Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy

Abstract

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Keywords: Alzheimer disease; Hyperintensity; Lacunar infarct; Leukoaraiosis; Microscopic infarct; Small vessel disease; Vascular cognitive impairment.

Figure 1.

Photographs of large-format sections of cerebral lobes, showing cerebral white matter rarefaction patterns and grading. (A–U) Stained with hematoxylin and eosin (H&E). (A–P) The typical, periventricular-centered pattern that is most common in aging humans. (Q–T) Asymmetrical white matter rarefaction patterns associated with small, local cerebral cortex infarcts. (U–X) The pattern of white matter rarefaction in the temporal lobe of 1 case appears consistent with different stains including H&E, silver (Campbell-Switzer), myelin-associated glycoprotein (MAG), and neurofilament (NF), supporting loss of both axons and myelin sheaths.

Figure 2.

Results of CWMR grading in cerebral lobes (A, B) and in groups defined by sex (B), clinicopathological diagnoses (C) and Braak neurofibrillary stages (D). See Supplementary Data Table S1 for all data and Supplementary Data Table S2 for all statistical results. All error bars = 95% confidence intervals. Front, frontal lobe; Temp, temporal lobe; Par, parietal lobe; Occ, occipital lobe; TOT, sum of regional scores; Norm, cognitively unimpaired; MCI, mild-cognitive impairment without a major neuropathological diagnosis; AD, intermediate or high NIA-Reagan classification; VaD, vascular dementia (49 also had AD); DLB, dementia with Lewy bodies (110 also had AD); PD, Parkinson disease (includes PD with dementia; 56 also had AD); PSP, progressive supranuclear palsy (36 also had AD); CBD, corticobasal degeneration (3 also had AD); MSA, multiple system atrophy (1 also had AD); Pick, Pick disease (2 also had AD); FT-TDP, frontotemporal lobar degeneration with TDP-43 proteinopathy (15 also had AD). Diagnoses are not mutually exclusive. (A) Regional and total CWMR scores for all cases. (B) Regional and total CWMR scores for all cases subdivided by sex. (C) Total CWMR scores for all cases by major clinicopathological diagnoses. (D) Total CWMR scores by Braak stage, excluding all major clinicopathological diagnoses shown in Figure 1A–C, other than AD but including the Normal and MCI categories, Cases with nondiagnostic α-synuclein and TDP-43 pathology were not excluded and not separately analyzed.