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

BACKGROUND AND PURPOSE: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). METHODS: Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). RESULTS: Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P=0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P=0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P=0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P=0.007). CONCLUSIONS: 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.

Obesity, inflammation and brachial artery flow-mediated dilatation: therapeutic targets in patients with microvascular angina (cardiac syndrome X).

BACKGROUND: The pathophysiology of microvascular angina (cardiac syndrome X, CSX), (effort-induced angina, a positive response to exercise stress testing and angiographically normal coronary arteries) has not been fully elucidated. Various pathogenic mechanisms have been proposed, amongst which coronary microvascular dysfunction features prominently. Management of patients with microvascular angina is often challenging as a substantial number of patients does not respond to conventional anti-anginal therapy. In this study, we sought to assess the association between brachial artery FMD, high-sensitive C-reactive protein (hs-CRP) and cardiovascular risk factors including obesity in patients with cardiac syndrome X. METHODS AND RESULTS: Thirty-four consecutive CSX patients (29 female, mean age 60 ± 9 years) were recruited from a specialised CSX clinic. Twelve asymptomatic subjects (10 female, mean age 51 ± 12 years) with comparable cardiovascular risk factor profile served as controls. All participants underwent standardized computer-assisted FMD measurements and assessment of hs-CRP concentrations at study entry. Body mass index (BMI), used as a general measure of obesity was calculated as weight (kilograms) divided by height (meters squared). Compared to controls, CSX patients had significantly higher hs-CRP concentrations (p = 0.003) and impaired FMD (p < 0.01). Moreover, among the CSX patients, a correlation between FMD and hs-CRP (r = -0.66, p < 0.01), FMD and BMI (r = 0.377, p = 0.028), and hs-CRP and BMI (r = -0.372, p = 0.030) was found. CONCLUSION: Impaired brachial artery FMD is significantly associated with elevated hs-CRP concentrations and BMI in patients with CSX. The results support the concept that low-grade inflammation and obesity may promote vascular dysfunction in these patients representing therapeutic targets for future research investigations.

The cGMP-Degrading Enzyme Phosphodiesterase-5 (PDE5) in Cerebral Small Arteries of Older People.

Cerebral small vessel disease in deep penetrating arteries is a major cause of lacunar infarcts, white matter lesions and vascular cognitive impairment. Local cerebral blood flow in these small vessels is controlled by endothelial-derived nitric oxide, which exerts a primary vasodilator stimulus on vascular myocytes, via cytoplasmic cyclic GMP. Here, we investigated whether the cGMP-degrading enzyme phosphodiesterase-5 (PDE5) is present in small penetrating arteries in the deep subcortical white matter of older people. Frontal cortical tissue blocks were examined from donated brains of older people (n = 42, 24 male: 18 female, median age 81, range: 59-100 years). PDE5, detected by immunohistochemical labeling, was graded as absent, sparse, or abundant in vascular cells within small arteries in subcortical white matter (vessel outer diameter: 20-100 µm). PDE5 labeling within arterial myocytes was detected in all cases. Degree of PDE5 expression (absent, sparse, or abundant) was not associated with age or with neuropathological diagnosis of small vessel disease. In conclusion, PDE5 is present in vascular myocytes within small penetrating arteries in older people. This is a potential molecular target for pharmacological interventions.

Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people.

The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD.