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Background and aim: The revised Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) add two radiological markers to the existing criteria: severe visible perivascular spaces in the centrum semiovale and white matter hyperintensities (WMHs) in a multispot pattern. This study aims to determine the sensitivity of the updated criteria in mutation carriers with Dutch-type hereditary CAA (D-CAA) in an early and later disease stage. Methods: In this cross-sectional study, we included presymptomatic and symptomatic D-CAA mutation carriers from our prospective natural history study (AURORA) at the Leiden University Medical Center between 2018 and 2021. 3-Tesla scans were assessed for CAA-related magnetic resonance imaging (MRI) markers. We compared the sensitivity of the Boston criteria v2.0 to the previously used modified Boston criteria v1.5. Results: We included 64 D-CAA mutation carriers (mean age 49 years, 55% women, 55% presymptomatic). At least one white matter (WM) feature was seen in 55/64 mutation carriers (86%: 74% presymptomatic, 100% symptomatic). Fifteen (23%) mutation carriers, all presymptomatic, showed only WM features and no hemorrhagic markers. The sensitivity for probable CAA was similar between the new and the previous criteria: 11/35 (31%) in presymptomatic mutation carriers and 29/29 (100%) in symptomatic mutation carriers. The sensitivity for possible CAA in presymptomatic mutation carriers increased from 0/35 (0%) to 15/35 (43%) with the new criteria. Conclusion: The Boston criteria v2.0 increase the sensitivity for detecting possible CAA in presymptomatic D-CAA mutation carriers and, therefore, improve the detection of the early phase of CAA. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). Aims: We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. Methods: Symptomatic patients with D-CAA (defined as ≥1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). Results: We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1–7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4–25%) symptomatic patients and none of the 21 (0%, 95%CI 0–0%) presymptomatic carriers had ≥ 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52–76) participants (median 1.0, range 0–159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. Conclusions: Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA. [ABSTRACT FROM AUTHOR]

Background: 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., Methods: 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 1987-2022 and included cohorts with ≥10 patients. We created forest plots, calculated pooled estimates and reported variability (heterogeneity plus sampling variability) and risk of bias., Results: We included 70 participants with D-CAA (47% women, mean age 53y). Sixteen (23%) had hypertension, 15 (21%) 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 1234 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 17% (95%CI:14%-20%), dyslipidemia 32% (95%CI:23%-41%), and tobacco use 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., Conclusions: 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., (The Author(s). Published by S. Karger AG, Basel.)

Introduction: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited., Methods: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls. Cognition was measured with a standardized test battery. Linear regression was performed to assess the association between MRI-cSVD burden and cognition., Results: D-CAA ICH- mutation carriers exhibited poorer global cognition and executive function compared to age-matched controls. Patients with sCAA performed worse across all cognitive domains compared to D-CAA ICH+ mutation carriers and age-matched controls. MRI-cSVD burden is associated with decreased processing speed., Discussion: CAA is associated with dysfunction in multiple cognitive domains, even before ICH, with increased MRI-cSVD burden being associated with slower processing speed., Highlights: Cognitive dysfunction is present in early disease stages of cerebral amyloid angiopathy (CAA) before the occurrence of symptomatic intracerebral hemorrhage (sICH). Presymptomatic Dutch-type CAA (D-CAA) mutation carriers show worse cognition than age-matched controls. More early awareness of cognitive dysfunction in CAA before first sICH is needed. Increased cerebral small vessel disease CAA-burden on magnetic resonance imaging is linked to a decrease in processing speed., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77-9.50]mm 2 /s × 10 -4 ) compared with presymptomatic mutation-carriers (2.62 [1.96-3.43]mm 2 /s × 10 -4 ) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16-0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08-0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22-0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13-0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = -0.42 [-0.69-0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N. Vlegels reports support by the Netherlands CardioVascular Research Initiative–the Dutch Heart Foundation (CVON 2018–28 & 2012–06). M.R. Schipper reports independent support from the TRACK D-CAA consortium, consisting of Alnylam, Biogen, the Dutch CAA foundation, Vereniging HCHWA-D, and researchers from Leiden, Boston, and Perth. A. De Luca reports independent support from Alzheimer Nederland (WE-03-2022-11) as well as from ZonMW. R. van Dort is funded by the TRACK D-CAA consortium, consisting of Biogen, Alnylam, the Dutch CAA foundation, Vereniging HCHWA-D, and researchers from Leiden, Boston, and Perth. G.M. Terwindt reports independent support from the Dutch Research Council (NWO), European Community, the Dutch Heart Foundation, the Dutch Brain Foundation, and the Dutch CAA foundation.M.J.P. van Osch reports support by a NWO-VICI grant (016.160.351) and a NWO-Human Measurement Models 2.0 grant (18969) as well as support from the Dutch Research Council (NWO), European Community, the Dutch Heart Foundation, and the Dutch Brain Foundation.M.J.H. Wermer reports independent support from de Nederlandse Organisatie voor Wetenschappelijk Onderzoek ZonMw (VIDI grant 91717337), the Netherlands Heart Foundation, and the Dutch CAA foundation. The others report no conflicts.

