Cerebral Amyloid Angiopathy Patients Research Articles

Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage.

There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

Novel inflammatory and insulin resistance indices provide a clue in cerebral amyloid angiopathy

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07–1.30, P < 0.001), and triglyceride–glucose index (TyG, OR = 0.56, 95% CI 0.36–0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764–0.865) in the training set and 0.830 (95% CI 0.718–0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.

Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage.

Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage, and a more hemorrhagic disease course compared to women. In this cohort study we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo MRI-markers and local cortical iron burden, and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodelling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. In 6120 individuals from the NACC database (45% women, mean age 80y), the presence of parenchymal amyloid-β (OR [95%CI]=0.68 [0.53-0.88]) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75y), a lower microbleed count (p<0.001), but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p<0.001) compared to women. CAA percentage area was comparable in men and women (p=0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p=0.03). Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodelling, may contribute, but future studies are necessary to replicate our findings in larger datasets and to further investigate the underlying mechanisms behind these complex sex differences.

Association of LDL-cholesterol

Recent intensive low-density lipoprotein cholesterol (LDL-C) lowering trials, including FOURIER, ODYSSEY OUTCOMES, and Treat Stroke to Target (TST) trials, have mostly refuted the concern surrounding statin use, LDL-C lowering, and intracerebral hemorrhage (ICH) risk. However, the results from these trials may not be fully applied to ICH survivors, as the populations studied were mainly patients without prior ICH, in whom the inherent ICH risk is more than 10 times lower than that of ICH survivors. Although available literature on statin use after ICH has demonstrated no excess risk of recurrent ICH, other potential factors that may modify ICH risk, especially hypertension control and ICH etiology, have not generally been considered. Notably, data on LDL-C levels following ICH are lacking. We aim to investigate the association between LDL-C levels and statin use with ICH risk among ICH survivors, and to determine whether the risk differed with patients' characteristics, especially ICH etiology. Follow-up data of consecutive spontaneous ICH survivors enrolled in the University of Hong Kong prospective stroke registry from 2011 to 2019 were retrospectively analyzed. ICH etiology was classified as cerebral amyloid angiopathy (CAA) using the modified Boston criteria or hypertensive arteriopathy, while the mean follow-up LDL-C value was categorized as <1.8 or ⩾1.8 mmol/L. The primary endpoint was recurrent ICH. The association of LDL-C level and statin use with recurrent ICH was determined using multivariable Cox regression. Pre-specified subgroup analyses were performed, including based on ICH etiology and statin prescription. Follow-up blood pressure was included in all the regression models. In 502 ICH survivors (mean age = 64.2 ± 13.5 years, mean follow-up LDL-C = 2.2 ± 0.6 mmol/L, 28% with LDL-C <1.8 mmol/L), 44 had ICH recurrence during a mean follow-up of 5.9 ± 2.8 years. Statin use after ICH was not associated with recurrent ICH (adjusted hazard ratio (AHR) = 1.07, 95% confidence interval (CI) = 0.57-2.00). The risk of ICH recurrence was increased for follow-up LDL-C <1.8 mmol/L (AHR = 1.99, 95% CI = 1.06-3.73). This association was predominantly observed in ICH attributable to CAA (AHR = 2.52, 95% CI = 1.06-5.99) and non-statin users (AHR = 2.91, 95% CI = 1.08-7.86). The association between post-ICH LDL-C <1.8 mmol/L and recurrent ICH was predominantly observed in CAA patients and those with intrinsically low LDL-C (non-statin users). While statins can be safely prescribed in ICH survivors, LDL-C targets should be individualized and caution must be exercised in CAA patients.

Cognitive profile in cerebral small vessel disease: comparison between cerebral amyloid angiopathy and hypertension-related microangiopathy

