Cortical Microbleeds Research Articles

Effect of high-fat diet on cerebral pathological changes of cerebral small vessel disease in SHR/SP rats.

Cerebral small vessel diseases (CSVD) are neurological disorders associated with microvessels, manifested pathologically as white matter (WM) changes and cortical microbleeds, with hypertension as a risk factor. Additionally, a high-fat diet (HFD) can affect peripheral vessel health. Our study explored how HFD affects cerebral small vessels in normotensive WKY, hypertensive SHR, and SHR/SP rats. The MRI results revealed that HFD specifically increased WM hyperintensity in SHR/SP rats. Pathologically, it increased WM pallor and vacuolation in SHR and SHR/SP rats. Levels of blood-brain barrier (BBB) protein claudin 5 were decreased in SHR and SHR/SP compared to WKY, with HFD having minimal impact on these levels. Conversely, collagen IV levels remained consistent among the rat strains, which were increased by HFD. Consequently, HFD caused vessel leakage in all rat strains, particularly within the corpus callosum of SHR/SP rats. To understand the underlying mechanisms, we assessed the levels of hypoxia-inducible factor-1α (HIF-1α), Gp91-phox, and neuroinflammatory markers astrocytes, and microglia were increased in SHR and SHR/SP compared to WKY and were further elevated by HFD in all rat strains. Gp91-phox was also increased in SHR and SHR/SP compared to WKY, with HFD causing an increase in WKY but little effect in SHR and SHR/SP. In conclusion, our study demonstrates that HFD, in combined with hypertension, intensifies cerebral pathological alterations in CSVD rats. This exacerbation involves increased oxidative stress and HIF-1α in cerebral vessels, triggering neuroinflammation, vascular basement membrane remodeling, IgG leakage, and ultimately WM damage.

Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)

To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. Atotal of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CAA is afrequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with ahigher number of cortical and subcortical microbleeds.

Sensitivity and Specificity of the Boston Criteria Version 2.0 for the Diagnosis of Cerebral Amyloid Angiopathy in a Community-Based Sample.

The Boston criteria are a set of clinical and neuroimaging features that enable accurate diagnosis of cerebral amyloid angiopathy (CAA) without invasive methods such as brain biopsies or autopsy. The last updates to the Boston criteria, named version 2.0, were recently released and incorporated new nonhemorrhagic MRI features. These criteria have been validated in symptomatic samples, with improved diagnostic yield. We set out to investigate the accuracy of the Boston criteria v2.0 for the diagnosis of CAA in a community-based sample. Participants were recruited from longitudinal clinical-pathologic studies of aging conducted at the Rush Alzheimer's Disease Center in Chicago: the Religious Orders Study and the Rush Memory and Aging Project. Deceased participants with in vivo 3T MRI and detailed pathologic data available were included in the analysis. We compared the diagnostic yield of the current and earlier versions of the Boston criteria in our sample. Among those classified as probable CAA according to the Boston criteria v2.0, we investigated the ability of each neuroimaging marker to distinguish between false-positive and true-positive cases. In total, 134 individuals were included in the study (mean age = 82.4 ± 6.0 years; 69.4% F), and 49 of them were considered pathology-proven definite cases with CAA (mean age = 82.9 ± 6.0 years; 63.3% F). The Boston criteria versions 1.0 and 1.5 yielded similar sensitivity (26.5%, both), specificity (90.6% and 89.4%, respectively), and predictive values (negative: 68.1% and 67.9%; positive: 61.9% and 59.1%, respectively). The recently released Boston criteria v2.0 offered higher sensitivity (38.8%) and slightly lower specificity (83.5%). Among those classified as probable CAA (v2.0), pathology-proven true-positive cases had higher numbers of strictly cortical lobar microbleeds compared with false-positive cases (p = 0.004). Similar to findings from symptomatic samples, the inclusion of nonhemorrhagic neuroimaging markers in the updated Boston criteria offered a 12.3% gain in sensitivity among community-dwelling individuals, at the expense of a 5.9% drop in specificity. In cases with probable CAA, the cortical location of microbleeds may represent a promising distinguishing feature between true-positive and false-positive cases. Despite its improved performance, the diagnostic sensitivity of the updated criteria in a community-based sample remains limited. This study provides Class II evidence that the Boston criteria v2.0 accurately distinguishes people with CAA from those without CAA.

