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.
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.
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).
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.
Fluid-attenuated inversion recovery (FLAIR) imaging is an important clinical ‘work horse’ for brain MRI and has proven to facilitate imaging of both intracortical lesions as well as cortical layers ...at 7T MRI. A prominent observation on 7T FLAIR images is a hyperintense rim at the cortical surface and around the ventricles. We aimed to clarify the anatomical correlates and underlying contrast mechanisms of this hyperintense rim.
Two experiments with post-mortem human brain tissue were performed. FLAIR and T2-weighted images were obtained at typical in vivo (0.8mm isotropic) and high resolution (0.25mm isotropic). At one location the cortical surface was partly removed, and scanned again. Imaging was followed by histological and immunohistochemical analysis. Additionally, several simulations were performed to evaluate the potential contribution from an artifact due to water diffusion.
The hyperintense rim corresponded to the outer – glia rich – layer of the cortex and disappeared upon removal of that layer. At the ventricles, the rim corresponded to the ependymal layer, and was not present at white matter/fluid borders at an artificial cut. The simulations supported the hypothesis that the hyperintense rim reflects the tissue properties in the outer cortical layers (or ependymal layer for the ventricles), and is not merely an artifact, although not all observations were explained by the simulated model of the contrast mechanism.
7T FLAIR seems to amplify the signal from layers I–III of the cortex and the ependyma around the ventricles. Although diffusion of water from layer I into CSF does contribute to this effect, a long T2 relaxation time constant in layer I, and probably also layer II–III, is most likely the major contributor, since the rim disappears upon removal of that layer. This knowledge can help the interpretation of imaging results in cortical development and in patients with cortical pathology.
•7T FLAIR images show a hyperintense rim at the outer layers of the cortex.•We performed ex vivo experiments to clarify the anatomical correlates of the rim.•We performed simulations to better understand potential underlying mechanisms.•The rim corresponds to layer I of the cortex on high resolution ex vivo FLAIR.•The rim can be explained by a long T2 in the outer layer, and is not an artifact.
Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla ...MRI.
To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI).
182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria.
Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains.
CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.
Blood-brain barrier (BBB) leakage is hypothesized to be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding vessel wall breakdown and hemorrhage. This study ...aims (1) to measure BBB leakage in vivo in the parenchyma and at the level of the leptomeningeal blood vessels in patients with CAA without lobar intracerebral hemorrhage compared to controls and (2) to study the relationship between BBB leakage and neuroimaging markers of CAA severity.
To date, 13 participants with probable CAA without prior intracerebral hemorrhage (age 67±9 years, 8 females) and 5 non-CAA controls with mild cognitive impairment (CDR 0.5 or 1) and no microbleeds (age 70±7 years, 1 female) have been included into the study. The 3T MRI protocol included pre- and post-contrast T1-weighted (0.9 × 0.9 × 0.9 mm3) and T2-FLAIR scans (0.9 × 0.9 × 0.9 mm3, TE 500 ms), an SWI (0.6 × 0.6 × 1.4 mm3), and a Dynamic Contrast Enhanced (DCE) scan (0.9 × 0.9 × 3.0 mm3). Participants received (0.2mL/kg) a gadolinium-based contrast agent (Dotarem) intravenously during the DCE scan. DCE scans were analyzed with ROCKETSHIP software to quantify the permeability-surface area product (PS), which represents the rate at which contrast agent leaks from the plasma into the parenchyma. Leptomeningeal CSF enhancement is measured by visually inspecting post-contrast versus pre-contrast T2-FLAIR scans.
Preliminary analysis revealed higher whole-brain PS in participants with CAA compared to non-CAA controls (Figure 1). Figure 2 shows an example of leptomeningeal CSF enhancement on post-contrast T2-FLAIR (2b) versus pre-contrast T2-FLAIR (2a). Ongoing analyses will compare PS-values in the cortex and white matter and in the occipital and frontal lobe. Furthermore, we aim to study the relationship between parenchymal and leptomeningeal contrast leakage with hemorrhagic neuroimaging markers (i.e. cortical microbleeds and cortical superficial siderosis) on SWI.