Cerebral amyloid angiopathy (CAA) is recognized as a cause of cognitive impairment, but its cognitive profile needs to be characterized, also respect to hypertension-related microangiopathy (HA). We aimed at comparing difference or similarity of CAA and HA patients’ cognitive profiles, and their associated factors. Participants underwent an extensive clinical, neuropsychological, and neuroimaging protocol. HA patients (n = 39) were more frequently males, with history of vascular risk factors than CAA (n = 32). Compared to HA, CAA patients presented worse performance at MoCA (p = 0.001) and semantic fluency (p = 0.043), and a higher prevalence of amnestic MCI (46% vs. 68%). In univariate analyses, multi-domain MCI was associated with worse performance at MoCA, Rey Auditory Verbal Learning Test (RAVLT), and semantic fluency in CAA patients, and with worse performance at Symbol Digit Modalities Test (SDMT) and phonemic fluency in HA ones. In multivariate models, multi-domain deficit remained as the only factor associated with RAVLT (β = − 0.574) in CAA, while with SDMT (β = − 0.364) and phonemic fluency (β = − 0.351) in HA. Our results highlight different patterns of cognitive deficits in CAA or HA patients. While HA patients’ cognitive profile was confirmed as mainly attentional/executive, a complex cognitive profile, characterized also by deficit in semantic memory, seems the hallmark of CAA patients.

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 150: Regional Molecular Alterations in Cerebral Amyloid Angiopathy-Related Hemorrhagic Lesions

Background: Previous case reports suggested co-localization of tau but not β-Amyloid with cortical superficial siderosis (cSS) in cerebral amyloid angiopathy (CAA). We thus hypothesized that the tau load represents a continuum with amyloid accumulation in the disease cascade and that the tau load would be higher in lobes with cSS and intracerebral hemorrhages (ICH) when compared to the contralateral lobes without hemorrhages in CAA patients. Methods: The study included 26 cognitively healthy probable CAA patients (mean age 71±7.5, 53.8% male) who underwent multimodal MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Mean global cortical PiB uptake and FTP uptake were calculated in each lobar region. The presence of ICH and cSS were identified in each lobar region independent of molecular imaging. A pairwise comparison of PiB and FTP uptake was done between lobes with any hemorrhagic lesion (ICH/cSS) and their corresponding lobes without hemorrhages. Results: The FTP uptake was significantly higher in 8 frontal, 16 temporal, and 11 occipital lobes with hemorrhages compared to their corresponding contralateral lobes without hemorrhages (1.18±0.1 vs. 1.13±0.1; p=0.002, 1.28±0.1 vs. 1.20±0.1; p=0.004, 1.29±0.1 vs. 1.10±0.1; p=0.002, respectively) but not in parietal lobes (p=0.107). The PiB uptake was significantly higher in occipital lobes with hemorrhages compared to their contralateral lobes without hemorrhages (1.41±0.3 vs. 1.35±0.3, p=0.004) but there was no difference in the comparison of amyloid burden for the remaining lobar regions with or without hemorrhage (p&gt;0.2 for all comparisons). Conclusions: Reduced PiB uptake at sites of larger hemorrhagic lesions (cSS/ICH) has been observed in the past so the lack of differences in amyloid between most lobes with and without hemorrhage was not surprising in our study. Our results otherwise show significantly increased tau load at most brain lobes with hemorrhagic lesions among CAA patients. Potential clinical effects of the tau burden related to cSS/ICH should be studied in larger CAA cohorts using appropriate clinical testing.

Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)

To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. Atotal of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CAA is afrequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with ahigher number of cortical and subcortical microbleeds.

Amyloid spell – A close mimic of transient ischemic attack!

Transient focal neurological episodes, also called amyloid spells occur as recurrent, transient episodes of spreading paresthesia seen in 14% of cerebral amyloid angiopathy (CAA) patients. An 81-year-old gentleman with coronary artery disease and a left ventricular clot was on anticoagulant treatment. He presented with three episodes of tingling in the left fingers spreading to the left arm and left leg, each lasting for 10 min. Magnetic resonance imaging of the brain with susceptibility imaging showed convexity hemorrhage, and curvilinear blooming in sulcal spaces of the right cerebral convexity and left precuneus. Warfarin was stopped. He was treated with clobazam, aspirin, and atorvastatin. He improved, so was discharged after 2 days. Amyloid spells can be confused with transient ischemic attack (TIA) or its mimics and the treatment given for TIA can lead to intracranial hemorrhage in CAA patients. Radiological features aid in the diagnosis of CAA and antiplatelets need to be administered cautiously in patients with suspected TIA.

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.

Aβ38 and Aβ43 do not differentiate between Alzheimer's disease and cerebral amyloid angiopathy.

Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aβ38 and Aβ43 to a standard AD biomarker panel (Aβ40, Aβ42, t-tau, p-tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques. We found excellent discrimination between AD and controls and between CAA and controls, but not between AD and CAA. Adding Aβ38 and Aβ43 to the panel did not improve the discrimination between AD and CAA.

Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort.

For the management of central nervous system (CNS) vasculitis, it is crucial to differentiate between primary and secondary CNS vasculitis and to understand the respective etiologies. We assessed the etiology, characteristics, and outcomes of patients with CNS vasculitis. A single-center retrospective chart review was conducted at the University of Utah, Department of Neurology, between February 2011 and October 2022. The median age of the 44 included patients at diagnosis was 54years; 25.0% were men. Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits higher fever incidence (observed in infectious and connective tissue disorder [CTD]-associated vasculitis), low glucose levels (mostly in infectious vasculitis) and unique cerebrospinal fluid oligoclonal bands (observed in infectious and CTD-associated vasculitis). Patients with inflammatory cerebral amyloid angiopathy (CAA) were older and more commonly had microhemorrhage than primary angiitis of the CNS (PACNS). All patients with CTD-associated vasculitis had a known history of CTD at presentation. Brain biopsies were performed on 10 of 17 PACNS patients and 4 of 8 inflammatory CAA patients, confirming vasculitis in 7 and 4 patients, respectively. Intravenous methylprednisolone was the predominant induction therapy (63.6%), and cyclophosphamide was the most used adjunctive therapy. Cyclophosphamide, rituximab, azathioprine, and mycophenolate mofetil were utilized as maintenance therapy, often with concurrent prednisone. Patients with inflammatory CAA had a higher tendency for relapse rates than PACNS. This study highlights the variations in patients' characteristics, symptoms, and treatment for CNS vasculitis. Understanding these differences can lead to more efficient diagnostic and management strategies.

Tissue inhibitor of matrix metalloproteinases 4: a novel marker associated with CAA

AbstractBackgroundWe have previously shown that matrix metalloproteinase 9 (MMP9) and tissue inhibitor of proteinases 3 (TIMP3) are specifically expressed in the vasculature of patients with cerebral amyloid angiopathy (CAA). Moreover, we have demonstrated increased MMP9 and decreased TIMP3 levels, as well as an altered MMP9:TIMP3 ratio in the vasculature of CAA patients that suffered from intracerebral haemorrhages (CAA‐ICH) compared to CAA patients without ICH (CAA‐nonICH). We now extended our studies to investigate whether TIMP4 may have a similar role in CAA, as this has not been studied before.MethodUsing immunohistochemistry, we studied occipital lobe tissue of 44 controls (mean age 78.4 years; 50% female) and 58 CAA patients (77.5 years; 55% female; 40 CAA‐nonICH and 18 CAA‐ICH). Vascular TIMP4 staining was scored in a semiquantitative manner. Using ELISA, we measured TIMP4 CSF levels of 33 CAA patients (mean age 72.2 years; 47% female) and 35 controls (mean age 71.2 years; 51% female). For a subset of CSF samples (11 CAA samples and 14 controls), the levels of MMP2, MMP9, and MMP14 have been determined previously, and now their ratios to TIMP4 were calculated. Differences between CAA patients and controls were assessed using (ordinal) linear regression analysis.ResultIn brain tissue, CAA cases had increased vascular TIMP4 expression when compared to controls (p = 0.00002, figure 1). TIMP4 expression did not differ between CAA‐nonICH and CAA‐ICH cases. In the absence of vascular TIMP4 staining, we often observed perivascular staining. Decreased levels of perivascular TIMP4 staining were observed in CAA‐ICH cases when compared to CAA‐nonICH cases (p = 0.045) and to controls (p = 0.035). CSF levels of TIMP4 were decreased in CAA patients compared to controls (p = 0.03, figure 2). In addition, the ratios of MMP2 (p = 0.038), MMP9 (p = 0.005), and MMP14 (p = 0.025) to TIMP4 were increased in CAA patients compared to controls.ConclusionWe demonstrated increased TIMP4 expression in vessel walls of CAA patients compared to controls. In contrast, TIMP4 CSF levels were decreased in CAA patients compared to controls, whereas MMP:TIMP4 ratios were increased, indicating a disbalance of MMP/TIMP4 levels in CAA pathophysiology.Funding: BIONIC project (no. 733050822, ZonMW) and CAFÉ project (no. 5R01NS104147‐02, NIH).

