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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-β 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-β (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-β (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53-0.88)) but not vascular amyloid-β 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., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.A.K. reports independent support in the form of travel grants from Alzheimer Nederland, the Dutch Heart Foundation and Academy Van Leersum grant of the Academy Medical Sciences Fund, Royal Netherlands Academy of Arts & Sciences, and from the Dutch CAA foundation. V.P. reports independent support from the German Research Foundation (DFG) (454245528). W.M.F. reports independent support from Alzheimer Nederland (WE.03-2018013) and the Alzheimer’s Disease Research program of the BrightFocus Foundation (A2021007F). H.L. reports no disclosures. M.G.K. reports independent support from a Heitman Foundation Career Development Award and a Rappaport Foundation Research Fellowship. G.T.C. reports independent support from the Alzheimer’s Association (AARF-23-1151259) and the Alzheimer’s Society of Canada (22-08). R.F..B reports support from the NIH (R00AG061238, DP2AG082342, R01AG079142). M.J.H.W. reports independent support from de Nederlandse Organisatie voor Wetenschappelijk Onderzoek ZonMw (VIDI grant 91717337), the Netherlands Heart Foundation (2016T86), and the Dutch CAA foundation. S.M.G. reports independent support from the NIH. S.J.v.V. reports independent support from NIH, the AHA/Bugher Foundation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek ZonMw (VENI grant 91619021).

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis., Methods: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes., Results: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function., Discussion: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID., Highlights: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Purpose- Hematoma location within the cerebellum may help identify the dominant small vessel disease type (cerebral amyloid angiopathy [CAA] versus nonamyloid small vessel disease). However, it is unknown whether this holds true for cerebral microbleeds (CMBs) within the cerebellum. We tested the hypothesis that cerebellar CMBs restricted to the cortex and vermis (defined as superficial regions) are associated with clinically diagnosed and pathology-verified CAA. Methods- Three hundred and seven consecutive spontaneous intracerebral hemorrhage (ICH) patients with a baseline magnetic resonance imaging that included susceptibility-weighted imaging or angiography were enrolled. Using a topographical template, cerebellar CMB patterns were defined as strictly superficial versus deep (cerebellar gray nuclei and white matter) or mixed (both regions involved). Thirty-six ICH patients with cerebellar CMBs and neuropathology data available were evaluated for the presence of CAA. Results- One hundred and thirty-five (44%) ICH patients had CMBs in the cerebellum. In the patient group with cerebellar CMBs, 85 (63%) showed a superficial pattern, and 50 (37%) had a deep/mixed pattern. Strictly superficial cerebellar CMBs were independently associated with a supratentorial pattern of probable CAA-ICH according to the Boston criteria (odds ratio, 1.6; CI, 1.03-2.5) and deep/mixed cerebellar CMBs with a pattern of deep/mixed ICH (odds ratio, 1.8; CI, 1.2-2.7). Pathologically verified CAA was present in 23 of 24 (96%) patients with superficial cerebellar CMBs versus 3 of 12 (25%) patients with deep/mixed cerebellar CMBs ( P<0.001). Conclusions- In ICH patients, cerebellar CMBs are relatively common and often restricted to superficial regions. A strictly superficial distribution of cerebellar CMBs is associated with clinically diagnosed and pathologically verified CAA.

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.

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, "high risk" elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58-2.89 and adj-HR: 2.09; 95% CI: 1.71-2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68-8.08 and adj-HR: 3.93; 95% CI: 2.71-5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24-1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00-1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Background: Cerebral amyloid angiopathy (CAA) is associated with hemorrhagic and nonhemorrhagic markers small vessel disease (SVD). A composite score to quantify the total burden of SVD on MRI specifically for CAA patients was recently developed. Brain network alterations related to individual MRI markers of SVD in CAA were demonstrated., Objectives: Considering diffusion based network measures sensitive to detect different relevant SVD-related brain injury, we investigated if increased overall SVD injury on MRI corresponds to worse global brain connectivity in CAA., Methods: Seventy-three patients (79.5% male, mean age 70.58±8.22years) with a diagnosis CAA were considered. SVD markers in total MRI SVD score included: lobar cerebral microbleeds, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and centrum semiovale-enlarged perivascular spaces. Diffusion imaging based network reconstruction was made. The associations between total MRI SVD score and global network efficiency (GNE) were analyzed., Results: A modest significant inverse correlation between total MRI SVD score and GNE existed (p=0.013; R 2 =0.07). GNE was related with the presence of cSS and moderate-severe WMHs., Conclusions: An increased burden of SVD neuroimaging markers corresponds to more reductions in global brain connectivity, implying a possible cumulative effect of overall SVD markers on disrupted physiology. GNE was related with some components of the score, specifically cSS and moderate-severe WMHs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: An MRI-based score of total small vessel disease burden (CAA-SVD-Score) in cerebral amyloid angiopathy (CAA) has been demonstrated to correlate with severity of pathologic changes. Evidence suggests that CAA-related intracerebral hemorrhage (ICH) recurrence risk is associated with specific disease imaging manifestations rather than overall severity. We compared the correlation between the CAA-SVD-Score with the risk of recurrent CAA-related lobar ICH versus the predictive role of each of its components., Methods: Consecutive patients with CAA-related ICH from a single-center prospective cohort were analyzed. Radiological markers of CAA related SVD damage were quantified and categorized according to the CAA-SVD-Score (0-6 points). Subjects were followed prospectively for recurrent symptomatic ICH. Adjusted Cox proportional hazards models were used to investigate associations between the CAA-SVD-Score as well as each of the individual MRI signatures of CAA and the risk of recurrent ICH., Results: In 229 CAA patients with ICH, a total of 56 recurrent ICH events occurred during a median follow-up of 2.8years [IQR 0.9-5.4years, 781 person-years). Higher CAA-SVD-Score (HR=1.26 per additional point, 95%CI [1.04-1.52], p=0.015) and older age were independently associated with higher ICH recurrence risk. Analysis of individual markers of CAA showed that CAA-SVD-Score findings were due to the independent effect of disseminated superficial siderosis (HR for disseminated cSS vs none: 2.89, 95%CI [1.47-5.5], p=0.002) and high degree of perivascular spaces enlargement (RR=3.50-95%CI [1.04-21], p=0.042)., Conclusion: In lobar CAA-ICH patients, higher CAA-SVD-Score does predict recurrent ICH. Amongst individual elements of the score, superficial siderosis and dilated perivascular spaces are the only markers independently associated with ICH recurrence, contributing to the evidence for distinct CAA phenotypes singled out by neuro-imaging manifestations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Findings: 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)., Interpretation: 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., Funding: USA National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 ± 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7 T magnetic resonance imaging. On the obtained high-resolution (200 μm isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no microinfarcts). None of them were visible on in vivo 1.5 T magnetic resonance imaging after a retrospective analysis. Of nine sampled microinfarcts that were matched on histology, five were confirmed as acute and four as old microinfarcts. Finally, we explored the proportion of microhaemorrhage and microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 μm isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: 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., Methods: 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., Results: 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)., Conclusions: White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages., (© 2016 American Heart Association, Inc.)

Importance: Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date., Objective: To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH., Design, Setting, and Participants: Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment., Main Outcomes and Measures: The ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models., Results: This study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion., Conclusions and Relevance: In patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion.

Importance: Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA., Objectives: To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes., Design, Setting, and Participants: This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study., Main Outcomes and Measures: Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression., Results: In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses., Conclusions and Relevance: This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

Background: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized., Objective: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA., Methods: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed., Results: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01)., Conclusions: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

Cortical superficial siderosis describes a distinct pattern of blood-breakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord. Although cortical superficial siderosis has many possible causes, it is emerging as a key feature of cerebral amyloid angiopathy, a common and important age-related cerebral small vessel disorder leading to intracerebral haemorrhage and dementia. In cerebral amyloid angiopathy cohorts, cortical superficial siderosis is associated with characteristic clinical symptoms, including transient focal neurological episodes; preliminary data also suggest an association with a high risk of future intracerebral haemorrhage, with potential implications for antithrombotic treatment decisions. Thus, cortical superficial siderosis is of relevance to neurologists working in neurovascular, memory and epilepsy clinics, and neurovascular emergency services, emphasizing the need for appropriate blood-sensitive magnetic resonance sequences to be routinely acquired in these clinical settings. In this review we focus on recent developments in neuroimaging and detection, aetiology, prevalence, pathophysiology and clinical significance of cortical superficial siderosis, with a particular emphasis on cerebral amyloid angiopathy. We also highlight important areas for future investigation and propose standards for evaluating cortical superficial siderosis in research studies., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET) would correlate with the extent of magnetic resonance imaging (MRI) white matter hyperintensities (WMH; or leukoaraiosis) in patients with high vascular amyloid deposition (cerebral amyloid angiopathy [CAA]) but not in patients with high parenchymal amyloid deposition (Alzheimer disease [AD]; mild cognitive impairment [MCI]) or in healthy elderly (HE) subjects., Methods: Forty-two nondemented CAA patients, 50 HE subjects, and 43 AD/MCI patients had brain MRI and PiB PET. Multivariate linear regression was used to assess the independent association between PiB retention and white matter disease volume, controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group., Results: CAA patients were younger than HE and AD subjects (68 ± 10 vs 73.3 ± 7 and 74 ± 7.4, p < 0.01) but had higher amounts of WMH (median = 21 vs 3.2 and 10.8 ml, respectively, p < 0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho = 0.52, p < 0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity, also remained as an independent predictor of WMH volume., Interpretation: Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlates with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity., (Copyright © 2012 American Neurological Association.)

