Cerebral Amyloid Angiopathy Pathology Research Articles

Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice.

The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain -amyloid () deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. Female APP/PS1 mice at 8 wk of age were administered either Pb-acetate (PbAc) (i.e., ) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed invivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to , higher ratios, strikingly lower levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384.

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

BackgroundPatients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated.MethodsTo explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups.ResultsOur study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization.ConclusionsOur findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aβ that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τb = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75–5.29] vs 3.60 ng/ml [IQR 3.11–4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aβ40 (spearman r (rs) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH.

Clinical Predictors of Postmortem Amyloid and Nonamyloid Cerebral Small Vessel Disease in Middle-Aged to Older Adults.

Sporadic cerebral small vessel disease (CSVD) is a class of important pathologic processes known to affect the aging brain and to contribute to cognitive impairment. We aimed to identify clinical risk factors associated with postmortem CSVD in middle-aged to older adults. We developed and tested risk models for their predictive accuracy of a pathologic diagnosis of nonamyloid CSVD and cerebral amyloid angiopathy (CAA) in a retrospective sample of 160 autopsied cases from the Edinburgh Brain Bank. Individuals aged 40 years and older covering the spectrum of healthy aging and common forms of dementia (i.e., highly-prevalent etiologies such as Alzheimer disease (AD), vascular cognitive impairment (VCI), and mixed dementia) were included. We performed binomial logistic regression models using sample splitting and cross-validation methods. Demographics, lifestyle habits, traditional vascular risk factors, chronic medical conditions, APOE4, and cognitive status were assessed as potential predictors. Forty percent of our sample had a clinical diagnosis of dementia (AD = 33, VCI = 26 and mixed = 5) while others were cognitively healthy (n = 96). The mean age at death was 73.8 (SD 14.1) years, and 40% were female. The presence of none-to-mild vs moderate-to-severe nonamyloid CSVD was predicted by our model with good accuracy (area under the curve [AUC] = 0.84, sensitivity [SEN] = 72%, specificity [SPE] = 95%), with the most significant clinical predictors being age, history of cerebrovascular events, and cognitive impairment. The presence of CAA pathology was also predicted with high accuracy (AUC = 0.86, SEN = 93%, SPE = 79%). Significant predictors included alcohol intake, history of cerebrovascular events, and cognitive impairment. In a subset of atypical dementias (n = 24), our models provided poor predictive performance for both nonamyloid CSVD (AUC = 0.50) and CAA (AUC = 0.43). CSVD pathology can be predicted with high accuracy based on clinical factors in patients within the spectrum of AD, VCI, and normal aging. Whether this prediction can be enhanced by the addition of fluid and neuroimaging biomarkers warrants additional study. Improving our understanding of clinical determinants of vascular brain health may lead to novel strategies in the prevention and treatment of vascular etiologies contributing to cognitive decline. This study provides Class II evidence that selected clinical factors accurately distinguish between middle-aged to older adults with and without cerebrovascular small vessel disease (amyloid and nonamyloid) pathology.

Prevalence of Cerebral Amyloid Angiopathy Pathology and Strictly Lobar Microbleeds in East-Asian Versus Western Populations: A Systematic Review and Meta-Analysis.

Possible differences in the prevalence of cerebral amyloid angiopathy (CAA) in East-Asian compared to Western populations have received little attention, and results so far have been ambiguous. Our aim is to compare the prevalence of CAA neuropathology and magnetic resonance imaging markers of CAA in East-Asian and Western cohorts reflecting the general population, cognitively normal elderly, patients with Alzheimer's disease (AD), and patients with (lobar) intracerebral hemorrhage (ICH). We performed a systematic literature search in PubMed and Embase for original research papers on the prevalence of CAA and imaging markers of CAA published up until February 17th 2022. Records were screened by two independent reviewers. Pooled estimates were determined using random-effects models. We compared studies from Japan, China, Taiwan, South Korea (East-Asian cohorts) to studies from Europe or North America (Western cohorts) by meta-regression models. We identified 12,257 unique records, and we included 143 studies on Western study populations and 53 studies on East-Asian study populations. Prevalence of CAA neuropathology did not differ between East-Asian and Western cohorts in any of the investigated patient domains. The prevalence of strictly lobar microbleeds was lower in East-Asian cohorts of population-based individuals (5.6% vs. 11.4%, P=0.020), cognitively normal elderly (2.6% vs. 11.4%, P=0.001), and patients with ICH (10.2% vs. 24.6%, P<0.0001). However, age was in general lower in the East-Asian cohorts. The prevalence of CAA neuropathology in the general population, cognitively normal elderly, patients with AD, and patients with (lobar) ICH is similar in East-Asian and Western countries. In East-Asian cohorts reflecting the general population, cognitively normal elderly, and patients with ICH, strictly lobar microbleeds were less prevalent, likely due to their younger age. Consideration of potential presence of CAA is warranted in decisions regarding antithrombotic treatment and potential new anti-amyloid-β immunotherapy as treatment for AD in East-Asian and Western countries alike.

