Haemorrhagic stroke and brain vascular malformations in women: risk factors and clinical features.

Haemorrhagic stroke is a severe condition with poor prognosis. Biological sex influences the risk factors, presentations, treatment, and patient outcomes of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and vascular malformations. Women are usually older at onset of intracerebral haemorrhage compared with men but have an increased risk of aneurysmal subarachnoid haemorrhage as they age. Female-specific factors such as pregnancy, eclampsia or pre-eclampsia, postmenopausal status, and hormone therapy influence a woman's long-term risk of haemorrhagic stroke. The presence of intracranial aneurysms, arteriovenous malformations, or cavernous malformations poses unique clinical dilemmas during pregnancy and delivery. In the absence of evidence-based guidelines for managing the low yet uncertain risk of haemorrhagic stroke during pregnancy and delivery in women with vascular malformations, multidisciplinary teams should carefully assess the risks and benefits of delivery methods for these patients. Health-care providers should recognise and address the challenges that women might have to confront when recovering from haemorrhagic stroke.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

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 Aß40 and Aß42 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*103pg/mL vs. 4.4*103pg/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*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/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*102pg/mL vs 7.8*102pg/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 Aß42 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.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

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.ß = 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.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-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.

Surgical intervention for cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: a systematic review.

OBJECTIVE: The risks and benefits of surgery for cerebral amyloid angiopathy (CAA)-related lobar intracerebral hemorrhage (ICH) are unclear. The aim of this study was to systematically review the literature on this topic. METHODS: The authors conducted a systematic review according to the 2020 PRISMA statement. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier were searched (on December 27, 2022) for relevant articles. Study inclusion criteria were: 1) randomized controlled trial (RCT), cohort study, cross-sectional design, or case series with more than 5 patients; 2) possible, probable, or definite CAA according to the Boston criteria (version 1.0 or 1.5) or autopsy; 3) surgical intervention for acute ICH; and 4) data on peri- and/or postoperative outcomes. Primary outcomes were the presence of intraoperative hemorrhage (IOH), postoperative hemorrhage (POH), and early ICH recurrence. Secondary outcomes were 3-month mortality, late ICH recurrence, functional outcome at discharge, and factors associated with poor outcome. Pooled estimates were calculated, and the Joanna Briggs Institute Critical Appraisal Tool was used to assess risk of bias. RESULTS: Four cohort studies and 15 case series (n = 738 patients, mean age 70 years, 56% women) were included. IOH occurred in 2 (0.6%) of 352 patients. Pooled estimates for POH were 13.0% (30/225) for less than 48 hours and 6.2% (3/437) for 48 hours to 14 days. Overall recurrent ICH (mean follow-up 19 months, n = 5 studies) occurred in 11% of patients. Outcome was predominantly poor with a pooled 3-month mortality rate of 19% and good outcome of 23%. Factors associated with poor outcome were advanced age, poor condition on admission, preexisting dementia, and concomitant intraventricular, subarachnoid, or subdural hemorrhage. All studies contained possible sources of bias and reporting was heterogeneous. CONCLUSIONS: Surgery in CAA-related ICH is safe with no substantial IOH, POH, and early recurrent hemorrhage risk. Outcome appears to be poor, however, especially in older patients, although good quality of evidence is lacking. Patients with CAA should not be excluded from ongoing surgery RCTs in ICH to enable future subgroup analysis of this specific patient population.

Uncommon Causes of Nontraumatic Intracerebral Hemorrhage.

Nontraumatic intracerebral hemorrhage is an important health issue. Although common causes such as hypertension and cerebral amyloid angiopathy predominantly affect the elderly, there exists a spectrum of uncommon etiologies that contribute to the overall incidence of intracerebral hemorrhage. The identification of these rare causes is essential for targeted clinical management, informed prognostication, and strategic secondary prevention where relevant. This topical review explores the uncommon intracerebral hemorrhage causes and provides practical clues for their clinical and imaging identification. By expanding the clinician's differential diagnosis, this review aims to bridge the gap between standard intracerebral hemorrhage classification systems and the nuanced reality of clinical practice.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

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-ß40 and amyloid-ß42 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-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 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.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-ß 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 ß = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (ß = 8.34 × 10-6, 95%CI [1.84 × 10-6, 1.48 × 10-5], p = 0.02, Adj. R2 = 0.25) and TTB (ß = 6.57 × 10-6, 95%CI [1.92 × 10-6, 1.12 × 10-5], p = 0.008, Adj. R2 = 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.

Plasma amyloid beta 42 is a biomarker for patients with hereditary, but not sporadic, cerebral amyloid angiopathy.