Introduction: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (&lt;10 mm) hemorrhages with a cystic cavity and/or irregular shape. Such hemorrhages, however, are often present in patients with cerebral amyloid angiopathy (CAA). In this study, we aimed to investigate the frequency, diameter, and volume distribution of these hemorrhages (which we called mesobleeds) in patients with CAA., Methods: We selected participants with Dutch-type hereditary CAA (D-CAA) and sporadic CAA (sCAA) and scored microbleeds, mesobleeds, and macrobleeds on 3T susceptibility-weighted images MRI. Hemorrhage diameter and volume were calculated in a subset of participants using a semi-automatic tool; their distribution was evaluated on a logarithmic scale., Results: We included 25 participants with D-CAA (mean age 56 years) and 25 with sCAA (mean age 73 years). In total, 11,007 microbleeds, 602 mesobleeds, and 195 macrobleeds were observed. Eighty-two percent of participants had ≥1 mesobleed. Hemorrhage diameter and volume were calculated in four participants with 272 microbleeds (median diameter 1.52 mm, volume 0.004 mL), 84 mesobleeds (median diameter 5.61 mm, volume 0.06 mL), and 37 macrobleeds (median diameter 19.58 mm, volume 1.33 mL). Mesobleed diameter and volume were larger than microbleeds (optimal cut-off 0.02 mL) but showed overlap with macrobleeds., Conclusion: Hemorrhages &lt;10 mm with an irregular shape and/or cystic cavity are frequently found in participants with CAA and have a distinct diameter and volume distribution. We propose to name these hemorrhage mesobleeds and to rate them separately from micro- and macrobleeds. Future research is necessary to investigate their pathophysiology and prognostic value., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from late thirties up to 70 years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring., Methods: We included (potential) D-CAA mutation carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s), their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as the covariate and the sex of the offspring as the factor. Next, we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter, and father/son. We used a random effect per household., Results: A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p = 0.87) for D-CAA parents (n = 60) and their offspring (n = 100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, standard deviation [SD] ± 7) than offspring with a paternal inheritance (54 years, SD ± 6, p = 0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio 0.99, 95% CI: 0.94-1.03, p = 0.51. The interaction between parent's sex and child's sex was not significant (p = 0.70). The results with and without random effect were essentially identical., Conclusion: We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA., Methods: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aβ40 and Aβ42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups., Results: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*10 3 pg/mL vs. 4.4*10 3 pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*10 2 pg/mL vs. 7.8*10 2 pg/mL; P=0.01 and GFAP:11.4*10 3 pg/mL vs. 7.5*10 3 pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*10 2 pg/mL vs 7.8*10 2 pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aβ42 levels (P=0.01/0.02)., Conclusions: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA., (© 2024. The Author(s).)

Background: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA., Methods: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences., Results: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.β = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.β=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.β=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women., Discussion: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately., (© 2024. The Author(s).)