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.

Profiling amyloid-β peptides as biomarkers for cerebral amyloid angiopathy.

Brain amyloid-β (Aβ) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aβ40 peptide, whereas Aβ42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aβ isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aβ isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aβ1-34, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, and Aβ1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aβ peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aβ1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aβ1-42, none of the Aβ peptides were decreased in AD-like subjects compared with controls. All Aβ peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aβ1-42 in the model (since decreased Aβ1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aβ profiles. Peptides shorter than Aβ1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aβ accumulation. This study supports the potential use of this panel of CSF Aβ peptides to indicate presence of CAA pathology with high accuracy.

Abstract TP161: Social Isolation Increases Liver Inflammation and Alters Hepatocyte Morphology in Cerebral Amyloid Angiopathy

Introduction: Social isolation (SI) is a growing yet understudied public health concern. Accumulating evidence suggests that SI has critical psychological implications and can also lead to considerable negative physiological outcomes, as in the case of cerebral amyloid angiopathy (CAA). CAA is characterized by the accumulation of amyloid-beta (Aβ) in the leptomeningeal vessels, which compromises the integrity of cerebral vasculature, thus increasing risk of intracerebral hemorrhages. Our preliminary data suggests SI induces metabolic changes including average weight gain in CAA mice compared to pair-housed (PH) counterparts (30g vs 25g, respectively; p&lt;0.01). Hence, it is imperative to investigate the effects of social isolation on liver physiology and energy metabolism in the context of CAA. Hypothesis: We hypothesize that SI leads to decreased Aβ clearance by the liver, and increased immune cell infiltration into the liver. Methods: 3-month-old C57BL/6 (WT, n=21) and TgSwDI mice (n=21) were either pair-housed (PH) or socially-isolated (SI) for 9 months. We assessed Aβ deposition, hepatocyte morphology, vascular structure, and liver immune cell composition through immunohistochemistry. We additionally quantified ALT/AST levels and LRP-1 levels as a measure of liver dysfunction and Aβ clearance, respectively. Neurobehavioral performance was measured by nesting and tail-suspension test. Results: Our findings show that socially isolated CAA mice exhibit sustained affective and cognitive impairments when compared to the PH group. Average nesting scores are significantly lower for male CAA SI mice compared to PH mice (1.67 vs 3.5, respectively; p&lt;0.01). SI CAA mice have larger hepatocytes and increased immune cell infiltration when compared to the PH counterparts and WT controls. Furthermore, Aβ signals were found to colocalize with liver-resident macrophages, implying a role of amyloid clearance by these cells. Discussion: Together we show that SI increases body weight and inflammation, and exacerbates cognitive and behavioral deficits. These changes may affect AB clearance, thereby potentially worsening CAA pathology. Further investigation into liver energy metabolism and macrophage-mediated inflammation is warranted.

Cerebrospinal fluid shotgun proteomics identifies distinct proteomic patterns in cerebral amyloid angiopathy rodent models and human patients

