Blood-brain barrier leakage and microvascular lesions in cerebral amyloid angiopathy

Background and Purpose-Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions.Methods-Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere.Results-Our results demonstrated increased IgG positivity in the frontotemporal (P=0.044) and parietooccipital (P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions (P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-beta-positive vessels (Spearman.=0.71, P=0.015 and Spearman.=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgGpositive vessels, but not amyloid-beta-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman.=0.77, P=0.005 and Spearman.=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds.Conclusions-Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAArelated brain injury

White matter hyperintensities mediate the association between blood-brain barrier leakage and information processing speed

Blood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine associations between BBB leakage, cSVD, neurodegeneration, and cognitive performance across the spectrum from normal cognition to dementia. Leakage was measured with dynamic contrast-enhanced magnetic resonance imaging in 80 older participants (normal cognition, n = 32; mild cognitive impairment, n 34; clinical AD-type dementia, n = 14). Associations between leakage and white matter hyperintensity (WMH) volume, hippocampal volume, and cognition (information processing speed and memory performance) were examined with multivariable linear regression and mediation analyses. Leakage within the gray and white matter was positively associated with WMH volume (gray matter, p = 0.03; white matter, p = 0.01). A negative association was found between white matter BBB leakage and information processing speed performance, which was mediated by WMH volume. Leakage was not associated with hippocampal volume. WMH pathology is suggested to form a link between leakage and decline of information processing speed in older individuals with and without cognitive impairment. (C) 2019 Elsevier Inc. All rights reserved

Application of contrast-enhanced magnetic resonance imaging in the assessment of blood-cerebrospinal fluid barrier integrity

VERHEGGEN, I.C.M., W. Freeze, J. de Jong, J. Jansen, A. Postma, M. van Boxtel, F. Verhey and W. Backes. The application of contrast-enhanced MRI in the assessment of blood-cerebrospinal fluid barrier integrity. Choroid plexus epithelial cells form a barrier that enables active, bidirectional exchange between the blood plasma and cerebrospinal fluid (CSF), known as the blood-CSF barrier (BCSFB). Through its involvement in CSF composition, the BCSFB maintains homeostasis in the central nervous system. While the relation between bloodbrain barrier disruption, aging and neurodegeneration is extensively studied using contrast-enhanced MRI, applying this technique to investigate BCSFB disruption in age-related neurodegeneration has received little attention. This review provides an overview of the current status of contrast-enhanced MRI to assess BCSFB permeability. Post-contrast ventricular gadolinium enhancement has been used to indicate BCSFB permeability. Moreover, new techniques highly sensitive to low gadolinium concentrations in the CSF, for instance heavily T2weighted imaging with cerebrospinal fluid suppression, seem promising. Also, attempts are made at using other contrast agents, such as manganese ions or very small superparamagnetic iron oxide particles, that seem to be cleared from the brain at the choroid plexus. Advancing and applying new developments such as these could progress the assessment of BCSFB integrity.Neuro Imaging Researc

Imaging markers associated with the development of post-stroke depression and apathy: results of the cognition and affect after stroke - a prospective evaluation of risks study

Introduction: It has been suggested that the development of post-stroke apathy (PSA) and depression (PSD) may be more strongly associated with generalised brain pathology, rather than the stroke lesion itself. The present study aimed to investigate associations between imaging markers of lesion-related and generalised brain pathology and the development of PSA and PSD during a one-year follow-up.Patients and methods: In a prospective cohort study, 188 stroke patients received 3-Tesla MRI at baseline (three months post-stroke) for evaluation of lesion-related, vascular, and degenerative brain pathology. Presence of lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces was summed to provide a measure of total cerebral small vessel disease (cSVD) burden (range 0-4). The Mini International Neuropsychiatric Interview and Apathy Evaluation Scale were administered at baseline and repeated at 6- and 12-month follow-up to define presence of PSD and PSA, respectively.Results: Population-averaged logistic regression models showed that global brain atrophy and severe cSVD burden (score 3-4) were significantly associated with the odds of having PSA (ORGEE 5.33, 95% CI 1.99-14.25 and 3.04, 95% CI 1.20-7.69, respectively), independent of stroke lesion volume and co-morbid PSD. Medium cSVD burden (score 2) was significantly associated with the odds of having PSD (ORGEE 2.92, 95% CI 1.09-7.78), independent of stroke lesion volume, co-morbid PSA, and pre-stroke depression. No associations were found with lesion-related markers.Conclusions: The results suggest that generalised degenerative and vascular brain pathology, rather than lesion-related pathology, is an important predictor for the development of PSA, and less strongly for PSD