Left atrial appendage occlusion in patients with spontaneous intracerebral hemorrhage: An observational study

BackgroundPatients with atrial fibrillation (AF) and intracerebral hemorrhage (ICH) are at high risk of ischemic and recurrent bleeding events. Therefore, the decision of restarting or avoiding anticoagulation is challenging. Left atrial appendage occlusion (LAAO) is an alternative for these patients. However, few data are available about safety of early LAAO and factors associated with ischemic stroke and ICH recurrence. MethodsA unicentric, observational, retrospective study including all patients with AF and a previous ICH who underwent LAAO. We analyzed baseline clinical and neuroimaging characteristics, procedural outcomes, post-procedural therapies and long-term follow-up. ResultsForty patients were included, whose mean age was 76.6 ±7.6 years and 73 % were men. In patients in whom a Magnetic Resonance (MR) was performed (n=22, 55 %), cortical microbleeds were detected in 15 (68 %) and cortical superficial siderosis in one patient. The procedure was successful and safe in 100 % of the patients and it was performed within 30 days of the ICH in 37 % of them. After a median follow up of 46.2 months [26-69], intracranial hemorrhage (ICrH) recurrence occurred in 6 patients (5 ICH and 1 subdural hematoma –SDH-) and the index ICH was lobar in all of them. Ischemic events were significantly lower than expected according to the CHA2DS2-VASc score (7.5 % vs. 16.6 %, p=0.048) and bleeding events were similar to expected by the HAS-BLED score (20 % vs 23.4 %, p=0.63). ConclusionsIn patients with ICH and AF, early LAAO was found to be safe and associated with a reduction in ischemic stroke. However, recurrent ICH risk remains high, and it appears to be mainly driven by cerebral amyloid angiopathy.

Posterior Reversible Leukoencephalopathy With Hemorrhagic Features: A Case Series.

Introduction Posterior reversible leukoencephalopathy syndrome (PRES) is a clinical-radiological condition characterized by reversible subcortical vasogenic cerebral edema of acute or subacute onset in circumstances that disrupt capillary permeability, unfrequently accompanied by cytotoxic and/or hemorrhagic lesions. We describe a case series of PRES with hemorrhagic features. Subjects and methods Electronic medical records of hospitalized patients diagnosed with PRES from January 2009 to December 2021 were collected. Demographic data, medical history, clinical presentation, and outcome were recorded. Variables were compared between patients with and without hemorrhagic features using the Wilcoxon-Mann-Whitney test with a statistical significance level of p<0.05. Results Over a 12-year period, 33 patients were diagnosed with PRES, of whom 10 had hemorrhagic features: seven cortical microbleeds, two intraparenchymal hematomas, and one subarachnoid hemorrhage. Half of the patients were women, with a median age of 45.8 years (interquartile range (IQR) 21.8), and were admitted for non-neurological reasons. The sample included nine transplant recipients (six solid organa, three bone marrowa), with four patients in the immediate post-transplant period. PRES occurred in the context of infections and blood pressure fluctuations under cytotoxic drugs, such as immunosuppressants. Seventy percent showed improvement/resolution on neuroimaging at a median of 70 days (IQR 62.9). The three major hemorrhages occurred in the context of thrombocytopenia. The recorded in-hospital mortality was 10%. When compared to PRES without hemorrhagic features, patients with hemorrhagic features had a lower use of corticosteroids (50% vs. 78.8%; p=0.02) and a higher presence of restrictive lesions on neuroimaging (60% vs. 17%; p=0.04), with no differences in the other analyzed variables. Conclusion Patients with PRES and hemorrhagic features had a lower use of corticosteroids and a higher presence of restrictive lesions on neuroimaging. Further studies are needed to better understand the clinical implications and management of PRES with hemorrhagic manifestations.

