Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging.

Substantial numbers of cortical and subcortical Lewy bodies are seen in approximately one quarter of patients whose brains show sufficient histopathologic changes for a neuropathologic diagnosis of definite Alzheimer disease (AD). This subset of cases has been named the Lewy body variant of AD (LBV). Despite comparable dementia and the presence of neocortical senile plaques in LBV patients, the overall burden of neuropathologic changes, in particular neurofibrillary tangles (NFT), is less than in classic AD. While NFT frequency correlates with dementia severity in classic AD, the cognitive impairment in patients with LBV cannot be completely explained by such changes. Since several studies have suggested a role for synapse loss in relation to dementia severity in classic AD, we decided to investigate the role of synapse loss as a candidate for the cognitive impairment of LBV. The Braak staging method is based upon the distribution and severity of neurofibrillary changes, and one therefore would expect LBV cases to be assigned to lower Braak stages. In the present study we assigned a Braak stage to 14 LBV cases, 31 classic AD cases, and a group of 10 non-demented aged controls. We compared the severity of synapse loss as determined by ELISA immunoassay for synaptophysin and Braak stage among the three diagnostic groups. When compared to normal controls, synaptophysin concentrations were statistically significantly lower in both demented groups. There was comparable synapse loss in LBV and AD despite significantly lower Braak stages in the LBV cases. These results suggest a major role for loss of synapses as the substrate of cognitive impairment in LBV.

Correlation of bcl-2, p53, and MIB-1 expression with ependymoma grade and subtype.

In this study, we report our results on the proliferative activity of ependymomas as determined by MIB-1 (also known as Ki-67) immunohistochemical analysis, and we compare our results with those obtained by immunolabeling with monoclonal antibodies to p53 and bcl-2 proteins to assess whether expression correlated with ependymoma subtype or tumor grade. The study included 4 myxopapillary ependymomas (Grade I of the World Health Organization [WHO] scale), 10 subependymomas (WHO Grade I), 17 ependymomas (WHO Grade II), 2 papillary ependymomas (WHO grade II), and 4 anaplastic ependymomas (WHO Grade III). The MIB-1 proliferation index was significantly higher in tumors diagnosed as anaplastic ependymoma (P < .001), with a moderate level of correlation (Kendall's tau-b = 0.557, asymptotic standard error = 108). In addition, one ependymoma (WHO Grade II) not considered overtly anaplastic by routine histologic criteria showed a high MIB-1 labeling index, suggesting that the MIB-1 proliferation index might be a more objective indicator of tumor grade. The remaining WHO Grade I and Grade II ependymomas showed low proliferative activity. bcl-2 oncoprotein expression was identified in all of the four myxopapillary and in both papillary ependymomas. An additional observation was the correlation of p53 expression with increasing WHO grade. These data suggest that high MIB-1 and p53 immunolabeling might be objective indicators of high grade in ependymomas that do not otherwise meet routine histologic criteria for high-grade ependymoma. Subsequent clinicopathologic analyses will be important in assessing whether these markers are useful as independent predictors of survival.

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Hormone receptor immunoreactivity in hemangioblastomas and clear cell renal cell carcinomas.

Several primary central nervous system (CNS) neoplasms, including meningiomas, spinal cord ependymomas, and acoustic nerve schwannomas, express hormone receptors. In the present study, we investigated hormone receptor immunoreactivity in hemangioblastomas on the basis of recent reports of these tumors complicating pregnancy. We also evaluated cases of renal cell carcinoma (RCC) metastatic to the CNS, hypothesizing that estrogen receptor (ER), progesterone receptor (PR), or androgen receptor (AR) immunoreactivity might help to distinguish between these histologically similar neoplasms. Immunohistochemical analysis for ERs, PRs, and ARs was performed on paraffin-embedded sections of 27 hemangioblastomas, 12 primary clear cell RCCs, and 5 clear cell RCCs metastatic to the CNS. All of the hemangioblastomas demonstrated PR immunoreactivity, whereas 10 of 12 primary RCCs were negative. In addition, four of the five metastatic RCC were PR positive. All but one primary RCC were ER negative. AR immunoreactivity was seen in three hemangioblastomas, five primary RCCs, and one metastatic RCC. Although hormone receptor immunoreactivity was unable to distinguish between hemangioblastoma and clear cell RCC metastatic to the CNS, the identification of PR immunoreactivity in hemangioblastomas is a new finding that might have adjuvant therapy treatment implications.