Brain Deep Medullary Veins on 7T MRI in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. OBJECTIVE: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. METHODS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. RESULTS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. CONCLUSION: This study indicates that vascular amyloid-ß deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.

Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. METHODS: In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. RESULTS: In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level-dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007). CONCLUSIONS: Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level-dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Association of cognitive function with increased risk of cancer death and all-cause mortality: Longitudinal analysis, systematic review, and meta-analysis of prospective observational studies.

BACKGROUND: Disturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death. METHODS: Risk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated. RESULTS: Participants of PROSPER had 1.65-fold (95%CI 1.11-2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46-2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36-1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57-3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00-1.20, P-value = 0.044). CONCLUSIONS: Lower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality.

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.

Hydropic Ear Disease: Correlation Between Audiovestibular Symptoms, Endolymphatic Hydrops and Blood-Labyrinth Barrier Impairment.

Research Objective: To investigate the correlation between clinical features and MRI-confirmed endolymphatic hydrops (EH) and blood-labyrinth barrier (BLB) impairment. Study Design: Retrospective cross-sectional study. Setting: Vertigo referral center (Haga Teaching Hospital, The Hague, the Netherlands). Methods: We retrospectively analyzed all patients that underwent 4 h-delayed Gd-enhanced 3D FLAIR MRI at our institution from February 2017 to March 2019. Perilymphatic enhancement and the degree of cochlear and vestibular hydrops were assessed. The signal intensity ratio (SIR) was calculated by region of interest analysis. Correlations between MRI findings and clinical features were evaluated. Results: Two hundred and fifteen patients with MRI-proven endolymphatic hydrops (EH) were included (179 unilateral, 36 bilateral) with a mean age of 55.9 yrs and median disease duration of 4.3 yrs. Hydrops grade is significantly correlated with disease duration (P < 0.001), the severity of low- and high-frequency hearing loss (both P < 0.001), and the incidence of drop attacks (P = 0.001). Visually increased perilymphatic enhancement was present in 157 (87.7%) subjects with unilateral EH. SIR increases in correlation with hydrops grade (P < 0.001), but is not significantly correlated with the low or high Fletcher index (P = 0.344 and P = 0.178 respectively). No significant differences were found between the degree of EH or BLB impairment and vertigo, tinnitus or aural fullness. Conclusion: The degree of EH positively correlates with disease duration, hearing loss and the incidence of drop attacks. The BLB is impaired in association with EH grade, but without clear contribution to the severity of audiovestibular symptoms.

Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional and Longitudinal Investigation.

Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.

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.

Wave Reflection at the Origin of a First-Generation Branch Artery and Target Organ Protection: The AGES-Reykjavik Study.

[Figure: see text].

Cerebral amyloid angiopathy is associated with decreased functional brain connectivity.

Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhage and neurological decline in the elderly. CAA results in focal brain lesions, but the influence on global brain functioning needs further investigation. Here we study functional brain connectivity in patients with Dutch type hereditary CAA using resting state functional MRI. Twenty-four DNA-proven Dutch CAA mutation carriers (11 presymptomatic, 13 symptomatic) and 29 age-matched control subjects were included. Using a set of standardized networks covering the entire cortex, we assessed both within- and between-network functional connectivity. We investigated group differences using general linear models corrected for age, sex and gray matter volume. First, all mutation carriers were contrasted against control subjects and subsequently presymptomatic- and symptomatic mutation carriers against control subjects separately, to assess in which stage of the disease differences could be found. All mutation carriers grouped together showed decreased connectivity in the medial and lateral visual networks, default mode network, executive control and bilateral frontoparietal networks. Symptomatic carriers showed diminished connectivity in all but one network, and between the left and right frontoparietal networks. Presymptomatic carriers also showed diminished connectivity, but only in the frontoparietal left network. In conclusion, global brain functioning is diminished in patients with CAA, predominantly in symptomatic CAA and can therefore be considered to be a late consequence of the disease.

Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. OBJECTIVE: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). METHODS: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). RESULTS: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p  < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aß40 (rs = 0.621, p = 0.024), CSF Aß42 (rs = 0.714, p = 0.006), and brain Aß load (rs = -0.527, p = 0.030). CONCLUSION: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aß neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

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.

