Prevalence of dementia disorders in the oldest-old: an autopsy study

The prevalence of Alzheimer disease (AD) and vascular dementia (VD) increases with advancing age, but less so after age 90 years. A retrospective hospital-based study of the relative prevalence of different disorders was performed in 1,110 consecutive autopsy cases of demented elderly in Vienna, Austria (66% females, MMSE <20; mean age 83.3 ± 5.4 SD years). It assessed clinical, general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7–10th decade) were evaluated. In the total cohort AD pathology was seen in 82.9% (“pure” AD 42.9%; AD + other pathologies 39.9%), VD in 10.8% (mixed dementia, MIX, i.e. AD + vascular encephalopathy in 5.5%); other disorders in 5.7%, and negative pathology in 0.8%. The relative prevalence of AD increased from age 60 to 89 years and decreased slightly after age 90+, while “pure” VD diagnosed in the presence of vascular encephalopathy of different types with low neuritic AD pathology (Braak stages <3; mean 1.2–1.6) decreased progressively from age 60 to 90+; 85–95% of these patients had histories of diabetes, morphologic signs of hypertension, 65% myocardial infarction/cardiac decompensation, and 75% a history of stroke(s). Morphologic subtypes, subcortical arteriosclerotic (the most frequent), multi-infarct encephalopathy, and strategic infarct dementia showed no age-related differences. The relative prevalence of AD + Lewy pathology remained fairly constant with increasing age. Mixed dementia and AD with minor cerebrovascular lesions increased significantly with age, while other dementias decreased. This retrospective study using strict morphologic criteria confirmed increased prevalence of AD with age, but mild decline at age 90+, and progressive decline of VD, while AD + vascular pathologies including MIX showed considerable age-related increase, confirming that mixed pathologies account for most dementia cases in very old persons. A prospective clinicopathologic study in oldest-old subjects showed a significant increase in both AD and cerebral amyloid angiopathy (CAA), but decrease in VD over age 85, while in a small group of old subjects CAA without considerable AD pathology may be an independent risk factor for cognitive decline.     

The enigma of vascular cognitive disorder and vascular dementia

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment, are a matter of discussion, and currently used clinical diagnostic criteria show moderate sensitivity (average 50%) and variable specificity (range 64–98%). In Western clinic-based series, VaD is suggested in 8–10% of cognitively impaired aged subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with reasonable values of 8–15%, while in Japan it is seen in 22–35%. Neuropathologic changes associated with cognitive impairment include multifocal and/or diffuse disease and focal lesions: multi-infarct encephalopathy, white matter lesions or arteriosclerotic subcortical (leuko)encephalopathy, multilacunar state, mixed cortico-subcortical type, borderline/watershed lesions, rare granular cortical atrophy, post-ischemic encephalopathy and hippocampal sclerosis. They result from systemic, cardiac and local large or small vessel disease. Recent data indicate that cognitive decline is commonly associated with widespread small ischemic/vascular lesions (microinfarcts, lacunes) throughout the brain with predominant involvement of subcortical and functionally important brain areas. Their pathogenesis is multifactorial, and their pathophysiology affects neuronal networks involved in cognition, memory, behavior and executive functioning. Vascular lesions often coexist with Alzheimer disease (AD) and other pathologies. Minor cerebrovascular lesions, except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease may interact synergistically. The lesion pattern of “pure” VaD, related to arteriosclerosis and microangiopathies, differs from that in mixed-type dementia (AD with vascular encephalopathy), more often showing large infarcts, which suggests different pathogenesis of both types of lesions. Due to the high variability of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are available, and a large variability across laboratories still exists in the procedures for morphologic examination and histology techniques. After a lecture at the XI International Congress of Neuropathology, San Francisco, CA, on 11 September 2006. Addendum In a recent clinicopathological evaluation of 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD), Chui et al. [555] found significant cerebrovascular lesions (CVL) in 30%, AD pathology in 54%, and hippocampal sclerosis (HS) in 18%. Statistical assessment showed that all three pathology variables contributed independently to cognitive status, but only the neuritic Braak scores contributed significantly to cognitive impairment, indicating that advancing AD pathology overwhelms the effects of the two other factors that, in the absence of considerable AD, contribute to mild cognitive impairment. A recent histologic-neuroimaging study in two patients with SIVD showed correspondence between subinsular T2 hyperintensive lesions and demyelination, gliosis, and dilated perivascular spaces [556].     

