Cerebral Amyloid Angiopathy Patients Research Articles

Abstract P339: Evaluating Ga68 Regional Distribution as a New Pet Tracerfor Diagnosis Cerebral Amyloid Angiopathy

Introduction: The deposition of β-amyloid in cerebral vessels is an important sign of CAA. Recently, the 68Ga-P14-032 has been used in animal research. It has the ability to selectively bind a β on the cerebral vessel wall, and may become a tracer for CAA. hypothesis: We aimed to investigate the distribution of [ 68 Ga]Ga-P14-032, a novel PET ligand that binds to vascular amyloid, in patients diagnosed clinically with probable cerebral amyloid angiopathy (CAA). Methods: This longitudinal cohort study of 7 subjects (2 probable CAA patients, 2 AD patients, 3 normal subjects) recruited from clinics in China. All participants were aged at least 55 years with underwent [ 68 Ga]Ga-P14-032 PET/CT and PET/MR, a Montreal Cognitive Assessment (Moca) score on initial assessment. The brain PET/CT and PET/MR scans assessed through quantitative analysis. The mean cortical standardized uptake value ratio (SUVr) was calculated using cerebellum as reference. The cortex and white matter were segmented with ITK-Snap based on a T1-weighed image as the mask, leaving the scalp and the blood vessels out of the regions of interest. The corresponding PET volumes were extracted according to the masks obtained on MR and were fused with the MR images, using a MATLAB script. The images were read and interpreted by 2 doctors in nuclear medicine.Plasma levels of total-tau, amyloid-b40 and amyloid-b42 were measured by a single molecule array (Simoa) SR-X analyzer (Quanterix). Results: Positive expression can be seen in the pathological part of microvascular in 2 CAA patients of whom had an ICH. No significant signal was seen in AD subjects or controls. Plasma levels of total-tau, amyloid-b40 and amyloid-b42 were not different among the groups. Conclusions: Our results provide early evidence that the [68Ga]Ga-P14-032 PET probe binds preferentially to vascular amyloid, and may be a useful tracer to diagnostic of CAA. The PET marker was more sensitive to group differences than plasma assays of tau and amyloid.

Abstract P409: Cerebellar Atrophy and Its Clinical Implications in Cerebral Amyloid Angiopathy

Background: Recent data show that cerebral amyloid angiopathy (CAA) might cause hemorrhagic lesions in cerebellar cortex as well as cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated. Methods: We compared cerebellar volumes in 70 nondemented patients with probable CAA to 70 age-matched healthy controls (HC) and 70 age-matched Alzheimer’s disease (AD) patients. Volumetric analyses including cerebellar cortical volume (pCbll-CV), cerebellar subcortical volume (pCbll-ScV), cerebral white matter volume (pWMV), and cerebral white matter hyperintensity volume (pWMH) were calculated as percent of total intracranial volume. Gait velocity (meters/seconds) was used to investigate the potential effect of cerebellar tissue loss on gait function. Results: Patients with CAA had significantly lower pCbll-ScV and pCbll-CV compared to HC (1.49%±0.17 vs 1.71%±0.23, p<0.001 and 6.03%±0.50 vs 6.23%±0.56, p<0.027 respectively). When compared to AD, pCbll-ScV but not pCbll-CV was significantly lower in CAA (1.49%±0.17 vs 1.670.24, p<0.001). Diagnosis of CAA was independently associated with lower pCbll-ScV in a general linear model adjusting for age, sex and presence of hypertension when compared to both HCs and patients with AD (p<0.0001 for all associations, after Bonferroni correction for multiple comparisons). Lower pCbll-ScV was associated with lower gait velocity score in univariate and multivariate analysis adjusted for relevant variables (adjusted β=0.826, 95%CI 0.357-1.295, p=0.001). Conclusion: Patients with CAA show cerebellar atrophy; predominantly in the subcortical cerebellum when compared to both HC and AD patients. Cerebellar tissue loss independently correlated with worse gait function in CAA patients. Overall, this study supports the view that CAA causes cerebellar injury which might mediate gait disturbance in patients with CAA.

