CSF β-amyloid and white matter damage: a new perspective on Alzheimer’s disease

Abstract

Objective: To assess the connection between amyloid pathology and white matter (WM) macro-and micro-structural damage in demented patients compared with controls.Methods: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment (MCI), and 20 age-and sex-matched heatlhy controls. β-amyloid 1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and 5 controls. Among patients, 42had pathological CSF Aβ levels (Aβ+), while 23 had normal CSF Aβ levels (Aβ-). All participants underwent neurological examination, neuropsychological testing and brain magnetic resonance imaging (MRI). We used T2-weighted scans to quantify white matter (WM) lesion loads (LL), and diffusion weighted images (DWI) to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. Results:We found an increased WM-LL in Aβ(+) compared to both, healthy controls (p=0.003) and Aβ(-) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient (ADC) value was higher in all patients than in controls (p=0.0001), and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001).Conclusions: WM damage is crucial in Alzheimer's disease (AD) pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macro-and microstructural damage.

White matter hypointensities and hyperintensities have equivalent correlations with age and CSF β‐amyloid in the nondemented elderly

“…AD‐related damage may cause white matter damage through Wallerian degeneration occurring secondary to neuronal insult (McAleese et al, ). A recent study by Pietroboni et al () found abnormal β‐amyloid to be the best predictor of WM lesion load within a cohort with AD. Low CSF β‐amyloid levels indicate impaired clearance from, and accumulation within, the brain and may detect abnormalities earlier than positron emission tomography (PET) (Palmqvist, Mattsson, & Hansson, ).…”

“…ADrelated damage may cause white matter damage through Wallerian degeneration occurring secondary to neuronal insult (McAleese et al, 2017). A recent study by Pietroboni et al (2018) found abnormal β-amyloid to be the best predictor of WM lesion load within a cohort Despite showing statistically significant associations with β-amyloid, we observed no associations with tau for either WM-hyper or WM-hypo ( Figure 6), but work by McAleese et al (2015) found a closer independent correlation between WM lesion load in AD with tau than β-amyloid. This difference may be related to a lower prevalence of tau in our cohort, which includes primarily cognitively intact, nondemented individuals (Harrington et al, 2013).…”

“…Though age‐related WM lesions are commonly attributed to chronic ischemic cerebrovascular disease, they are nonspecific. A growing number of studies (King, ; Lee et al, ; Pietroboni et al, ) are finding direct correlations of WM disease with β‐amyloid and tau accumulation, supporting significant overlap between WM lesion development and neurodegeneration (Erten‐Lyons et al, ; McAleese et al, ). Ischemic white matter lesions may indicate a vascular susceptibility to AD (Hughes et al, ; King, ; King et al, ).…”

“…Though age-related WM lesions are commonly attributed to chronic ischemic cerebrovascular disease, they are nonspecific. A growing number of studies (King, 2014;Lee et al, 2016;Pietroboni et al, 2018) are finding direct correlations of WM disease with β-amyloid and tau accumulation, F I G U R E 1 White matter lesions appear bright (WM-hyper) on T2-FLAIR (a) and dark (WM-hypo) on T1-FSPGR (c) from a representative individual. Automatically identified WM lesions are shown overlaid on anatomic images with a yellow mask for WM-hyper in (b) and with a blue mask for WM-hypo in (d)…”

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

“…These data gain interest since we previously demonstrated in a paper about CSF biomarkers of neurodegeneration and WM damage in patients with Alzheimer's disease (AD) 26 that CSF Aβ levels were instead a predictor for WM-LL accumulation. The myelin model combines the occurrence of WM metabolic damage with Aβ deposition 27 .…”