RESUMEN
BACKGROUND: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 ('normal' cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. METHODS: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. RESULTS: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. CONCLUSIONS: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic.
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Cognición/fisiología , Disfunción Cognitiva/fisiopatología , Ataque Isquémico Transitorio/fisiopatología , Memoria/fisiología , Accidente Cerebrovascular/fisiopatología , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/psicología , Humanos , Escala del Estado Mental , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.
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Apolipoproteínas E/genética , Encéfalo/fisiología , Cognición/fisiología , Esperanza de Vida , Imagen por Resonancia Magnética/métodos , Memoria/fisiología , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/epidemiología , Apolipoproteína E4/sangre , Encéfalo/crecimiento & desarrollo , Portador Sano/epidemiología , Circulación Cerebrovascular/fisiología , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tiempo de Reacción , Valores de Referencia , Factores de RiesgoRESUMEN
BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.
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Apolipoproteínas E/genética , Trastornos del Conocimiento/genética , Cognición , Demencia/genética , Trastornos del Conocimiento/epidemiología , Demencia/clasificación , Demencia/epidemiología , Europa (Continente)/epidemiología , Frecuencia de los Genes , Humanos , Valores de Referencia , Topografía MédicaRESUMEN
OBJECTIVE: To review studies investigating the brain correlates of unawareness of cognitive and behavioural symptoms in people with dementia. DESIGN: A detailed search of the literature was conducted to include all the peer-reviewed studies published in English aimed at identifying the structural or functional brain correspondents of unawareness in dementia patients. Their results were interpreted in relation to the methodological differences in terms of type of dementia studied, the protocol adopted to measure lack of awareness, the imaging techniques employed, the experimental designs and statistical analyses performed. RESULTS: Eighteen studies undertaken to explore the functional and structural correlates of unawareness of cognitive symptoms in dementia were identified. Although their results showed a disparate range of brain correlates, they were mainly localized in frontal and temporo-parietal regions. CONCLUSIONS: Although the anatomical correlates of unawareness of disease in dementia have not yet been exhaustively explored, understanding the correlates of unawareness may also contribute to understand the brain correlates of self-awareness and self-reflection. We discuss the current knowledge base and consider potential future directions for research.
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Agnosia/patología , Agnosia/psicología , Concienciación , Demencia/patología , Demencia/psicología , Encéfalo/irrigación sanguínea , Humanos , Imagen por Resonancia Magnética/métodos , Pruebas Neuropsicológicas , Autoimagen , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
BACKGROUND: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium. METHODS: Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up. RESULTS: Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Guías como Asunto/normas , Tamizaje Masivo/normas , Actividades Cotidianas/psicología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/normas , Pruebas Neuropsicológicas/normas , Estudios ProspectivosAsunto(s)
Enfermedad de Alzheimer/genética , alfa-Macroglobulinas/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/epidemiología , Autopsia , Inglaterra/epidemiología , Frecuencia de los Genes , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo GenéticoRESUMEN
Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system. NGF binds with high affinity to the extracellular region of the tyrosine kinase receptor TrkA. This domain comprises leucine and cysteine rich motifs, followed by two immunoglobulin like (Ig-like) domains. We describe the expression and purification of recombinant Ig-like domains. Fluorescence and circular dichroism spectroscopy show that the protein is folded into a compact globular structure and contains mainly beta-sheet secondary structure. Recombinant protein binds to NGF and can inhibit NGF bioactivity both in vitro and in vivo.
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Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión/genética , Unión Competitiva , Biotecnología , Dicroismo Circular , Humanos , Inmunoglobulinas/química , Técnicas In Vitro , Masculino , Datos de Secuencia Molecular , Factores de Crecimiento Nervioso/antagonistas & inhibidores , Células PC12 , Pliegue de Proteína , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas/química , Ratas , Ratas Wistar , Proteínas Tirosina Quinasas Receptoras/química , Receptor trkA , Receptores de Factor de Crecimiento Nervioso/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometría de FluorescenciaRESUMEN
Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.
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Amnesia/fisiopatología , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Navegación Espacial/fisiología , Interfaz Usuario-Computador , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas NeuropsicológicasRESUMEN
The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer's Dementia (EPAD) and the Global Alzheimer's Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.
RESUMEN
Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.
