoreactivity of neuropil in both the molecular and granule cell layers and within the dentate nucleus was noted with alpha 4, alpha 7 and beta 4 subunits. Astrocytes and astrocytic cell processes appeared to be immunoreactive for alpha 7 and cell processes observed in white matter, also possibly astrocytic, were immunoreactive for beta2. Immunoreactivity to all subunits was noted in association with blood vessels. We suggest that nicotinic acetylcholine receptor subunits may be involved in the modulation of cerebellar activity. Further investigations are warranted to evaluate the participation of nicotinic acetylcholine receptors in cerebellar pathology associated with both developmental and age-related disorders.
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Cerebelo/química , Receptores Nicotínicos/análisis , Adulto , Autopsia , Cerebelo/citología , Cerebelo/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Células de Purkinje/química , Receptores Nicotínicos/inmunologíaAsunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , alfa-Sinucleína/metabolismo , Southern Blotting , Encéfalo/metabolismo , Encéfalo/patología , Análisis Mutacional de ADN , ADN Polimerasa gamma , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Inmunohistoquímica , Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Vaina de Mielina/patología , Reacción en Cadena de la Polimerasa , Médula Espinal/patología , Canales Aniónicos Dependientes del Voltaje/metabolismoRESUMEN
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels composed of alpha and beta subunits with specific structural, functional and pharmacological properties. In this study the distribution of alpha3, alpha4, alpha7, beta2 and beta4 nAChR subunits in the human hippocampus was investigated using immunohistochemistry. Most pyramidal neurons, pre-alpha cells of the entorhinal cortex and dentate granule cells were immunoreactive for all subunits. Small islands of alpha7 immunoreactive cells were present in the outer presubiculum. alpha4 and beta2, and alpha3, alpha4 and beta2 immunoreactive fibre tracts were present in the stratum radiatum and subiculum, respectively, suggesting nAChRs may play a role in modulating inputs to the hippocampus via Schaffer collaterals and along the perforant pathway. Some astrocytes were immunoreactive for alpha3, alpha7 and beta4 subunits. Immunoreactivity to all subunits was noted in association with blood vessels. These results indicate the involvement of multiple nAChR subtypes in the modulation of both neuronal and non-neuronal functions in the human hippocampus.
Asunto(s)
Hipocampo/metabolismo , Receptores Nicotínicos/biosíntesis , Adulto , Astrocitos/química , Astrocitos/citología , Astrocitos/metabolismo , Femenino , Expresión Génica/fisiología , Hipocampo/química , Hipocampo/citología , Humanos , Masculino , Persona de Mediana Edad , Células Piramidales/química , Células Piramidales/citología , Células Piramidales/metabolismo , Receptores Nicotínicos/análisisRESUMEN
Recently it has been reported that a missense G(88)C mutation within exon 3 and a missense G(209)A mutation within exon 4 of the alpha-synuclein gene were linked to familial Parkinson's Disease (PD). We decided to investigate if these and any other mutations in exons 3 and 4 of the alpha-synuclein gene could be detected in sixty two sporadic PD and dementia with Lewy bodies (DLB) patients. Four cases of familial DLB were also studied, two of which were from the same family. Single stranded conformational polymorphism, DNA sequencing analyses and PCR-RFLP of exons 3 and 4 failed to reveal any nucleotide changes. However, three nucleotide differences occurred in the intron 4 sequence compared to the published sequence. This study adds further support to the idea that these particular mutation in the alpha-synuclein gene are a rare case of PD and now, as we have shown here, also of DLB.