Cerebral amyloid angiopathy (CAA) is a form of small vessel disease characterised by the progressive deposition of amyloid β protein in the cerebral vasculature, inducing symptoms including cognitive impairment and cerebral haemorrhages. Due to their accessibility and homogeneous disease phenotypes, animal models are advantageous platforms to study diseases like CAA. Untargeted proteomics studies of CAA rat models (e.g. rTg-DI) and CAA patients provide opportunities for the identification of novel biomarkers of CAA. We performed untargeted, data-independent acquisition proteomic shotgun analyses on the cerebrospinal fluid of rTg-DI rats and wild-type (WT) littermates. Rodents were analysed at 3 months (n = 6/10), 6 months (n = 8/8), and 12 months (n = 10/10) for rTg-DI and WT respectively. For humans, proteomic analyses were performed on CSF of sporadic CAA patients (sCAA) and control participants (n = 39/28). We show recurring patterns of differentially expressed (mostly increased) proteins in the rTg-DI rats compared to wild type rats, especially of proteases of the cathepsin protein family (CTSB, CTSD, CTSS), and their main inhibitor (CST3). In sCAA patients, decreased levels of synaptic proteins (e.g. including VGF, NPTX1, NRXN2) and several members of the granin family (SCG1, SCG2, SCG3, SCG5) compared to controls were discovered. Additionally, several serine protease inhibitors of the SERPIN protein family (including SERPINA3, SERPINC1 and SERPING1) were differentially expressed compared to controls. Fifteen proteins were significantly altered in both rTg-DI rats and sCAA patients, including (amongst others) SCG5 and SERPING1. These results identify specific groups of proteins likely involved in, or affected by, pathophysiological processes involved in CAA pathology such as protease and synapse function of rTg-DI rat models and sCAA patients, and may serve as candidate biomarkers for sCAA.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography.

Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

GWAS identifies genetic factors associated with severity of cerebral amyloid angiopathy pathology

AbstractBackgroundCerebral amyloid angiopathy (CAA) commonly co‐occurs with Alzheimer’s disease (AD) pathologies, leading to an increased risk and severity of cognitive decline. While CAA is known to impact cognitive impairment, the genetics of CAA are not well understood, and most previous sample sizes have been small. To address this gap, we conducted a genome‐wide association study (GWAS) of CAA pathology to identify genetic factors that are associated with this understudied AD‐related amyloidosis.MethodWe utilized data from 6,038 autopsied and genotyped individuals from the National Alzheimer’s Coordinating Centers (NACC) who were evaluated for CAA pathology upon autopsy. Participants were age 50+ at death and non‐Hispanic white. Genetic data were available from SNP arrays imputed to TOPMed and analyses were conducted only on common variants (MAF &gt;0.01). GWAS performed ordinal logistic regression to determine the effects of genetic variants on CAA pathology (coded as 0, none; 1, mild; 2, moderate; 3, severe). Models adjusted for sex, age at death, and the first three genetic principal components (PC‐AiR; GENESIS; R v4.2). We then meta‐analyzed across the cohorts (METAL).ResultWe observed genome‐wide significant associations with CAA severity at established AD loci, including APOE (top SNP: rs429358, MAF = 0.155, P = 1.6E−86) and BIN1 (top SNP: rs6733839, MAF = 0.397, P = 3.9E−08). We observed a novel association with CAA pathology on chromosome 9 (top SNP: rs10908023, MAF = 0.258, P = 4.3E−11).ConclusionThis is the largest study to date aimed at identifying genetics factors associated with CAA pathology. Our findings offer new insights into the genetics of CAA, a common player in the AD landscape. We acknowledge the need for a larger dataset and are now expanding the study by sample size and by including additional ADRD phenotypes to gain a better understanding of the full spectrum AD/ADRD. Continuing to uncover the genetic underpinnings of CAA could potentially help us think about AD treatment in new ways and mitigate the negative side‐effects of brain swelling and bleeding that have been observed in recent clinical trials.

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy

BackgroundCortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury.MethodsAccordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls’ Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells.ResultsWe observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits.ConclusionIron deposition resulting from cSS is associated with local reactive astrogliosis.

Morphological characteristics differentiate dementia with Lewy bodies from Parkinson disease with and without dementia.