Background: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date., Methods: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-β 40 and amyloid-β 42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots., Results: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-β 40 and amyloid-β 42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-β 40 and amyloid-β 42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis)., Conclusions: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed., Competing Interests: Disclosures Dr van der Zwet and M. R. Schipper report support from the TRACK D-CAA consortium (Alnylam, Biogen, the Dutch CAA foundation, Vereniging HCHWA-D, researchers from Leiden, Boston, Perth). Dr van Osch reports support by a Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)-VICI grant (016.160.351) and a NWO-Human Measurement Models 2.0 grant (18969), European Community, the Dutch Heart Foundation, the Dutch Brain Foundation VSNU Netherlands and the TRACK D-CAA consortium. Dr Verbeek reports independent support from ZonMw (09120012110098, 10510032120006, and 10510032120003), the Galen and Hilary Weston Foundation (NR170024), Maag-Lever-Darm Stichting (21-05), Parkinson NL (P2021-18), Stichting Alkemade-Keuls, National Institutes of Health (5R01NS104147). Dr Terwindt reports independent support from de NWO, European Community, the Dutch Heart Foundation, the Dutch Brain Foundation, and the Dutch CAA foundation, compensation from Teva Pharmaceutical Industries, H. Lundbeck A S, Novartis Pharma, and Eli Lilly and Company for consultant services. Dr Greenberg reports independent support from the US National Institutes of Health. Dr Wermer independent support from the NWO ZonMw (VIDI grant 91717337), the Netherlands Heart Foundation (2016T86). The other authors report no conflicts.

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p  = 0.02, Adjusted R 2  = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10 -6 , 95%CI [1.84 × 10 -6 , 1.48 × 10 -5 ], p  = 0.02, Adj. R 2  = 0.25) and TTB (β = 6.57 × 10 -6 , 95%CI [1.92 × 10 -6 , 1.12 × 10 -5 ], p  = 0.008, Adj. R 2  = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.R. Schipper reports independent support from the TRACK D-CAA consortium, consisting of Alnylam, Biogen, the Dutch CAA foundation, Vereniging HCHWA-D, and researchers from Leiden, Boston, and Perth.N. Vlegels reports support by the Dutch Heart Foundation.T.W. van Harten reports no disclosures.I. Rasing reports no disclosures.E.A. Koemans reports no disclosures.S. Voigt reports no disclosures.A. de Luca reports independent support from Alzheimer Nederland (WE-03-2022-11) as well as from ZonMW.K. Kaushik reports no disclosures.E.S. van Etten reports no disclosures.E.W. van Zwet reports no disclosures.G.M. Terwindt reports independent support from the Dutch Research Council (NWO), European Community, the Dutch Heart Foundation, the Dutch Brain Foundation, and the Dutch CAA foundation.G.J. Biessels reports support through the HBC (Heart-Brain Connection) Consortium, funded by the Netherlands CardioVascular Research Initiative, involving the Dutch Heart Foundation (CVON 2018-28 & 2012-06 Heart Brain Connection), Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences.M.J.P. van Osch reports support by a NWO-VICI grant (016.160.351) and a NWO-Human Measurement Models 2.0 grant (18969) as well as support from the Dutch Research Council (NWO), European Community, the Dutch Heart Foundation, and the Dutch Brain Foundation.M.A.A. van Walderveen reports no disclosures.M.J.H. Wermer reports independent support from the Dutch Research Council (NWO) ZonMw (VIDI grant 91717337), the Netherlands Heart Foundation (Dekker grant 2016T86), and the Dutch CAA foundation.

Background: The diagnosis of probable cerebral amyloid angiopathy (CAA) is currently mostly based on characteristics of brain MRI. Blood biomarkers would be a cost-effective, easily accessible diagnostic method that may complement diagnosis by MRI and aid in monitoring disease progression. We studied the diagnostic potential of plasma Aβ38, Aβ40, and Aβ42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA)., Methods: All Aβ peptides were quantified in the plasma by immunoassays in a discovery cohort (11 patients with presymptomatic D-CAA and 24 patients with symptomatic D-CAA, and 16 and 24 matched controls, respectively) and an independent validation cohort (54 patients with D-CAA, 26 presymptomatic and 28 symptomatic, and 39 and 46 matched controls, respectively). In addition, peptides were quantified in the plasma in a group of 61 patients with sCAA and 42 matched controls. We compared Aβ peptide levels between patients and controls using linear regression adjusting for age and sex., Results: In the discovery cohort, we found significantly decreased levels of all Aβ peptides in patients with presymptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.009; Aβ42: p < 0.001) and patients with symptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.01; Aβ42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aβ38, Aβ40, and Aβ42 were similar in patients with presymptomatic D-CAA and controls (Aβ38: p = 0.18; Aβ40: p = 0.28; Aβ42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aβ38 and Aβ40 were similar (Aβ38: p = 0.14; Aβ40: p = 0.38), whereas plasma Aβ42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aβ38, Aβ40, and Aβ42 levels were similar in patients with sCAA and controls (Aβ38: p = 0.092; Aβ40: p = 0.64. Aβ42: p = 0.68)., Conclusions: Plasma Aβ42 levels, but not plasma Aβ38 and Aβ40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aβ38, Aβ40, and Aβ42 levels do not appear to be applicable as a biomarker in patients with sCAA., (© 2023. The Author(s).)