Abstract 6: The Effect of Vascular Amyloid on White Matter Disease is Mediated by Vascular Dysfunction in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with white matter hyperintensities (WMH) but the physiopathological mechanisms remain unclear. We hypothesized that the relationship between vascular amyloid load and WMH is mediated by vascular dysfunction. Methods: The study cohort included 38 non-demented probable CAA patients who underwent advanced multimodal structural and functional MRI (fMRI) and amyloid PET scans. White matter hyperintensity volume was quantified using FreeSurfer and expressed as a percent of total intracranial volume (pWMHv). Time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response to visual stimulation using fMRI was used as an established measure of vascular dysfunction. Mean cortical Pittsburg Compound B uptake representing amyloid load was calculated. A bootstrapping procedure was used to test the mediation hypothesis adjusting for age, sex, and presence of intracerebral hemorrhage (ICH). Results: Of 38 patients with CAA (mean age 70±7.1, 86.8% male), 25 (65.8%) had ICH, while the remaining 13 patients (34.2%) presented with multiple strictly cortical microbleeds. Higher amyloid load correlated with prolonged TTP response (r=0.373, p=0.021) and higher pWMHv (r=0.337, p=0.039), and prolonged TTP response correlated with higher pWMHv (r=0.485, p=0.002). Amyloid load no longer predicted pWMHv (p=0.254) after controlling for TTP. In the bootstrapping model, TTP response had a significant indirect effect (ab=0.977, 95% CI: 0.15-2.42), showing that the association between amyloid load and pWMHv is mediated by TTP. Discussion: Our findings confirm the hypothesis that the effect of vascular amyloid load on the extent of white matter disease is mediated by vascular dysfunction in patients with CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Abstract P442: The Association of Amyloid and Tau Burden With Centrum Semiovale Perivascular Spaces in Cerebral Amyloid Angiopathy

Background: The mechanisms linking cerebral amyloid angiopathy (CAA) to enlarged perivascular spaces in centrum semiovale (CSO-EPVS) and whether other Alzheimer’s Disease (AD) pathologies might affect CSO-EPVS are unclear. We hypothesized that amyloid but not tau load would independently correlate with CSO-EPVS in CAA. Methods: Fifty prospectively enrolled nondemented probable CAA patients underwent high-resolution structural MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Microbleeds (all lobar, LMB) were counted and white matter hyperintensity volume (WMH) was quantified. CSO-EPVS were counted on T 2 -MRI sequence and graded using a previously validated scale (range 0-4). A multivariate ordinal regression model was used to assess the independent associations between CSO-EPVS and mean cortical amyloid as well as tau deposition, after adjusting for relevant covariates. Results: Patients had a mean age of 69.3±7.2. Age, sex, presence of hypertension, intracerebral hemorrhage (ICH), LMB counts, and WMH were not associated with CSO-EPVS grades (p>0.2 for all comparisons). Higher PiB uptake significantly correlated with increased CSO-EPVS (rho=0.45, p=0.001). Higher FTP showed a trend for correlation with CSO-EPVS (rho=0.26, p=0.069). In an ordinal regression model with CSO-EPVS grade as the dependent variable and both amyloid and tau levels included as predictors along with covariates presented above, the association of CSO-EPVS remained significant with higher PiB uptake (β=3.97, 95%CI 1.1-6.8, p=0.007) but not with FTP uptake (p=0.167). Conclusion: Results of this study suggest that CSO-EPVS is independently associated with amyloid but not with tau deposition in CAA. CSO-EPVS was not associated with age or classical vascular risk factors or presence of ICH. Our results support the view that vascular amyloid but not other AD pathologies such as tau might contribute to EPVS in patients with CAA.

