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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.

SUBMITTER: Beach TG

PROVIDER: S-EPMC10209646 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Beach Thomas G TG Sue Lucia I LI Scott Sarah S Intorcia Anthony J AJ Walker Jessica E JE Arce Richard A RA Glass Michael J MJ Borja Claryssa I CI Cline Madison P MP Hemmingsen Spencer J SJ Qiji Sanaria S Stewart Analisa A Martinez Kayleigh N KN Krupp Addison A McHattie Rylee R Mariner Monica M Lorenzini Ileana I Kuramoto Angela A Long Kathy E KE Tremblay Cécilia C Caselli Richard J RJ Woodruff Bryan K BK Rapscak Steven Z SZ Belden Christine M CM Goldfarb Danielle D Choudhury Parichita P Driver-Dunckley Erika D ED Mehta Shyamal H SH Sabbagh Marwan N MN Shill Holly A HA Atri Alireza A Adler Charles H CH Serrano Geidy E GE

Journal of neuropathology and experimental neurology 20230501 6

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 ...[more]

PMID: 37071794

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Project description:ImportanceChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions.ObjectiveTo investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE.Design, setting, and participantsThis cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data.ExposuresThe number of years of football play as a proxy for repetitive head impacts.Main outcomes and measuresNeuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences.ResultsA total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: β, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: β, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (β, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (β, 0.21 [95% CI, 0.07-0.35]; P = .003).Conclusions and relevanceAmong older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.

Project description:The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brains of elderly people with a history of hypertension (n = 17) and age-matched normotensive individuals (n = 5). MRI images were co-registered to (immuno-)histopathological data including stainings for microglia and astroglia to assess changes in MRI-based WMH at microscopic resolution. Perivascular inflammation was carefully assessed based on the severity of perivascular astrogliosis of the smallest vessels throughout white matter regions. Hypertension was associated with a larger inflammatory response in both WMH and NAWM. Notably, the presence of close-range perivascular inflammation was twice as common among those with hypertension than in controls both in WMH and NAWM, suggesting that neurovascular inflammation is critical in the etiology of WMH. Moreover, a higher degree of microglial activation was related to a higher burden of WMH. Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as neuroinflammation may ameliorate WMH progression.

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Dataset Information

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

Publications

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

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