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: MRI evidence of small vessel disease is common in intracerebral hemorrhage (ICH). We hypothesized that ICH caused by cerebral amyloid angiopathy (CAA) or hypertensive vasculopathy would have different distributions of MRI T2 white matter hyperintensity (WMH) and microbleeds., Methods: Data were analyzed from 133 consecutive patients with primary supratentorial ICH and adequate MRI sequences. CAA was diagnosed using the Boston criteria. WMH segmentation was performed using a validated semiautomated method. WMH and microbleeds were compared according to site of symptomatic hematoma origin (lobar versus deep) or by pattern of hemorrhages, including both hematomas and microbleeds, on MRI gradient recalled echo sequence (grouped as lobar only-probable CAA, lobar only-possible CAA, deep hemispheric only, or mixed lobar and deep hemorrhages)., Results: Patients with lobar and deep hemispheric hematoma had similar median normalized WMH volumes (19.5 cm versus 19.9 cm(3), P=0.74) and prevalence of >or=1 microbleed (54% versus 52%, P=0.99). The supratentorial WMH distribution was similar according to hemorrhage location category; however, the prevalence of brain stem T2 hyperintensity was lower in lobar hematoma versus deep hematoma (54% versus 70%, P=0.004). Mixed ICH was common (23%). Patients with mixed ICH had large normalized WMH volumes and a posterior distribution of cortical hemorrhages similar to that seen in CAA., Conclusions: WMH distribution is largely similar between CAA-related and non-CAA-related ICH. Mixed lobar and deep hemorrhages are seen on MRI gradient recalled echo sequence in up to one fourth of patients; in these patients, both hypertension and CAA may be contributing to the burden of WMH.

Background and Purpose: Validation of the Boston criteria for the in vivo diagnosis of cerebral amyloid angiopathy (CAA) is challenging, because noninvasive diagnostic tests do not exist. Hereditary cerebral hemorrhage with amyloidosis-Dutch type is an accepted monogenetic model of CAA and diagnosis can be made with certainty based on DNA analysis. The aim of this study was to analyze and refine the existing Boston criteria in patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type., Methods: We performed T2*-weighted MRI in 27 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type to assess the presence and location of microbleeds, intracranial hemorrhages, and superficial siderosis. Using the Boston criteria, subjects were categorized as having: no hemorrhages, possible CAA, probable CAA, and hemorrhagic lesions not qualifying for CAA. The sensitivity of the Boston criteria was calculated separately using intracranial hemorrhages only and using intracranial hemorrhages and microbleeds., Results: The sensitivity of the Boston criteria for probable CAA increased from 48% to 63% when microbleeds were included. For symptomatic subjects only, the sensitivity was 100%. No hemorrhages were identified in the deep white matter, basal ganglia, thalamus, or brainstem. Superficial siderosis, observed in 6 patients, did not increase the sensitivity of the Boston criteria in our study group., Conclusions: Our data show that using T2*-weighted MRI and including microbleeds increase the sensitivity of the Boston criteria. The exclusion of hemorrhages in the deep white matter, basal ganglia, thalamus, and brainstem does not lower the sensitivity of the Boston criteria.