Dementia with Lewy bodies (DLB) and Parkinson disease (PD) with and without dementia are entities of a spectrum of Lewy body diseases. About 26.3% of all PD patients develop dementia increasing up to 83%. Parkinson disease-dementia (PDD) and DLB share many clinical and morphological features that separate them from non-demented PD (PDND). Clinically distinguished by the temporal sequence of motor and cognitive symptoms, the pathology of PDD and DLB includes variable combinations of Lewy body (LB) and Alzheimer (AD) lesions, both being more severe in DLB, but much less frequent and less severe in PDND. The objective of this study was to investigate the morphological differences between these three groups. 290 patients with pathologically confirmed PD were reviewed. 190 of them had clinical dementia; 110 met the neuropathological criteria of PDD and 80 of DLB. The major demographic and clinical data were obtained from medical records. Neuropathology included semiquantitative assessment of LB and AD pathologies including cerebral amyloid angiopathy (CAA). PDD patients were significantly older than PDND and DLB ones (83.9 vs 77.9years, p < 0.05); the age of DLB patients was between them (80.0years), while the disease duration was shortest in DLB. Brain weight was lowest in DLB, which showed higher Braak LB scores (mean 5.2 vs 4.2) and highest Braak tau stages (mean 5.2 vs 4.4 and 2.3, respectively). Thal Aβ phases were also highest in DLB (mean 4.1 vs 3.0 and 1.8, respectively). Major findings were frequency and degree of CAA, being highest in DLB (95% vs 50% and 24%, with scores 2.9 vs 0.7 and 0.3, respectively), whereas other small vessel lesions showed no significant differences. Striatal Aβ deposits also differentiated DLB from the other groups. This and other studies of larger cohorts of PD patients indicate that the association of CAA and cortical tau-but less-LB pathologies are associated with more severe cognitive decline and worse prognosis that distinguish DLB from PDD and PDND. The particular impact of both CAA and tau pathology supports the concept of a pathogenic continuum ranging from PDND to DLB + AD within the spectrum of age-related synucleinopathies.

Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

BackgroundAlzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.MethodsWe generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity.ResultsReducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.ConclusionIn a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer's disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. Results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

Alzheimer Disease candidate variants are associated with cerebral amyloid angiopathy

AbstractBackgroundThe hallmark lesions of Alzheimer Disease (AD) include tangles and plaques; however, these seldom appear alone. Lesions of AD‐related dementias such as vascular dementias and Lewy body dementias often co‐occur with AD. These co‐occurring lesions and total lesion burden are associated with a higher likelihood of dementia and severe cognitive impairment. Even amongst other lesions, cerebral amyloid angiopathy (CAA) presents a strong risk for more severe cognitive impairment. CAA also shows moderate correlations to AD (rho = 0.31), suggesting that CAA pathology could present an underlying or related process of AD pathology. We hypothesize that there is a genetic overlap between CAA and AD and therefore we investigate the influence of known AD genes on CAA.MethodData come from 3,495 autopsied individuals with neuropathology and array data from the National Alzheimer’s Coordinating Centers (NACC). CAA was measured according to NACC neuropathology form guidelines. We used ordinal logistic regression to model APOE genotype and 22 other known AD variants with CAA severity while adjusting for sex, age at death, and AD pathology. For the 22 other known AD variants, we tested the lead variants reported by Kunkle et al. and labeled by closest gene. We modeled APOE by carrier status and genotype.ResultWe confirmed associations for APOE with CAA severity, when modeling APOE as e4 dosage (OR=2.34, p&lt;0.001) or by genotype (e3/e4: OR=1.96, p&lt;0.001; e4/e4: OR=5.76, p&lt;0.001). However, we did not see a significant association between CAA severity and APOEe2 carriers, as others have reported. Association persisted when including AD pathology terms in the model, even when extending to interaction‐based models. Genetic variations in 7 of the 22 known AD genes (BIN1, HLA‐DRB1, TREM2, CLU, PICALM, SORL1, SLC24A4) showed significant associations with CAA while accounting for AD pathology.ConclusionWe confirmed strong associations of APOEe4 with CAA in a large clinical population. We modeled other known AD genes and 7 of them showed significant associations with CAA, demonstrating genetic overlap between AD and CAA pathologies. This study suggests that there is genetic overlap between CAA and AD pathology that could point to shared disease mechanisms for the targeting and treatment of AD.

