Neuropathology of White Matter Lesions, Blood–Brain Barrier Dysfunction, and Dementia

Hainsworth, Atticus H.; Minett, Thaı́s; Andoh, Joycelyn; Forster, G.; Bhide, Ishaan; Barrick, Thomas R.; Elderfield, Kay; Jeevahan, J.; Markus, Hugh S.; Bridges, Leslie

doi:10.1161/strokeaha.117.018101

Cited by 76 publications

(70 citation statements)

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“…In the cerebral deep white matter, BBB dysfunction and the leakage of "neurotoxic" blood-derived plasma proteins are proposed to initiate inflammatory responses in the surrounding white matter parenchyma, exacerbating the development of WML. In agreement with previous human neuropathological studies (6,16,57), we found no associations between extravascular fibrinogen measure in the WML itself or the surrounding NAWM with WML severity or specifically axonal loss or demyelination in either AD or non-demented individuals. This supports the notion that AD related degenerative mechanisms and hypoxia, as a consequence of type 1 arteriolosclerosis SVD, have the strongest impact on the development of WML (30).…”

Section: Discussionsupporting

confidence: 93%

“…Numerous immunohistochemical studies have found a positive association between markers of plasma proteins and a dementia diagnosis (16,18,34,47), which has led to the intensive investigation of plasma proteins as a possible biomarker of AD. Increased plasma fibrinogen γ-chain has been shown to be specific for AD (7,21) as well as a risk factor for conversion of MCI to AD (34,46,54,56).…”

Section: Discussionmentioning

confidence: 99%

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Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

et al. 2019

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The blood–brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood‐derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer’s disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid‐β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post‐mortem brains, parietal tissue from 20 AD and 22 non‐demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML‐ and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML‐ and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non‐demented and AD brains and was not associated with the burden of AD‐associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non‐demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

et al. 2019

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“…; Hainsworth et al . ). The intricately linked gliovascular unit appears a key factor in WM degeneration associated with dementia in which WM changes are prominent, particularly VaD.…”

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confidence: 97%

“…Animal models of cerebral hypoperfusion have also enabled better understanding on how different cellular and molecular components of the WM alter during ageing-related cerebral hypoperfusion. Although changes in several substrates likely contribute to cognitive impairment, clearly the integrity of the blood-brain barrier (BBB) is an important factor (Wardlaw et al 2013a;Hainsworth et al 2017). The intricately linked gliovascular unit appears a key factor in WM degeneration associated with dementia in which WM changes are prominent, particularly VaD.…”

mentioning

confidence: 99%

White matter degeneration in vascular and other ageing‐related dementias

Hase

Horsburgh

Ihara

et al. 2018

Journal of Neurochemistry

154

152

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Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. Keywords: astrocytes, blood-brain barrier, post-stroke dementia, stroke, vascular dementia, white matter. Ageing-related cognitive impairment involves multiple substrates affecting brain structure and function. Neuroimaging evidence shows that white matter (WM) changes are associated with various clinical, sensorimotor, lifestyle, behavioural and cognitive abnormalities, particularly related to the small vessel disease (SVD) syndrome (Pantoni 2010).

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“…Studies showed that high levels of fibrinogen are related to brain atrophy, cognitive deficits, and Alzheimer's disease (AD) (Ahn et al, 2014;Tampubolon, 2016), and elevated levels of FIB were also found in the cerebrospinal fluid (CSF) of AD patient (Vafadar-Isfahani et al, 2012). Atticus H and colleagues reported that increased extravascular FIB may reduce the risk of dementia in individuals with no detectable white matter lesions, whereas extravascular FIB is harmful to cognitive function in individuals with histological lesions (Hainsworth et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

High levels of plasma fibrinogen are related to post‐stroke cognitive impairment

et al. 2019

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Introduction Studies have shown that high levels of the fibrinogen (FIB) are related to cognitive deficits. However, the relationship between fibrinogen and cognitive deficit after stroke remains unclear. Therefore, we explored the relationship between plasma fibrinogen and post‐stroke cognitive impairment (PSCI). Methods This study is carried out in the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. A total of 210 patients with acute ischemic stroke were enrolled in this study. Ultimately, 134 patients completed 3‐month follow‐up. Blood samples were collected at hospital admission. Cognitive function was evaluated 3 months after stroke. All patients underwent the Mini‐Mental State Examination (MMSE) after 3 months. Results Higher levels of fibrinogen were observed in patients with post‐stroke cognitive impairment compared with the non‐PSCI group (p < .001). Additionally, elevated plasma fibrinogen levels were independently associated with PSCI (odds ratio [OR] = 2.000, 95% CI 1.062–3.770 p = .032). The plasma fibrinogen levels were negatively correlated with the 3‐month MMSE scores (r = −.171, p = .048). In a multivariate linear regression, FIB was negatively associated with the 3‐month MMSE scores after adjustment for the other variables (β = −0.782, p = .035). Conclusion High levels of plasma fibrinogen were associated with the presence and severity of PSCI.

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Neuropathology of White Matter Lesions, Blood–Brain Barrier Dysfunction, and Dementia

Abstract: Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers.

Cited by 76 publications

References 35 publications

Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

White matter degeneration in vascular and other ageing‐related dementias

High levels of plasma fibrinogen are related to post‐stroke cognitive impairment

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