Severe Cerebral Amyloid Angiopathy Research Articles

Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy

Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls' Prussian blue, and immunohistochemistry was performed against amyloid-β and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls'-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P < 0.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas.

Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease.

Introduction:Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer’s disease (AD) cases.Methods:We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aβ40], Aβ42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.Results:Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.Discussion:Refining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

This study investigated clinical and neuropathological differences between DLB and PDD. 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. CAA was more common in DLB than in PDD (P=0.003). The severity of CAA was greater in DLB than in PDD (P=0.009), with significantly higher CAA scores in the parietal lobe (P=0.043), and the occipital lobe (P=0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Left Atrial Appendage Closure for Patients with Cerebral Amyloid Angiopathy and Atrial Fibrillation: the LAA-CAA Cohort

Anticoagulation increases the risk of intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA), so the management of stroke-risk in patients with both atrial fibrillation (AF) and CAA is controversial. Advances in left atrial appendage closure (LAAC) techniques provide a stroke-risk-reduction option which avoids long-term oral anticoagulation (OAC). We aimed to evaluate the safety of this intervention in patients with CAA. This is an observational cohort study of patients with severe CAA (with or without ICH) and AF who were treated with LAA closure. The Watchman™ and Amulet® LAAC devices and Lariat procedure or open surgical closure of the LAA were all considered acceptable means of closure. Patients with symptomatic ICH and those naïve to anticoagulation were placed on clopidogrel and/or aspirin for 6weeks after the procedure; patients who previously tolerated anticoagulation remained on warfarin or a DOAC for 6weeks post-procedure. All anticoagulation therapy was discontinued after confirmation of LAAC. All patients had aggressively optimized blood pressure and fall precautions in addition to surgical intervention. Safety, tolerability, stroke, and hemorrhage rates were documented. Twenty-six patients with a mean CHA2DS2-VASc score of 4.6 were treated, 13 with a history of symptomatic lobar hemorrhage and 13 without. All patients who completed LAAC tolerated the device implantation. There were no documented ischemic strokes or symptomatic ICH during the 30days after device implantation. Patients were followed for an average of 25months. One patient who underwent Lariat LAAC had an ischemic stroke in follow-up, but recovered well; there were no other thromboemboli in this cohort. This cohort study provides evidence that LAAC appears to be a safe and tolerable treatment to reduce stroke risk in patients with CAA. Because of the small size of the cohort and relatively short follow-up, the efficacy for stroke and ICH prevention is not conclusive, but the preliminary results are encouraging. LAA closure may be a good alternative to anticoagulation in patients with CAA and atrial fibrillation.

White matter atrophy in cerebral amyloid angiopathy.

We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. Patients with CAA (n = 72) had significantly lower pWMV (27.97% ± 2.63) when compared to age-matched HC (n = 72; mean difference [MD], 2.38%; p < 0.0001) and patients with AD (n = 72; MD, 1.57%; p < 0.0001). Differences were most pronounced in the posterior occipital regions in both comparisons. When comparisons were restricted to groups of patients with CAA but no intracerebral hemorrhage (n = 32) or hypertension (n = 32), and age-matched HC and AD, the significant differences were unaltered. Within the CAA cohort, higher age, lobar microbleed counts, and presence of hypertension were associated with lower pWMV (p = 0.0007, p = 0.031, and p = 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.

Amyloid-β plaques may be reduced in advanced stages of cerebral amyloid angiopathy in the elderly.

We examined 29 cases in which cerebral amyloid angiopathy (CAA) was detected among routine aged autopsies. Most cases with severe CAA had many amyloid-β (Aβ) plaques in the occipital cortex. Nonetheless, two cases had few Aβ plaques with many small vessels and capillaries with CAA. In the two cases, severe CAA was widely distributed, except in the frontal lobes. Aβ deposits in capillaries often showed the characteristic pattern of dysphoric amyloid angiopathy. A few naked plaques were present. Although Aβ plaques were sparse near small vessels with CAA, there were many Aβ plaques distant from small vessels with CAA. Some of the remaining plaques had a moth-eaten appearance. Based on Aβ-positive star-like appearance and results of double immunohistochemistry for glial fibrillary acidic protein and Aβ1-42 , some astrocytes appeared to contain Aβ. Ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia were scattered within the neuropil, with some present around small vessels with CAA. Iba1-positive microglia also seemed to phagocytose Aβ in several senile plaques by double immunostaining. Neurons and neurites identified with a monoclonal antibody against phosphorylated tau (clone AT8) were occasionally detected in sparse plaque areas, with AT8-identified dot-like structures present around capillaries with CAA. Accumulation of T lymphocytes was detected around vessels in the subarachnoid space in one case. The morphological changes detected in our two cases were similar to those of morphological markers of plaque clearance after Aβ immunotherapy. Nonetheless, our cases did not receive Aβ immunotherapy, but similar pathologies were observed. Overall, advanced CAA cases, including our two cases, may be examples of plaque clearance without Aβ immunotherapy. Further studies are needed to resolve the mechanism of Aβ plaque clearance using these cases.

Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier \u2013 phenotypic variability in autosomal dominant Alzheimer\u2019s disease

The discovery of mutations associated with familial forms of Alzheimer’s disease (AD), has brought imperative insights into basic mechanisms of disease pathogenesis and progression and has allowed researchers to create animal models that assist in the elucidation of the molecular pathways and development of therapeutic interventions. Position 717 in the amyloid precursor protein (APP) is a hotspot for mutations associated with autosomal dominant AD (ADAD) and the valine to isoleucine amino acid substitution (V717I) at this position was among the first ADAD mutations identified, spearheading the formulation of the amyloid cascade hypothesis of AD pathogenesis. While this mutation is well described in multiple kindreds and has served as the basis for the generation of widely used animal models of disease, neuropathologic data on patients carrying this mutation are scarce. Here we present the detailed clinical and neuropathologic characterization of an APP V717I carrier, which reveals important novel insights into the phenotypic variability of ADAD cases. While age at onset, clinical presentation and widespread parenchymal beta-amyloid (Aβ) deposition are in line with previous reports, our case also shows widespread and severe cerebral amyloid angiopathy (CAA). This patient also presented with TDP-43 pathology in the hippocampus and amygdala, consistent with limbic predominant age-related TDP-43 proteinopathy (LATE). The APOE ε2/ε3 genotype may have been a major driver of the prominent vascular pathology seen in our case. These findings highlight the importance of neuropathologic examinations of genetically determined AD cases and demonstrate striking phenotypic variability in ADAD cases.

Association of Hypercholesterolemia with Alzheimer's Disease Pathology and Cerebral Amyloid Angiopathy.

Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer's disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer's Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy.

In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.

The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease.

Background:Variable rate of cognitive decline among individuals with Alzheimer’s disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus.Objective:To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD.Methods:Neuropsychology test and autopsy data was pulled from the National Alzheimer’s Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD.Results:Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62[1.0] versus 1.13[1.0], p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (χ2 = 25.8, p = 0.002), but not to clinical utility (AUC < 0.70; 95% CI).Conclusion:Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.

Different microvascular alterations underlie microbleeds and microinfarcts.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292.

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer's disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52-6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p's < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02-2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.

Cortical microinfarcts in patients with multiple lobar microbleeds on 3T MRI.

The pathogenesis of cortical microinfarcts (CMIs) is considered to be heterogeneous including cerebral small vessel disease (SVD) such as hypertensive vasculopathy (HV) and cerebral amyloid angiopathy (CAA). Recent advances in MRI have enabled the detection of CMIs in vivo. To investigate the characteristics of CMIs in advanced cerebral SVD, we performed a retrospective analysis of 85 patients with cognitive impairment who had multiple lobar cerebral microbleeds (CMBs) on 3T MRI. Among them, 41 (48.2%) patients were classified into the strictly lobar CMB group (i.e. probable-CAA group), and 44 (51.8%) patients were classified into the non-lobar with lobar CMBs group (i.e. mix-CMBs group). The relationship between CMIs and CMBs, cortical superficial siderosis (cSS) and white matter hyperintensity was evaluated. Nine of the 41 (22.0%) patients with probable-CAA had a total of 19 CMIs, while 12 of the 44 (27.3%) patients with mix-CMBs had a total of 38 CMIs. In the probable-CAA group, the presence of CMIs was significantly associated with the presence of cSS (p < 0.001). In addition, a close spatial association between CMIs and cSS was observed. On the contrary, in the mix-CMB group, the presence of CMIs was significantly associated with the number of lobar CMBs in the frontal lobe (p = 0.034). Our results suggest that CMIs in the probable-CAA may be attributable to more severe CAA, while CMIs in the mix-CMBs indicate an advanced HV, especially when observed with more numerous lobar CMBs.

Osteopontin and phospho-SMAD2/3 are associated with calcification of vessels in D-CAA, an hereditary cerebral amyloid angiopathy.

In severe forms of cerebral amyloid angiopathy (CAA) pathology, vascular calcification has been observed in the cerebral cortex, both in vivo on MRI and CT, and post‐mortem using histopathology. However, the pathomechanisms leading to calcification of CAA‐laden arteries are unknown. Therefore, we investigated the correlation between calcification of cortical arterioles and several potential modulators of vascular calcification using immunohistochemistry in a unique collection of brain material of patients with a hereditary form of CAA, namely hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D or D‐CAA).We show a topographical association of osteopontin (OPN) and TGFβ signaling factor phospho‐SMAD2/3 (pSMAD2/3) in calcified CAA vessel walls. OPN and pSMAD2/3 gradually accumulate in vessels prior to calcification. Moreover, we found that the vascular accumulation of Collagen 1 (Col1), OPN and pSMAD2/3 immunomarkers correlated with the CAA severity. This was independently of the vessel size, including capillaries in the most severe cases. We propose that calcification of CAA vessels in the observed HCHWA‐D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.

Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry.

The neuropathology of Alzheimer's disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. The Aβ peptides, composed of 40 amino acids, are generated from amyloid precursor proteins (APP) by β- and γ-secretases. Aβ is deposited not only in cerebral parenchyma but also in leptomeningeal and cerebral vessel walls, known as cerebral amyloid angiopathy (CAA). While a variety of Aβ peptides were identified, the detailed production and distribution of individual Aβ peptides in pathological tissues of AD and CAA have not been fully addressed. Here, we develop a protocol of matrix-assisted laser desorption/ionization-based imaging mass spectrometry (MALDI-IMS) on human autopsy brain tissues to obtain comprehensive protein mapping. For this purpose, human cortical specimens were obtained from the Brain Bank at the Tokyo Metropolitan Institute of Gerontology. Frozen cryosections are cut and transferred to indium-tin-oxide (ITO)-coated glass slides. Spectra are acquired using the MALDI system with a spatial resolution up to 20 µm. Sinapinic acid (SA) is uniformly deposited on the slide using either an automatic or a manual sprayer. With the current technical advantages of MALDI-IMS, a typical data set of various Aβ species within the same sections of human autopsied brains can be obtained without specific probes. Furthermore, high-resolution (20 µm) imaging of an AD brain and severe CAA sample clearly shows that Aβ1-36 to Aβ1-41 were deposited into leptomeningeal vessels, while Aβ1-42 and Aβ1-43 were deposited in cerebral parenchyma as senile plaque (SP). It is feasible to adopt MALDI-IMS as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD, CAA, and other neurological diseases based on the current strategy.

A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer’s disease

Cerebral amyloid angiopathy (CAA) is a type of vascular disease present in more than 50% of demented elderly and more than 80% of Alzheimer’s disease (AD) patients. Both CAA and AD are characterized by extracellular Aβ deposits with the distinction that CAA has vascular deposits while AD has amyloid plaques. In this study, we used immunoprecipitation (IP) in combination with mass spectrometry (MS) to test the hypothesis that the Aβ peptide pattern differs between subjects having Aβ plaque pathology only and subjects with Aβ plaque pathology together with CAA pathology. Occipital lobes from 12 AD brains, ranging from no CAA to severe CAA, were extracted using 70% formic acid followed by IP-MS analysis. The Aβ peptide pattern differed greatly between subjects with no CAA compared to subjects with CAA. In cases with CAA, the most abundant Aβ peptides ended at amino acid 40 including Aβ1-40 (P = .048) and Aβ 2–40 (P = .0253) which were significantly increased compared to cases with no CAA. This was in contrast to subjects with no CAA where the most abundant Aβ peptides ended at amino acid 42 of which Aβ1-42 (P = .0101) and Aβ2-42 (P = .0051) as well as the pyroglutamate (pGlu)-modified peptides pGlu Aβ3-42 (P = .0177), and pGlu Aβ11-42 (P = .0088) were significantly increased compared to CAA subjects. The results are in line with earlier immunohistochemistry data and show that the molecular composition of the Aβ deposits found in blood vessels are different to the parenchymal deposits, suggesting they arise from distinct pathogenic pathways. This information may be useful in the development of pathology-specific biomarkers.

Abstract TMP109: Loss of Gray-White Contrast in Cerebral Amyloid Angiopathy: An in-vivo and Ex-Vivo Exploratory Approach