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 Aß38, Aß40, and Aß42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA). METHODS: All Aß 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 Aß 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 Aß peptides in patients with presymptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.009; Aß42: p < 0.001) and patients with symptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.01; Aß42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aß38, Aß40, and Aß42 were similar in patients with presymptomatic D-CAA and controls (Aß38: p = 0.18; Aß40: p = 0.28; Aß42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aß38 and Aß40 were similar (Aß38: p = 0.14; Aß40: p = 0.38), whereas plasma Aß42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aß38, Aß40, and Aß42 levels were similar in patients with sCAA and controls (Aß38: p = 0.092; Aß40: p = 0.64. Aß42: p = 0.68). CONCLUSIONS: Plasma Aß42 levels, but not plasma Aß38 and Aß40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aß38, Aß40, and Aß42 levels do not appear to be applicable as a biomarker in patients with sCAA.

Progression of cerebral amyloid angiopathy: a pathophysiological framework.

Cerebral amyloid angiopathy, which is defined by cerebrovascular deposition of amyloid ß, is a common age-related small vessel pathology associated with intracerebral haemorrhage and cognitive impairment. Based on complementary lines of evidence from in vivo studies of individuals with hereditary, sporadic, and iatrogenic forms of cerebral amyloid angiopathy, histopathological analyses of affected brains, and experimental studies in transgenic mouse models, we present a framework and timeline for the progression of cerebral amyloid angiopathy from subclinical pathology to the clinical manifestation of the disease. Key stages that appear to evolve sequentially over two to three decades are (stage one) initial vascular amyloid deposition, (stage two) alteration of cerebrovascular physiology, (stage three) non-haemorrhagic brain injury, and (stage four) appearance of haemorrhagic brain lesions. This timeline of stages and the mechanistic processes that link them have substantial implications for identifying disease-modifying interventions for cerebral amyloid angiopathy and potentially for other cerebral small vessel diseases.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

BACKGROUND: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). METHODS: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. RESULTS: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. CONCLUSIONS: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Spatial and temporal intracerebral hemorrhage patterns in Dutch-type hereditary cerebral amyloid angiopathy.

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.

Trigger Factors for Spontaneous Intracerebral Hemorrhage: A Case-Crossover Study.

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.

Occipital Cortical Calcifications in Cerebral Amyloid Angiopathy.

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, 11­29]) D-CAA mutation carriers (15/69 symptomatic and 0/12 presymptomatic) and in 1/59 (2% [95% CI, 0­9]) 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, 0.9­54.9], 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.

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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

CSF enhancement on post-contrast fluid-attenuated inversion recovery images; a systematic review.

Cerebrospinal fluid (CSF) enhancement on T2-weighted post-contrast fluid-attenuated inversion recovery (pcT2wFLAIR) images is a relatively unknown neuroradiological marker for gadolinium-based contrast agent extravasation due to blood-brain barrier (BBB) disruption. We systematically reviewed human studies reporting on CSF enhancement on pcT2wFLAIR images to provide a comprehensive overview of prevalence of this new biomarker in healthy and diseased populations as well as its etiology and optimal detection methodology. We extracted information on the prevalence of CSF enhancement, its vascular risk factor and neuroimaging correlates, and methodological attributes of each study. Forty-four eligible studies were identified. By pooling data, we found that the prevalence of CSF enhancement was 82% (95% confidence interval (CI) 80-89) in meningitis (4 studies, 65 patients), 73% (95%CI 62-81) in cases with (post-) acute intracerebral hemorrhage (2 studies, 77 cases), 64% (95% CI 54-73) in cases who underwent surgery for aneurysm treatment (2 studies, 99 patients), 40% (95% CI 30-51) in cases who underwent surgery for carotid artery disease treatment (3 studies, 76 patients), 27% (95% CI 25-30) in cases with acute ischemic stroke (9 studies, 1148 patients), 21% (95% CI 17-23) in multiple sclerosis (6 studies, 897 patients), and 13% (95% CI 7-21) in adult controls (4 studies, 112 cases). Presence of CSF enhancement was associated with higher age in eleven studies, with lobar cerebral microbleeds in one study, and with cerebral atrophy in four studies. PcT2wFLAIR imaging represents a promising method that can provide novel perspectives on BBB leakage into CSF compartments, with the potential to reveal important new insights into the pathophysiological mechanisms of varying neurological diseases.

Migraine With Aura as Early Disease Marker in Hereditary Dutch-Type Cerebral Amyloid Angiopathy.

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.

