Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0752347 (Dementia with Lewy bodies)
 1,653 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An autopsied case of juvenile parkinsonism and dementia is described. The patient is a 48-year-old man who had a ten-year history of parkinsonian syndrome and progressive dementia. Neuropathological examination revealed a widespread occurrence of Lewy bodies and spheroids in the central nervous system. Lewy bodies were found not only in the brain stem and diencephalon, but also in the cerebral cortex. Massive numbers of small spheroids were observed in the globus pallidus, substantia nigra, mamillary bodies and hippocampus. Electron microscopical examination showed that most spheroids were composed of degenerative organelles with only a few neurofilaments, and were different from those of Hallervorden-Spatz disease. There was also marked neuronal loss with gliosis in the CA3-4 of the hippocampus. Some neurofibrillary tangles occurred in the hippocampus, subcortical and brain stem nuclei, but senile plaques were absent. This case may represent an atypical form of pure diffuse Lewy body disease.
 ...
PMID:An autopsied case of juvenile parkinsonism and dementia, with a widespread occurrence of Lewy bodies and spheroids. 131 91

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4-70.1%, mean 41.3%), LBV (19.0-42.5%, mean 26.8%) and DLBD (19.9-31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex (r = -0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.
 ...
PMID:Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease. 789 80

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB. However, elevated parv levels are found in the cerebrospinal fluid of patients suffering from dementia with Lewy bodies. We performed an immunohistochemical analysis of hippocampal parv-immunoreactive neurons in well-characterised DLB cases and from controls using a specific antibody against the calcium binding protein. In addition, an analysis of the regional and cellular distribution of alpha-synuclein was carried out. Subfield and laminar distribution of parv-immunoreactive (ir) neurons on the hippocampus in subjects with DLB and controls were present exclusively as non-granule cells of the dentate gyrus (DG)/hilus and non-pyramidal cells of CA1, CA2, CA3 and CA4 areas of the hippocampus. The distribution patterns did not differ qualitatively between DLB and controls. Quantitative estimation of parv-ir neuron density revealed significant decreases in the dentate (DG)/hilus region as well as in the CA1 subfield. Double immunolabelling experiments showed that only 2% of parv expressing interneurons were laden with alpha-synuclein immunoreactive material. No significant changes were found for the total neuron densities in DLB cases. Our results show a partial loss of parv-expressing hippocampal interneurons in DLB, which might be the result of long-lasting calcium overload in combination with a proposed impaired mitochondrial function. It remains to be elucidated if the numerical decrease of this particular subset of hippocampal interneurons has consequences for the gamma (20-80 Hz) frequency activity in DLB patients.
 ...
PMID:Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies. 2048 8

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relationship to alpha-syn remain unclear. For this study we proposed that accumulation of alpha-syn might result in alterations in metabotropic glutamate receptors (mGluR), particularly mGluR5 which has been linked to deficits in murine models of PD. In this context, levels of mGluR5 were analyzed in the brains of PD and DLB human cases and alpha-syn transgenic (tg) mice and compared to age-matched, unimpaired controls, we report a 40% increase in the levels of mGluR5 and beta-arrestin immunoreactivity in the frontal cortex, hippocampus and putamen in DLB cases and in the putamen in PD cases. In the hippocampus, mGluR5 was more abundant in the CA3 region and co-localized with alpha-syn aggregates. Similarly, in the hippocampus and basal ganglia of alpha-syn tg mice, levels of mGluR5 were increased and mGluR5 and alpha-syn were co-localized and co-immunoprecipitated, suggesting that alpha-syn interferes with mGluR5 trafficking. The increased levels of mGluR5 were accompanied by a concomitant increase in the activation of downstream signaling components including ERK, Elk-1 and CREB. Consistent with the increased accumulation of alpha-syn and alterations in mGluR5 in cognitive- and motor-associated brain regions, these mice displayed impaired performance in the water maze and pole test, these behavioral alterations were reversed with the mGluR5 antagonist, MPEP. Taken together the results from study suggest that mGluR5 may directly interact with alpha-syn resulting in its over activation and that this over activation may contribute to excitotoxic cell death in select neuronal regions. These results highlight the therapeutic importance of mGluR5 antagonists in alpha-synucleinopathies.
 ...
PMID:Alterations in mGluR5 expression and signaling in Lewy body disease and in transgenic models of alpha-synucleinopathy--implications for excitotoxicity. 2110 59

Hippocampal networks are particularly susceptible to dysfunction in many neurodegenerative diseases and neuropsychiatric disorders including Alzheimer's disease, Lewy body dementia, and schizophrenia. CA1, a major output region of the hippocampus, receives glutamatergic input from both hippocampal CA3 and entorhinal cortex, via the Schaffer collateral (SC) and temporoammonic (TA) pathways, respectively. SC and TA inputs to CA1 are thought to be differentially involved in the retrieval of previously stored memories versus the encoding of novel information, and switching between these two crucial hippocampal functions is thought to critically depend on acetylcholine (ACh) acting at muscarinic receptors. In this study, we aimed to determine the roles of specific subtypes of muscarinic receptors in mediating the neuromodulatory effects of ACh on glutamatergic synaptic transmission in the SC and TA pathways of CA1. Using selective pharmacological activation of M1 or M4 receptors along with extracellular and intracellular electrophysiology recordings from adult rat hippocampal slices, we demonstrate that activation of M1 receptors increases spontaneous spike rates of neuronal ensembles in CA1 and increases the intrinsic excitability of pyramidal neurons and interneurons. Selective activation of M4 receptors inhibits glutamate release in the SC pathway, while leaving synaptic transmission in the TA pathway comparatively intact. These results suggest specific mechanisms by which M1 and M4 activation may normalize CA1 circuit activity following disruptions of signaling that accompany neurodegenerative dementias or neuropsychiatric disorders. These findings are of particular interest in light of clinical findings that xanomeline, an M1/M4 preferring agonist, was able to improve cognitive and behavioral symptoms in patients with Alzheimer's disease or schizophrenia.
 ...
PMID:Effects of M1 and M4 activation on excitatory synaptic transmission in CA1. 2842 71