Cerebral Amyloid Angiopathy presenting as Cognitive Decline

Cerebral amyloid angiopathy (CAA) is a disorder seen as age advances, characterized by the accumulation of amyloid within the leptomeninges and cerebral blood vessels. Lobar hemorrhages are the most common clinical manifestation seen. Cognitive decline due to repeated cerebral microhemorrhages in one of the rare presentations seen mainly in the elderly. We present here a case of a seventy year old female patient who presented with a one year history of progressive cognitive impairment. She was detected to have CAA on imaging with both cortical microbleeds and extensive superficial siderosis. She was started on cholinesterase inhibitors and antipsychotics for her symptoms. Antiplatelet agents were avoided due to increased risk of hemorrhage. This report highlights the importance of CAA as a cause of cognitive decline in elderly patients and also its therapeutic implications

Frequency of deep-seated cerebral microbleeds in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a common disease and the most common cause of lobar hemorrhages in the elderly. Usually, deep-seated microhemorrhages preclude the diagnosis of CAA. In this study, we sought to estimate the frequency of deep-seated microbleeds on MRI in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy. In addition, we describe a cohort of patients with cortical and deep-seated microbleeds on MRI and a histopathological specimen available from lobar hematoma evacuation. Retrospective database search for histopathological specimens from lobar hematoma evacuation and review of imaging findings (CT and MRI) and patient charts was performed. Between 1 January 2012 and 31 December 2020, 88 specimens from 88 patients were available. A total of 56 specimens were excluded (no brain tissue in the specimen n = 4, other diagnosis n = 8, no MRI n = 43, and no BOLD-based sequence n = 1). Of the remaining 32 patients, 25 patients (78%) did not harbor deep-seated lesions on MRI, of which 17 patients had histopathological features of CAA. A total of seven patients harbored deep-seated CMB. Of these seven patients, three (3/20, 15%) had histopathological features of CAA. Approximately 15% of patients with histopathologically diagnosed CAA harbor deep-seated microbleeds. This finding may add to the discussion on how to identify patients with CAA and deep-seated CMB.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p=0.004] for SeLECT-S and 0.88 [p=0.001] for CAVE-S at the testing data). Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy–related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood–brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy–related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood–brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood–brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood–brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2–4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood–brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood–brain barrier leakage as a potential trigger for subsequent perivascular inflammation.

Cerebral microangiopathy according to magnetic resonance imaging of the brain in patients undergoing longterm programmed hemodialysis

Introduction. Cerebral microangiopathy (CMA), being the leading cause of vascular cognitive impairment and strokes, has a number of causes, among which chronic kidney disease (CKD) and programmed hemodialysis (HD) are the least studied.Purpose of the study: to determine the frequency of CMA neuroimaging markers and risk factors for its development in patients receiving renal replacement therapy for a long time using the programmed HD.Material and methods: the study involved 70 patients who had been on programmed HD for 10 months or more. Clinical neurological examination, laboratory tests and brain MRI were performed. The analysis of CMA neuroimaging markers was carried out in accordance with the STRIVE recommendations. Cerebral Small Vessel Disease Score (CSVDS) was used to quantify the overall severity of MR imaging markers of CMA.Results. Among 70 examined (29 men and 41 women) aged 53.0 ± 14.2 years, average HD experience – 70.0 ± 39.5 months, the main clinical manifestations of CMA were cognitive impairment (82.9%, n = 58), emotional disorders (61.4%, n = 43), sleep disorders (38.6%, n = 27), pseudobulbar syndrome (17.1%, n = 12), walking disorders (8.6%, n = 6), acute lacunar syndromes (7.1%, n = 5) and pelvic dysfunction (4.3%, n = 3). CMA neuroimaging markers of varying severity were found in 100% of cases. Expansion of perivascular spaces (100%, n = 70) and white matter hyperintensities (81.4%, n = 57) prevailed in the structure of CMA imaging markers. Cortical atrophy (67%, n = 47), cerebral microbleeds (47%, n = 33), asymptomatic lacunae (35.7%, n = 25) and minor subcortical infarctions (2.9%, n = 3) were less common. Mild CMA (1–2 points on the CSVDS scale) was determined in 38 patients (54.3%), severe CMA (3–4 points on the CSVDS scale) – in 32 patients (45.7%). The presence of uncontrolled arterial hypertension (OR 1.85, p &lt; 0.05), intradialysis hypertension (OR 2.8, p &lt; 0.05), dialysis vegetative polyneuropathies (OR 2.75, p &lt; 0.05), type 2 diabetes mellitus (OR 5.7, p &lt; 0.05) and the experience of programmed HD (more than 50 months) (OR 3.1, p &lt; 0.05) were prognostic signifi cance for the development of severe CMA in dialysis patients.Conclusion. All patients with end-stage CKD who have been on programmed HD for a long time are shown to undergo the brain MRI in order to timely diagnose CMA imaging markers and possible correction of therapy.