Background and Purpose: Intracerebral hemorrhage (ICH) accounts for a majority of long-term morbidity and mortality associated with bleeding while on warfarin. Both ICH and warfarin-related ICH appear to have a genetic component. Furthermore, advanced neuroimaging using MRI can now identify individuals at increased risk of ICH. We explore whether screening strategies that include genetic profiling and neuroimaging might improve the safety of chronic anticoagulation for atrial fibrillation by identifying individuals from whom warfarin should be withheld., Methods: We used a Markov state transition decision model. Effectiveness was measured in quality-adjusted life-years. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles along with empirical data from our institutions. The base case was a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation., Results: For patients at average risk for thromboembolic events and known to possess a hypothetical genetic profile increasing risk for warfarin ICH, anticoagulation remains the preferred strategy until the relative hazard of ICH exceeds 23.8. Genetic profiling would be favored for patients at low risk of thromboembolism (1.5% per year) if the hypothetical gene variant(s) conferred a relative risk of ICH >4.1. Screening strategies in which patients underwent genotyping and MRI before anticoagulation did not improve aggregate patient outcomes unless the predictive power of MRI exceeded current best guess estimates and patients were at low to moderate risk of thromboembolism., Conclusions: Currently identified genetic markers of bleeding risk do not confer a risk of ICH sufficiently high to warrant routine genetic testing for patients at average risk of thromboembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin ICH do not support use of these tests for withholding anticoagulation in patients with atrial fibrillation.

Background and Purpose: White-matter hyperintensities (WMHs) detected by magnetic resonance imaging are thought to represent the effects of cerebral small-vessel disease and neurodegenerative changes. We sought to determine whether the spatial distribution of WMHs discriminates between different disease groups and healthy aging individuals and whether these distributions are related to local cerebral perfusion patterns., Methods: We examined the pattern of WMHs by T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging in 3 groups of subjects: cerebral amyloid angiopathy (n=32), Alzheimer disease or mild cognitive impairment (n=41), and healthy aging (n=29). WMH frequency maps were calculated for each group, and spatial distributions were compared by voxel-wise logistic regression. WMHs were also analyzed as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography atlas., Results: Although WMH volume was greater in cerebral amyloid angiopathy and Alzheimer disease/mild cognitive impairment than in healthy aging, there was no consistent difference in the spatial distributions when controlling for total WMH volume. Hyperintensities were most frequent in the deep periventricular WM in all 3 groups. A strong inverse correlation between hyperintensity frequency and normal perfusion was demonstrated in all groups, demonstrating that WMHs were most common in regions of relatively lower normal cerebral perfusion., Conclusions: WMHs show a common distribution pattern and predilection for cerebral WM regions with lower atlas-derived perfusion, regardless of the underlying diagnosis. These data suggest that across diverse disease processes, WM injury may occur in a pattern that reflects underlying tissue properties, such as relative perfusion.

Background and Purpose: We sought to determine whether mid-sagittal intracranial area (ICA) is a valid surrogate of intracranial volume (ICV) when using retrospective data with relatively thick (6-7 mm) sagittal slices., Methods: Data were retrospectively analyzed from 47 subjects who had two MRI scans taken at least nine months apart. Twenty-three subjects had manual segmentation of ICV on the T2-weighted sequence for comparison., Results: Intraclass correlation coefficient (ICC) for intraobserver, interobserver, and intraobserver scan-rescan comparisons were 0.96, 0.97 and 0.95. Pearson correlation coefficients between ICV and ICA, averaging the cumulative 1, 2, 3, and 4 most midline slices, were 0.89, 0.94, 0.93, and 0.95. There was a significant marginal increase in explained variance of ICV by measuring two, rather than one, slices (P= 0.001)., Conclusions: These data suggest that ICA, even measured without high-resolution imaging, is a reasonable substitute for ICV.

BackgroundWhite matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.ObjectiveConducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.MethodsThe NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity.ResultsICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression.ConclusionsThe present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

IntroductionTo describe the protocol and findings of the instrumental validation of three imaging-based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1-weighted imaging.MethodsThe instrumental validation of imaging-based biomarker kits included inter-rater reliability among participating sites, test-retest repeatability, and inter-scanner reproducibility across three types of magnetic resonance imaging (MRI) scanners using intra-class correlation coefficients (ICC).ResultsThe three biomarkers demonstrated excellent inter-rater reliability (ICC >0.94, P-values 0.98, P-values 0.98, P-values

