Vascular Dementia vs. Alzheimer's

Vascular Conditions

Neurobiol Aging 2000 Mar-Apr;21(2):357-61
Vascular abnormalities: the insidious pathogenesis of Alzheimer's disease*.
Shi J, Perry G, Smith MA, Friedland RP
Laboratory of Neurogeriatrics, Department of Neurology, Case Western Reserve University, 44106, Cleveland, OH, USA.

Alzheimer's disease (AD) and cerebrovascular dementia (CVD) are two major causes of senile dementia in elderly individuals. Mounting evidence from epidemiological, clinical, and neuropathological studies suggests that there is considerable overlap between AD and CVD with respect to risk factors, prevalence, and pathological changes. Although our lack of understanding on the important contribution of vascular disturbance to pathogenesis of AD has further hindered our understanding of AD, data on the roles of cerebrovascular diseases and systemic vascular diseases in AD need to be carefully analyzed to avoid misinterpretation. Here, we review studies on the cerebral vasculature, cardiac vasculature, and apoE that lead us to contend that vascular abnormalities are likely an important mechanism underlying dementia. Because early and aggressive intervention is available to prevent and treat a number of vascular diseases, therapies that attenuate vascular risk factors could be valuable in preventing and treating AD.

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J Neurol 2000 Feb;247(2):81-7
Vascular risk factors in dementia.
Schmidt R, Schmidt H, Fazekas F
Department of Neurology, Karl-Franzens University Graz, Austria. reinhold.schmidt@kfunigraz.ac.at

This review describes differing profiles of vascular risk factors in different types of dementia. Although vascular risk factors are related to various types of strokes, their independent effect on the occurrence of poststroke dementia appears to be small. Various risk factors have been identified for microangiopathy-related cerebral abnormalities, such as white matter changes and lacunae, which are the core lesions for the development of a vascular dementia syndrome without stroke symptoms. Most consistently, arterial hypertension and diabetes mellitus have been found to be associated with such brain abnormalities. Diastolic blood pressure seems to be of particular importance as recent investigations demonstrate that this factor is related to the course of multiple lacunar strokes and the progression of white matter disease. Epidemiological studies report that various vascular risk factors including arterial hypertension, diabetes mellitus, and atrial fibrillation may also be associated with Alzheimer's disease. There is also evidence of a direct relationship between Alzheimer's disease and general atherosclerosis. Further investigations are needed to determine whether these associations are due to the weakness of diagnostic criteria, or whether vascular risk factors indeed modulate the clinical expression of primary degenerative dementia. Common susceptibility genes leading to shared risk factors may be one of the reasons for a higher coincidence of Alzheimer's disease and vascular dementia than can be expected by chance. A modulatory effect of vascular risk factors in the development of primary degenerative dementia may extend treatment options.
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Ann N Y Acad Sci 1999;893:113-25
The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease.
Kalaria RN
Institute for Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. r.n.kalaria@ncl.ac.uk

The pathology of Alzheimer's disease (AD) is not limited to amyloid plaques and neurofibrillary tangles. Recent evidence suggests that more than 30% of AD cases exhibit cerebrovascular pathology, which involves the cellular elements that represent the blood-brain barrier. Certain vascular lesions such as microvascular degeneration affecting the cerebral endothelium, cerebral amyloid angiopathy and periventricular white matter lesions are evident in virtually all cases of AD. Furthermore, clinical studies have demonstrated blood-brain barrier dysfunction in AD patients who exhibit peripheral vascular abnormalities such as hypertension, cardiovascular disease and diabetes. Whether these vascular lesions along with perivascular denervation are coincidental or causal in the pathogenetic processes of AD remains to be defined. In this chapter, I review biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described in AD. I also consider genetic influences such as apolipoprotein E in relation to cerebrovascular lesions that may shed light on the pathophysiology of the cerebral vasculature. The compelling vascular pathology associated with AD suggests that transient and focal breach of the blood-brain barrier occurs in late onset AD and may involve an interaction of several factors, which include perivascular mediators as well as peripheral circulation derived factors that perturb the endothelium. These vascular abnormalities are likely to worsen cognitive disability in AD.

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Neurobiol Aging 2000 Mar-Apr;21(2):321-30
The role of cerebral ischemia in Alzheimer's disease.
Kalaria RN
Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, NE4 6BE, Newcastle upon Tyne, United Kingdom.