Cerebral blood flow and cerebrovascular reactivity are preserved in a mouse model of cerebral microvascular amyloidosis.

Impaired cerebrovascular function is an early biomarker for cerebral amyloid angiopathy (CAA), a neurovascular disease characterized by amyloid-β accumulation in the cerebral vasculature, leading to stroke and dementia. The transgenic Swedish Dutch Iowa (Tg-SwDI) mouse model develops cerebral microvascular amyloid-β deposits, but whether this leads to similar functional impairments is incompletely understood. We assessed cerebrovascular function longitudinally in Tg-SwDI mice with arterial spin labeling (ASL)-magnetic resonance imaging (MRI) and laser Doppler flowmetry (LDF) over the course of amyloid-β deposition. Unexpectedly, Tg-SwDI mice showed similar baseline perfusion and cerebrovascular reactivity estimates as age-matched wild-type control mice, irrespective of modality (ASL or LDF) or anesthesia (isoflurane or urethane and α-chloralose). Hemodynamic changes were, however, observed as an effect of age and anesthesia. Our findings contradict earlier results obtained in the same model and question to what extent microvascular amyloidosis as seen in Tg-SwDI mice is representative of cerebrovascular dysfunction observed in CAA patients.

Early MRI imaging and follow-up study in cerebral amyloid angiopathy.

AimTo study the imaging features of leukoaraiosis (LA) and hemorrhage in cerebral amyloid angiopathy (CAA) patients.MethodsThe earliest MRI images of probable CAA patients and non-CAA patients were collected. The characteristics of LA in the two groups were analyzed. Cerebral micro bleeding (CMB), superficial siderosis (SS), and intracranial hemorrhage (ICH) were recorded in the follow-up study. The space relationship between CMB or SS and ICH was assessed.ResultsWe found that 10/21 (47.6%) patients had occipital prominent LA and 14/21 (66.7%) patients had subcortical punctate LA before the ICH, which was higher than that of the ones in the control group (p = 0.015 and 0.038, respectively). The recurrence rate of ICH was 100% (3/3) in patients with diffuse SS and 36.4% (4/11) in patients without. The recurrence rate of ICH was 60% (3/5) in patients with multiple-lobe CMBs and 44.4% (4/9) in those without. The location of the ICH and CMB was inconsistent. ICH occurred in the ipsilateral cerebral hemisphere of SS in three patients with diffuse SS.ConclusionLA, diffuse SS, and multiple-lobe CMBs are important imaging characteristics of CAA, which may help make early diagnosis and predict the recurrence of ICH.

Platelet‐derived growth factor receptor‐beta as a potential CSF biomarker for Alzheimer’s disease

AbstractBackgroundThere is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid‐β (Aβ) in the cerebral vasculature, is commonly found in AD. Platelet‐derived growth factor receptor‐β (PDGFRβ) is expressed by pericytes and since blood‐brain barrier (BBB) dysfunction is associated with pericyte degeneration, release of PDGFRβ protein may be a biomarker for BBB dysfunction, that is expected in CAA. Indeed, it has recently been described that PDGFRβ levels are elevated in cerebrospinal fluid (CSF) from patients with mild cognitive impairment (MCI) as compared to controls1. The aim of our study was to investigate the diagnostic and discriminative value of PDGFRβ in CSF in patients at various clinical stages of AD and in patients with CAA.MethodCSF PDGFRβ, Aβ42, total tau (t‐tau) and phosphorylated tau (p‐tau) levels were quantified by ELISA. Cohorts of controls (n=47), CAA patients (n=27) and AD patients (n=59; 19 patients with MCI (clinical dementia rating (CDR) = 0.5), 28 patients with CDR 1.0 and 12 patients with a CDR of ≥ 2.0) were studied.ResultCSF PDGFRβ levels were similar in controls, AD and CAA patients. Moreover, PDGFRβ levels were similar in patients at the various clinical stages of AD. PDGFRβ levels also did not correlate with blood‐CSF barrier dysfunction (i.e. elevated albumin ratio). We observed a strong correlation of CSF PDGFRβ levels with t‐tau and p‐tau levels, the degree of which was dependent on the CDR score. Interestingly, CSF PDGFRβ levels were significantly elevated in a selection of MCI/AD patients with an AD‐positive CSF biomarker profile (A+T+) as compared to controls with a completely normal profile of AD biomarkers (A‐T‐N‐).ConclusionWe could neither confirm previously reported elevated CSF PDGFRβ levels in MCI patients1, nor did we find elevated PDGFRβ levels in CAA patients. Our results suggest that CSF PDGFRβ levels are not useful as marker of BBB integrity, but instead may, as previously reported, be associated with AD (tau) pathology2.