SWI versus GRE-T2*: Assessing cortical superficial siderosis in advanced cerebral amyloid angiopathy

Background and purposeCortical superficial siderosis (cSS) is a key neuroimaging marker of cerebral amyloid angiopathy (CAA) detected on blood-sensitive magnetic resonance imaging (MRI). We aimed to assess cSS in advanced CAA patients and explore differences in its evaluation between susceptibility weighted imaging (SWI) and gradient recalled echo-T2* (GRE-T2*). Materials and methodsNeuroimaging data gathered from a prospective cohort of CAA patients with probable or definite CAA were retrospectively analyzed by two independent raters. SWI and GRE-T2*were used to assess presence and severity (absent, focal [≤3 sulci] or disseminated [>3 sulci]) of cSS and number of foci. Ratings were compared between sequences and inter-rater agreement was determined. Post hoc analysis explored differences in cSS multifocality scores. ResultsWe detected cSS in 38 patients with SWI and in 36 with GRE-T2* (70.4% versus 66.7%; P=0.5). The two raters agreed in detecting more disseminated cSS when using SWI: 16 focal (29.63%) and 20 disseminated (37.04%) cases of cSS seen on GRE-T2* and 11 (20.37%) focal and 27 (50%) disseminated cSS cases seen using SWI (P=0.008). Inter-rater agreement was equivalent for the two sequences (κpresence 0.7 versus 0.69; κseverity 0.74 versus 0.66) for assessing both presence and severity of cSS. Post hoc analysis showed higher multifocality scores from both raters’ SWI evaluations, with agreement equivalent to that for T2* evaluations. ConclusionsOur findings suggest that SWI ratings could show more disseminated cSS and higher multifocality scores in advanced CAA patients with inter-rater reliability equivalent to that obtained using GRE-T2*, regardless of level of experience.

Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy. We have previously shown that transcription regulating proteins- inhibitor of DNA binding protein 3 (ID3) and the nuclear respiratory factor 1 (NRF1) contribute to vascular dysregulation. In this study, we have identified sex specific ID3 and NRF1-mediated gene networks in CAA patients diagnosed with Alzheimer's Disease (AD). High expression of ID3 mRNA coupled with low NRF1 mRNA levels was observed in the temporal cortex of men and women CAA patients. Low NRF1 mRNA expression in the temporal cortex was found in men with severe CAA. High ID3 expression was found in women with the genetic risk factor APOE4. Low NRF1 expression was also associated with APOE4 in women with CAA. Genome wide transcriptional activity of both ID3 and NRF1 paralleled their mRNA expression levels. Sex specific differences in transcriptional gene signatures of both ID3 and NRF1 were observed. These findings were further corroborated by Bayesian machine learning and the GeNIe simulation models. Dynamic machine learning using a Monte Carlo Markov Chain (MCMC) gene ordering approach revealed that ID3 was associated with disease severity in women. NRF1 was associated with CAA and severity of this disease in men. These findings suggest that aberrant ID3 and NRF1 activity presumably plays a major role in the pathogenesis and severity of CAA. Further analyses of ID3- and NRF1-regulated molecular drivers of CAA may provide new targets for personalized medicine and/or prevention strategies against CAA.

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study

BackgroundAge-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA. ObjectiveTo compare the prevalence of CAA in patients with or without AMD matched for age. MethodsWe conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD). ResultsOur analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669). ConclusionsAMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model

Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Incidence and risk factors associated with seizures in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a common cause of intracranial hemorrhage (ICH), which is a risk factor for seizures. The incidence and risk factors of seizures associated with a heterogeneous cohort of CAA patients have not been studied. We conducted a retrospective study of patients with CAA treated at Mayo Clinic Florida between 1 January 2015 and 1 January 2021. CAA was defined using the modified Boston criteria version 2.0. We analyzed electrophysiological and clinical features, and comorbidities including lobar ICH, nontraumatic cortical/convexity subarachnoid hemorrhage (cSAH), superficial siderosis, and inflammation (CAA with inflammation [CAA-ri]). Cognition and mortality were secondary outcomes. Univariate and multivariate analyses were performed to determine risk of seizures relative to clinical presentation. Two hundred eighty-four patients with CAA were identified, with median follow-up of 35.7 months (interquartile range = 13.5-61.3 months). Fifty-six patients (19.7%) had seizures; in 21 (37.5%) patients, seizures were the index feature leading to CAA diagnosis. Seizures were more frequent in females (p = 0.032) and patients with lobar ICH (p = 0.002), cSAH (p = 0.030), superficial siderosis (p < 0.001), and CAA-ri (p = 0.005), and less common in patients with microhemorrhage (p = 0.006). After controlling for age and sex, lobar ICH (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.1-4.2), CAA-ri (OR = 3.8, 95% CI = 1.4-10.3), and superficial siderosis (OR = 3.7, 95% CI = 1.9-7.0) were independently associated with higher odds of incident seizures. Seizures are common in patients with CAA and are independently associated with lobar ICH, CAA-ri, and superficial siderosis. Our results may be applied to optimize clinical monitoring and management for patients with CAA.