The impact of cerebrovascular lesions in Alzheimer disease

BACKGROUND: Recent epidemiological and clinico-pathological data suggest overlaps and some synergistic effects between Alzheimer disease (AD) and cerebrovascular pathology, but the results of studies of the relationship between the two types of lesion have been controversial. OBJECTIVE: Comparison of the frequency of cerebral infarcts, hemorrhages and minor cerebrovascular lesions in AD and age-matched control brains. SUBJECTS AND METHODS: 730 consecutive cases of autopsy-proven AD and 535 age-matched controls were compared using current routine and immunohistochemical methods. Results The total prevalence of cerebrovascular pathology in AD was significantly higher than in controls (48.0 vs 32.8%, p<0.01). Minor to moderate cerebrovascular lesions (lacunes, amyloid angiopathy with and without minor vascular lesions) were more frequent in AD than in controls (31.6 vs 23.4 %), the frequency of severe vascular pathology (old and recent infarcts and hemorrhages) in AD was significantly higher than in controls (16.7 % and 7.4 % vs 2.1% and 3.2%, respectively, p<0.01). There was no correlation between the severity of cerebral amyloid angiopathy with minor to severe subcortical lacunes and Ammon's horn sclerosis or to acute and old ischemic infarcts. On the other hand, acute and old cerebral hemorrhages were significantly correlated with severe amyloid angiopathy. The brain weight and severity of cognitive decline did not correspond to the degree of vascular pathology, but higher neuritic Braak scores and reduced brain weight contributed to the production of cognitive impairment. CONCLUSION: In accordance with previous findings in AD and in Parkinson disease, our data indicate a higher incidence of cerebrovascular lesions and greater susceptibility to death from stroke in AD in the population studied, but further prospective clinicopathological studies are warranted.     

Prevalence of vascular lesions in Dementia with Lewy Bodies. A postmortem study

Summary. The frequency of vascular lesions in dementia with Lewy bodies (DLB) has been suggested to be less common than for Parkinson disease (PD), but exact data on the relationship between DLB and stroke are not available. 387 consecutive cases of autopsy-proven Lewy body disease – 291 cases of idiopathic PD (Lewy body disease of brainstem type) and 96 cases of DLB – and 390 age-matched controls were compared using current routine stains and immunohistological methods. The frequency of cerebrovascular lesions of various intensity (lacunes, amyloid angiopathy, old ischemic infarcts and hemorrhages) was lower in DLB than in both PD and controls (34.4% vs. 36.7% and 33.3%) (p > 0.03). While acute ischemic strokes and hemorrhages were rarely present in both PD and controls (4.1 vs. 3.3%), no such lesions were observed in DLB. At variance to previous findings in autopsy-proven PD and Alzheimer disease (AD), these data suggest a protective effect against stroke and no greater susceptibility to death from stroke in the DLB population studied, but the reasons remain unclear. On the other hand, like in PD and AD, cognitive impairment in DLB appears to be independent from coexisting vascular pathology and is mainly related to neuritic Alzheimer pathology. Received November 5, 2002; accepted February 12, 2003 Published online April 22, 2003 Acknowledgements We thank the medical staff of Lainz Hospital, Wienerwald Geriatric Hospital, and Otto-Wagner Hospital, Vienna, for the clinical and neuropsychological data, the pathologists of all three hospitals for autopsy reports and brain material, Mrs. V. Rappelsberger for excellent laboratory work, and E. Mitter-Ferstl, PhD, for secretarial and computer work. Part of the study was granted by the Society for the Support of Research in the Field of Experimental Neurology, Vienna, Austria. Author's address: K. A. Jellinger, MD, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria, e-mail: kurt.jellinger@univie.ac.at     

Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Aβ plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Aβ plaque load and CAA except for much lower intensities in non-demented ε3/3 patients. Despite increasing evidence suggesting synergistic reactions between α-synuclein (αSyn), tau and Aβ-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation. Dedicated to the memory of Professor Dr. Franz Seitelberger, a pioneer of modern neuropathology and neurosciences.     

Vascular-ischemic dementia: an update

Both the clinical criteria and morphologic substrates of dementia resulting from cerebrovascular disease and its relation to Alzheimer disease and other age-related brain changes are controversial. In clinical and autopsy studies in the Western world the prevalence of vascular-ischemic dementia (VID) is around 7-10%, while vascular cognitive impairment without dementia is much more frequent and the risk of poststroke dementia is increased in patients with prestroke cognitive decline. In contrast to previous suggestions that VID was largely the result of large hemispheral infarcts, according to recent studies, it is most commonly associated with widespread small ischemic or vascular lesions (microinfarcts, lacunes) throughout the CNS with predominant subcortical lesions in the basal ganglia and white matter or in strategically important brain regions (thalamus, hippocampus). The lesion pattern of rare "pure" VID, which is related to arteriolosclerotic and hypertensive microangiopathy, differs from that in mixed type dementia (Alzheimer disease and cerebrovascular lesions) that more often shows larger hemispheral infarcts. Another form of VID that is not infrequent in very old subjects is hippocampal sclerosis, a selective damage to the hippocampus that is often accompanied by multiple other cerebrovascular lesions. Both, mild Alzheimer type pathology and small vessel disease-associated subcortical vascular pathology appear to be common and may interact in causing cognitive decline, but the impact of cerebrovascular lesions on cognitive impairment and dementia needs to be further elucidated.     