Hypertensive Arteriopathy and Cerebral Amyloid Angiopathy in Patients with Cognitive Decline and Mixed Cerebral Microbleeds.

Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. The two scores were positively correlated (ρ= 0.449, p < 0.001). The prevalence of lobar dominant CMB distribution (p < 0.001) and lacunes in the centrum semiovale (p < 0.001) and the severity of WMH in the parieto-occipital lobes (p = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed.

Sensitivity of the Edinburgh Criteria for Lobar Intracerebral Hemorrhage in Hereditary Cerebral Amyloid Angiopathy.

The Edinburgh computed tomography and genetic criteria enable diagnosis of cerebral amyloid angiopathy (CAA) associated lobar intracerebral hemorrhage (ICH) but have not been validated in living patients. We assessed the sensitivity of the Edinburgh criteria in patients with acute lobar ICH due to Dutch-type hereditary CAA; a genetic and pure form of CAA. We retrospectively analyzed computed tomography-scans from a cohort of consecutive Dutch-type hereditary CAA patients who presented with ≥1 episode(s) of acute lobar ICH at the Leiden University Medical Center. Presence of subarachnoid hemorrhage (SAH) and finger-like projections (FLP) were determined. Association of SAH and FLP with ICH volume was analyzed using multivariate linear regression. We included 55 Dutch-type hereditary CAA patients (mean age 56 years, 55% men) with a total of 107 episodes of acute lobar ICH. SAH was present in 82/107 (76%) and FLP in 62/107 (58%), resulting in a sensitivity of 76% for SAH and 58% for FLP. In 56 (52%), both markers were present. Nineteen (18%) lobar ICH showed no SAH extension or FLP. ICH volume was significantly associated with presence of SAH (median volume 4 versus 28 mL; P=0.001) and presence of FLP (median volume 7 versus 39 mL; P<0.001). With an ICH volume of ≥40 mL, the sensitivity of the presence of both SAH and FLP was >81% (95% CI, 70%-92%), whereas in ICH volumes <15 mL the sensitivity was <50%. The computed tomography-based Edinburgh criteria seem to be a sensitive diagnostic test for CAA-associated lobar ICH, although they should be used with caution in small-sized lobar ICH.

MRI phenotyping of underlying cerebral small vessel disease in mixed hemorrhage patients

