Alzheimer Disease: Hachinski VC

Desmond DW, Erkinjuntti T, Sano M, Cummings JL, Bowler JV, Pasquier F, Moroney JT, Ferris SH, Stern Y, Sachdev PS, Hachinski VC. · Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609678 No free full text.

Abstract: Dementia is common among patients with cerebrovascular disease, particularly in a setting of one or more clinically evident strokes. Prior cohort and case studies have suggested that the cognitive syndrome of vascular dementia is characterized by predominant executive dysfunction, in contrast to the deficits in memory and language function that are typical of patients with Alzheimer disease. The course of cognitive decline may also differ between those dementia subtypes, with many, but not all, patients with vascular dementia exhibiting a stepwise course of decline caused by recurrent stroke and most patients with Alzheimer disease exhibiting a gradually progressive course of decline. The findings of prior studies of the cognitive syndrome of vascular dementia must be interpreted with caution, however, because of (1) possible inaccuracies in the determination of the dementia subtype and the loss of precision that might result from pooling heterogeneous subgroups of patients with vascular dementia, (2) difficulties inherent in identifying a pattern of strengths and weaknesses in patients who are required to have memory impairment and other deficits to meet operationalized criteria for dementia, and (3) the use of limited test batteries whose psychometric properties are incompletely understood. Specific questions that should be addressed by future studies are discussed.

Whitehead SN, Cheng G, Hachinski VC, Cechetto DF. · Department of Anatomy and Cell Biology, Medical Sciences Bldg, University of Western Ontario, London, Ontario, Canada. · Stroke. · Pubmed #17962591 links to  free full text

Abstract: BACKGROUND AND PURPOSE: In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer's disease and CI. METHODS: beta-amyloid toxicity was modeled using bilateral intracerebroventricular injections of beta-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum. RESULTS: Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer's disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the beta-amyloid-treated rats that were even greater when beta-amyloid treatment was combined with CI. CONCLUSIONS: CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits.

Whitehead SN, Hachinski VC, Cechetto DF. · Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada. · Stroke. · Pubmed #15591213 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Inflammatory mechanisms are involved in AD pathology and stroke and may be the mediator between AD and stroke toxicity. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta[25-35]) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined using immunohistochemical analysis. Memory and motor tasks were assessed using the Montoya staircase test. RESULTS: Abeta injections elicited increases in pathological and inflammatory correlates of AD in multiple forebrain sites. Increases in astrocytosis and reactive microglia in the hippocampus were enhanced with the combination of endothelin and Abeta(25-35). Abeta(25-35) treatment decreased performance in the Montoya staircase behavioral test. CONCLUSIONS: The enhanced inflammatory response with Abeta toxicity and ischemia may mediate the inability to improve behavioral performance caused by the stroke. Anti-inflammatory treatment may ameliorate the pathological and behavioral deficits associated with the combination of AD and stroke.

Helmes E, Bowler JV, Merskey H, Munoz DG, Hachinski VC. · University of Western Ontario, London, Ont., Canada. · Dement Geriatr Cogn Disord. · Pubmed #12566594 No free full text.

Abstract: Increased interest in types of dementia has developed as more cases are identified in aging populations. Here we compare the rates of cognitive decline over time in three groups with dementia from the University of Western Ontario Dementia Study: Alzheimer's disease (AD), dementia with Lewy bodies and a group with both AD and Lewy bodies. All diagnoses were verified by autopsy using standard diagnostic methods. Cognitive impairment was measured with the Extended Scale for Dementia (ESD). Members of each group with dementia were age and sex matched with individuals without dementia as controls. The 15 cases of AD, 7 cases with Lewy bodies and 8 cases with both conditions were all free of significant vascular disease. Linear regression was used to determine the rate of changes in ESD scores over time in months. All three control groups showed no change in cognitive status over time. As expected, all groups with dementia showed progressive cognitive impairment. Analysis of the slope parameter showed that all groups deteriorated at the same rate of approximately 2 ESD points per month. Quadratic models fit better than simple linear models in all groups. Results suggest that the final rate of cognitive decline in dementia may not necessarily reflect the underlying cause.

Helmes E, Merskey H, Fox H, Bowler JV, Hachinski VC. · Department of Psychiatry, University of Western Ontario, London, Ontario, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #12040308 No free full text.

Abstract: Most recent studies have used only two observations to estimate the rate of cognitive decline in patients with Alzheimer disease (AD); few have data taken from more than a 2-year period; and none report on autopsy-verified cases. Repeated observations over the complete course of the disease are necessary to quantitatively evaluate hypotheses such as the triphasic linear model of Brooks et al. (1993). The goal of this study is to compare the triphasic linear and quadratic models of decline in a group of 12 AD patients confirmed at autopsy with a group of age- and sex-matched normal control subjects. Both groups were taken from the University of Western Ontario Dementia Study, and the Extended Scale for Dementia was used as the outcome measure. The squared multiple correlation as a measure of goodness of fit suggested the superiority of the more parsimonious quadratic model over the triphasic linear model. Quantitative models more accurately reflect the profiles of change in AD and may prove more sensitive in measuring the effects of drugs on these patterns.