Objective: Vascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD)., Methods: Aβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI)., Results: We found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aβ43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aβ peptides except Aβ43 were also decreased in sCAA compared to AD (CSF Aβ38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aβ40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aβ42: AUC = 0.79, 95% CI = 0.66-0.92)., Interpretation: A combined biomarker panel of CSF Aβ38, Aβ40, Aβ42, and Aβ43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cerebral Amyloid Angiopathy (CAA) disease course is highly variable even in hereditary forms. Sex may be a possible modifying factor. We investigated biological sex differences in clinical disease course and magnetic resonance imaging-markers in sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA)., Methods: Patients with D-CAA and sCAA were included from hospital and research databases of the Leiden University Medical Center (2012-2020) and Massachusetts General Hospital (1994-2012). Key outcomes were: sex differences in symptomatic intracerebral hemorrhage (sICH) onset, recurrence and survival (analyzed using Kaplan Meier survival and regression analyses), and sex differences in magnetic resonance imaging-markers in D-CAA (explored using scatterplots), and in sCAA (investigated using regression analysis)., Results: We included 136 patients with D-CAA (mean age 57 years, 56% women, 64% with previous sICH) and 370 patients with sCAA (mean age 76 years, 51% women, all with previous sICH). Men and women with D-CAA did not differ for sICH onset (median age 54 in men and 56 in women [ P =0.13]). Men with D-CAA had a slightly higher number of sICH compared with women (median 2 versus 1; adjusted RR, 1.5 [95% CI, 1.1-1.9]) and a shorter interval between the first and second sICH (median 1.8 years for men and 3.1 years for women, P =0.02). Men with sCAA had their first sICH at an earlier age (median 75 versus 78 years, respectively, P =0.003) and more lobar microbleeds (median 1 versus 0, P =0.022) compared with women with sCAA. No substantial differences were found in the other magnetic resonance imaging markers. Survival after first sICH was comparable between sexes for D-CAA ( P =0.12) and sCAA ( P =0.23)., Conclusions: Men with CAA seem to have an earlier onset (sCAA) and more hemorrhagic disease course (sCAA and D-CAA) compared with women. Future studies are necessary to confirm these findings and determine the underlying role of sex-related factors.

Background: To evaluate the potential of cerebrospinal fluid (CSF) levels of matrix metalloproteinases and tissue-type inhibitors (MMP; TIMP), and ratios of MMPs to TIMPs, to function as biomarkers for sporadic or hereditary cerebral amyloid angiopathy (CAA)., Methods: CSF concentrations of the matrix metalloproteinases MMP-2, MMP-9 and MMP-14, as well as the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, were determined using immunoassays. These assays were applied to two, independent study groups of sporadic CAA (sCAA) (n = 28/43) and control subjects (n = 40/40), as well as to groups of pre-symptomatic (n = 11) and symptomatic hereditary Dutch-CAA (D-CAA) patients (n = 12), and age-matched controls (n = 22/28, respectively)., Results: In the sCAA/control cohorts, inconsistent differences were found for individual MMPs and TIMPs, but MMP-2/TIMP-2 (discovery/validation: p = 0.004; p = 0.02) and MMP-14/TIMP-2 ratios (discovery/validation: p < 0.001; p = 0.04) were consistently decreased in sCAA, compared to controls. Moreover, MMP-14 was decreased in symptomatic D-CAA (p = 0.03), compared to controls. The MMP-14/TIMP-1 (p = 0.03) and MMP-14/TIMP-2 (p = 0.04) ratios were decreased in symptomatic D-CAA compared to controls and also compared to pre-symptomatic D-CAA (p = 0.004; p = 0.005, respectively)., Conclusion: CSF MMP-2/TIMP-2 and MMP-14/TIMP-2 were consistently decreased in sCAA, compared to controls. Additionally, MMP-14/TIMP-2 levels were also decreased in symptomatic D-CAA, compared to both pre-symptomatic D-CAA and controls, and can therefore be considered a biomarker for sporadic and late-stage hereditary forms of CAA., (© 2023. The Author(s).)