ObjectiveTo investigate underlying cerebral small vessel disease (CSVD) in patients with mixed cerebral hemorrhages patterns and phenotype them according to the contribution of the two most common sporadic CSVD subtypes: cerebral amyloid angiopathy (CAA) vs. hypertensive arteriopathy (HA). MethodsBrain MRIs of patients with intracerebral hemorrhages (ICHs) and/or cerebral microbleeds (CMBs) were assessed for the full spectrum of CSVD markers using validated scales: ICHs, CMBs, cortical superficial siderosis (cSS), white matter hyperintensities, MRI-visible perivascular spaces (PVS). PVS predominance pattern was grouped as centrum-semiovale (CSO)-PVS predominance, basal-ganglia (BG)-PVS predominance, CSO-PVS and BG-PVS equality. Patients with mixed cerebral hemorrhages were classified into mixed CAA-pattern or mixed HA-pattern according to the existence of cSS and/or a CSO-PVS predominance pattern and comparisons were performed. ResultsWe included 110 patients with CAA (strictly lobar ICHs/CMBs), 33 with HA (strictly deep ICHs/CMBs) and 97 with mixed lobar/deep ICHs/CMBs. Mixed patients were more similar to HA with respect to their MRI-CSVD markers, vascular risk profile and cerebrospinal fluid (CSF) measures. In the mixed patients, 33 (34%) had cSS, a CSO-PVS predominance pattern, or both, and were defined as mixed CAA-pattern cases. The mixed CAA-pattern patients were more alike CAA patients regarding their MRI-CSVD markers, CSF and genetic profile. ConclusionOur findings suggest that the heterogeneous group of patients with mixed cerebral hemorrhages distribution can be further phenotyped according to the predominant underlying CSVD. cSS presence and a CSO-PVS predominance pattern could serve as strongly suggestive markers of a contribution from CAA among patients with mixed hemorrhages.

PREVALENCE OF CEREBRALAMYLOID ANGIOPATHY (CAA)-RETROSPECTIVE SINGLE CENTRE ANALYSIS FROM 2009 TO 2019

OBJECTIVE: The present study aims to analyse the prevalence of Cerebral Amyloid Angiopathy (CAA) among the various neuro surgical tissue samples, to study the histomorphological changes of CAA in neural tissue and to analyse their association with increasing age &amp; neurological disorders. METHOD: Retrospective analysis and review of all neurosurgical specimens received during the period from 2009 to 2019 was carried out. Review of the clinical details including radiological images, and review of paraffin sections was conducted by two pathologists after appropriate special stains like Congo red. RESULTS: Among the 301 cases studied, 14(4.65%) had evidence of CAA. Of the 14, 6(42.86%) were males and 8(57.14%) were female All of the 14(10.77%) cases were above the age group of 50 years. In the more than 50 age group, this contributes to 9.68% of males and 11.76% of females. CONCLUSIONS: CAA is found to be a diagnosis more common in the older age group (&gt;50 years) and with a female preponderance. Familiarising &amp; understanding the pathological sequence and morphological changes of CAA, will help in diagnosis, formulating treatment options for the better clinical outcome of CAA patients

Efficacy and Safety of Direct Oral Anticoagulant for Treatment of Atrial Fibrillation in Cerebral Amyloid Angiopathy

A 75-year-old man with a history of atrial fibrillation (AF) and anticoagulant therapy presented with a headache. Cerebral amyloid angiopathy (CAA) was diagnosed after MRI of the brain revealed cortical superficial siderosis, lobar intracerebral hemorrhage, and lobar microbleeds. Anticoagulant therapy was carefully discontinued. Several years later, he was admitted with sudden onset left upper-extremity weakness. In addition to CAA bleeding lesions, a diffusion-weighted brain MRI showed multiple infarct lesions of high signal intensity. The administration of edoxaban 7.5 mg/day (later increased up to 30 mg/day) prevented ischemic stroke recurrence without exacerbation of cerebral bleeding. This could indicate that CAA patients with AF who had previous adverse effects from warfarin can safely use newer direct oral anticoagulants, such as edoxaban, to prevent ischemic stroke without danger of cerebral hemorrhage. The superiority of edoxaban as compared with warfarin might be due to its antioxidant effect because vascular oxidative stress plays a causal role in CAA-induced cerebrovascular dysfunction, CAA-induced cerebral hemorrhage, and CAA formation itself. We explained the beneficial effect of edoxaban for CAA by the mechanism of oxidative stress in the paper.