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Encéfalo/patología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/patología , Trastornos de la Memoria/etiología , Memoria a Corto Plazo/fisiología , Anciano , Análisis de Varianza , Encéfalo/irrigación sanguínea , Mapeo Encefálico , Función Ejecutiva , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/patología , Pruebas Neuropsicológicas , Oxígeno/sangre , Desempeño Psicomotor , Tiempo de ReacciónRESUMEN
Following the introduction of tacrine hydrochloride (Cognex) in the United States and several other countries, researchers are pursuing two broad therapeutic strategies for Alzheimer's disease (AD). The first involves identifying agents or combinations of agents whose actions can compensate for the considerable cerebral damage that has typically occurred by the time the diagnosis of AD is made. Such therapeutic approaches include the development of additional cholinesterase inhibitors, agents that work on the receptors of other systems damaged by the disease process, and anti-inflammatory and immunomodulatory agents. The second and ultimately more promising strategy involves the development of approaches to retard, halt, or even prevent disease progression. Such protective approaches, which depend on the development of more effective methods for predicting and diagnosing AD, include the administration of nerve growth factor and other neurotrophins and the use of pharmacologic or genetic interventions to limit amyloid deposition and the formation of neurofibrillary tangles.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Predicción , HumanosRESUMEN
OBJECTIVE: To assess the value of serum measurements of tacrine hydrochloride and its metabolite in predicting risk of adverse reaction in Alzheimer's disease. METHODS: The study was an outpatient-based controlled clinical trial. Study subjects were 35 female and 31 male patients who were receiving 50 to 150 mg tacrine hydrochloride per day. RESULTS: Serum concentration of tacrine hydrochloride and ratio of tacrine hydrochloride to metabolite were significantly higher in the 45 patients with symptomatic adverse effects (p < 0.001). The tacrine hydrochloride to metabolite ratio was significantly higher (p < 0.05) in the 30 patients in whom abnormal liver function developed, but concentration of tacrine hydrochloride was not significantly higher. Women showed a higher incidence of adverse effects (p < 0.05), and tacrine hydrochloride concentrations were higher (p < 0.05). Tacrine hydrochloride concentration and tacrine hydrochloride to metabolite ratio were higher in both men and women in whom adverse effects developed. CONCLUSION: Tacrine hydrochloride concentration is valuable in predicting the development of adverse effects, and its measurement may improve the use of the drug.
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Enfermedad de Alzheimer/tratamiento farmacológico , Tacrina/efectos adversos , Tacrina/sangre , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Tacrina/metabolismoRESUMEN
The clinical pharmacokinetics of tacrine hydrochloride have been characterized in patients who have Alzheimer's disease. Serum concentrations of the drug and of its probable metabolite were monitored in eight patients after a 25 mg oral dose, in six patients after a 50 mg oral dose, in four patients after repeated administration of 50 mg, and in two patients after a small intravenous dose. Urinary excretion of drug and metabolite for 24 hours was measured in one of the patients who received a small intravenous dose. The serum half-life was 1.59 +/- 0.15 hours (mean +/- SEM) after the 25 mg dose, 2.14 +/- 0.24 hours after the 50 mg dose, and 2.91 +/- 0.39 hours after continuous treatment. After intravenous administration, clearance was above 600 ml/min in both patients, and oral bioavailability was calculated at below 5%. Urine recovery was less than 3% of the dose. The low bioavailability of tacrine hydrochloride is partly explained by presystemic metabolism.
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Enfermedad de Alzheimer/metabolismo , Aminoacridinas/farmacocinética , Tacrina/farmacocinética , Administración Oral , Anciano , Anciano de 80 o más Años , Disponibilidad Biológica , Bradicardia/inducido químicamente , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Análisis de los Mínimos Cuadrados , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Tacrina/administración & dosificación , Tacrina/efectos adversosRESUMEN
The distribution of neurons expressing the receptor for beta-nerve growth factor has been examined immunohistochemically in serial coronal sections of basal forebrain from aged normal human subjects. Neurons expressing the receptor were observed in the nucleus of the diagonal band of Broca and in the anterior, the intermediate, and the posterior portions of the nucleus basalis of Meynert. Neurons could also be seen in the medial septal nucleus and embedded in myelinated fibre tracts such as those of the external capsule, cingulum, medullary laminae of the globus pallidus, ansa penduncularis, ansa lenticularis, and anterior commissure. In situ hybridization with a 35S cDNA probe to the human beta-nerve growth factor receptor confirms a neuronal location as the site of synthesis of beta-nerve growth factor receptors in the nucleus basalis of Meynert in a fifth brain. A high percentage of Nissl-stained hyperchromic magnocellular neurons expressed the receptor for beta-nerve growth factor, suggesting that most neurons in the human cholinergic magnocellular basal forebrain system express these receptors. Recent data suggest that beta-nerve growth factor functions as a neurotrophic factor in basal forebrain cholinergic neurons. In Alzheimer's disease there is known to be a reduction in cholinergic function and an apparent loss of neurons in the cholinergic nucleus basalis of Meynert. For this reason we have examined the distribution of receptors for beta-nerve growth factor in the normal human basal forebrain in order to form a basis for comparison to those with Alzheimer's disease.