The Alzheimer type of dementia and stroke are known to increase at comparable rates with age. Recent advances suggest that vascular risk factors linked to cerebrovascular disease and stroke in the elderly significantly increase the risk of developing Alzheimer's disease (AD). These include atherosclerosis, atrial fibrillation, coronary artery disease, hypertension, and diabetes mellitus. Moreover, review of various autopsy series shows that 60-90% of AD cases exhibit variable cerebrovascular pathology. Although some vascular lesions such as cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions are evident in most cases of AD, a third will exhibit cerebral infarction. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that the co-existence of stroke and AD occurs more than by chance alone. Strokes known to occur in patients with Alzheimer syndrome and most frequently in the oldest old substantially worsen cognitive decline and outcome, implicating some interaction between the disorders. Nevertheless, the nature of a true relationship between the two disorders seems little explored. What predisposes to strokes in underlying cognitive decline or AD? Is it possible that cerebral ischemia is a causal factor for AD? I examined several vascular factors and the vascular pathophysiology implicated in stroke and AD, and propose that cerebral ischemia or oligemia may promote Alzheimer type of changes in the aging brain. Irrespective of the ultimate pathogenetic mechanism, these approaches implicate that management of peripheral vascular disease is important in the treatment or prevention of Alzheimer's disease or mixed dementia.

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Eur J Neurol 2000 Mar;7(2):159-69
An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors.
Kumar V, Anand R, Messina J, Hartman R, Veach J
Florida Institute of Neurosciences and Clinical Research, 530 S. Nokomis Avenue, Suite 14, Venice, FL 34284, USA.

We evaluated the efficacy and safety of the centrally acting cholinesterase inhibitor, rivastigmine tartrate, for patients with mild to moderately severe Alzheimer's disease (AD) with or without concurrent vascular risk factors (VRF). Patients (45-90 years of age) were randomized to placebo (n = 235), low-dose rivastigmine (1-4 mg/day, n = 233), or high-dose rivastigmine (6-12 mg/day, n = 231) for 26 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Clinician's Interview Based Impression of Change (CIBIC-Plus), the Progressive Deterioration Scale (PDS), the Global Deterioration Scale (GDS), and the Mini-Mental State Examination (MMSE). For efficacy and safety analysis, patients were categorized by baseline Modified Hachinski Ischemic Score (MHIS) for the determination of VRF (MHIS > 0: presence of VRF; MHIS = 0: absence of VRF). As early as 12 weeks, the mean change from the baseline ADAS-Cog score was significantly different for those patients treated with high-dose rivastigmine compared with placebo controls in both MHIS categories. However, the treatment difference between high-dose rivastigmine and placebo at each time-point was larger for patients with MHIS > 0. The proportion of responders was significantly greater in the high-dose rivastigmine group for each level of improvement. No differences were noted between treatment groups regarding safety evaluations. Rivastigmine is effective in both categories of patients, and those with VRF experience greater clinical benefit (cognition, activities of daily living, and disease severity).

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Neurobiol Aging 2000 Mar-Apr;21(2):331-42
Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis.
de la Torre JC
Department of Neurosciences (MTF-0624), University of California, San Diego, 9500 Gilman Drive, 92093-0624, La Jolla, CA, USA.

This review discusses the experimental and clinical data which indicate that chronic cerebral hypoperfusion can affect metabolic, anatomic, and cognitive function adversely. In aged but not young animals, chronic brain hypoperfusion results in regional pre- and post-synaptic changes, protein synthesis abnormalities, energy metabolic dysregulation, reduced glucose utilization, cholinergic receptor loss, and visuo-spatial memory deficits. Additionally, aging animals that are kept for prolonged periods of time after chronic brain hypoperfusion, also develop brain capillary degeneration in CA1 hippocampus and neuronal damage extending from the hippocampal region to the temporo-parietal cortex where neurodegenerative tissue atrophy eventually forms. All these pathologic events occur in rodents in the absence of senile plaques and neurofibrillary tangles. Alzheimer brains reveal similar biochemical and structural changes as those experimentally induced in aging animals. Moreover, regional cerebral hypoperfusion is one of the earlier (if not the earliest) clinical manifestations in both the sporadic and familial forms of Alzheimer's disease. In addition, therapy that improves or increases cerebral perfusion is generally of some benefit to Alzheimer patients. Conversely, a variety of disorders with different etiologies that impair or diminish cerebral perfusion are reported to be risk factors for this dementia. These findings have prompted us to propose the concept that advanced aging in the presence of a vascular risk factor can converge to create a critically attained threshold of cerebral hypoperfusion (CATCH) that triggers regional brain microcirculatory disturbances and impairs optimal delivery of energy substrates needed for normal brain cell function. The outcome of this defect generates a chain of events leading to the progressive evolution of brain metabolic, cognitive and tissue pathology that characterize Alzheimer's disease. The possible role of CATCH in familial and early onset Alzheimer's disease is briefly discussed from a theoretical vantagepoint. The growing and most recent evidence in support of the CATCH concept is the focus of this review.