These preliminary results indicate that we can capture BBB leakage in vivo in our cohort, and that parenchymal BBB leakage is higher in patients with CAA compared to controls. Successful completion of this ongoing study will aid our understanding of the role of BBB leakage in the pathophysiology of CAA and the potential added value of BBB imaging as an early disease biomarker in CAA.
In this retrospective case series study, we used 7.0 tesla MRI to describe patterns of intracranial vessel wall abnormalities in relation to ischemic infarcts in 9 patients with different ...intracranial vessel wall pathologies.
A patient-specific clinical imaging protocol was obtained after regular clinical workup, including a fluid-attenuated inversion recovery and an intracranial vessel wall sequence before and after contrast administration using 7.0 tesla MRI. An attempt was made to describe patterns by grouping the patients by intracranial vessel wall abnormalities (eccentric or concentric; enhancing or nonenhancing), then on the presence of macroinfarcts and cortical microinfarcts (CMIs), and lastly on type of macroinfarct (lacunar, small macroinfarct, or large macroinfarct).
Intracranial vessel wall abnormalities were identified in all patients, totaling 45 lesions, 12 of which enhanced after contrast administration. CMIs were found in 5 patients. Two patients had eccentric, enhancing wall thickening but differed based on presence or absence of CMIs. Four patients also had eccentric but nonenhancing wall thickening, 2 of whom showed CMIs. The 2 patients lacking CMIs could be subdivided based on the type of macroinfarct. Concentric, enhanced wall thickening was observed in 2 patients with CMIs who differed regarding macroinfarct types. One patient with previous vasculitis showed concentric, nonenhancing wall thickening.
Our results suggest that the combination of intracranial vessel wall abnormalities and infarct type is related to different stroke etiologies.
We present here a case report of a patient with a family history of intracerebral hemorrhages (ICHs) who presented with multiple large lobar hemorrhages in rapid succession, with cognitive sparing, ...who was found to have a mutation in the β-amyloid coding sequence of amyloid precursor protein (Leu705Val), termed the Piedmont-type mutation, the second ever reported case of this form of hereditary cerebral amyloid angiopathy (CAA).
Targeted pathologic examination was performed aided by the use of ex vivo MRI.
Severe CAA was observed mainly involving the leptomeningeal vessels and, to a far lesser extent, cortical vessels, with no amyloid plaques or neurofibrillary tangles.
This leptomeningeal pattern of β-amyloid deposition coupled with multiple large hemorrhages demonstrates unique pathophysiologic characteristics of CAA associated with the Piedmont-type mutation, suggesting a potential association between leptomeningeal CAA and larger ICHs.
Abstract
Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid β immunotherapy trials in patients with Alzheimer’s disease. The ...underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used ex vivo MRI in cases that underwent amyloid β immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe cerebral amyloid angiopathy. Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid β immunization with AN1792 for Alzheimer’s disease. Eleven matched non-immunized Alzheimer’s disease cases from an independent brain brank were used as ‘controls’. Formalin-fixed occipital brain slices were imaged at 7 T MRI to screen for haemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without haemorrhagic lesions were cut and stained. Artificial intelligence-assisted quantification of amyloid β plaque area, cortical and leptomeningeal cerebral amyloid angiopathy area, the density of iron and calcium positive cells and reactive astrocytes and activated microglia was performed. On ex vivo MRI, cortical superficial siderosis was observed in 5/10 immunized Alzheimer’s disease cases compared with 1/11 control Alzheimer’s disease cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the immunized Alzheimer’s disease group, areas with siderosis on MRI revealed greater leptomeningeal cerebral amyloid angiopathy and concentric splitting of the vessel walls compared with areas without siderosis. Moreover, greater density of iron-positive cells in the cortex was associated with lower amyloid β plaque area and a trend towards increased post-vaccination antibody titres. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid β immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid β with available in vivo MRI during life.
Scherlek et al. report haemorrhagic lesions on ex vivo MRI in brain tissue samples of Alzheimer’s disease patients who received anti-amyloid immunotherapy during life. These lesions were associated with severe leptomeningeal cerebral amyloid angiopathy, suggesting a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities.