Utility of HAS-BLED and CHA2DS2-VASc Scores Among Patients With Atrial Fibrillation and Imaging Evidence of Cerebral Amyloid Angiopathy

ObjectiveTo determine the utility of the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly) and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack–VAScular disease) scores among patients on anticoagulation (AC) therapy for atrial fibrillation (AF) who have evidence of cerebral amyloid angiopathy (CAA). Patients and MethodsPatients older than 55 years with a diagnosis of AF who had a nontraumatic intracerebral hemorrhage (ICH) while on AC therapy between 1995 and 2016 were identified using the Rochester Epidemiology Project Database. Medical records were reviewed, including imaging of the brain, to identify baseline characteristics, AC use, and outcomes. ResultsA total of 65 patients were identified (mean age, 81.3 years); 35 (53.8%) had evidence of possible/probable CAA. Mean HAS-BLED score in the CAA group was significantly lower (2.1) than that of the non-CAA group (2.9; P<.001). Mortality after ICH, adjusted for HAS-BLED scores, was not significantly different among patients with and without CAA. Sixteen patients restarted on AC therapy after ICH; CHA2DS2-VASc scores were no different between this group and those who were not restarted. Among patients with CAA, the overall rate of ICH recurrence was 8.6% over 93.5 person-years of follow-up. Among patients with CAA, the rate of ICH recurrence was 3.2 per 100 patient-years, higher than their HAS-BLED scores would predict (1.9 bleeds/100 patient-years). ConclusionHAS-BLED scores were lower in patients who had evidence of CAA compared with those without, suggesting underestimation of ICH risk in patients with CAA. CHA2DS2-VASc scores did not affect resumption of AC therapy. ICH recurrence was higher in patients with CAA than their HAS-BLED scores predicted. Current risk assessment scoring systems do not accurately account for CAA in patients with AF on AC.

Clinical and radiological differences between patients with probable cerebral amyloid angiopathy and mixed cerebral microbleeds

BackgroundThe key imaging features of cerebral amyloid angiopathy (CAA) are lobar, cortical, or cortico-subcortical microbleeds, macrohaemorrhages and cortical superficial siderosis (cSS). In contrast, hypertensive angiopathy is characterized by (micro) haemorrhages in the basal ganglia, thalami, periventricular white matter or the brain stem. Another distinct form of haemorrhagic microangiopathy is mixed cerebral microbleeds (mixed CMB) with features of both CAA and hypertensive angiopathy. The distinction between the two entities (CAA and mixed CMB) is clinically relevant because the risk of haemorrhage and stroke should be well balanced if oral anticoagulation is indicated in CAA patients. We aimed to comprehensively compare these two entities.MethodsPatients with probable CAA according to the modified Boston criteria and mixed CMB without macrohaemorrhage were retrospectively identified from our database. Comprehensive comparison regarding clinical and radiological parameters was performed between the two cohorts.ResultsPatients with CAA were older (78 ± 8 vs. 74 ± 9 years, p = 0.036) and had a higher prevalence of cSS (19% vs. 4%, p = 0.027) but a lower prevalence of lacunes (73% vs. 50%, p = 0.018) and deep lacunes (23% vs. 51%, p = 0.0003) compared to patients with mixed CMB. Logistic regression revealed an association between the presence of deep lacunes and mixed CMB. The other collected parameters did not reveal a significant difference between the two groups.ConclusionsCAA and mixed CMB demonstrate radiological differences in the absence of macrohaemorrhages. However, more clinically available biomarkers are needed to elucidate the contribution of CAA and hypertensive angiopathy in mixed CMB patients.

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as ‘the prion hypothesis’ have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.

Background:There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).Objective:To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.Methods:We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.Results:We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile.Conclusion:CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.

