Neuropathology in older people with disequilibrium of unknown cause.

OBJECTIVE: To identify the neuropathologic features associated with disequilibrium in older people. BACKGROUND: Disequilibrium of unknown cause is common in older people. Postmortem specimens from six patients and four control subjects, who were part of a longitudinal study of older people with disequilibrium, were studied. METHODS: Cerebral atrophy, ventriculomegaly, and histologic appearance were assessed. Astrocytic hypertrophy, arteriolar sclerotic index (1 - [inner diameter/outer diameter]), and arteriolar density were quantified in the frontal periventricular white matter (FPVWM). RESULTS: In comparison with control subjects, most patients had prominent frontal atrophy and ventriculomegaly. There were no other gross pathologic findings, microscopic infarcts, or areas of necrosis in patients or control subjects. Markedly reactive astrocytes were found in FPVWM of most patients and not in control subjects. Patients tended to have higher mean sclerotic indices compared with control subjects, but arteriolar density was no different in the two groups. Senile plaques and neurofibrillary tangles were no different in patients and control subjects except in one patient, in whom AD developed after entry. One patient had cerebral amyloid angiopathy (CAA) without intraparenchymal hemorrhage. CONCLUSION: Although there was some overlap between the two groups, the main differences between patients and control subjects were prominent frontal atrophy and ventriculomegaly, reactive astrocytes in FPVWM, and increased arteriolar wall thickness (sclerotic index). These findings suggest an association between subcortical leukoencephalopathy and disequilibrium in older nonhypertensive patients.

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.

Internal auditory artery infarction: clinicopathologic correlation.

OBJECTIVE: To study the pathophysiology of labyrinthine infarction. BACKGROUND: The syndrome of sudden onset vertigo or hearing loss is commonly attributed to inner ear vascular disease, yet histologic studies of isolated labyrinthine infarction in humans have been rare and have not included a complete examination of the vertebrobasilar vascular system. METHODS: Temporal bones, brainstem, cerebellum, and the supplying blood vessels were subjected to gross and microscopic postmortem examinations in a 92-year-old woman who had a sudden onset of vertigo and hearing loss in the right ear 7 years before death. RESULTS: There were prominent atherosclerotic changes at the vertebrobasilar junction, but the internal auditory artery and its branches were patent on both sides. Histologic studies showed degenerative changes in the cochlea and vestibular labyrinth on the right. The posterior canal ampulla and saccular macule were relatively preserved showing partial areas of intact sensory epithelium with underlying nerve fibers. The right vestibulocochlear nerve showed a fibrotic scar and multiple patchy areas of degeneration. These findings are most consistent with a transient period of reduced perfusion of the internal auditory artery. CONCLUSION: The partial sparing of the inferior vestibular labyrinth may indicate a decreased vulnerability to ischemia because of its better collateral blood supply.

Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus.

Microglial cells are the main component of the brain's resident immune system and are activated in Alzheimer disease (AD). We quantified the density of activated microglial cells (AMG) in 8 sectors of human hippocampus to determine if their density is correlated with senile plaque (SP) and neurofibrillary tangle (NFT) formation. Ferritin-stained microglia, Bielschowsky-stained neuritic plaques, and perikarya containing NFTs were counted in 8 young adults, 9 nondemented elderly adults, and 9 demented patients with AD. Microglial cell activation was moderately higher in elderly nondemented subjects. In AD there was a more striking activation in all sectors of the hippocampus. Most AMGs were distributed diffusely in neuropil and were not delimited to SPs or NFTs. Senile plaque counts were not linked with AMG counts within any sector. Neurofibrillary tangle counts were correlated significantly with AMG counts within one sector, the subiculum. When variations within and between sectors were factored out statistically, the burden of AMGs was correlated significantly with the burden of NFTs (r = 0.34; p < 0.005), but not SPs. Neuropathologic changes at the origin of the perforant pathway were correlated significantly with orthograde microglial cell activation in the termination field. These observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant. When significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.