Cerebral amyloid angiopathy interacts with parenchymal beta‐amyloid to promote tau and cognitive decline

AbstractBackgroundPrior work has shown that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and progression toward AD dementia. Cerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology that results from the buildup of β‐amyloid (Aβ) in the vessel walls. CAA commonly co‐occurs with AD pathology and increases the risk of AD dementia. Here, we examined whether CAA influences tau deposition and cognitive decline, independently or synergistically with parenchymal Aβ burden. Secondarily, we examined whether tau burden mediates the association between CAA and cognitive decline.MethodWe included data from autopsied subjects recruited from one of three longitudinal clinical‐pathological cohort studies at Rush University. Participants completed annual cognitive evaluations and underwent brain autopsy. CAA pathology was rated as none, mild, moderate, or severe. We used linear regression and linear mixed models to test independent versus interactive effects of CAA and neuritic plaques on tau burden and cognitive decline. We used causal mediation models to examine whether tau mediates the association between CAA and cognitive decline at low and high neuritic plaque burden.ResultWe included 1722 autopsied subjects (mean age at baseline = 80.2+7.1; mean age at death = 8.9+6.7; 68% women). CAA interacted with neuritic plaques to promote tau burden and cognitive decline, such that those with more severe CAA and higher neuritic plaque burden exhibited greater tau and faster cognitive decline (Figures 1 and 2). Tau mediated the effect of CAA on cognitive decline among participants with high neuritic plaque burden. Specifically, increased tau pathology due to the presence of severe CAA led to a 5‐year decline in cognition that was 0.10 (95% CI: 0.03 ‐ 0.19) SD units greater than those with no CAA. A direct effect of CAA on cognitive decline (i.e., an effect not mediated by tau) was not significant in the low or high neuritic plaque groups (Figure 3).ConclusionThese results highlight the dynamic interplay between cerebrovascular and AD pathways in the progression of AD. The present findings have implications for AD clinical trials and therapeutic development, and further support the idea that improving and/or preserving the brain’s vasculature might be an effective target for AD prevention

Multi‐parametric Neuroimaging in a Non‐Human Primate Model of Sporadic Cerebral Amyloid Angiopathy (Saimiri boliviensis boliviensis)

AbstractBackgroundSquirrel monkeys (SQMs) are a unique non‐human primate model (NHP), which unlike other NHPs, develops extensive age‐associated cerebral amyloid angiopathy (CAA). The growing recognition of CAA contribution to clinical decline and CAA‐related complications in current clinical trials underscore the utility of the SQM model for studying CAA pathology development. Neuroimaging can play a key role in noninvasively detecting and monitoring disease progression in conjunction with histological methods. We have previously shown the utility of quantitative R2 * to map age‐related differences in SQM neuropathology cross‐sectionally and longitudinally. Here we aim to complement our protocol with advanced MRI approaches sensitive to brain microstructure to enable early and specific detection of alteration in tissue integrity. Our overarching goals aim to establish the in vivo and ex vivo MRI metrics profile of young and geriatric SQM cohorts.Method2D T2‐w (a) Turbo‐spin‐echo (TSE) and (b) FLAIR MRIs were acquired in vivo and ex vivo, while (c) multi‐shell diffusion‐weighted MRI (DWI) was limited to ex vivo imaging. Diffusion tensor imaging (DTI) and Diffusion kurtosis imaging (DKI) metrics were derived from comprehensive DWI datasets. Immunohistochemistry was subsequently performed to characterize the microstructural underpinnings of MRI abnormalities.ResultBothin vivo and ex vivo T2‐w TSE and FLAIR helped identify spontaneous asymmetric hyperintensities (ARIA‐E) in geriatric SQMs (21‐23yrs), predominantly in the parieto‐occipital WM, not seen in the young cohort (5‐yrs). Importantly, DKI‐derived mean kurtosis proved to be the most sensitive of DWI metrics for detecting lesions in the parieto‐occipital region. Widely adopted DTI metrics were far less sensitive in identifying microstructural changes. Histological assessment of region‐matched sections revealed Iba1 microgliosis, as well as immunoreactivity for both extravascular fibrinogen and decreased MBP when compared to the contralateral side. Aß immunohistochemistry (6E10/4G8) confirmed presence of CAA in the affected regions.ConclusionAdvanced DWI models are sensitive and specific neuroimaging tools for identifying abnormalities associated with tissue integrity that are potentially linked to age‐associated cerebrovascular dysfunction. Ex vivo conventional MRI detected similar abnormalities observed in vivo and proved to be a useful step to validate the performance of advanced imaging strategies, which can help bridge the gap between in vivo MRI and histology.