The MarkVCID consortium was formed under cooperative agreements with the National Institute of Neurologic Diseases and Stroke (NINDS) and National Institute on Aging (NIA) in 2016 with the goals of developing and validating biomarkers for the cerebral small vessel diseases associated with the vascular contributions to cognitive impairment and dementia (VCID). Rigorously validated biomarkers have consistently been identified as crucial for multicenter studies to identify effective strategies to prevent and treat VCID, specifically to detect increased VCID risk, diagnose the presence of small vessel disease and its subtypes, assess prognosis for disease progression or response to treatment, demonstrate target engagement or mechanism of action for candidate interventions, and monitor disease progression during treatment. The seven project sites and central coordinating center comprising MarkVCID, working with NINDS and NIA, identified a panel of 11 candidate fluid- and neuroimaging-based biomarker kits and established harmonized multicenter study protocols (see companion paper "MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols" for full details). Here we describe the MarkVCID neuroimaging protocols with specific focus on validating their application to future multicenter trials. MarkVCID procedures for participant enrollment; clinical and cognitive evaluation; and collection, handling, and instrumental validation of fluid samples are described in detail in a companion paper. Magnetic resonance imaging (MRI) has long served as the neuroimaging modality of choice for cerebral small vessel disease and VCID because of its sensitivity to a wide range of brain properties, including small structural lesions, connectivity, and cerebrovascular physiology. Despite MRI's widespread use in the VCID field, there have been relatively scant data validating the repeatability and reproducibility of MRI-based biomarkers across raters, scanner types, and time intervals (collectively defined as instrumental validity). The MRI protocols described here address the core MRI sequences for assessing cerebral small vessel disease in future research studies, specific sequence parameters for use across various research scanner types, and rigorous procedures for determining instrumental validity. Another candidate neuroimaging modality considered by MarkVCID is optical coherence tomography angiography (OCTA), a non-invasive technique for directly visualizing retinal capillaries as a marker of the cerebral capillaries. OCTA has theoretical promise as a unique opportunity to visualize small vessels derived from the cerebral circulation, but at a considerably earlier stage of development than MRI. The additional OCTA protocols described here address procedures for determining OCTA instrumental validity, evaluating sources of variability such as pupil dilation, and handling data to maintain participant privacy. MRI protocol and instrumental validation The core sequences selected for the MarkVCID MRI protocol are three-dimensional T1-weighted multi-echo magnetization-prepared rapid-acquisition-of-gradient-echo (ME-MPRAGE), three-dimensional T2-weighted fast spin echo fluid-attenuated-inversion-recovery (FLAIR), two-dimensional diffusion-weighted spin-echo echo-planar imaging (DWI), three-dimensional T2*-weighted multi-echo gradient echo (3D-GRE), three-dimensional T2 -weighted fast spin-echo imaging (T2w), and two-dimensional T2*-weighted gradient echo echo-planar blood-oxygenation-level-dependent imaging with brief periods of CO2 inhalation (BOLD-CVR). Harmonized parameters for each of these core sequences were developed for four 3 Tesla MRI scanner models in widespread use at academic medical centers. MarkVCID project sites are trained and certified for their instantiation of the consortium MRI protocols. Sites are required to perform image quality checks every 2 months using the Alzheimer's Disease Neuroimaging Initiative phantom. Instrumental validation for MarkVCID MRI-based biomarkers is operationally defined as inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility. Assessments of these instrumental properties are performed on individuals representing a range of cerebral small vessel disease from mild to severe. Inter-rater reliability is determined by distribution of an independent dataset of MRI scans to each analysis site. Test-retest repeatability is determined by repeat MRI scans performed on individual participants on a single MRI scanner after a short (1- to 14-day) interval. Inter-scanner reproducibility is determined by repeat MRI scans performed on individuals performed across four MRI scanner models. OCTA protocol and instrumental validation The MarkVCID OCTA protocol uses a commercially available, Food and Drug Administration-approved OCTA apparatus. Imaging is performed on one dilated and one undilated eye to assess the need for dilation. Scans are performed in quadruplicate. MarkVCID project sites participating in OCTA validation are trained and certified by this biomarker's lead investigator. Inter-rater reliability for OCTA is assessed by distribution of OCTA datasets to each analysis site. Test-retest repeatability is assessed by repeat OCTA imaging on individuals on the same day as their baseline OCTA and a different-day repeat session after a short (1- to 14-day) interval. Methods were developed to allow the OCTA data to be de-identified by the sites before transmission to the central data management system. The MarkVCID neuroimaging protocols, like the other MarkVCID procedures, are designed to allow translation to multicenter trials and as a template for outside groups to generate directly comparable neuroimaging data. The MarkVCID neuroimaging protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the neuroimaging MarkVCID kits will undergo biological validation to determine its ability to measure important aspects of VCID such as cognitive function. The analytic methods for the neuroimaging-based kits and the results of these validation studies will be published separately. The results will ultimately determine the neuroimaging kits' potential usefulness for multicenter interventional trials in small vessel disease-related VCID.

BackgroundCerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage.ObjectiveTo optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy.MethodsAdditional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions.Expected outcomesWith the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine.DiscussionThe project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

IntroductionMany consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease.MethodsSurveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis.ResultsA framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository.ConclusionsThe HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi‐site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. Highlights: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR).CVR was positively associated with global cognition in older adults.This finding was observed in three independent cohorts at three sites.Our statistical analysis plan was predefined before beginning data collection. [ABSTRACT FROM AUTHOR]

IntroductionThe Boston criteria are the basis for a noninvasive diagnosis of cerebral amyloid angiopathy (CAA) in the setting of lobar intracerebral hemorrhage (ICH). We assessed the accuracy of these criteria in individuals with lobar microbleeds (MBs) without ICH.MethodsWe identified individuals aged >55 years having brain magnetic resonance imaging (MRI) and pathological assessment of CAA in a single academic hospital and a community-based population (Framingham Heart Study [FHS]). We determined the positive predictive value (PPV) of the Boston criteria for CAA in both cohorts, using lobar MBs as the only hemorrhagic lesion to fulfill the criteria.ResultsWe included 102 individuals: 55 from the hospital-based cohort and 47 from FHS (mean age at MRI 74.7 ± 8.5 and 83.4 ± 10.9 years; CAA prevalence 60% and 46.8%; cases with any lobar MB 49% and 21.3%; and cases with ≥2 strictly lobar MBs 29.1% and 8.5%, respectively). PPV of "probable CAA" (≥2 strictly lobar MBs) was 87.5% (95% confidence interval [CI], 60.4-97.8) and 25% (95% CI, 13.2-78) in hospital and general populations, respectively.DiscussionStrictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited.

Objective: A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false‐positive CAA cases. Methods: In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified. Results: Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false‐positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon. Interpretation: These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856–870 [ABSTRACT FROM AUTHOR]

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-β 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. [ABSTRACT FROM AUTHOR]

Background: Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined. Aims: Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH. Methods: Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria). Results: Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p = 0.52) patients with P-IPH. Conclusions: Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%—both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH. [ABSTRACT FROM AUTHOR]

Background: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. Methods: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110–139 mm Hg versus 140–179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. Results: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00–5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71–1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. Conclusions: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565). [ABSTRACT FROM AUTHOR]

Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls' Prussian blue, and immunohistochemistry was performed against amyloid-β and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls'-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P < 0.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas. [ABSTRACT FROM AUTHOR]

Background: It is not clear whether subsets of patients with intracerebral hemorrhage (ICH) benefit from intensive blood pressure (BP) lowering. We evaluated whether white matter hyperintensities (WMH) burden influences response to this therapy.Methods: Retrospective secondary analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Patients were randomized to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment with intravenous nicardipine within 4.5 h from onset between May 2011 and September 2015. WMH were rated on magnetic resonance images (fluid-attenuated inversion recovery sequences), defining moderate-severe WMH as total Fazekas scale score ≥ 3 (range 0-6). The main outcome was death or major disability at 90 days (modified Rankin scale ≥ 3). The secondary outcome was ICH expansion, defined as hematoma growth > 33% from baseline to follow-up CT scan. Predictors of the outcomes of interest were explored with multivariable logistic regression.Results: A total of 195/1000 patients had MRI images available for analysis, of whom 161 (82.6%) had moderate-severe WMH. When compared to patients with none-mild WMH, those with moderate-severe WMH did not have an increased risk of death or major disability (adjusted relative risk: 1.83, 95% CI 0.71-4.69) or ICH expansion (adjusted relative risk: 1.14, 95% CI 0.38-3.37). WMH burden did not modify the effect of intensive BP treatment on outcome (all p for interaction ≥ 0.2).Conclusion: The majority of acute ICH patients have moderate-severe WMH, but advanced small vessel disease burden marked by WMH does not influence ICH-related outcomes or response to intensive BP reduction. [ABSTRACT FROM AUTHOR]

