Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

Smallwood, Aidan; Oulhaj, Abderrahim; Joachim, C; Christie, Sharon; Sloan, Carolyn; Smith, A.D.; Esiri, Margaret M.

doi:10.1111/j.1365-2990.2011.01221.x

Cited by 116 publications

(95 citation statements)

References 36 publications

(44 reference statements)

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“…27 These results confirmed our initial findings: MAG levels and the MAG/PLP ratio were significantly reduced with increasing SVD severity whereas PLP concentration was significantly positively correlated with SVD. We also assessed SVD in the frontal white matter in these cases using our own scoring system, and although paraffin sections from many of the cases included only superficial rather than deep white matter, there was nonetheless a significant negative correlation between MAG concentration and SVD severity.…”

Section: Discussionsupporting

confidence: 90%

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Assessing White Matter Ischemic Damage in Dementia Patients by Measurement of Myelin Proteins

Barker

Wellington

Esiri

et al. 2013

J Cereb Blood Flow Metab

107

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White matter ischemia is difficult to quantify histologically. Myelin-associated glycoprotein (MAG) is highly susceptible to ischemia, being expressed only adaxonally, far from the oligodendrocyte cell body. Myelin-basic protein (MBP) and proteolipid protein (PLP) are expressed throughout the myelin sheath. We compared MAG, MBP, and PLP levels in parietal white matter homogenates from 17 vascular dementia (VaD), 49 Alzheimer's disease (AD), and 33 control brains, after assessing the post-mortem stability of these proteins. Small vessel disease (SVD) and cerebral amyloid angiopathy (CAA) severity had been assessed in paraffin sections. The concentration of MAG remained stable post-mortem, declined with increasing SVD, and was significantly lower in VaD than controls. The concentration of MBP fell progressively post-mortem, limiting its diagnostic utility in this context. Proteolipid protein was stable post-mortem and increased significantly with SVD severity. The MAG/PLP ratio declined significantly with SVD and CAA severity. The MAG and PLP levels and MAG/PLP did not differ significantly between AD and control brains. We validated the utility of MAG and MAG/PLP measurements on analysis of 74 frontal white matter samples from an Oxford cohort in which SVD had previously been scored. MAG concentration and the MAG/PLP ratio are useful post-mortem measures of ante-mortem white matter ischemia.

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Section: Discussionsupporting

confidence: 90%

“…In the previous study on the Oxford cohort, 27 SVD had been scored on a 12-point scale. To facilitate comparison with the data from the SWDBB cohort, the SVD scores on the Oxford brains were grouped for analysis into four categories: 1 to 3, 4 to 6, 7 to 9, and 10 to 12.…”

Section: Discussionmentioning

confidence: 99%

Assessing White Matter Ischemic Damage in Dementia Patients by Measurement of Myelin Proteins

Barker

Wellington

Esiri

et al. 2013

J Cereb Blood Flow Metab

107

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“…Monogenic forms and some sporadic cases of SVD occur at young ages, which supports SVD as a disease rather than simply being a consequence of aging (3). In addition to dementia, SVD causes cognitive impairment, gait and balance problems (2,4,5), and trebles the risk of stroke (6). Its diagnosis relies on clinical presentation of lacunar stroke, or cognitive or gait/balance problems with magnetic resonance imaging (MRI) features such as white matter hyperintensities (WMH) (7).…”

Section: Main Text: Introductionmentioning

confidence: 99%

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

et al. 2018

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One Sentence Summary: In cerebral small vessel disease, endothelial dysfunction leads to white matter vulnerability which is reversible in a rat model with endothelial stabilizing drugs.Abstract: Dementia is a major social and economic problem for our ageing population. One of the commonest causes of dementia in the elderly is cerebral small vessel disease (SVD).Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood brain barrier as the primary cause. Here, in a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90-alpha, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with ECstabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B which caused the EC dysfunction in the rat SVD model, and a single nucleotide polymorphism (SNP) in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model which may also be of relevance to human SVD.

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“…If cerebral microembolisation does occur during HD, then the resulting pathology could be expected to mimic that seen in cerebral small vessel disease, which is linked to cognitive decline in a range of clinical populations [14,15]. Neuropsychological tests can be used to selectively measure components of cognitive function and performance has been shown to discriminate between underlying pathologies [16].…”

Section: Introductionmentioning

confidence: 99%

Does a Patent Foramen Ovale Influence Cognitive Function in Dialysis Patients?

George¹,

Holt

Medford

et al. 2013

Nephron Clin Pract

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Background: Patients with chronic kidney disease on dialysis treatment have poorer cognitive function than age- and sex-matched controls. One proposed mechanism is cerebral microembolisation due to material from the dialysis circuit crossing a patent foramen ovale (PFO). Methods: Cognitive testing was carried out in haemodialysis (HD) patients and peritoneal dialysis (PD) patients. Transthoracic echocardiography was used to identify PFO. Follow-up testing 1 year later enabled comparison of cognitive decline between patients with and without a PFO, and between those undergoing different dialysis modalities. Results: 80 patients (aged 60.4 ± 15.0 years) were recruited (51 HD patients and 29 PD controls). A PFO was found in 21% of patients. 83% of dialysis patients suffered a decline in one or more cognitive function tests over 1 year. There was a significant difference in only one test between HD patients with or without a PFO. PD patients showed a more rapid cognitive decline than those on HD. Conclusions: Cognitive decline in dialysis patients is rapid and affects most patients. The presence of a PFO made only subtle differences to the rates of cognitive decline during 1 year of follow-up. Patients with a PFO should not be prevented from considering HD because of concerns of cerebral decline due to microembolisation.

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Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

Abstract: An image-based scoring system for SVD in a group of 70 elderly subjects enabled the severity of SVD pathology to be assessed with results that showed a significant correlation between SVD pathology severity and cognitive impairment.

Cited by 116 publications

References 36 publications

Assessing White Matter Ischemic Damage in Dementia Patients by Measurement of Myelin Proteins

Assessing White Matter Ischemic Damage in Dementia Patients by Measurement of Myelin Proteins

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

Does a Patent Foramen Ovale Influence Cognitive Function in Dialysis Patients?

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