The Role of Vascular Risk Factors in Biomarker-Based AT(N) Groups: A German-Dutch Memory Clinic Study.

The relation between vascular risk factors (VRFs) and Alzheimer's disease (AD) is important due to possible pathophysiological association. To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context. We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site. We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition. VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia.

Personality Impact on Alzheimer's Disease - Signature and Vascular Imaging Markers: A PET-MRI Study.

Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. This study explores the impact of personality on widely used Alzheimer's disease (AD) and vascular imaging markers. We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age.

Characteristics of Cortical Atrophy and White Matter Lesions Between Dementia With Lewy Bodies and Alzheimer's Disease: A Case-Control Study.

Introduction: Currently, there is still clinical overlap between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients, which may affect the accuracy of the early diagnosis of DLB. For better diagnosis and prognosis, further exploration of local cortical atrophy patterns and white matter lesions is needed.Methods: We reviewed the outpatient medical records of 97 DLB patients and 173 AD patients from January 2018 to September 2020 along with 30 matched outpatient clinic normal elderly people. MRI visual rating scales, including medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale (GCA-F), posterior atrophy (PA), Fazekas scale, Evans Index and cerebral microbleeds were evaluated and analyzed in DLB and AD patients with different severities and normal controls.Results: Overall, patients with DLB had higher scores on all visual rating scales than the normal controls. Meanwhile, compared with AD, DLB had lower MTA scores in the mild to moderate groups (both p ≤ 0.001), but the GCA-F and PA scores were similar (all p > 0.05). The Fazekas scores in the moderate to severe DLB group were lower than those in the AD group (p = 0.024 and p = 0.027, respectively). In addition, the diagnostic performance and sensitivity of multiple imaging indicators for DLB were better than that of MTA alone (the combination of MTA, GCA-F, PA, Fazekas visual rating scales, AUC = 0.756, 95%CI: 0.700–0.813, sensitivity = 0.647, specificity = 0.804 and MTA visual rating scale, AUC = 0.726, 95%CI: 0.667–0.785, sensitivity = 0.497, specificity = 0.876, respectively).Conclusion: The medial temporal lobe of DLB patients was relatively preserved, the frontal and parietal lobes were similarly atrophied to AD patients, and the white matter hyperintensity was lighter than that in AD patients. Combined multiple visual rating scales may provide a novel idea for the diagnosis of early DLB.

Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy

Although evidence accumulates that the cerebellum is involved in cerebral amyloid angiopathy (CAA), cerebellar superficial siderosis is not considered to be a disease marker. The objective of this study is to investigate cerebellar superficial siderosis frequency and its relation to hemorrhagic magnetic resonance imaging markers in patients with sporadic and Dutch-type hereditary CAA and patients with deep perforating arteriopathy-related intracerebral hemorrhage. We recruited patients from 3 prospective 3 Tesla magnetic resonance imaging studies and scored siderosis and hemorrhages. Cerebellar siderosis was identified as hypointense linear signal loss (black) on susceptibility-weighted or T2*-weighted magnetic resonance imaging which follows at least one folia of the cerebellar cortex (including the vermis). We included 50 subjects with Dutch-type hereditary CAA, (mean age 50 years), 45 with sporadic CAA (mean age 72 years), and 43 patients with deep perforating arteriopathy-related intracerebral hemorrhage (mean age 54 years). Cerebellar superficial siderosis was present in 5 out of 50 (10% [95% CI, 2-18]) patients with Dutch-type hereditary CAA, 4/45 (9% [95% CI, 1-17]) patients with sporadic CAA, and 0 out of 43 (0% [95% CI, 0-8]) patients with deep perforating arteriopathy-related intracerebral hemorrhage. Patients with cerebellar superficial siderosis had more supratentorial lobar (median number 9 versus 2, relative risk, 2.9 [95% CI, 2.5-3.4]) and superficial cerebellar macrobleeds (median number 2 versus 0, relative risk, 20.3 [95% CI, 8.6-47.6]) compared with patients without the marker. The frequency of cortical superficial siderosis and superficial cerebellar microbleeds was comparable. We conclude that cerebellar superficial siderosis might be a novel marker for CAA.

