Dushyant P. Purohit

Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits.

Abstract: Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimers disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin‐releasing factor, serotonin, and 5‐hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin‐releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.

Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease

Cyclooxygenase‐2 (COX‐2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimers disease (AD). In the present study, we explored the regulation of COX‐2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age‐matched controls) neurons of the CA1–CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX‐2 signal; COX‐2 levels correlated with amyloid plaque density. In contrast, the level of COX‐2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX‐2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX‐2 are more susceptible to β‐amyloid (Aβ) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX‐2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Aβ‐mediated oxidative stress. J. Neurosci. Res. 57:295–303, 1999.

Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies

The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications.

Role of the Neuropathology of Alzheimer Disease in Dementia in the Oldest-Old

BACKGROUND Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the brain, especially in the hippocampus, entorhinal cortex, and isocortex, are hallmark lesions of Alzheimer disease and dementia in the elderly. However, this association has not been extensively studied in the rapidly growing population of the very old. OBJECTIVE To assess the relationship between estimates of cognitive function and NP and NFT pathologic conditions in 317 autopsied persons aged 60 to 107 years. DESIGN We studied the relationship between severity of dementia and the density of these characteristic lesions of Alzheimer disease in young-old, middle-old, and oldest-old persons. The relationship of the severity of dementia as measured by the Clinical Dementia Rating scale to the density of NPs and NFTs was then assessed in each age group. PARTICIPANTS Three hundred seventeen brains of persons aged 60 years and older were selected to have either no remarkable neuropathological lesions or only NP and NFT lesions. Brains with any other neuropathological conditions, either alone or in addition to Alzheimer disease findings, were excluded. The study cohort was then stratified into the youngest quartile (aged 60-80 years), middle 2 quartiles (aged 81-89 years), and oldest quartile (aged 90-107 years). RESULTS While the density of NPs and NFTs rose significantly by more than 10-fold as a function of the severity of dementia in the youngest-old group, significant increases in the densities of NPs and NFTs were absent in the brains of the oldest-old. This lack of difference in the densities of NPs and NFTs was due to reduced lesion densities in the brains of oldest-old persons with dementia rather than to increased density of these lesions in the brains of nondemented oldest-old persons. CONCLUSIONS These findings suggest that the neuropathological features of dementia in the oldest-old are not the same as those of cognitively impaired younger-old persons and compel a vigorous search for neuropathological indices of dementia in this most rapidly growing segment of the elderly population.

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons

Objective: To test the hypothesis that use of antihypertensive medication is associated with lower Alzheimer disease (AD) neuropathology. Methods: This was a postmortem study of 291 brains limited to those with normal neuropathology or with uncomplicated AD neuropathology (i.e., without other dementia-associated neuropathology) in persons with or without hypertension (HTN) who were and were not treated with antihypertensive medications. Neuritic plaque (NP) and neurofibrillary tangle (NFT) densities, quantified in selected brain regions according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathologic criteria, with additional cortical NP counts, yielded 24 neuropathologic regional measures or summaries. Medicated hypertension (HTN-med; n = 77), nonmedicated HTN (HTN-nomed; n = 42), and non-HTN (no-HTN; n = 172) groups were compared by analyses of variance. Results: The HTN-med group had significantly less neuropathology than the no-HTN group. The no-HTN group averaged over 50% higher mean NP and NFT ratings, and double the mean NP count, of the HTN-med group. The HTN-nomed group had significantly more neuropathology than the HTN-med group, but not significantly less than the no-HTN group. Conclusions: There was substantially less Alzheimer disease (AD) neuropathology in the medicated hypertension group than the nonhypertensive group, which may reflect a salutary effect of antihypertensive medication against AD-associated neuropathology.

