Related Experiment Video
Updated: Apr 1, 2026
Evaluation of the Cognitive Performance of Hypertensive Patients with Silent Cerebrovascular Lesions
Published on: April 23, 2021
Cortical tau load is associated with white matter hyperintensities
Kirsty E McAleese1, Michael Firbank2, Madhurima Dey2
1Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK. Kirsty.McAleese@ncl.ac.uk.
Introduction:
Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer's disease (AD) pathologies i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ). Here we investigate the influence of HPτ, Aβ and SVD on WMH severity.
Results:
36 human post-mortem right fixed cerebral hemispheres (mean age 84.4 ± 7.7 years; male: 16, female: 20) containing varying amounts of AD-pathology (AD: 23, controls: 13) underwent T2- weighted MRI with WMH assessed according to the age related white matter change scale (ARWMC). After dissection, using tissue samples from the frontal, temporal, parietal and occipital regions from the right hemisphere, we quantitatively assessed cortical HPτ and Aβ pathology burden by measuring the percentage area covered by AT8 immunoreactivity (HPτ-IR) and 4G8 immunoreactivity (Aβ-IR), and assessed the severity of WM SVD by calculating the sclerotic index (SI) of WM arteries/arterioles. HPτ-IR, Aβ-IR, and SI were compared with ARWMC scores. HPτ-IR, Aβ-IR and WM ARWMC scores were all significantly higher in AD cases compared to controls, while SI values were similar between groups. ARWMC scores correlated with HPτ-IR, Aβ-IR and SI in various regions, however, linear regression revealed that only HPτ-IR was a significant independent predictor of ARWMC scores.
Conclusions:
Here we have shown that increasing cortical HPτ burden independently predicted the severity of WMH indicating its potentially important role in the pathogenesis of WM damage. Moreover, our findings suggest that in AD patients the presence of WMH may indicate cortical AD-associated pathology rather than SVD. Further studies are warranted to elucidate the pathological processes that lead to WM damage and to clarify if WMH may serve as a general biomarker for cortical AD-associated pathology.
Insights
Alzheimer's disease (AD) brain pathology, specifically hyperphosphorylated tau (HPτ), independently predicts white matter lesion (WML) severity. This suggests WMLs in AD patients may signal tau pathology rather than small vessel disease.
Area of Science:
- Neuroscience
- Neuropathology
- Radiology
Background:
- Cerebral white matter lesions (WMLs), or white matter hyperintensities (WMH), are linked to small vessel disease (SVD).
- Alternatively, WMH may result from axonal damage secondary to Alzheimer's disease (AD) pathologies like hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ).
Purpose of the Study:
- To investigate the independent contributions of HPτ, Aβ, and SVD to the severity of WMH.
- To determine if WMH in AD patients are primarily associated with AD pathology or SVD.
Main Methods:
- Post-mortem MRI of 36 human cerebral hemispheres assessed WMH using the Age Related White Matter Change scale (ARWMC).
- Quantitative assessment of cortical HPτ and Aβ burden (using AT8 and 4G8 immunoreactivity) and WM SVD severity (sclerotic index).
- Statistical comparison of ARWMC scores with HPτ, Aβ, and SVD markers in AD cases versus controls.
Main Results:
- AD cases showed higher HPτ, Aβ, and WMH scores than controls; SVD severity was similar.
- WMH scores correlated with HPτ, Aβ, and SVD markers.
- Linear regression identified cortical HPτ burden as the sole independent predictor of WMH severity.
Conclusions:
- Elevated cortical HPτ burden independently predicts WMH severity, highlighting its role in white matter damage pathogenesis.
- WMH in AD patients may reflect underlying cortical AD pathology, not solely SVD.
- Further research is needed to understand WMH pathogenesis and its potential as a biomarker for AD-associated pathology.