Predictors of localization, outcome, and etiology of spontaneous intracerebral hemorrhages: focus on cerebral amyloid angiopathy

Despite its clinical relevance, cerebral amyloid angiopathy (CAA) is underdiagnosed worldwide. This retrospective study aimed to assess the incidence, etiology, predictors, and outcome of intracerebral hemorrhages (ICHs) in this region, with special focus on possible underlying CAA. Database screening of acute cares with intracranial hemorrhage diagnosis within 01/07/2014–01/07/2018 were conducted analyzing medical records and imaging. Spontaneous ICHs were classified as deep (basal ganglionic/thalamic/brainstem) and lobar/cerebellar (i.e., CAA-compatible) ICHs. Probable/definite CAA was established using the modified Boston criteria in a subgroup with ‘complete’ radiological/neuropathological work-up. The ability of several factors to discriminate between deep and lobar/cerebellar ICHs, between probable/definite CAA and non-probable CAA cases, and to predict 1-month case fatality was assessed. Of the 213 ICHs identified, 121 were in deep and 92 in lobar/cerebellar localization. Sub-analysis of 47 lobar/cerebellar ICHs with ‘complete’ work-up identified 16 probable/definite CAA patients, yielding an estimated 14.7% prevalence of CAA-related ICHs. Chronic hypertension was the most prevalent risk factor for all types of ICHs (including CAA-related), with hypertensive excess and younger age being independent predictors of deep whereas antiplatelet use of lobar/cerebellar localization. The 1-month case fatality was 33.8%, driven predominantly by age and INR > 1.4. Probable/definite CAA diagnosis was independently predicted by age, prior intracranial hemorrhage, and antiplatelet use. First in this region and among the few in the literature, this study reports a remarkable prevalence of CAA-related ICHs, emphasizing the need for an increased awareness of CAA and its therapeutic implications, especially regarding antiplatelets among the elderly.

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy.

We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n=9), Alzheimer's disease (AD) (n=11) and healthy control cases (n=11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n=31), AD patients (n=27) and non-neurological controls (n=67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85years), and paired CSF and serum samples. ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P=0.0008). Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

Abstract 16: Functional Magnetic Resonance Imaging as a Predictor of Cognitive Impairment in Cerebral Amyloid Angiopathy

Background: Cerebral Amyloid Angiopathy (CAA) emerged as an important contributor to cognitive impairment (CI) in elderly. Multiple lines of evidence suggest the presence of vascular dysfunction in CAA but its relationship to CI has not been tested. We hypothesized that the degree of vascular dysfunction identified by functional magnetic resonance imaging (fMRI) is a predictor of subsequent development of CI in patients with CAA. Methods: Thirty nondemented probable CAA patients diagnosed with Boston criteria were prospectively enrolled. They underwent high-resolution structural MRI and fMRI at baseline and cognitive assessment both at baseline and follow up. Structural MRI markers (microbleed counts, superficial siderosis, enlarged perivascular spaces, cortical microinfarcts) and FreeSurfer based volumetric analyses (cortical thickness, white matter hyperintensity volume) were obtained. An fMRI measure of vascular reactivity to visual stimulation, time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response, was the main physiologic marker of interest. Main outcome measure was the development of CI defined based on structured cognitive assessments. Results: Patients had a mean age of 69.1±7.6 years. During a median follow-up of 23 months, 13 patients (43.3%) developed CI. Patients who developed CI did not differ from the patients without CI in terms of age, sex, risk factors and structural MRI markers (all p&gt;0.2). Patients with CI trended towards fewer years of education (16±2.8 years vs 18±2.8 years, p=0.069). Baseline TTP of BOLD response was significantly higher in patients with incident CI as compared to patients without CI (12.7 ± 5.8 vs 7.8 ± 2.9, p=0.005). In a cox regression analysis, higher TTP was independently associated with future CI risk, after adjusting for age, sex, WMH volumes and education years (hazard ratio: 1.23; 95% CI: 1.06-1.42; p=0.006). Conclusion: The severity of baseline vascular dysfunction is associated with future CI in CAA. Unlike markers of parenchymal injury that are typically irreversible, vascular dysfunction might be reversible making our findings potentially relevant to future therapeutic development efforts.