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Neurobiol Aging 2000 Mar-Apr;21(2):215-24
Are cerebrovascular factors involved in Alzheimer's disease?
Kudo T, Imaizumi K, Tanimukai H, Katayama T, Sato N, Nakamura Y, Tanaka T, Kashiwagi Y, Jinno Y, Tohyama M, Takeda M
Department of Clinical Neuroscience, Psychiatry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan.

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.

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Neurobiol Aging 2000 Mar-Apr;21(2):153-60
Vascular risk factors for Alzheimer's disease: An epidemiologic perspective.
Breteler MM
Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands.

Vascular disease and Alzheimer's disease are both common disorders, in particular among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemiological studies have suggested that risk factors for vascular disease and stroke are associated with cognitive impairment and Alzheimer's disease, and that the presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer's disease. In this paper, current knowledge on the relation between vascular risk factors and risk indicators and Alzheimer's disease will be reviewed.

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Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl 3:S106-14
Vascular factors and Alzheimer disease.
Skoog I, Kalaria RN, Breteler MM
Institute of Clinical Neuroscience, Section of Psychiatry, Sahlgrenska University Hospital, Goteborg, Sweden.

Vascular risk factors are normally associated with cerebrovascular disease, which may lead to vascular dementia (VaD). Several recent studies suggest that there is increased risk of developing Alzheimer disease when exposed to these same vascular risk factors. In addition to old age, hypertension, peripheral arterial disease, certain types of cardiovascular disorders, diabetes mellitus, and smoking are now considered risk factors for late-onset Alzheimer disease. In this review, we examine several vascular factors and peripheral vascular pathophysiology implicated in Alzheimer disease and suggest certain mechanisms that might promote the association of vascular factors and late-onset Alzheimer disease. We support the implication that prevention or management of peripheral vascular disease may prevent or delay the onset of Alzheimer disease or mixed dementia.

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Aust N Z J Psychiatry 1999 Dec;33(6):809-13
Vascular risk factors and Alzheimer's disease.
Stewart R, Prince M, Mann A
Section of Old Age Psychiatry, Institute of Psychiatry, London, United Kingdom.

OBJECTIVE: We aim to summarise the recent and accumulating epidemiological research which suggests that cardiovascular disease and vascular risk factors play an important role as risk factors for Alzheimer's disease (AD) in later life. METHOD: The epidemiological literature is summarised in considering the evidence for such an association, focusing on optimally designed population-based studies. Potential mechanisms of association are considered, drawing on relevant findings from neuroscience. RESULTS: Cardiovascular disease and vascular risk disorders appear to be important factors in the aetiology of AD. However, there is a paucity of prospective studies with an adequate duration of follow-up to investigate the apparent age- and time-dependent nature of these associations. CONCLUSIONS: Vascular disorders represent potentially preventable risk factors with an important population impact due to their high prevalence in developed countries. The concept of AD and vascular dementia as clearly distinguishable disorders clinically or aetiologically is becoming increasingly tenuous. A better understanding of the relationship between AD and vascular disorders will depend on a more flexible diagnostic and conceptual framework.

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Lancet 1999 Sep 11;354(9182):919-20
Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease.
Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD

Cerebrovascular disease and Alzheimer's disease commonly occur together in the elderly and each may contribute to dementia. Here we present evidence that cerebrovascular disease significantly worsens cognitive performance in the earliest stages of Alzheimer's disease.

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