Hereditary Cerebral Hemorrhage Research Articles

Genetic repair of a human induced pluripotent cell line from patient with Dutch-type cerebral amyloid angiopathy

Dutch-type cerebral amyloid angiopathy (D-CAA), also known as hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), is an autosomal dominant disorder caused by a G to C transversion in codon 693 of the amyloid precursor protein (APP) that results in a Gln-to-Glu amino acid substitution. CRISPR-Cas9 editing was used for genetic correction of the mutation in a human induced pluripotent stem cell (hiPSC-) line established previously. The isogenic hiPSCs generated showed typical pluripotent stem cell morphology, expressed all markers of undifferentiated state, displayed a normal karyotype and had the capacity to differentiate into the three germ layers.

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC–MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.

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.

Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer\u2019s disease and not in other tauopathies

We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition. APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain. CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies. This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

Osteopontin and phospho-SMAD2/3 are associated with calcification of vessels in D-CAA, an hereditary cerebral amyloid angiopathy.

In severe forms of cerebral amyloid angiopathy (CAA) pathology, vascular calcification has been observed in the cerebral cortex, both in vivo on MRI and CT, and post‐mortem using histopathology. However, the pathomechanisms leading to calcification of CAA‐laden arteries are unknown. Therefore, we investigated the correlation between calcification of cortical arterioles and several potential modulators of vascular calcification using immunohistochemistry in a unique collection of brain material of patients with a hereditary form of CAA, namely hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D or D‐CAA).We show a topographical association of osteopontin (OPN) and TGFβ signaling factor phospho‐SMAD2/3 (pSMAD2/3) in calcified CAA vessel walls. OPN and pSMAD2/3 gradually accumulate in vessels prior to calcification. Moreover, we found that the vascular accumulation of Collagen 1 (Col1), OPN and pSMAD2/3 immunomarkers correlated with the CAA severity. This was independently of the vessel size, including capillaries in the most severe cases. We propose that calcification of CAA vessels in the observed HCHWA‐D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.

Multiple Approaches to Diffusion Magnetic Resonance Imaging in Hereditary Cerebral Amyloid Angiopathy Mutation Carriers

BackgroundCerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage in elderly adults; however, presymptomatic diagnosis of CAA is difficult. Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA‐D) is a rare autosomal‐dominant disease that leads to pathology similar to sporadic CAA. Presymptomatic HCHWA‐D mutation carriers provide a unique opportunity to study CAA‐related changes before any symptoms have occurred. In this study we investigated early CAA‐related alterations in the white matter.Methods and ResultsWe investigated diffusion magnetic resonance imaging (dMRI) data for 15 symptomatic and 11 presymptomatic HCHWA‐D mutation carriers and 30 noncarrier control participants using 4 different approaches. We looked at (1) the relation between age and global dMRI measures for mutation carriers versus controls, (2) voxel‐wise dMRI, (3) independent component‐clustered dMRI measures, and (4) structural connectomics between presymptomatic or symptomatic carriers and controls. Fractional anisotropy decreased, and mean diffusivity and peak width of the skeletonized mean diffusivity increased significantly over age for mutation carriers compared with controls. In addition, voxel‐wise and independent component‐wise fractional anisotropy, and mean diffusivity, and structural connectomics were significantly different between HCHWA‐D patients and control participants, mainly in the periventricular frontal and occipital regions and in the occipital lobe. We found no significant differences between presymptomatic carriers and control participants.ConclusionsThe dMRI technique is sensitive in detecting alterations in symptomatic HCHWA‐d carriers but did not show alterations in presymptomatic carriers. This result indicates that dMRI may be less suitable for identifying early white matter changes in CAA.

Generation of 3 human induced pluripotent stem cell lines LUMCi005-A, B and C from a Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch type patient

Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant hereditary disease caused by a point mutation in exon 17 of the APP gene. We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic HCHWA-D patient by using non-integrating Sendai virus (SeV). The newly generated hiPSCs express all pluripotency markers, have a normal karyotype, carry the Dutch mutation, can differentiate in the three germ layers in vitro and are SeV free.

Cerebral Amyloid Angiopathy With Vascular Iron Accumulation and Calcification.

