Apolipoprotein E (APOE) genotype influences the presence, course and severity of sporadic cerebral amyloid angiopathy (sCAA). We investigated the effect of the APOE ε4-allele on clinical and neuroradiological outcomes in mutation-carriers with Dutch-type hereditary (D-)CAA. Participants with D-CAA from a prospective cohort study, with data collected on history of symptomatic intracerebral hemorrhages (sICH) and vascular risk factors, underwent 3 Tesla magnetic resonance imaging (MRI) scans to assess macrobleeds, cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH) volume and WMH multispot lesions. Global cognition was measured using Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores. Associations between ≥1 APOE ε4-allele and age of first sICH, time to recurrence, cognition and radiological data were analyzed with adjustments for confounders. Eighty-one participants (mean age 47 years, 54% women, 38% with sICH history) were included. The APOE ε4-allele was not associated with earlier sICH onset (median age 56 versus 57 years; p = 0.6) or time to recurrence (5.0 versus 3.9 years; p = 0.4), nor was it associated with macrobleeds (β 2.0; 95%CI 2.4- -2.7; p = 0.4), CMBs (β 2.9; 95%CI 1.0-8.9; p = 0.06), cSS (aOR 0.5; 95%CI 0.1-2.0; p = 0.3), EPVS (aOR 0.4; 95%CI 0.1-1.5; p = 0.6), WMH volume (β 6.8; 95%CI -1.9-15.4; p = ), a multispot pattern (OR 0.7; 95%CI 0.2-2.7, p = 0.6), or cognition (β -0.3; 95%CI -0.4- -0.5; p = 0.5). APOE ε4 does not affect key clinical parameters or D-CAA neuroradiological markers and therefore does not explain the large variation in disease course in D-CAA.

Knowledge on the short-term progression of cerebral amyloid angiopathy (CAA) is important for clinical practice and the design of clinical treatment trials. We investigated the 1-year progression of CAA-related MRI markers in sporadic (sCAA) and Dutch-type hereditary (D-CAA). Participants were included from 2 prospective cohort studies. 3T-MRI was performed at baseline and after 1 year. We assessed macrobleeds, cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), convexity subarachnoid hemorrhages (cSAHs), white matter hyperintensities (WMH), enlarged centrum semiovale perivascular spaces (CSO-EPVS), and visually stimulated blood oxygenation level-dependent (BOLD) fMRI parameters. Progression was defined as increase in number of macrobleeds or CMBs, new focus or extension of cSS, increase in CSO-EPVS category, or volume increase of >10% of WMH. Multivariable regression analyses were performed to determine factors associated with progression and the association between events related to parenchymal injury (cSAH, macrobleeds) and radiologic progression. We included 98 participants (47% women): 55 with sCAA (mean age 70 years), 28 with symptomatic D-CAA (mean age 59 years), and 15 with presymptomatic D-CAA (mean age 45 years). Progression of >1 MRI markers was seen in all 83 (100%) participants with sCAA and symptomatic D-CAA and in 9 (60%) with presymptomatic D-CAA. The number of CMBs showed the largest progression in sCAA (98%; median increase 24) and symptomatic D-CAA (100%; median increase 58). WMH volume (>10% increase in 70%; mean increase 1.2 mL) was most progressive in presymptomatic D-CAA. A decrease in the upslope of the visually evoked BOLD response was observed for most patients. Symptomatic D-CAA status was associated with more overall progression (adjusted odds ratio [aOR] 9.7; 95% CI 1.7-54.2), CMB (adjusted relative risk [aRR] 2.47; 95% CI 1.5-4.1), and WMH volume progression (β 2.52; 95% CI 0.3-4.8). Baseline CMB count (aRR 1.002; 95% CI 1.001-1.002) was associated with CMB progression and cSS presence at baseline (aOR 8.16; 95% CI 2.6-25.4) with cSS progression. cSS progression was also associated with cSAH and macrobleeds (aOR 21,029; 95% CI 2.042-216.537). CAA is a radiologically progressive disease even in the short-term. After 1 year, all symptomatic and most of the presymptomatic participants showed progression of at least 1 MRI-marker. CMBs and WMH volume (in symptomatic CAA) and WMH volume (in presymptomatic CAA) are the most promising markers to track short-term progression in future trials.

