The Temporal Relationships between White Matter Hyperintensities, Neurodegeneration, Amyloid β, and Cognition

Abstract

INTRODUCTION:Cognitive decline in Alzheimer's disease is associated with amyloid-β accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established. METHODS:Data included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at one-year follow-up. RESULTS: Baseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42. DISCUSSION: Baseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage. Keywords: White matter hyperintensities, small-vessel disease, neurodegenerative disease, Alzheimer's disease, mild cognitive impairment Research in Context 1. Systematic Review: Both amyloid β and neurodegeneration are primary pathologies in Alzheimer's disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimer's. However, the temporal relationship between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline is still unclear. Interpretation:Our results establish a potential temporal order between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid β deposition, in turn, precedes accumulation of white matter hyperintensities. Future Directions:The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimer's disease patients, in particular.

Amyloid ß Impacts Future Freezing of Gait in Parkinson’s Disease Via White Matter Hyperintensities

“…WMH burden is associated with gait deficits both in the aging population in general and in PD patients specifically 7,17,[20][21][22]51,52 . Given that WMH load is also associated with CSF amyloid β levels 31,32,57,35 and they both impact gait in PD, we hypothesized that they might impact future FOG through the same pathway. To investigate this, we used a mediation analysis, assessing the effect of WMH burden as the mediator on the relationship between amyloid β and future FOG.…”

“…In addition to cognitive impairment and executive dysfunction, WMHs have been associated with rigidity and gait impairment in individuals with 7,[17][18][19][20][21][22][23] and without PD [24][25][26][27][28][29][30] . Interestingly, amyloid β deposition has further been linked to an increase in the WMH burden through acceleration of processes such as neuroinflammation, reactive oxygen species production, and oxidative stress [31][32][33][34][35] .…”