Background and Purpose- Previous studies of symptomatic and asymptomatic hereditary cerebral amyloid angiopathy (CAA) patients offered the possibility to study the radiological manifestations of CAA in the early stages of the disease. Recently, a striped cortex, observable as hypointense lines perpendicular to the pial surface on T2*-weighted 7T magnetic resonance imaging (MRI), was detected in 40% of the symptomatic hereditary CAA patients. However, the origin of these MRI contrast changes is unknown. This study aimed at defining the underlying pathology associated with the in vivo observed striped pattern. Methods- Formalin-fixed postmortem brain material including the occipital lobe of 4 hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) cases and 6 sporadic CAA cases were selected from local neuropathology tissue collections. Depending on the availability of the material, intact hemispheres or brain slabs including the occipital lobe of these patients were screened for the presence of a striped cortex. Regions containing the striped cortex were then subjected to high-resolution 7T MRI and histopathologic examination. Results- We found 2 hereditary cerebral hemorrhage with amyloidosis-Dutch type cases and 1 sporadic CAA case with striped patterns in the occipital cortex resembling the in vivo signal. Histopathologic examination showed that the striped pattern in the cortex at 7T MRI is because of iron accumulation and calcification of penetrating arteries. The presence of both nonheme iron and calcification on penetrating arteries causes signal loss and hence the abnormal striped patterns in the cortical ribbon on T2*-weighted MRI. Conclusions- We identified iron accumulation and calcification of the vessel wall in hereditary cerebral hemorrhage with amyloidosis-Dutch type as the histopathologic correlates of the striped cortex observed on in vivo 7T MRI.

Perivascular Spaces Volume in Sporadic and Hereditary (Dutch-Type) Cerebral Amyloid Angiopathy.

Background and Purpose- Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. Methods- We studied a retrospective hospital-based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73.6±8.5; 46% female), and a separate cohort consisting of 26 carriers, and 28 noncarriers of the hereditary cerebral hemorrhage with amyloidosis-Dutch type (mean age, 46.7±12.8; 61.1% female). CSO-PVS volume was quantified on a single magnetic resonance imaging slice using a computer-assisted segmentation method and expressed as the relative volume of the intracranial volume in that particular slice (CSO-PVS relative volume). We compared CSO-PVS relative volume (1) between subjects with and without the disease in both cohorts; (2) between non-CAA, CAA without hemorrhage, and CAA with hemorrhage cases in the sporadic CAA cohort. All variables reaching P<0.1 in bivariate analyses were entered in logistic regression models. Results- In both sporadic and Dutch cohorts, cases with CAA had significantly higher CSO-PVS relative volume than cases without (median [IQR]: 3.7% [2.5-5.3] versus 1.8% [1.2-2.4], P<0.0001; 3.8% [0.6-6.2] versus 0.7% [0.4-1.6], P=0.007; respectively). In linear regression models, sporadic CAA was associated with higher CSO-PVS relative volume ( P=0.008). In the sporadic CAA cohort, compared with non-CAA cases, CSO-PVS relative volume was higher in both CAA with hemorrhage and without hemorrhage (4.4% [2.6-6.1] and 3% [2.4-3.6] versus 1.8% [1.2-2.4], P<0.001 and P=0.005, respectively). Higher CSO-PVS relative volume was associated with CAA in regression models, both when hemorrhage was present (odds ratio, 2.63; [95% confidence interval, 1.33-5.18]; P=0.005) and absent (odds ratio, 4.55; [95% confidence interval, 0.98-21.04]; P=0.05). Conclusions- Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations.

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

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. 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. 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. 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.

Brain Transcriptomic Analysis of Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch Type.

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)–receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGFβ) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM–receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism.

TGFβ pathway deregulation and abnormal phospho-SMAD2/3 staining in hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) pathology, caused by the E22Q mutation in the amyloid β (Aβ) peptide. Transforming growth factor β1 (TGFβ1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGFβ pathway is involved in HCHWA‐D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGFβ pathway were analyzed with quantitative RT‐PCR. TGFβ1 and TGFβ Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA‐D in comparison to the controls, in both frontal and occipital lobes. TGFβ‐induced pro‐fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho‐SMAD2/3 (pSMAD2/3), a direct TGFβ down‐stream signaling mediator, using immunohistochemistry. We found abnormal pSMAD2/3 granular deposits specifically on HCHWA‐D angiopathic frontal and occipital vessels. We graded pSMAD2/3 accumulation in angiopathic vessels and found a positive correlation with the CAA load independent of the brain area. We also observed pSMAD2/3 granules in a halo surrounding occipital vessels, which was specific for HCHWA‐D. The result of this study indicates an upregulation of TGFβ1 in HCHWA‐D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGFβ pathway deregulation in the microvasculature in HCHWA‐D. These findings identify the TGFβ pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA‐D.

Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study

Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls. In this case-control study, we included presymptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis. Between May 15, 2012, and December 22, 2015, we investigated cross-sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11·1 mL/100 g per min, 95% CI -2·8 to -19·3; uncorrected p=0·010) and decreased flux in the basilar artery (mean difference -0·9 mL/s, 95% CI -1·5 to -0·2; uncorrected p=0·019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1·1% [SD 0·5], mean difference -0·4% change, 95% CI -0·7 to -0·2; p=0·001; mean time to baseline 10·1 s [SD 7·6], mean difference 4·6 s, 95% CI 0·4 to 8·8; p=0·032) and symptomatic carriers (mean BOLD change 0·4% [SD 0·1], mean difference -0·9%, 95% CI -1·1 to -0·6; p<0·0001; mean time to baseline 20·3 s [SD 8·4], mean difference 13·1 s, 95% CI 9·4 to 16·9; p<0·0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12·2 s, 95% CI 8·6 to 15·9; p<0·0001). Our findings suggest that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component. USA National Institutes of Health.

β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy.

To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of β-amyloid (Aβ). HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Aβ40, Aβ42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. We included 10 symptomatic patients with HCHWA-D (mean age 55 ± 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 ± 13 years), 31 controls <50 years old (mean age 31 ± 7 years), and 50 controls ≥50 years old (mean age 61 ± 8 years). After correction for age, CSF Aβ40 and Aβ42 were significantly decreased in symptomatic carriers vs controls (median Aβ40 1,386 vs 3,867 ng/L, p < 0.001; median Aβ42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ40 3,501 vs 4,684 ng/L, p = 0.011; median Aβ42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). Decreased levels of CSF Aβ40 and Aβ42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aβ species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aβ40 and Aβ42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.

Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy.

Early markers for cerebral amyloid angiopathy are largely unknown. We aimed to identify which magnetic resonance imaging (MRI) (performed at 7 and 3T) and cognitive markers are an early sign in (pre) symptomatic subjects with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Twenty-seven DNA-proven Dutch-type mutation carriers (15 symptomatic and 12 presymptomatic) (mean age of 45.9 years) and 33 controls (mean age of 45.6 years) were included. 7T and 3T MRI was performed, cerebral amyloid angiopathy and small-vessel disease type MRI markers were estimated, and cognitive performance was assessed. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education. In symptomatic patients, all established cerebral amyloid angiopathy MRI markers (microbleeds, intracerebral hemorrhages, subarachnoid hemorrhages, superficial siderosis, microinfarcts, volume of white matter hyperintensities, and dilated perivascular spaces in centrum semiovale) were increased compared with controls (P<0.05). In presymptomatic subjects, the prevalence of microinfarcts and median volume of white matter hyperintensities were increased in comparison to controls (P<0.05). Symptomatic patients performed worse on all cognitive domains, whereas presymptomatic subjects did not show differences in comparison with controls (P<0.05). White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages.

Hereditary vs. Sporadic Cerebral Hemorrhage with Amyloidosis

Hereditary cerebral hemorrhage with amyloidosis–Dutch (HCHWA-D) is a rare autosomal dominant hereditary disease caused by a point mutation in the

Recurrent hemorrhage risk and mortality in hereditary and sporadic cerebral amyloid angiopathy.

To determine whether hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease model for the sporadic variant of amyloid angiopathy (sCAA), has a comparable recurrent intracerebral hemorrhage (ICH) risk and mortality after a first symptomatic ICH. We included patients with HCHWA-D from the Leiden University Medical Center and patients with sCAA from the Massachusetts General Hospital in a cohort study. Baseline characteristics, hemorrhage recurrence, and short- and long-term mortality were compared. Hazard ratios (HRs) adjusted for age and sex were calculated with Cox regression analyses. We included 58 patients with HCHWA-D and 316 patients with sCAA. Patients with HCHWA-D had fewer cardiovascular risk factors (≥1 risk factor 24% vs 70% in sCAA) and were younger at the time of presenting hemorrhage (mean age 54 vs 72 years in sCAA). Eight patients (14%) with HCHWA-D and 46 patients (15%) with sCAA died before 90 days. During a mean follow-up time of 5 ± 4 years (total 1,550 person-years), the incidence rate of recurrent ICH in patients with HCHWA-D was 20.9 vs 8.9 per 100 person-years in sCAA. Patients with HCHWA-D had a long-term mortality of 8.2 vs 8.4 per 100 person-years in patients with sCAA. After adjustments, patients with HCHWA-D had a higher risk of recurrent ICH (HR 2.8; 95% confidence interval 1.6-4.9; p < 0.001) and a higher long-term mortality (HR 2.8; 95% confidence interval 1.5-5.2; p = 0.001). Patients with HCHWA-D have worse long-term prognosis after a first ICH than patients with sCAA. The absence of cardiovascular risk factors in most patients with HCHWA-D suggests that vascular amyloid is responsible for the recurrent hemorrhages. HCHWA-D is therefore a pure form of cerebral amyloid angiopathy with an accelerated clinical course and provides a good model to study the pathophysiology and future therapeutic interventions of amyloid-related hemorrhages.