Locus coeruleus pathology is associated with cerebral microangiopathy at autopsy

INTRODUCTIONWe investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets. METHODSWe included data from the National Alzheimer's Coordinating Center (NACC) database (n = 2197) and Religious Orders Study and Rush Memory and Aging Project (ROSMAP; n = 1637). Generalized estimating equations and logistic regression were used to examine associations between LC hypopigmentation and presence of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, correcting for age at death, sex, cortical Alzheimer's disease (AD) pathology, ante mortem cognitive status, and presence of vascular and genetic risk factors. RESULTSLC hypopigmentation was associated with higher odds of overall CAA in the NACC dataset, leptomeningeal CAA in the ROSMAP dataset, and arteriolosclerosis in both datasets. DISCUSSIONLC pathology is associated with cerebral microangiopathy, independent of cortical AD pathology. LC degeneration could potentially contribute to the pathways relating vascular pathology to AD. Future studies of the LC-norepinephrine system on cerebrovascular health are warranted. HighlightsWe associated locus coeruleus (LC) pathology and cerebral microangiopathy in two large autopsy datasets.LC hypopigmentation was consistently related to arteriolosclerosis in both datasets.LC hypopigmentation was related to cerebral amyloid angiopathy (CAA) presence in the National Alzheimer's Coordinating Center dataset.LC hypopigmentation was related to leptomeningeal CAA in the Religious Orders Study and Rush Memory and Aging Project dataset.LC degeneration may play a role in the pathways relating vascular pathology to Alzheimer's disease

Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy

Kozberg et al. examined blood-brain barrier leakage and perivascular inflammation at the individual vessel level in cerebral amyloid angiopathy. They report blood-brain barrier leakage at early stages of vascular pathology, a potential trigger for perivascular inflammation and vascular remodelling leading to haemorrhage.Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-beta deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-beta at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-beta, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-beta deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-beta (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation.</p

Rich-Club Connectivity of the Structural Covariance Network Relates to Memory Processes in Mild Cognitive Impairment and Alzheimer's Disease

Background: Though mediotemporal lobe volume changes are well-known features of Alzheimer's disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN).Objective: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club.Methods: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n = 37; mild cognitive impairment, n = 41; Alzheimer-type dementia, n = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression.Results: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume.Conclusion: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy.Radiolog

Rich-Club Connectivity of the Structural Covariance Network Relates to Memory Processes in Mild Cognitive Impairment and Alzheimer's Disease

Background: Though mediotemporal lobe volume changes are well-known features of Alzheimer's disease (AD), grey matter volume changes may be distributed throughout the brain. These distributed changes are not independent due to the underlying network structure and can be described in terms of a structural covariance network (SCN).Objective: To investigate how the cortical brain organization is altered in AD we studied the mutual connectivity of hubs in the SCN, i.e., the rich-club.Methods: To construct the SCNs, cortical thickness was obtained from structural MRI for 97 participants (normal cognition, n = 37; mild cognitive impairment, n = 41; Alzheimer-type dementia, n = 19). Subsequently, rich-club coefficients were calculated from the SCN, and related to memory performance and hippocampal volume using linear regression.Results: Lower rich-club connectivity was related to lower memory performance as well as lower hippocampal volume.Conclusion: Therefore, this study provides novel evidence of reduced connectivity in hub areas in relation to AD-related cognitive impairments and atrophy

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-beta

Contains fulltext : 170424.pdf (publisher's version ) (Closed access)Cerebral small vessel disease (cSVD) and amyloid-beta (Abeta) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Abeta have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Abeta pathology was assessed as cerebrospinal fluid-derived Abeta1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Abeta on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Abeta and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Abeta and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Abeta42 levels, but not in individuals with normal CSF Abeta42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Abeta levels are at an increased risk of accelerated disease progression when concomitant cSVD is present