Background and Objective: Cerebral amyloid angiopathy (CAA) accounts for the majority of lobar intracerebral hemorrhage (ICH); however, the risk factors for dementia conversion after ICH occurrence in CAA patients are unknown, especially in the long-term period after ICH. Therefore, we aimed to unravel the predictors for late post-ICH dementia (6 months after ICH event) in probable CAA patients.Methods: From a large consecutive MRI prospective cohort of spontaneous ICH (2006-2017), we identified probable CAA patients (modified Boston criteria) without dementia 6 months post-ICH. Cognitive outcome during follow-up was determined based on the information from standardized clinical visit notes. We used Cox regression analysis to investigate the association between baseline demographic characteristics, past medical history, MRI biomarkers, and late post-ICH dementia conversion (dementia occurred after 6 months).Results: Among 97 non-demented lobar ICH patients with probable CAA, 25 patients (25.8%) developed dementia during a median follow-up time of 2.5 years (IQR 1.5-3.8 years). Pre-existing mild cognitive impairment, increased white matter hyperintensities (WMH) burden, the presence of disseminated cortical superficial siderosis (cSS), and higher total small vessel disease score for CAA were all independent predictors for late dementia conversion.Conclusion: In probable CAA patients presenting with lobar ICH, high WMH burden and presence of disseminated cSS are useful neuroimaging biomarkers for dementia risk stratification. These findings have implications for clinical practice and future trial design. [ABSTRACT FROM AUTHOR]

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods: We scanned intact formalin‐fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results: In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole‐brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ‐positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation: These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279–292 [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is a common cause of cognitive impairment in older individuals. This study aimed to investigate predictors of dementia in CAA patients without intracerebral hemorrhage (ICH). A total of 158 non-demented patients from the Stroke Service or the Memory Clinic who met the modified Boston Criteria for probable CAA were included. At baseline, neuroimaging markers, including lobar microbleeds (cerebral microbleeds (CMBs)), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), magnetic resonance imaging (MRI)-visible centrum semiovale perivascular spaces (CSO-PVS), lacunes, and medial temporal atrophy (MTA) were assessed. The overall burden of small vessel disease (SVD) for CAA was calculated by a cumulative score based on CMB number, WMH severity, cSS presence and extent and CSO-PVS severity. The estimated cumulative dementia incidence at 1 year was 14% (95% confidence interval (CI): 5%–23%), and 5 years 73% (95% CI: 55%, 84%). Age (hazard ratio (HR) 1.05 per year, 95% CI: 1.01–1.08, p = 0.007), presence of MCI status (HR 3.40, 95% CI: 1.97–6.92, p < 0.001), MTA (HR 1.71 per point, 95% CI: 1.26–2.32, p = 0.001), and SVD score (HR 1.23 per point, 95% CI: 1.20–1.48, p = 0.030) at baseline were independent predictors for dementia conversion in these patients. Cognitive deterioration of CAA patients appears attributable to cumulative changes, from both vasculopathic and neurodegenerative lesions. [ABSTRACT FROM AUTHOR]

Background: Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer’s dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension. Methods: In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET) scan with Pittsburgh Compound B (PiB-PET) to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed. Results: Mean age was 75.0 (standard deviation, SD, 7.3). Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23), executive function -0.40 (SD 1.10), processing speed -0.24 (SD 0.88); 22 of the 67 subjects met criteria for mild cognitive impairment (MCI) and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01). This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores. Conclusions: Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) has never been more relevant. The last 5 years have seen a rapid increase in publications and research in the field, with the development of new biomarkers for the disease, thanks to advances in MRI, amyloid positron emission tomography and cerebrospinal fluid biomarker analysis. The inadvertent development of CAA-like pathology in patients treated with amyloid-beta immunotherapy for Alzheimer's disease has highlighted the importance of establishing how and why CAA develops; without this information, the use of these treatments may be unnecessarily restricted. Our understanding of the clinical and radiological spectrum of CAA has continued to evolve, and there are new insights into the independent impact that CAA has on cognition in the context of ageing and intracerebral haemorrhage, as well as in Alzheimer's and other dementias. While the association between CAA and lobar intracerebral haemorrhage (with its high recurrence risk) is now well recognised, a number of management dilemmas remain, particularly when considering the use of antithrombotics, anticoagulants and statins. The Boston criteria for CAA, in use in one form or another for the last 20 years, are now being reviewed to reflect these new wide-ranging clinical and radiological findings. This review aims to provide a 5-year update on these recent advances, as well as a look towards future directions for CAA research and clinical practice. [ABSTRACT FROM AUTHOR]

