Neuropathologic basis of white matter hyperintensity accumulation with advanced age

Abstract

Objective: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation.Methods: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and .1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p , 0.1.Results: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p 5 0.003).Conclusion: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter. Disruption of white matter integrity, frequently observed as white matter hyperintensities (WMH) on T2-weighted MRI sequences, has detrimental effects on cognitive function, motor performance, and functional status in the elderly [1][2][3] and is associated with increased risk of all types of dementia, including Alzheimer disease (AD).4 Furthermore, WMH accumulation over time has been shown to increase risk of cognitive decline. 3,[5][6][7] While the general consensus is that the etiology of white matter accumulation is secondary to small-vessel ischemic changes, [8][9][10][11][12][13] it is not well established whether those with faster WMH accumulation may have contributions from other pathologies. Because accumulation of WMH increases risk of cognitive decline, identifying the pathologic correlates of faster WMH accumulation could potentially guide interventions targeting specific risks for prevention and treatment to preserve cognitive function in the elderly. Furthermore, while there are previous observations supporting a link between cerebrovascular disease (CVD) and AD, 14 it is not clearly established whether WMH progression is associated with neurodegenerative changes of AD. Thus, our aim was to bette...

Antemortem MRI findings associated with microinfarcts at autopsy

“…15,[20][21][22] Imaging and autopsy correlation studies indicate that WMH are surrogates for small-vessel ischemic disease and increase the risk of cognitive decline and mild cognitive impairment. 15,[22][23][24][25][26][27][28][29][30] Our finding that WMH fractional volume was not associated with presence of microinfarcts may reflect a lack of power to detect the weak commonalities between WMH accumulation and microinfarcts. WMH burden may be a poor proxy for microinfarcts because WMH is also associated with CAA.…”

“…WMH burden may be a poor proxy for microinfarcts because WMH is also associated with CAA. 29,31 While WMH burden is associated with cognitive decline, this association is also weak. 17,24-32 An association has previously been found between microinfarct burden and CAA severity.…”

Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer’s disease subjects

“…Chief among the additional pathologies of the aging brain are vascular brain injury, histologically manifest as large and small vessel sclerosis and microvascular ischaemic injury to brain parenchyma, and white matter lesions, identifiable by magnetic resonance imaging scanning as areas of hyperintensity and histopathologically as myelin pallor (5,6). However, many cognitively intact individuals have morphologic evidence of disease of this nature (7)(8)(9)(10).…”

“…However, many cognitively intact individuals have morphologic evidence of disease of this nature (7)(8)(9)(10). The picture is further complicated by the observation that elderly subjects usually also harbour at least some burden of the lesions of AD, namely amyloid plaques and neurofibrillary tangles (4,(6)(7)(8)(9)(10).…”

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.…”