Background: We observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with cortical superficial siderosis (cSS), in participants with cerebral amyloid angiopathy (CAA). To systemically evaluate these CSF hyperintensities we investigated their frequency and anatomical and temporal relationship with cSS on 7T and 3T MRI in hereditary Dutch-type CAA (D-CAA), sporadic CAA (sCAA), and non-CAA controls., Methods: CAA participants were included from two prospective natural history studies and non-CAA controls from a 7T study in healthy females and females with ischemic stroke. CSF hyperintensities were scored by two independent observers., Results: We included 38 sCAA participants (mean age 72y), 50 D-CAA participants (mean age 50y) and 44 non-CAA controls (mean age 53y, 15 with stroke). In total 27/38 (71 %, 95 %CI 56-84) sCAA and 23/50 (46 %, 95 %CI 33-60) D-CAA participants had subarachnoid CSF hyperintensities at baseline 7T. Most (96 %) of those had cSS, in 54 % there was complete topographical overlap with cSS. The remaining 46 % had ≥1 sulcus with CSF hyperintensities without co-localizing cSS. None of the healthy controls and 2/15 (13 %, 95 %CI 2-41, 100 % cSS overlap) of the stroke controls had CSF hyperintensities. In 85 % of the CAA participants CSF hyperintensities could retrospectively be identified at 3T. Of the 35 CAA participants with follow-up 7T after two years, 17/35 (49 %) showed increase and 6/35 (17 %) decrease of regional CSF hyperintensities. In 2/11 (18 %) of participants with follow-up who had baseline CSF hyperintensities without overlapping cSS, new cSS developed at those locations., Conclusions: Subarachnoid CSF hyperintensities at 7T FLAIR MRI occur frequently in CAA and are associated with cSS, although without complete overlap. We hypothesize that the phenomenon could be a sign of subtle plasma protein or blood product leakage into the CSF, resulting in CSF T1-shortening., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate whether there is a topographical and temporal pattern of index and recurrent intracerebral hemorrhages (ICH) in Dutch-type hereditary Cerebral Amyloid Angiopathy (D-CAA) to increase our understanding on CAA-related ICH development., Methods: We included patients with DNA confirmed D-CAA or a history with ≥1 lobar ICH and ≥1 first-degree relative with D-CAA. Topographical pattern was studied by location (proportion frontal/parietal/temporal/occipital; infra/supratentorial and occurrence ratios relative to lobe volume) and volume of index and recurrent ICHs were determined on CT. Temporal pattern was examined by time between recurrent ICHs was retrieved from medical records., Results: We included 72 patients with D-CAA (mean age at index ICH 55 years) with in total 214 ICH. The median follow-up time was 7 years (range 0.8 to 28 years). All ICH were lobar and supratentorial. The index ICH was most frequently located in the occipital lobe (34% vs. 22% in the other three lobes; with index ICH occurrence ratios relative to lobe volume of 1.9 for occipital, 1.0 for temporal, 1.2 for parietal, and 0.5 for frontal, p = 0.001). In 16/47 (34%) patients with multiple ICH, the second ICH was located in the same lobe as the index ICH. The median time-interval between subsequent ICH was #1-2 ICH 27 months, #2-3 ICH 14 months, and #3-4 ICH 7 months (p = 0.6) There was no difference in volume between index and recurrent ICHs., Conclusions: We found that index and recurrent ICHs in D-CAA have a preference for the occipital lobe and are least frequent in the frontal lobe, which adds to the existing knowledge of histopathological studies on amyloid load in CAA. Surprisingly, there was no acceleration in time nor gradual increase of hematoma volume between subsequent ICHs.

Aims: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA)., Materials and Methods: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-β (Aβ) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA)., Results: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aβ deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aβ deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objective: Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH., Methods: We selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI., Results: We included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1-19). Median ICH volume was 17.0 mL (IQR 1.4-88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = -0.003, 95% CI -0.003-0.03, p = 0.83), nor for any of the individual radiological cSVD markers., Conclusion: We found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cliteur, Sondag, Wolsink, Rasing, Meijer, Jolink, Wermer, Klijn and Schreuder.)