The impact of cerebral amyloid angiopathy on the occurrence of cerebrovascular lesions in demented patients with Alzheimer features: a neuropathological study

Objective: The aim of this neuropathological study was to determine the prevalence of the different cerebrovascular lesions to be attributed to cerebral amyloid angiopathy (CAA) and of those associated with the severity of the Alzheimer dementia (AD) itself. Patients and methods: The cerebrovascular lesions were compared separately in 40 brains of patients with mild and 50 with severe AD features. In the two groups, the number of lesions were compared between the brains with severe and those with mild of absent CAA. Results: The age of the patients, the vascular risk factors and antithrombotic treatment were similar in all the compared groups. The brains with mild and severe AD features and with CAA contained more haematomas, cortical micro‐infarcts and micro‐bleeds, and more severe white matter changes, and cortico‐subcortical and white matter mini‐bleeds. In the CAA brains with severe AD features, also more cortical territorial infarcts were observed, compared to those with mild AD features. Conclusions: The increase in cortical infarcts cannot be attributed to the CAA alone, but also to the severity of the degenerative features, implying additional vascular factors in the pathogenesis of AD.     

Incidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study

Recent epidemiological and clinico-pathological data suggest overlaps between Alzheimer's disease (AD) and cerebrovascular lesions (CVL) that may show some synergistic effects, but the results of studies of the relationship between AD and stroke have been controversial. The objective of this study was to compare the frequency of cerebral infarcts, hemorrhages and minor cerebrovascular lesions in autopsy-confirmed AD and age-matched control brains. Using current routine and immunohistochemical methods 173 consecutive cases of autopsy-confirmed AD and 130 age-matched controls were compared. The total incidence of vascular pathology (56.5%) in AD was significantly less than in a previously reported smaller AD autopsy cohort (82.3%) (P<0.01), and was higher than in controls (42.4%). The incidence of severe CVL (old and recent infarcts, hemorrhages) in our cohort was slightly higher (12.7%) than in controls (8.5%), that of minor to moderate CVL (lacunes, cerebral amyloid angiopathy with or without minor vascular lesions) was more frequent in AD (43.8%) than in controls (33.9%), but the results were not statistically significant (P<0.03). The brain weight and severity of cognitive decline did not correspond to the degree of vascular pathology, but higher neuritic Braak scores and reduced brain weight contributed to the production of cognitive impairment. Like previous findings in Parkinson's disease, our data do not indicate a protective effect from stroke or a significantly greater susceptibility to death from stroke in AD in the population studied, but further prospective clinico-pathological studies are necessary.     

Why are stroke patients prone to develop dementia?

Stroke patients are more likely to develop dementia than age- and sex-matched controls but the pathogenesis of dementia remains unresolved in most of them. The aim of this review is to determine, from the available literature, the theoretical reasons for a stroke patient to become demented. We found three distinct factors that may explain the occurrence of dementia after a stroke. Firstly, post-stroke dementia may be the direct consequence of the vascular lesions of the brain: this is the most likely cause in patients with normal cognitive functions before a strategic infarct, especially in young patients, in Icelandic-type hereditary amyloid angiopathy and in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Secondly, post-stroke dementia may be due to an associated asymptomatic Alzheimer pathology; the reasons for such an association are that (1) some cases of dementia occurring after a stroke are progressive and Alzheimer’s disease (AD) is the most frequent cause of progressive dementia; (2) age and APOE ɛ 4 genotype are risk factors for both AD and ischaemic stroke; (3) a vasculopathy is often associated with AD. Lastly, white matter changes may also contribute to dementia because they often indicate small-vessel disease and a higher risk of stroke recurrence, and may lead to slight cognitive impairment. Finally, the summation of vascular lesions of the brain, white matter changes, and Alzheimer pathology might lead to dementia, even when each type of lesion, on its own, is not severe enough to induce dementia. Therefore, in patients followed up after a stroke, the term “post-stroke dementia” is probably more appropriate than that of vascular dementia because it includes all possible causal factors. Received: 15 July 1996 Accepted: 19 October 1996     

The pathology of "vascular dementia": a critical update

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer's disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.