Graphical Abstract
Small cerebellar cavities (≤15 mm) are often observed coincidentally in ageing subjects and have also been associated with migraine. Although generally assumed to be of ischaemic origin, descriptive ...imaging studies are sparse and imaging findings have not been correlated with histopathology. We aimed to investigate whether small ischaemic cavities in the cerebellum show characteristic infarct patterns that might be helpful for diagnostic imaging.
We examined 40 whole postmortem cerebella with 7-tesla MRI ex vivo for the presence of small ischaemic cavities. The scan protocol included a T2-, T2*- and fluid-attenuated inversion recovery-weighted sequence for all specimens. We investigated to which degree small ischaemic cavities affect the cortical, juxtacortical and/or deep subcortical regions of the cerebellum. In a subset of the cavities identified, we correlated the imaging data with histopathological findings. This was performed by cutting the particular cerebellar specimen into 5-mm-thick slices. Serial sections were performed if cavities remained unidentified macroscopically.
Twenty-two cavities were seen on ex vivo MRI in 8 out of 40 examined cerebella. Twenty out of 22 cerebellar cavities were located in the cortex, and only 2 in the deep white matter, with no cavities located in the juxtacortical white matter. None of the 20 cerebellar cortical cavities showed extension into the juxtacortical white matter on MRI, although in 1 cortical cavity some surrounding gliosis was seen to extend into the juxtacortical white matter. Nine out of 22 cavities were sampled for pathological correlation, including 7 cerebellar cortical cavities and both cavities or lacunes in the deep white matter. Three out of 7 cortical and both the deep cavities were histopathologically verified as cavities of ischaemic origin, while the remaining cortical cavities could not be retrieved upon histopathologic examination. Some microscopic gliosis was seen to extend into the juxtacortical white matter of all confirmed cortical cavities.
Knowledge of typical infarct patterns may facilitate the detection and characterisation of cerebellar ischaemic cavities in vivo. Cerebellar cortical cavities appeared to be much more common than deep cavities and presented on imaging as a full-thickness defect in the cerebellar cortex without extension in the adjacent white matter.
Hippocampal focal T2 hyperintensities (HT2Hs), also referred to as hippocampal sulcal cavities, are a common finding on Magnetic Resonance (MR) images. There is uncertainty about their etiology and ...clinical significance. In this study we aimed to describe these HT2Hs in more detail using high resolution 7 Tesla MR imaging, addressing 1) the MR signal characteristics of HT2Hs, 2) their occurrence frequency, 3) their location within the hippocampus, and 4) their relation with age. We also performed an explorative post-mortem study to examine the histology of HT2Hs. Fifty-eight persons without a history of invalidating neurological or psychiatric disease (mean age 64 ± 8 years; range 43-78 years), recruited through their general practitioners, were included in this study. They all underwent 7 Tesla MRI, including a T1, T2, and FLAIR image. MR signal characteristics of the HT2Hs were assessed on these images by two raters. Also, the location and number of the HT2Hs were assessed. In addition, four formalin-fixed brain slices from two subjects were scanned overnight. HT2Hs identified in these slices were subjected to histopathological analysis. HT2Hs were present in 97% of the subjects (median number per person 10; range 0-20). All HT2Hs detected on the T2 sequence were hypointense on T1 weighted images. Of all HT2Hs, 94% was hypointense and 6% hyperintense on FLAIR. FLAIR hypointense HT2Hs were all located in the vestigial sulcus of the hippocampus, FLAIR hyperintense HT2Hs in the hippocampal sulcus or the gray matter. Post-mortem MRI and histopathological analysis suggested that the hypointense HT2Hs on FLAIR were cavities filled with cerebrospinal fluid. A hyperintense HT2H on FLAIR proved to be a microinfarct upon microscopy. In conclusion, hippocampal T2Hs are extremely common and unrelated to age. They can be divided into two types (hypo- and hyperintense on FLAIR), probably with different etiology.
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