Background: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset., Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors., Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8-3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3-6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2-19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7-60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8-55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4-63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6-37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1-95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7-6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9-4.2)., Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

Background and Purpose: Although evidence accumulates that the cerebellum is involved in cerebral amyloid angiopathy (CAA), cerebellar superficial siderosis is not considered to be a disease marker. The objective of this study is to investigate cerebellar superficial siderosis frequency and its relation to hemorrhagic magnetic resonance imaging markers in patients with sporadic and Dutch-type hereditary CAA and patients with deep perforating arteriopathy-related intracerebral hemorrhage., Methods: We recruited patients from 3 prospective 3 Tesla magnetic resonance imaging studies and scored siderosis and hemorrhages. Cerebellar siderosis was identified as hypointense linear signal loss (black) on susceptibility-weighted or T2*-weighted magnetic resonance imaging which follows at least one folia of the cerebellar cortex (including the vermis)., Results: We included 50 subjects with Dutch-type hereditary CAA, (mean age 50 years), 45 with sporadic CAA (mean age 72 years), and 43 patients with deep perforating arteriopathy-related intracerebral hemorrhage (mean age 54 years). Cerebellar superficial siderosis was present in 5 out of 50 (10% [95% CI, 2-18]) patients with Dutch-type hereditary CAA, 4/45 (9% [95% CI, 1-17]) patients with sporadic CAA, and 0 out of 43 (0% [95% CI, 0-8]) patients with deep perforating arteriopathy-related intracerebral hemorrhage. Patients with cerebellar superficial siderosis had more supratentorial lobar (median number 9 versus 2, relative risk, 2.9 [95% CI, 2.5-3.4]) and superficial cerebellar macrobleeds (median number 2 versus 0, relative risk, 20.3 [95% CI, 8.6-47.6]) compared with patients without the marker. The frequency of cortical superficial siderosis and superficial cerebellar microbleeds was comparable., Conclusions: We conclude that cerebellar superficial siderosis might be a novel marker for CAA.

Background and Purpose: Cortical calcifications have been reported in patients with cerebral amyloid angiopathy (CAA), although their prevalence and pathophysiology are unknown. We investigated the frequency of calcifications on computed tomography, their association with intracerebral hemorrhage (ICH) and their coexistence with a striped pattern of the occipital cortex reflecting microcalcifications on ultra-high-field 7T-magnetic resonance imaging in Dutch-type hereditary CAA (D-CAA) and sporadic CAA., Methods: We included D-CAA mutation carriers with a proven APP (amyloid precursor protein) mutation or ≥1 lobar ICH and ≥1 first-degree relative with D-CAA and sporadic CAA patients with probable CAA according to the modified Boston criteria. D-CAA carriers were regarded symptomatic when they had a history of symptomatic ICH. We assessed the presence, location, and progression of calcifications and their association with ICH and the striped occipital cortex., Results: We found cortical calcifications in 15/81 (19% [95% CI, 11–29]) D-CAA mutation carriers (15/69 symptomatic and 0/12 presymptomatic) and in 1/59 (2% [95% CI, 0–9]) sporadic CAA patients. Calcifications were all bilateral located in the occipital lobes. In 3/15 (20%) of the symptomatic D-CAA patients the calcifications progressed over a period up to 10 years. There was evidence of an association between cortical calcifications and new ICH development (hazard ratio, 7.1 [95% CI, 0.9–54.9], log-rank P=0.03). In 7/25 D-CAA symptomatic carriers in whom a 7T-magnetic resonance imaging was performed, a striped pattern of the occipital cortex was present; in 3/3 (100%) of those with calcifications on computed tomography and 4/22 (18%) of those without calcifications., Conclusions: Occipital cortical calcifications are frequent in D-CAA but seem to be rare in sporadic CAA. Their absence in presymptomatic carriers and their association with ICH might suggest that they are a marker for advanced CAA. Cortical calcifications on computed tomography seem to be associated with the striped occipital cortex on 7T-magnetic resonance imaging which may possibly represent an early stage of calcification.