Cortical atrophy in patients with cerebral amyloid angiopathy: a case-control study

Loss of cortical grey matter is a diagnostic marker of many neurodegenerative diseases, and is a key mediator of cognitive impairment. We postulated that cerebral amyloid angiopathy (CAA), characterised by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer's disease pathology. We tested this hypothesis in patients with hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease with minimal or no concomitant Alzheimer's disease pathology, as well as in patients with sporadic CAA and healthy and Alzheimer's disease controls. In this observational case-control study, we included six groups of participants: patients diagnosed with HCHWA-D using genetic testing; healthy controls age-matched to the HCHWA-D group; patients with probable sporadic CAA without dementia; two independent cohorts of healthy controls age-matched to the CAA group; and patients with Alzheimer's disease age-matched to the CAA group. De-identified (but unmasked) demographic, clinical, radiological, and genetic data were collected at Massachusetts General Hospital (Boston, MA, USA), at Leiden University (Leiden, Netherlands), and at sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The primary outcome measure was cortical thickness. The correlations between cortical thickness and structural lesions, and blood-oxygen-level-dependent time-to-peak (BOLD-TTP; a physiological measure of vascular dysfunction) were analysed to understand the potential mechanistic link between vascular amyloid and cortical thickness. The radiological variables of interest were quantified using previously validated computer-assisted tools, and all results were visually reviewed to ensure their accuracy. Between March 15, 2006, and Dec 1, 2014, we recruited 369 individuals (26 patients with HCHWA-D and 28 age-matched, healthy controls; 63 patients with sporadic CAA without dementia; two healthy control cohorts with 63 and 126 individuals; and 63 patients with Alzheimer's disease). The 26 patients with HCHWA-D had thinner cortices (2·31 mm [SD 0·18]) than the 28 healthy controls (mean difference -0·112 mm, 95% CI -0·190 to -0·034, p=0·006). The 63 patients with sporadic CAA without dementia had thinner cortices (2·17 mm [SD 0·11]) than the two healthy control cohorts (n=63, mean difference -0·14 mm, 95% CI -0·17 to -0·10, p<0·0001; and n=126, -0·10, -0·13 to -0·06, p<0·0001). All differences remained independent in multivariable analyses. The 63 patients with Alzheimer's disease displayed more severe atrophy than the patients with sporadic CAA (2·1 mm [SD 0·14], difference 0·07 mm, 95% CI 0·11 to 0·02, p=0·005). We found strong associations between cortical thickness and vascular dysfunction in the patients with HCHWA-D (ρ=-0·58, p=0·003) or sporadic CAA (r=-0·4, p=0·015), but not in controls. Vascular dysfunction was identified as a mediator of the effect of hereditary CAA on cortical atrophy, accounting for 63% of the total effect. The appearance of cortical thinning in patients with HCHWA-D indicates that vascular amyloid is an independent contributor to cortical atrophy. These results were reproduced in patients with the more common sporadic CAA. Our findings also suggest that CAA-related cortical atrophy is at least partly mediated by vascular dysfunction. Our results also support the view that small vessel diseases such as CAA can cause cortical atrophy even in the absence of Alzheimer's disease, a conclusion that can help radiologists, neurologists, and other clinicians who diagnose these common geriatric conditions. National Institutes of Health.

Do Attachment Style and Emotion Regulation Strategies Indicate Distress in Predictive Testing?

Predictive genetic testing for a neurogenetic disorder evokes strong emotions, and may lead to distress. The aim of this study is to investigate whether attachment style and emotion regulation strategies are associated with distress in persons who present for predictive testing for a neurogenetic disorder, and whether these psychological traits predict distress after receiving test results. Self-report scales were used to assess attachment insecurity (anxiety and avoidance) and maladaptive emotion regulation strategies (self-blame, rumination, catastrophizing) in adults at 50 % risk for Huntington’s Disease (HD), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Hereditary Cerebral Hemorrhage With Amyloidosis - Dutch type (HCHWA-D), when they presented for predictive testing. Distress was measured before testing and twice (within 2 months and between 6 and 8 months) after receiving test results. Pearson correlations and linear regression were used to analyze whether attachment style and emotion regulation strategies indicated distress. In 98 persons at risk for HD, CADASIL, or HCHWA-D, attachment anxiety and catastrophizing were associated with distress before predictive testing. Attachment anxiety predicted distress up to 2 months after testing. Clinicians may consider looking for signs of attachment anxiety and catastrophizing in persons who present for predictive testing, to see who may be vulnerable for distress during and after testing.