Raj N. Kalaria

The role of cerebral ischemia in Alzheimer’s disease

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 Alzheimers 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 Alzheimers disease or mixed dementia.

Towards defining the neuropathological substrates of vascular dementia

Cerebrovascular disease is highly heterogeneous but can culminate in vascular cognitive impairment or vascular dementia (VaD). As much as the clinical diagnosis warrants scrutiny, the neuropathological substrates of VaD also need to be better defined. Atherosclerosis and small vessel disease are the main causes of brain infarction. Lacunar infarcts or multiple microinfarcts in the basal ganglia, thalamus, brainstem and white matter are associated with more than half of VaD cases consistent with subcortical ischaemic VaD. White matter changes including regions of incomplete infarction are usually widespread in VaD, but their contribution to impairment is not explicit. Other pathologies including hippocampal injury and Alzheimer type of lesions may also modify the course of dementia. Similar to other common dementias consensus criteria for VaD need unambiguous definition to impact on preventative and treatment strategies and are critical for selective recruitment to clinical trials.

Small Vessel Disease and Alzheimer’s Dementia: Pathological Considerations

Current evidence suggests that the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of Alzheimer disease (AD) cases may exhibit significant cerebrovascular pathology, which constitutes distinct small vessel disease (SVD). Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis and fibrosis are often evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. Amyloid β protein may cause degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. In addition, macro- and microinfarctions, haemorrhages, lacunes and ischaemic white matter changes are also present in AD. The development of SVD in late-onset AD may engage an interaction of perivascular mediators as well as circulation-derived factors that perturb the brain vasculature. Peripheral vascular disease such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease and diabetes could further modify the cerebral circulation such that a sustained hypoperfusion or oligaemia is impacted upon the ageing brain.

The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease.

ABSTRACT: The pathology of Alzheimers 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.

Vascular factors in Alzheimer's disease

Vascular involvement in Alzheimer disease (AD) is not necessarily coincident. Current evidence suggests the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of recognized AD cases may exhibit cerebrovascular pathology, which also constitutes distinct small vessel disease. Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis, and fibrosis are frequently evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. In addition, amyloid beta protein appears directly involved in the degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. The cerebrovascular pathology in AD also encompasses macro- and micro-infarctions, hemorrhages, lacunas, and ischemic white-matter changes. An interaction of both perivascular mediators and derived factors would perturb the brain vasculature. Peripheral vascular factors such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease, and diabetes mellitus are also apparent in AD. These factors would modify the cerebral circulation such that a sustained hypoperfusion or oligemia is impacted upon the aging processes to induce the characteristic pathology.

Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors

Stroke is an important risk factor for dementia, but the exact mechanisms involved in cognitive decline remain unclear. In this study, we related baseline MRI brain measures with later cognitive decline. Seventy-nine stroke survivors aged 75+ years without dementia were recruited 3-month post-stroke. They underwent yearly neuropsychological assessments and had an MRI at baseline and 2 years. Medial temporal lobe atrophy (MTA) was scored and volume of white matter hyperintensities (WMH) was measured at baseline. The rate of ventricular enlargement was measured by comparing the baseline and repeat images. Linear regression indicated that memory loss was related to both baseline memory and MTA (p=0.001; standardized regression coefficient beta=-0.35) but not WMH volume. The only independent predictor of ventricular enlargement was MTA (p=0.003; beta=0.47). However, no baseline MRI variable differed between those who did (18%) and did not (82%) develop dementia. The association of MTA but not WMH with subsequent cognitive decline and increasing brain atrophy suggests a greater role for Alzheimer type than vascular pathology in delayed cognitive impairment after stroke.

Association between mild vascular cognitive impairment and impaired activities of daily living in older stroke survivors without dementia.

Objectives: To determine the relationship between mild vascular cognitive impairment (mVCI) and functional disability in older stroke survivors without dementia.

Advances in molecular genetics and pathology of cerebrovascular disorders.

Progress in molecular genetics has enabled the dissection of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes might induce pathological changes in intracranial vessels, resulting in cerebral haemorrhages and ischaemic strokes. Such pathologies, however, might also result from systemic vascular disease caused by mutations or polymorphisms in genes that regulate cardiovascular physiology, blood coagulation, lipid metabolism and metabolic functions. Interestingly, several mutations that directly affect CNS vasculature involve genes that control inter- or intracellular signalling functions. Although highly variable phenotypes make it difficult to pinpoint the genotypes, genetic characterization of cerebrovascular disorders is valuable for understanding the pathogenesis and management of sporadic disease.

NINDS AIREN neuroimaging criteria do not distinguish stroke patients with and without dementia.

Objective: To determine the utility of the neuroimaging component within the National Institute of Neurological Disorders and Stroke (NINDS) Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) criteria for vascular dementia for distinguishing between patients with and without dementia in the context of cerebrovascular disease. Method: One hundred twenty-five poststroke patients age ≥75 (27 with and 98 without poststroke dementia) from representative hospital-based stroke registers in the North East of England were evaluated using a 1.5 T MR scanner. The proportion of patients with and without poststroke dementia meeting the imaging component of the NINDS AIREN criteria was determined, and hippocampal atrophy (measured using the Schelten scale) was compared between the two groups. Results: There were no significant differences between the patients with and without poststroke dementia on any criteria of the imaging parameters within the NINDS AIREN criteria. In addition, there were no significant differences in the number or size of cortical or subcortical infarcts between the two groups, with 13 patients without dementia having cortical infarcts >50 mm. Patients with dementia had greater hippocampal atrophy (right: Mann–Whitney U test, Z = 2.5, p = 0.01; left: Mann–Whitney U test, Z = 2.5, p = 0.01). Conclusion: The neuroimaging component of the NINDS AIREN criteria does not distinguish between older patients with and without poststroke dementia.

Blood Brain Barrier Dysfunction and Cerebrovascular Degeneration in Alzheimer’s Disease

The neuropathology of Alzheimer’s disease (AD) extends beyond 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. However, 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 clearly 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 accumulated biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described to be associated with 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 clinical presentation of AD and progression of dementia.