Background: Cerebral amyloid angiopathy (CAA) is an important cause of cognitive impairment and spontaneous lobar intracerebral haemorrhage in older individuals. When necessary, anticoagulant treatment in these patients comes with two dilemmas; significant intracerebral bleeding risk with treatment vs. high risk of embolic stroke with no treatment., Case Summary: A 66-year-old female patient presented to the emergency clinic with a ST-elevation myocardial infarction. Her past medical history revealed cognitive problems associated with lobar cerebral microbleeds on magnetic resonance imaging suspect for probable CAA. A primary percutaneous coronary intervention of the left anterior descending artery with implantation of drug eluting stent was performed. Dual antiplatelet treatment was started initially. During hospitalization, an impaired left ventricular (LV) function was observed with an apical aneurysm. Six months after the initial event, LV function remained stable however a LV thrombus was observed. Apixaban 5 mg twice daily was started based on multidisciplinary consensus and on its efficacy and safety profile in patients with atrial fibrillation. Despite treatment, patient suffered a new ischaemic stroke probably from the LV thrombus, for which vitamin K antagonist treatment was initiated and Apixaban discontinued., Discussion: Evidence for LV thrombus treatment with direct oral anticoagulants in CAA patients is scarce, however feasible based on its efficacy and safety profile. For CAA patients, the cardinal role of both clinical and radiological characteristics in determining the risk-benefit ratio for anticoagulant initiation in this specific subset of patients, is crucial. The clinical course described highlights the therapeutical dilemma of coexisting CAA and the clinical challenge it creates., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Purpose- To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology, we assessed migraine and its correlation with magnetic resonance imaging markers in Hereditary Dutch-Type Cerebral Amyloid Angiopathy (D-CAA or Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch type). Methods- All D-CAA mutation carriers who visited our clinic between 2012 and 2018 were included. Migraine was diagnosed by an interview and classified according to the International Classification of Headache Disorders . Magnetic resonance imaging scans were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis. Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cortical superficial siderosis were calculated with Poisson regression analysis adjusted for confounders. Results- We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women, P <0.05; men, P <0.001). Migraine was the inaugural symptom in 77% and an isolated symptom in 35% of the carriers. Carriers with and without migraine did not differ for age of first ICH, cortical superficial siderosis prevalence, or occipital ICH. Time between migraine onset and first ICH was 8.5 years. Aura attacks lasting ≥60 minutes signaled acute ICH in 55%. Conclusions- Migraine with aura is an important, often inaugural, symptom in D-CAA. Aura attacks lasting ≥60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years.

Background: Genetic risk factors for intracranial aneurysms may influence the size of aneurysms., Objective: To assess the association between genetic risk factors and the size of aneurysms at the time of rupture., Methods: Genotypes of 7 independent single-nucleotide polymorphisms (SNPs) of the 6 genetic risk loci identified in genome-wide association studies of patients with intracranial aneurysms were obtained from 700 Dutch patients with an aneurysmal subarachnoid hemorrhage (1997-2007) previously genotyped in the genome-wide association studies; 255 additional Dutch patients with an aneurysmal subarachnoid hemorrhage (2007-2011) were genotyped for these SNPs. Aneurysms were measured on computerized tomography angiography or digital subtraction angiography. The mean aneurysm size (with standard error) was compared between patients with and without a genetic risk factor by the use of linear regression. The association between SNPs and size was assessed for single SNPs and for the combined effect of SNPs by using a weighted genetic risk score., Results: Single SNPs showed no association with aneurysm size, nor did the genetic risk score., Conclusion: The 6 genetic risk loci have no major influence on the size of aneurysms at the time of rupture. Because these risk loci explain no more than 5% of the genetic risk, other genetic factors for intracranial aneurysms may influence aneurysm size and thereby proneness to rupture.

Background: Smoking and hypertension increase the risk of aneurismal subarachnoid haemorrhage (SAH) two to threefold whereas a familial predisposition increases the risk sixfold. We assessed the additional risk of smoking and hypertension for the presence of an intracranial aneurysm (IA) in first-degree relatives of patients with familial SAH., Methods: We studied first-degree relatives of patients with familial SAH who were screened for the presence of aneurysms. RRs with corresponding 95% CIs for the risk of IA were calculated for smoking and hypertension., Results: The RRs were 1.5 (95% CI 0.7 to 3.2) for smoking, 1.9 (95% CI 1.0 to 3.7) for hypertension and 2.7 (95% CI 1.4 to 5.3) for smoking plus hypertension. The increased RR for hypertension was found in both women and men, but the increased RR for smoking was found in women only., Conclusion: The extent of the increased risk of smoking and hypertension for the presence of IA in first-degree relatives of patients with familial SAH is similar to that in patients without familial predisposition. Risk factor profiles should be included in future genetic studies.