Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre

1 Department of Pathology and Laboratory Medicine, Institute on Ageing, Centre for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Brain (Impact Factor: 9.2). 07/2013; 136(9). DOI: 10.1093/brain/awt188
Source: PubMed


Cerebrovascular disease and vascular risk factors are associated with Alzheimer's disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer's Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer's disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 'unremarkable brain' cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer's disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer's disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer's disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer's disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease.

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Available from: Walter A Kukull, Dec 28, 2015
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    • "focus toward understanding the role of vasculopathy, vascular brain injury, and the management of vascular risk factors [9] [10], in the context of AD pathophysiology [11] [12] [13]. As recently defined by an international consensus process , white matter hyperintensities (WMH) of presumed vascular origin, visible on structural magnetic resonance imaging (MRI), are commonly used markers of cerebrovascular disease [7]. "
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    ABSTRACT: Given the recent acknowledgement of the complex mixed pathologies that contribute to the clinical expression of dementia, various cohort studies have aimed to examine Alzheimer's disease and cerebrovascular disease as comorbid pathologies, with neuroimaging playing a central role in these studies. Using white matter hyperintensities (WMH) as a biomarker of cerebrovascular disease, we compared WMH burden between the Sunnybrook Dementia Study, the Alzheimer's Disease Neuroimaging Initiative (ADNI1), the Three-City Study, and various other studies around the world. Based on our findings, it was evident that ADNI1 had minimal WMH burden relative to other large studies that examine aging and dementia. This low WMH burden in ADNI1 may be considered as both an advantage, representing a relatively "pure" sample with little confounding vasculopathy, and a disadvantage, as it limits generalizability to "real-world" patient populations with mixed pathologies and to nondemented groups with baseline vascular disease. We explore possible reasons for this distinction, including management of vascular risk factors, gaps in diagnostic criteria, and future directions for clinical research. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    • "ere neurodegeneration , may have resulted in a similar extent of age - normalized cognitive dysfunction when compared NV - bvFTD patients who had no cerebrovascular disease and probably the most severe neurodegenerative changes ( Baborie et al . , 2011 ; Chui et al . , 2006 ; De Reuck et al . , 2012 ; Esiri et al . , 1999 ; Norton et al . , 2014 ; Toledo et al . , 2013 ) . There are some limitations to the present study that should be taken into consideration . First , although presenting a large size sample , the proportion of available neuropsychological assess - ments and clinical diagnoses from the NACC database were limited . Also , the battery for neuropsychological testing used in the NACC is n"
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    ABSTRACT: Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD vs. bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer's Coordinating Centre database. We included 391 neuropathologically diagnosed cases of frontotemporal lobe degeneration (FTLD). We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n=62) were older at the time of onset of cognitive decline (71.6 vs. 62.5years, p<0.001) and death (78.7 vs. 69.6, p<0.001), more likely to be hypertensive (75.8 vs. 45.7%, p=0.002), and to have a history of stroke (21.2 vs. 6.1%, p=0.007) than those with NV-bvFTD (n=329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that FTLD-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD.
    Full-text · Article · Jul 2015
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    • " are observed [1] [2]. It is often difficult to judge whether these concomitant factors are clinically relevant and thus contribute to the dementia syndrome. "
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    ABSTRACT: Hypothesizing that non-significant cerebrovascular lesions on structural brain imaging lead to overdiagnosis of a vascular etiology of dementia as compared to autopsy-confirmed diagnosis, we set up at study including 71 patients with autopsy-confirmed diagnoses. Forty-two patients in the population (59%) appeared to have definite Alzheimer's disease (AD), whereas 29 (41%) had a non-AD dementia form. The panel clinically diagnosed possible or probable vascular dementia (VaD) in 27 (38%) patients, whereas only five (19%) patients (p = 0.017) had an autopsy-confirmed diagnosis of VaD. Patients with vascular lesions on structural brain imaging were often misdiagnosed as possible or probable VaD as compared to autopsy-confirmed diagnosis.
    Full-text · Article · Jan 2015 · Journal of Alzheimer's disease: JAD
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