Vascular burden and Alzheimer disease pathologic progression

Abstract

Objective: To investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers. Methods:The Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden ϫ time) or timevarying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden.Results: Cardiovascular risk profiles were not predictive of progression in CSF ␤ 42 -amyloid, [ 18 F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4. Conclusion:Increased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway. Neurology Both Alzheimer disease (AD) and vascular pathology are common in the elderly population, and multiple brain pathologic conditions account for most patients with dementia.1 Many cardiovascular risk factors including midlife hypertension, diabetes, dyslipidemia, and smoking seem to increase the risk of AD, suggesting a vascular contribution to the etiology of AD.2,3 Within the framework of the neurovascular unit, vascular dysfunction may reduce the clearance of ␤-amyloid (A␤) via the bloodbrain barrier or indirectly increase A␤ deposition. 4 Amyloid deposition is considered the pivotal event in the AD pathologic cascade, 5 but whether the accumulation is accelerated by vascular risks remains unclear.White matter hyperintensities (WMHs) on brain MRI reflect cardiovascular risk profiles, and greater WMH volume is associated with cerebral hypometabolism and cognitive decline.6-8 White

Frequency and topography of small cerebrovascular lesions in vascular and in mixed dementia: a post-mortem 7-tesla magnetic resonance imaging study with neuropathological correlates

“…Their heterogeneity was already previously suspected [16,22,25]. Our previous neuropathological study demonstrated that LIs due to arteriosclerotic angiopathy are the most common lesions in VaD, while CAA related lesions are more frequent in MixD, suggesting that the latter represent the natural end-stage evolution of Alzheimer's disease [9].…”

The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies

“…96 In additional studies with relatively modest samples, findings of CMRgl as assessed with FDG-PET have been described in association with CVRFs such as insulin resistance 97 and obesity 98 as well as with WMH volume, which has been considered a marker of cerebrovascular burden. 81,99 Taken together, these studies show a significant association between those risk factors and reduced CMRgl, variably implicating the precuneus, posterior cingulate gyrus, lateral parietal neocortex, and lateral temporal neocortex, 96,97 as well as the lateral prefrontal cortex. 96,98 Both type 1 and type 2 diabetes mellitus have also been associated with neurofunctional deficits.…”

“…80 However, there has also been reports of WMH being associated with cognitive decline but not with brain amyloid deposition or longitudinal change in AD-specific biomarkers, such as CSF Ab 42 . 81,82 Other brain lesions of vascular origin, such as silent infarcts, have also been associated with the diagnosis of AD. 74,75 Finally, morphometric MRI studies have shown that CVRFs are associated with gray matter volume reductions in the medial temporal cortex as well as in other brain regions implicated in the pathophysiology of AD, such as the precuneus and posterior cingulate gyrus.…”

Clinical and neuropsychological features of Alzheimer’s disease in the combination with cerebrovascular disease

“…приближался к СоД), в то время как на сопутствующий альцгейме-ровский процесс указывали лишь выраженная атро-фия гиппокампа и корковые ЦМК [51][52][53]. Хотя у пациентов с БА также выявлялся лейкоареоз, преи-мущественно перивентрикулярный в виде «шапо-чек» и узких «полос» по краю боковых желудочков, он не коррелировал с клинической картиной [6,11,23].…”