Amyloid imaging of dutch-type hereditary cerebral amyloid angiopathy carriers.

OBJECTIVE: To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular ß-amyloid (Aß) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation. METHODS: PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+ ; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M- ). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+ , 8 M- ). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aß concentrations in 17 M+ and 11 M- participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aß in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. RESULTS: D-CAA M+ showed greater age-dependent FLR PiB retention (p < 0.001) than M- , and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+ , greater FLR PiB retention associated with reduced CSF concentrations of Aß40 (r = -0.55, p = 0.021) but not Aß42 (r = 0.01, p = 0.991). Despite comparably low CSF Aß40 and Aß42, PiB retention was substantially less in D-CAA than ADAD (p < 0.001). INTERPRETATION: Increased PiB retention in D-CAA and correlation with reduced CSF Aß40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616-625.

Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques.

Microvascular changes are increasingly recognised not only as primary drivers of radiotherapy treatment response in brain tumours, but also as an important contributor to short- and long-term (cognitive) side effects arising from irradiation of otherwise healthy brain tissue. As overall survival of patients with brain tumours is increasing, monitoring long-term sequels of radiotherapy-induced microvascular changes in the context of their potential predictive power for outcome, such as cognitive disability, has become increasingly relevant. Ideally, radiotherapy-induced significant microvascular changes in otherwise healthy brain tissue should be identified as early as possible to facilitate adaptive radiotherapy and to proactively start treatment to minimise the influence on these side-effects on the final outcome. Although MRI is already known to be able to detect significant long-term radiotherapy induced microvascular effects, more recently advanced MR imaging biomarkers reflecting microvascular integrity and function have been reported and might provide a more accurate and earlier detection of microvascular changes. However, the use and validation of both established and new techniques in the context of monitoring early and late radiotherapy-induced microvascular changes in both target-tissue and healthy tissue currently are minimal at best. This review aims to summarise the performance and limitations of existing methods and future opportunities for detection and quantification of radiotherapy-induced microvascular changes, as well as the relation of these findings with key clinical parameters.

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

Background Cerebral 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 Results We 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 d MRI , (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. Conclusions The d MRI technique is sensitive in detecting alterations in symptomatic HCHWA -d carriers but did not show alterations in presymptomatic carriers. This result indicates that d MRI may be less suitable for identifying early white matter changes in CAA .

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.

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 (TGFß) 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.

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.

TGFß 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 ß (Aß) peptide. Transforming growth factor ß1 (TGFß1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGFß pathway is involved in HCHWA-D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGFß pathway were analyzed with quantitative RT-PCR. TGFß1 and TGFß Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA-D in comparison to the controls, in both frontal and occipital lobes. TGFß-induced pro-fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho-SMAD2/3 (pSMAD2/3), a direct TGFß 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 TGFß1 in HCHWA-D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGFß pathway deregulation in the microvasculature in HCHWA-D. These findings identify the TGFß pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA-D.

Postmortem MRI and histology demonstrate differential iron accumulation and cortical myelin organization in early- and late-onset Alzheimer's disease.

Previous MRI studies reported cortical iron accumulation in early-onset (EOAD) compared to late-onset (LOAD) Alzheimer disease patients. However, the pattern and origin of iron accumulation is poorly understood. This study investigated the histopathological correlates of MRI contrast in both EOAD and LOAD. T2*-weighted MRI was performed on postmortem frontal cortex of controls, EOAD, and LOAD. Images were ordinally scored using predefined criteria followed by histology. Nonlinear histology-MRI registration was used to calculate pixel-wise spatial correlations based on the signal intensity. EOAD and LOAD were distinguishable based on 7T MRI from controls and from each other. Histology-MRI correlation analysis of the pixel intensities showed that the MRI contrast is best explained by increased iron accumulation and changes in cortical myelin, whereas amyloid and tau showed less spatial correspondence with T2*-weighted MRI. Neuropathologically, subtypes of Alzheimer's disease showed different patterns of iron accumulation and cortical myelin changes independent of amyloid and tau that may be detected by high-field susceptibility-based MRI.