Iatrogenic cerebral amyloid angiopathy is a rare yet clinically relevant condition that may develop decades after cadaveric dura mater transplantation. We present the case of a 48-year-old man who experienced recurrent, bilateral, multilobar intracerebral hemorrhages approximately 40 years after childhood dura mater transplantation. Pathological examination confirmed amyloid β protein deposition around small cerebral blood vessels in the brain parenchyma. Genetic testing excluded mutations associated with hereditary cerebral amyloid angiopathy. According to the patient's operative record, at age 7 years, a left parietal bone tumor and the adjacent dura mater were removed, and a cadaveric dural patch was transplanted onto the intact brain surface. This case suggests that exogenous amyloid β protein can be transmitted through cadaveric dura mater, even when placed on intact brain tissue with preserved glymphatic and dural lymphatic drainage function, manifesting decades after transplantation.

Cerebral amyloid angiopathy (CAA) has a remarkably variable disease course, even in monogenetic hereditary forms. Our aim was to investigate the prevalence of vascular risk factors and their effect on disease onset and course in Dutch-type hereditary (D-)CAA and sporadic CAA. We performed a cohort study in D-CAA to investigate the association between vascular risk factors (hypertension, hypercholesterolemia, smoking, and alcohol use) and age of intracerebral hemorrhage (ICH) onset and time of ICH recurrence with survival analyses. In addition, we performed a systematic review to assess the prevalence of vascular risk factors and their effect on clinical outcome in sporadic CAA. We searched PubMed, Embase, Web of Science, and Cochrane Library from 1987 to 2022 and included cohorts with ≥10 patients. We created forest plots, calculated pooled estimates, and reported variability (heterogeneity plus sampling variability) and risk of bias. We included 70 participants with D-CAA (47% women, mean age 53 years). Sixteen (23%) had hypertension, 15 (21%) had hypercholesterolemia, 45 (64%) were smokers, and 61 (87%) used alcohol. We found no clear effect of vascular risk factors on age of first ICH (log-rank test hypertension: p = 0.35, hypercholesterolemia: p = 0.41, smoking: p = 0.61, and alcohol use: p = 0.55) or time until ICH recurrence (log-rank test hypertension: p = 0.71, hypercholesterolemia: p = 0.20, and smoking: p = 0.71). We identified 25 out of 1,234 screened papers that assessed the prevalence of risk factors in CAA and 6 that reported clinical outcomes. The pooled prevalence estimates of hypertension was 62% (95% CI: 55-69%), diabetes was 17% (95% CI: 14-20%), dyslipidemia was 32% (95% CI: 23-41%), and tobacco use was 27% (95% CI: 18-36%). One study reported study diabetes and hypertension to be associated with a lower risk of recurrent ICH, whereas another study reported hypertension to be associated with an increased risk. All other studies showed no association between vascular risk factors and clinical outcome. High-quality studies focusing on vascular risk factors were lacking. In patients with D-CAA and sporadic CAA, the prevalence of vascular risk factors is high. Although this suggests an opportunity for prevention, there is no clear association between these risk factors and CAA-related ICH onset and recurrence.

Cerebral small vessel disease (cSVDs) account for 25% of stroke and are a frequent cause of cognitive or motor disability in adults. In a small number of patients, cSVDs result from monogenic diseases, the most frequent being cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An early disease onset, a suggestive family history, and a low vascular risk profile contrasting with a high load of cSVD imaging markers represent red flags that must trigger molecular screening. To date, a dozen of genes is involved in Mendelian cSVDs, most of them are responsible for autosomal dominant conditions of variable penetrance. Some of these mendelian cSVDs (CADASIL, HTRA1-related cSVD, pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), cathepsin-A related arteriopathy with strokes and leukoencephalopathy (CARASAL), and cSVD related to LAMB1 mutations) are causing ischemic stroke. Others (COL4A1/COL4A2-related angiopathy and hereditary cerebral amyloid angiopathy) preferentially lead to intracerebral hemorrhages. The clinical features of different Mendelian cSVDs can overlap. Therefore, the current approach is based on simultaneous screening of all genes involved in these conditions through a panel-targeted sequencing gene or exome sequencing. Nevertheless, a pathogenic variant is identified in less than 15% of patients with a suspected genetic cerebrovascular disease, suggesting that many additional genes remain to be identified.