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Ganglios Basales/metabolismo , Lóbulo Frontal/metabolismo , Receptores de Superficie Celular/metabolismo , Sustancia Innominada/metabolismo , Anciano , Anciano de 80 o más Años , Lóbulo Frontal/citología , Humanos , Inmunohistoquímica , Receptores de Factor de Crecimiento Nervioso , Sustancia Innominada/citologíaRESUMEN
Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
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Demencia/patología , Enfermedad de Parkinson/patología , HumanosRESUMEN
Caring for the chronically ill is associated with chronic distress. In view of the adverse effects of distress on cellular immune function, such distress may have implications for health. Indeed, it has been proposed that the hypothalamic-pituitary-adrenal (HPA) axis is a potential psychobiological mediator of these effects. In this study, we observed that elderly caregivers experienced greater distress and increased salivary cortisol than non-caregivers. In addition, caregivers had blunted mitogen-induced lymphocyte proliferation, lower mitogen-induced IL-2 production, and reduced lymphocyte sensitivity to glucocorticoids. These results indicate that chronic distress is associated with impaired cell-mediated immunity which is, in turn, associated with elevated basal steroid levels and altered steroid immunoregulation at the level of the lymphocyte.
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Cuidadores , Glucocorticoides/farmacología , Activación de Linfocitos/efectos de los fármacos , Estrés Fisiológico/inmunología , Anciano , Enfermedad Crónica , Demencia , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Interleucina-2/biosíntesis , Masculino , Fenómenos Fisiológicos de la Nutrición , Sistema Hipófiso-Suprarrenal/fisiologíaRESUMEN
A truncated form of the human trkB gene has been cloned and sequenced. This gene is related to the trk family of tyrosine kinases, the products of which act as receptors for the neurotrophins. Of these, brain-derived neurotrophic factor and mammalian neurotrophin-4 are the known ligands for the TrkB receptor. Catalytic and non-catalytic (or truncated) forms of the trkB gene have been cloned for rat and mouse. In this study, using in situ hybridization, we describe the distribution of trkB messenger RNA in fetal and adult human brain.
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Química Encefálica , Proteínas del Tejido Nervioso/genética , ARN Mensajero/análisis , Receptor trkB/genética , Receptores de Factor de Crecimiento Nervioso/genética , Secuencia de Aminoácidos , Animales , Encéfalo/embriología , Catálisis , Clonación Molecular , Sondas de ADN , ADN Complementario/genética , Hipocampo/química , Hipocampo/embriología , Humanos , Hibridación Fluorescente in Situ , Ratones , Datos de Secuencia Molecular , Familia de Multigenes , Proteínas del Tejido Nervioso/análisis , ARN Mensajero/genética , Ratas , Proteínas Tirosina Quinasas Receptoras/análisis , Proteínas Tirosina Quinasas Receptoras/genética , Receptor de Factor Neurotrófico Ciliar , Receptor trkA/análisis , Receptor trkA/genética , Receptor trkB/análisis , Receptor trkC , Receptores de Factor de Crecimiento Nervioso/análisis , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
Nerve growth factor (NGF) receptor mRNA was found to be widely distributed throughout the human central nervous system, with the highest levels in the basal forebrain; this suggests that NGF may function as a retrograde trophic messenger for basal forebrain magnocellular cholinergic nerve cells. The degeneration of the latter constitutes one of the main features of Alzheimer's disease and it may be responsible for some of the cognitive impairment that characterizes the disease. No evidence was obtained for an insufficient synthesis of NGF receptor mRNA in the basal forebrain in Alzheimer's disease, where NGF receptor-like immunoreactivity was confined to neuronal cell bodies. NGF could thus be therapeutically beneficial. It could be expected to induce basal forebrain cholinergic cells to hypertrophy, synthesize more choline acetyltransferase and extend neurites.
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Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Factores de Crecimiento Nervioso/metabolismo , ARN Mensajero/genética , Receptores de Superficie Celular/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Humanos , Neuronas/metabolismo , Neuronas/patología , Hibridación de Ácido Nucleico , Receptores de Factor de Crecimiento Nervioso , Valores de ReferenciaRESUMEN
Mutations in the presenilin 1 gene have been shown to result in Alzheimer's disease. Presenilin 1 is a multi-transmembrane protein with a large hydrophilic loop near the C-terminus. This region is required for known functions of presenilin 1. We have constrained this loop within the active site of the bacterial protein, thioredoxin, to mimic its native conformational state. This hybrid protein was used as bait in a yeast two hybrid screen in an attempt to identify presenilin binding proteins. By this method syntaxin 1A, a synaptic plasma membrane protein, was identified as a novel binding protein for presenilin 1. In vitro experiments confirm the two-hybrid results suggesting that PS1 binds syntaxin under physiological conditions.