Frontal white matter lesions in Alzheimer's disease are associated with both small vessel disease and AD-associated cortical pathology

Abstract

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer's disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

Keywords: Alzheimer’s disease; Amyloid-beta; Hyperphosphorylated tau; Small vessel disease; White matter hyperintensity; White matter lesion.

Fig. 1

a LFB and hematoxylin-stained section of frontal lobe tissue illustrating a white matter lesion in the deep white matter (black dashed line; note pallor). (ai) Magnified photoimage of normal appearing white matter; (aii) magnified image of white matter lesion area showing rarefaction of tissue and associated gliosis (black arrow heads); b normal white matter arteriole; c white matter arteriole with severe arteriolosclerosis exhibiting vessel wall hyalinosis (black arrow) and complete loss of smooth muscle cells (red arrowhead). LFB, luxol fast blue; SVD, small vessel disease; Scale bar, 0.5 cm valid for image a; 20 μm valid for ai and aii; 50 μm valid for image b; 100 μm valid for image c

Fig. 2

a 3 × 3 large image acquisition of frontal cortical AT8-IR (HPτ pathology). (ai) Image A with applied bespoke AT8-IR threshold (red outline). b 3 × 3 large image acquisition of frontal cortical 4G8-IR (Aβ pathology). (bi) Image b with applied bespoke 4G8-IR threshold (red outline) inclusive of size restriction to eliminate the measurement of physiological cellular APP (black arrows). Mean area covered by IR was stated as a percentage of the total image area and the respective values are expressed as AT8-IR or 4G8-IR. IR, immunoreactivity. Scale bar, 100 μm valid for all images

Fig. 3

Scatter graphs a A correlation between WMLA (i.e., white matter lesions severity) and WML-LFB-IOD (i.e., demyelination) was seen in both AD and control cases. b A negative correlation between WMLA and WML-BiA (axonal density) in AD cases only. p values and associated correlation coefficients are shown in main text. WML, white matter lesion; WMLA, white matter lesion area; LFB-IOD, luxol fast blue integrated optical density (demyelination); BiA, Bielschowsky’s area (axonal density decrease)

Fig. 4

Box plots; a No significant differences were revealed in calpain2 measures between AD and controls nor between WML and NAWM measures within groups. No significant differences were revealed in MAG:PLP measures between AD and controls nor between WML and NAWM measures within groups. p values are shown in main text. AD, Alzheimer’s disease; MAG, myelin-associated glycoprotein; PLP, proteolipid protein