Case Report: Probable Cerebral Amyloid Angiopathy-Related Inflammation During Bevacizumab Treatment for Metastatic Cervical Cancer

Bevacizumab is an anti-angiogenic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) that induces the proliferation and migration of vascular endothelial cells thus, promoting vasculogenesis. Bevacizumab inhibits cancer angiogenesis, which is fundamental for either tumor development, exponential growth, or metastatic spread by supplying nutrients and oxygen. We report a new possible adverse event of bevacizumab, a Cerebral Amyloid Angiopathy-Related Inflammation (CAARI), in a 72-year-old woman with metastatic cervical cancer. After six cycles every three weeks of chemotherapy (cisplatin, paclitaxel, bevacizumab) and following two maintenance bevacizumab administrations, the patient presented a worsening confusional state. The MRI scan showed bilateral asymmetric temporo-parieto-occipital hyperintensity with numerous cortical microbleeds indicative of a CAARI. After stopping bevacizumab treatment, steroid therapy was administered resulting in rapid clinical improvement. The subsequent neurological and oncological follow-up was negative for recurrence. The patient was a heterozygote carrier for apolipoprotein-E ε4 that increases the risk of sporadic Cerebral Amyloid Angiopathy (CAA), which is characterized by beta-amyloid accumulation and fibrinoid necrosis in cerebral vasculature leading to micro/macrohemorrhages and dementia. Moreover, CAA is present in 30% of people aged over 60 years without dementia. In the brains of CAA patients, there is a proinflammatory state with cerebrovascular endothelial cell alteration and elevated levels of either adhesion molecules or inflammatory interleukins that increase the blood–brain barrier permeability. Moreover, CAARI is an inflammatory form of CAA. Inhibition of VEGF, which has anti-apoptotic, anti-inflammatory, and pro-survival effects on endothelial cells, impairs their regenerative capacity and increases expression of proinflammatory genes leading to weakened supporting layers of blood vessels and, hence, to damaged vascular integrity. In our patient, bevacizumab administration may have further increased permeability of cerebral microvasculature likely impaired by an underlying, asymptomatic CAA. To our knowledge, this is the first case reporting on the development of probable CAARI during bevacizumab treatment, which should alert the clinicians in case of neurological symptom onset in older patients under anti-angiogenic therapy.

Prediction of Subtle Cognitive Decline in Normal Aging: Added Value of Quantitative MRI and PET Imaging.

Quantitative imaging processing tools have been proposed to improve clinic-radiological correlations but their added value at the initial stages of cognitive decline is still a matter of debate. We performed a longitudinal study in 90 community-dwelling elders with three neuropsychological assessments during a 4.5 year follow-up period, and visual assessment of medial temporal atrophy (MTA), white matter hyperintensities, cortical microbleeds (CMB) as well as amyloid positivity, and presence of abnormal FDG-PET patterns. Quantitative imaging data concerned ROI analysis of MRI volume, amyloid burden, and FDG-PET metabolism in several AD-signature areas. Multiple regression models, likelihood-ratio tests, and areas under the receiver operating characteristic curve (AUC) were used to compare quantitative imaging markers to visual inspection. The presence of more or equal to four CMB at inclusion and slight atrophy of the right MTL at follow-up were the only parameters to be independently related to the worst cognitive score explaining 6% of its variance. This percentage increased to 24.5% when the ROI-defined volume loss in the posterior cingulate cortex, baseline hippocampus volume, and MTL metabolism were also considered. When binary classification of cognition was made, the area under the ROC curve increased from 0.69 for the qualitative to 0.79 for the mixed imaging model. Our data reveal that the inclusion of quantitative imaging data significantly increases the prediction of cognitive changes in elderly controls compared to the single consideration of visual inspection.

