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.

Decreased Cerebrospinal Fluid Amyloid ß 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy.

OBJECTIVE: Vascular amyloid ß (Aß) 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 Aß38, Aß40, Aß42, and Aß43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). METHODS: Aß 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 Aß peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aß42 (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 Aß43 (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 Aß peptides except Aß43 were also decreased in sCAA compared to AD (CSF Aß38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aß40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aß42: AUC = 0.79, 95% CI = 0.66-0.92). INTERPRETATION: A combined biomarker panel of CSF Aß38, Aß40, Aß42, and Aß43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186.

One Size Does Not Fit All: Micro-, Meso-, and Macrobleeds in Cerebral Amyloid Angiopathy.

INTRODUCTION: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (<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 <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.

Parental Influence on Intracerebral Hemorrhage Onset in Hereditary Dutch-Type Cerebral Amyloid Angiopathy.

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.

Sex Differences in Onset and Progression of Cerebral Amyloid Angiopathy.

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.

Impact of region of interest definition on visual stimulation-based cerebral vascular reactivity functional MRI with a special focus on applications in cerebral amyloid angiopathy.

Cerebral vascular reactivity quantified using blood oxygen level-dependent functional MRI in conjuncture with a visual stimulus has been proven to be a potent and early marker for cerebral amyloid angiopathy. This work investigates the influence of different postprocessing methods on the outcome of such vascular reactivity measurements. Three methods for defining the region of interest (ROI) over which the reactivity is measured are investigated: structural (transformed V1), functional (template based on the activation of a subset of subjects), and percentile (11.5 cm3 most responding voxels). Evaluation is performed both in a test-retest experiment in healthy volunteers (N = 12), as well as in 27 Dutch-type cerebral amyloid angiopathy patients and 33 age- and sex-matched control subjects. The results show that the three methods select a different subset of voxels, although all three lead to similar outcome measures in healthy subjects. However, in (severe) pathology, the percentile method leads to higher reactivity measures than the other two, due to circular analysis or "double dipping" by defining a subject-specific ROI based on the strongest responses within each subject. Furthermore, while different voxels are included in the presence of lesions, this does not necessarily result in different outcome measures. In conclusion, to avoid bias created by the method, either a structural or a functional method is recommended. Both of these methods provide similar reactivity measures, although the functional ROI appears to be less reproducible between studies, because slightly different subsets of voxels were found to be included. On the other hand, the functional method did include fewer lesion voxels than the structural method.

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.

Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy.

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.

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.

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.

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.

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

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

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.

Microstructural white matter damage on MRI is associated with disease severity in Dutch-type cerebral amyloid angiopathy.

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]mm2/s × 10-4) compared with presymptomatic mutation-carriers (2.62 [1.96-3.43]mm2/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.

Subarachnoid CSF hyperintensities at 7 tesla FLAIR MRI: A novel marker in cerebral amyloid angiopathy.

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.

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.

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.

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.