Cerebrospinal fluid biomarkers for cerebral amyloid angiopathy.

Integrating cerebrospinal fluid-biomarkers into diagnostic workup of patients with sporadic cerebral amyloid angiopathy may support early and correct identification. We aimed to identify and validate clinical- and cerebrospinal fluid-biomarkers for in vivo diagnosis of cerebral amyloid angiopathy. This observational cohort study screened 2795 consecutive patients admitted for cognitive complaints to the academic departments of neurology and psychiatry over a 10-year period (2009-2018). We included 372 patients with available hemosiderin-sensitive MR imaging and cerebrospinal fluid-based neurochemical dementia diagnostics, i.e. Aβ40, Aβ42, t-tau, p-tau. We investigated the association of clinical- and cerebrospinal fluid-biomarkers with the MRI-based diagnosis of cerebral amyloid angiopathy, applying confounder-adjusted modelling, receiver operating characteristic and unsupervised cluster analyses. We identified 67 patients with cerebral amyloid angiopathy, 76 patients with Alzheimer's disease, 75 patients with mild cognitive impairment due to Alzheimer's disease, 76 patients with mild cognitive impairment with unlikely Alzheimer's disease and 78 healthy controls. Patients with cerebral amyloid angiopathy showed a specific cerebrospinal fluid pattern: average concentration of Aß40 [13 792 pg/ml (10 081-18 063)] was decreased compared to all controls (P < 0.05); Aß42 [634 pg/ml (492-834)] was comparable to Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease (P = 0.10, P = 0.93) but decreased compared to mild cognitive impairment and healthy controls (both P < 0.001); p-tau [67.3 pg/ml (42.9-91.9)] and t-tau [468 pg/ml (275-698)] were decreased compared to Alzheimer's disease (P < 0.001, P = 0.001) and mild cognitive impairment due to Alzheimer's disease (P = 0.001, P = 0.07), but elevated compared to mild cognitive impairment and healthy controls (both P < 0.001). Multivariate modelling validated independent clinical association of cerebral amyloid angiopathy with older age [odds-ratio: 1.06, 95% confidence interval (1.02-1.10), P < 0.01], prior lobar intracerebral haemorrhage [14.00 (2.64-74.19), P < 0.01], prior ischaemic stroke [3.36 (1.58-7.11), P < 0.01], transient focal neurologic episodes (TFNEs) [4.19 (1.06-16.64), P = 0.04] and gait disturbance [2.82 (1.11-7.15), P = 0.03]. For cerebrospinal fluid-biomarkers per 1 pg/ml, both lower Aß40 [0.9999 (0.9998-1.0000), P < 0.01] and lower Aß42 levels [0.9989 (0.9980-0.9998), P = 0.01] provided an independent association with cerebral amyloid angiopathy controlled for all aforementioned clinical confounders. Both amyloid biomarkers showed good discrimination for diagnosis of cerebral amyloid angiopathy among adjusted receiver operating characteristic analyses (area under the receiver operating characteristic curves, Aß40: 0.80 (0.73-0.86), P < 0.001; Aß42: 0.81 (0.75-0.88), P < 0.001). Unsupervised Euclidian clustering of all cerebrospinal fluid-biomarker-profiles resulted in distinct segregation of cerebral amyloid angiopathy patients from all controls. Together, we demonstrate that a distinctive set of cerebrospinal fluid-biomarkers effectively differentiate cerebral amyloid angiopathy patients from patients with Alzheimer's disease, mild cognitive impairment with or without underlying Alzheimer's disease, and healthy controls. Integrating our findings into a multiparametric approach may facilitate diagnosing cerebral amyloid angiopathy, and may aid clinical decision-making, but warrants future prospective validation.

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)