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) is associated with cortical and white matter atrophy. We hypothesized that changes in neural tissue signal properties could reflect microstructural alterations in diffusion, and hence demyelination. Methods: Two cohorts of non-demented CAA patients were examined (3T: 45 CAA patients vs 16 age-matched Healthy Controls [HC]; 1.5T: 66 CAA patients vs 18 matched HC), and dichotomized into moderate (3T: n=19; 1.5T: n=24) and severe CAA. FreeSurfer was employed to calculate gray and white (GW) matter signal intensities from a T1-weighted sequence, and their ratio was used to assess GW contrast. Two diffusion markers (fractional anisotropy [FA]; apparent diffusion coefficient [ADC]) were measured via Diffusion Weighted Imaging. In addition, brains of 13 deceased patients with CAA were scanned ex-vivo, sectioned, and stained using Luxol Fast Blue, to assess myelin content. GW ratio was calculated the same way as in the in-vivo cohorts. Results: CAA patients displayed loss of GW contrast, expressed by increased GW intensity ratio (3T: 0.802±0.01; 1.5T: 0.757±0.02), when compared to HC (3T: 0.789±0.01,p=0.003; 1.5T: 0.738±0.01,p&lt;0.0001). Patients with severe CAA showcased even lower GW contrast (3T: 0.806±0.01; 1.5T: 0.763±0.02) than patients with moderate CAA (3T: 0.797±0.01,p&lt;0.05; 1.5T: 0.745±0.02,p&lt;0.05) [ Fig ]. Moreover, loss of GW contrast within CAA correlated with lower FA (r=-0.30,p=0.049) and increased ADC (r=0.52,p&lt;0.0001). Within the ex-vivo CAA cohort, loss of GW contrast was highly linked to a decrease in underlying myelin concentration (p=0.0025). Conclusions: CAA patients consistently displayed lower GW contrast compared to HC. This loss of contrast became more pronounced with increased disease severity, and correlated with lower anisotropy and increased water diffusivity. Indeed, an ex-vivo CAA cohort revealed that loss of GW contrast corresponded to a decrease in myelin concentration.

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-β-positive vessels (Spearman ρ=0.71, P=0.015 and Spearman ρ=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P=0.005 and Spearman ρ=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 CAA-related brain injury.

Histopathology of diffusion imaging abnormalities in cerebral amyloid angiopathy.

We sought to determine the underlying mechanism for altered white matter diffusion tensor imaging (DTI) measures at the histopathologic level in patients with cerebral amyloid angiopathy (CAA). Formalin-fixed intact hemispheres from 9 CAA cases and 2 elderly controls were scanned at 3-tesla MRI, including a diffusion-weighted sequence. DTI measures (i.e., fractional anisotropy [FA] and mean diffusivity [MD]) and histopathology measures were obtained from 2 tracts: the anterior thalamic radiation and inferior longitudinal fasciculus. FA was reduced in both tracts and MD was increased in cases with CAA compared to controls. Regional FA was significantly correlated with tissue rarefaction, myelin density, axonal density, and white matter microinfarcts. MD correlated significantly with tissue rarefaction, myelin density, and white matter microinfarcts, but not axonal density. FA and MD did not correlate with oligodendrocytes, astrocytes, or gliosis. Multivariate analysis revealed that tissue rarefaction (β = -0.32 ± 0.12, p = 0.009) and axonal density (β = 0.25 ± 0.12, p = 0.04) were both independently associated with FA, whereas myelin density was independently associated with MD (β = -0.32 ± 0.12, p = 0.013). Finally, we found an association between increased MD in the frontal white matter and CAA severity in the frontal cortex (p = 0.035). These results suggest that overall tissue loss, and in particular axonal and myelin loss, are major components underlying CAA-related alterations in DTI properties observed in living patients. The findings allow for a more mechanistic interpretation of DTI parameters in small vessel disease and for mechanism-based selection of candidate treatments to prevent vascular cognitive impairment.

The Impact of Cerebral Amyloid Angiopathy in Various Neurodegenerative Dementia Syndromes: A Neuropathological Study

Purpose The Boston criteria for cerebral amyloid angiopathy (CAA) have to be confirmed by postmortem examination. The present study investigates the incidence and the cerebrovascular impact of the severity of CAA in various neurodegenerative dementia diseases. Material and Methods 208 patients underwent an autopsy. They consisted of 92 brains with Alzheimer's disease (AD), 46 with frontotemporal lobar degeneration (FTLD), 24 with progressive supranuclear palsy (PSP), 21 with Lewy body dementia (LBD), 5 with corticobasal degeneration (CBD), and 20 controls. In addition to the macroscopic examination, a whole coronal section of a cerebral hemisphere, at the level of the mamillary body, was taken for semiquantitative microscopic evaluation of the small cerebrovascular lesions. Results CAA is present in 2/3% of the AD brains of which half of them have a severe form, grade 3. Only the latter displays more cerebrovascular lesions. CAA is present in 45% of the LBD brains. Cortical microinfarcts are only more frequent in the CAA grade 3 group. In LBD additional AD pathology is present in 41% of the CAA grade 0, 83% in grade 1-2, and 100% in grade 3. In PSP only 21% had CAA grade 1-2. In FTLD, CBD, and normal controls no CAA pathology is observed. Conclusions The present study shows that CAA is most frequently associated to AD but that only the severe form displays more cerebrovascular lesions. LBD is the second most frequent disease associated to CAA with a clear correlation between the incidence of the associated AD features and the increasing severity of the CAA. In PSP only 21% display mild CAA features. PSP, tau-FTLD, and CBD are part of the Pick complex diseases, who are known to have a favourable vascular profile which can explain their low incidence of cerebrovascular lesions, in contrast to AD and LBD brains.