Increased Neurofibrillary Tangles in Patients With Alzheimer Disease With Comorbid Depression

OBJECTIVE Recent evidence suggests that a history of major depression may lead to increases in hippocampal neuropathology in Alzheimer disease (AD). The authors tested the hypothesis that neuritic plaques and neurofibrillary tangles are more pronounced in the brains of patients with AD with comorbid depression as compared with patients with AD without depression. METHODS Brain samples from patients were selected from the U.S. National Alzheimers Coordinating Center database. The primary analysis included 7164 individuals: 6468 had AD as the primary neuropathologic diagnosis and 696 were considered neuropathologically normal. Depression at study inclusion was rated as present or absent in consensus conferences. Neuropathologic ratings from the Consortium to Establish a Registry in Alzheimers Disease rating of neuritic plaques and Braak staging of neurofibrillary tangles were used for between-group analyses. RESULTS Brains of patients with AD with comorbid depression showed higher levels of cortical tangle formation than brains of patients with AD without comorbid depression. Results remained stable when controlling for age, gender, level of education, and cognitive status. Within patients with AD, comorbid depression increased the odds for advanced neuropathologic disease stage (odds ratio: 1.47; 95% confidence interval: 1.03-2.08). CONCLUSION In AD, the presence of depression comorbidity corresponds to increases in AD-related neuropathologic changes beyond age, gender, level of education, and cognitive status, suggesting an interaction between depression and the neuropathologic processes in AD.

Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology

Objective: To examine the association between treatment for diabetes and Alzheimer disease (AD) neuropathology. Methods: This postmortem study matched 124 subjects with diabetes to 124 without diabetes from the Mount Sinai School of Medicine Brain Bank, on age (mean = 81.2 + 9.3), sex (57.3% F), and severity of dementia (Clinical Dementia Rating [CDR] 2.4 + 1.7). Densities of neuritic plaques (NPs) and of neurofibrillary tangles (NFTs) were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Diabetic subjects were classified according to their recorded lifetime antidiabetic medications: none (n = 29), insulin only (n = 49), diabetes medications other than insulin only (n = 28), or concomitant use of both insulin and any oral antidiabetic medications (n = 18). For each dependent variable, analysis of covariance controlling for age at death, sex, and CDR distinguished among the nondiabetic patients and four diabetic subgroups. Results: There were differences among the five groups for NP ratings in the entorhinal cortex (p = 0.003), amygdala (p = 0.009), and overall NP (p = 0.014) as well as counts of NPs in all regions examined (p values ranging from 0.009 to 0.04). NP ratings in the hippocampus (p = 0.057) and the combined neocortical measure (p = 0.052) approached significance. In each analysis, the concomitant medication group had significantly fewer NPs (∼20%) than any of the other groups, which were relatively similar. No significant NFT differences were found. Conclusion: The results of this study suggest that the combination of insulin with other diabetes medication is associated with substantially lower neuritic plaque density consistent with the effects of both on the neurobiology of insulin.

Severe cognitive impairment in elderly schizophrenic patients: A clinicopathological study ☆

The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimers disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.

Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique

Using a cDNA microarray representing 6794 distinct human genes, we identified candidate genes whose expression is altered in cerebral cortex of cases of early Alzheimers disease (AD); among these was the synaptic vesicle protein synapsin II, which plays an important role in neurotransmitter release. While other candidate genes are presently under investigation in our lab, in this study we discuss the regulation of synapsin gene expression during the transition from normal cognitive function to early AD. We found a selective decrease in the expression of the synapsin splice variants I-III of the a-type isoform in the entorhinal (EC, BM36) but not visual cortex (VC, BM17) of cases characterized by the earliest clinically detectable stage of AD. In contrast, we found no changes in synapsin splice variant II of the b-type isoform. Alteration of synapsin expression at the earliest clinical stage of AD may suggest novel strategies for improved treatment.

Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex

Neuropeptide concentrations were determined in the postmortem cerebral cortex from 19 cognitive-impaired schizophrenics, 4 normal elderly subjects, 4 multi-infarct dementia (MID) cases, and 13 Alzheimers disease (AD) patients. Only AD patients met criteria for AD. The normal elderly and MID cases were combined into one control group. Somatostatin concentrations were reduced in both schizophrenia and AD. Neuropeptide Y concentrations were reduced only in schizophrenia, and corticotropin-releasing hormone concentrations were primarily reduced in AD. Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y. In AD, cholecystokinin and vasoactive intestinal peptide were unchanged. Neuropeptide deficits in schizophrenics were more pronounced in the temporal and frontal lobes than in the occipital lobe. The mechanisms underlying these deficits in schizophrenia and AD are likely distinct. In schizophrenia, a common neural element, perhaps the cerebral cortical gaba-aminobutyric acid (GABA)-containing neuron, may underlie these deficits.