Background: Recovery of functional independence is possible in patients with brainstem traumatic axonal injury (TAI), also referred to as "grade 3 diffuse axonal injury," but acute prognostic biomarkers are lacking. We hypothesized that the extent of dorsal brainstem TAI measured by burden of traumatic microbleeds (TMBs) correlates with 1-year functional outcome more strongly than does ventral brainstem, corpus callosal, or global brain TMB burden. Further, we hypothesized that TMBs within brainstem nuclei of the ascending arousal network (AAN) correlate with 1-year outcome.Methods: Using a prospective outcome database of patients treated for moderate-to-severe traumatic brain injury at an inpatient rehabilitation hospital, we retrospectively identified 39 patients who underwent acute gradient-recalled echo (GRE) magnetic resonance imaging (MRI). TMBs were counted on the acute GRE scans globally and in the dorsal brainstem, ventral brainstem, and corpus callosum. TMBs were also mapped onto an atlas of AAN nuclei. The primary outcome was the disability rating scale (DRS) score at 1 year post-injury. Associations between regional TMBs, AAN TMB volume, and 1-year DRS score were assessed by calculating Spearman rank correlation coefficients.Results: Mean ± SD number of TMBs was: dorsal brainstem = 0.7 ± 1.4, ventral brainstem = 0.2 ± 0.6, corpus callosum = 1.8 ± 2.8, and global = 14.4 ± 12.5. The mean ± SD TMB volume within AAN nuclei was 6.1 ± 18.7 mm3. Increased dorsal brainstem TMBs and larger AAN TMB volume correlated with worse 1-year outcomes (R = 0.37, p = 0.02, and R = 0.36, p = 0.02, respectively). Global, callosal, and ventral brainstem TMBs did not correlate with outcomes.Conclusions: These findings suggest that dorsal brainstem TAI, especially involving AAN nuclei, may have greater prognostic utility than the total number of lesions in the brain or brainstem. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 ± 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7 T magnetic resonance imaging. On the obtained high-resolution (200 μm isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no microinfarcts). None of them were visible on in vivo 1.5 T magnetic resonance imaging after a retrospective analysis. Of nine sampled microinfarcts that were matched on histology, five were confirmed as acute and four as old microinfarcts. Finally, we explored the proportion of microhaemorrhage and microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 μm isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Background: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA.Objective: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds.Methods: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student's t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds.Results: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p = 0.179 and p = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds.Conclusions: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA. [ABSTRACT FROM AUTHOR]

Background: Traumatic axonal injury (TAI) may be reversible, yet there are currently no clinical imaging tools to detect axonal recovery in patients with traumatic brain injury (TBI). We used diffusion tensor imaging (DTI) to characterize serial changes in fractional anisotropy (FA) within TAI lesions of the corpus callosum (CC). We hypothesized that recovery of FA within a TAI lesion correlates with better functional outcome.Methods: Patients who underwent both an acute DTI scan (≤day 7) and a subacute DTI scan (day 14 to inpatient rehabilitation discharge) at a single institution were retrospectively analyzed. TAI lesions were manually traced on the acute diffusion-weighted images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured within the TAI lesions at each time point. FA recovery was defined by a longitudinal increase in CC FA that exceeded the coefficient of variation for FA based on values from healthy controls. Acute FA, ADC, AD, and RD were compared in lesions with and without FA recovery, and correlations were tested between lesional FA recovery and functional recovery, as determined by disability rating scale score at discharge from inpatient rehabilitation.Results: Eleven TAI lesions were identified in 7 patients. DTI detected FA recovery within 2 of 11 TAI lesions. Acute FA, ADC, AD, and RD did not differ between lesions with and without FA recovery. Lesional FA recovery did not correlate with disability rating scale scores.Conclusions: In this retrospective longitudinal study, we provide initial evidence that FA can recover within TAI lesions. However, FA recovery did not correlate with improved functional outcomes. Prospective histopathological and clinical studies are needed to further elucidate whether lesional FA recovery indicates axonal healing and has prognostic significance. [ABSTRACT FROM AUTHOR]