Contrast leakage distant from the hematoma in patients with spontaneous ICH: A 7 T MRI study.

Disruption of the blood-brain barrier (BBB) might play a role in the pathophysiology of cerebral small vessel disease-related ICH. The aim of this study was to assess presence and extent of contrast agent leakage distant from the hematoma as a marker of BBB disruption in patients with spontaneous ICH. We prospectively performed 7 tesla MRI in adult patients with spontaneous ICH and assessed contrast leakage distant from the hematoma on 3D FLAIR images. Thirty-one patients were included (mean age 60 years, 29% women). Median time between ICH and MRI was 20 days (IQR 9-67 days). Seventeen patients (54%; seven lobar, nine deep, one infratentorial ICH) had contrast leakage, located cortical in 16 and cortical and deep in one patient. Patients with contrast leakage more often had lobar cerebral microbleeds (CMBs; 77%) than those without (36%; RR 2.5, 95% CI 1.1-5.7) and a higher number of lobar CMBs (patients with contrast leakage: median 2, IQR 1-8 versus those without: median 0, IQR 0-2; p = 0.02). This study shows that contrast leakage distant from the hematoma is common in days to weeks after spontaneous ICH. It is located predominantly cortical and related to lobar CMBs and therefore possibly to cerebral amyloid angiopathy.

Innovative Magnetic Resonance Imaging Markers of Hereditary Cerebral Amyloid Angiopathy at 7 Tesla.

BACKGROUND AND PURPOSE: The aim of the present study is to explore whether using 7 Tesla magnetic resonance imaging, additional brain changes can be observed in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) patients as compared with the established magnetic resonance imaging features of sporadic cerebral amyloid angiopathy. METHODS: The local institutional review board approved this prospective cohort study. In all cases, informed consent was obtained. This prospective parallel cohort study was conducted between 2012 and 2014. We performed T2*-weighted magnetic resonance imaging performed at 7 Tesla in presymptomatic mutation carriers (n=11, mean age 35±12 years), symptomatic HCHWA-D patients (n=15, mean age 45±14 years), and in control subjects (n=29, mean age 45±14 years). Images were analyzed for the presence of changes that have not been reported before in sporadic cerebral amyloid angiopathy and HCHWA-D. Innovative observations comprised intragyral hemorrhaging and cortical changes. The presence of these changes was systematically assessed in all participants of the study. RESULTS: Symptomatic HCHWA-D-patients had a higher incidence of intragyral hemorrhage (47% [7/15], controls 0% [0/29], P<0.001), and a higher incidence of specific cortical changes (40% [6/15] versus 0% [0/29], P<0.005). In presymptomatic HCHWA-D-mutation carriers, the prevalence of none of these markers was increased compared with control subjects. CONCLUSIONS: The presence of cortical changes and intragyral hemorrhage are imaging features of HCHWA-D that may help recognizing sporadic cerebral amyloid angiopathy in living patients.

Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: A prospective study.

OBJECTIVE: In order to explore the mechanisms of cortical superficial siderosis (cSS) multifocality and its clinical implications for recurrent intracerebral hemorrhage (ICH) risk in patients with cerebral amyloid angiopathy (CAA), we used a new rating method that we developed specifically to evaluate cSS extent at spatially separated foci. METHODS: Consecutive patients with CAA-related ICH according to Boston criteria from a single-center prospective cohort were analyzed. The new score that assesses cSS multifocality (total range 0-4) showed excellent interrater reliability (k = 0.87). The association of cSS with markers of CAA and acute ICH was investigated. Patients were followed prospectively for recurrent symptomatic ICH. RESULTS: The cohort included 313 patients with CAA. Multifocal cSS prevalence was 21.1%. APOE ε2 allele prevalence was higher in patients with multifocal cSS. In probable/definite CAA, cSS multifocality was independently associated with neuroimaging markers of CAA severity, including lobar microbleeds, but not with acute ICH features, which conversely, were determinants of cSS in possible CAA. During a median follow-up of 2.6 years (interquartile range 0.9-5.1 years), the annual ICH recurrence rates per cSS scores (0-4) were 5%, 6.5%, 13.5%, 16.2%, and 26.9%, respectively. cSS multifocality (presence and spread) was the only independent predictor of increased symptomatic ICH risk (hazard ratio 3.19; 95% confidence interval 1.77-5.75; p < 0.0001). CONCLUSIONS: The multifocality of cSS correlates with disease severity in probable CAA; therefore cSS is likely to be caused by discrete hemorrhagic foci. The new cSS scoring system might be valuable for clinicians in determining annual risk of ICH recurrence.