Abstract 6: The Effect of Vascular Amyloid on White Matter Disease is Mediated by Vascular Dysfunction in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with white matter hyperintensities (WMH) but the physiopathological mechanisms remain unclear. We hypothesized that the relationship between vascular amyloid load and WMH is mediated by vascular dysfunction. Methods: The study cohort included 38 non-demented probable CAA patients who underwent advanced multimodal structural and functional MRI (fMRI) and amyloid PET scans. White matter hyperintensity volume was quantified using FreeSurfer and expressed as a percent of total intracranial volume (pWMHv). Time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response to visual stimulation using fMRI was used as an established measure of vascular dysfunction. Mean cortical Pittsburg Compound B uptake representing amyloid load was calculated. A bootstrapping procedure was used to test the mediation hypothesis adjusting for age, sex, and presence of intracerebral hemorrhage (ICH). Results: Of 38 patients with CAA (mean age 70±7.1, 86.8% male), 25 (65.8%) had ICH, while the remaining 13 patients (34.2%) presented with multiple strictly cortical microbleeds. Higher amyloid load correlated with prolonged TTP response (r=0.373, p=0.021) and higher pWMHv (r=0.337, p=0.039), and prolonged TTP response correlated with higher pWMHv (r=0.485, p=0.002). Amyloid load no longer predicted pWMHv (p=0.254) after controlling for TTP. In the bootstrapping model, TTP response had a significant indirect effect (ab=0.977, 95% CI: 0.15-2.42), showing that the association between amyloid load and pWMHv is mediated by TTP. Discussion: Our findings confirm the hypothesis that the effect of vascular amyloid load on the extent of white matter disease is mediated by vascular dysfunction in patients with CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Post-Mortem 7.0-Tesla Magnetic Resonance Imaging of the Hippocampus in Progressive Supranuclear Palsy with and without Cerebral Amyloid Angiopathy

Introduction and Purpose: Cerebral amyloid angiopathy (CAA) can be observed in patients with progressive supranuclear palsy (PSP), though to a lesser degree than in Alzheimer’s disease. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) evaluates whether CAA has an influence on the degree of hippocampal atrophy (HA) and on the incidence of associated micro-infarcts (HMIs) and cortical micro-bleeds (HMBs). Material and Methods: Eight brains with PSP-CAA were compared to 20 PSP brains without CAA. In addition to the neuropathological examination, the hippocampus was evaluated on the most representative coronal section with T2 and T2*-weighted MRI sequences. The average degree of HA was determined in both groups. The incidence of HMIs and HMBs was also compared as well as the frequency of cortical micro-infarcts (CoMIs) and cortical micro-bleeds (CoMBs) in the hemispheric neocortex. Results: The neuropathological examination showed a higher incidence of lacunar infarcts in the PSP-CAA brains compared to the PSP ones. With magnetic resonance imaging (MRI), the severity of HA and the incidence of HMIs and HMBs was similar between both groups. Additionally, the frequency of CoMIs and CoMBs in the neocortex was comparable. Conclusions: The association of CAA in PSP brains has no influence on the degree of HA and on the incidence of the small cerebrovascular lesions in the hippocampus as well as in the neocortex.

Post-mortem 7.0-Tesla Magnetic Resonance Imaging of the Hippocampus in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is reported to be probably linked to frontotemporal lobar degeneration (FTLD). Since FTLD is characterized by severe frontotemporal degeneration along with hippocampal atrophy (HA), the present study used post-mortem 7.0-tesla magnetic resonance imaging to investigate whether a certain degree of HA occurs in the ALS brains as well. The examined post-mortem brain samples comprised 9 from the ALS cases and 17 from the age-matched controls. The hippocampus samples were examined on the most representative coronal section using T2 and T2* MRI sequences, and the average degree of HA was determined for both groups. The occurrence of hippocampal micro-infarcts (HMIs) and hippocampal micro-bleeds (HMBs), as well as the frequency of cortical micro-infarcts (CoMIs) and cortical micro-bleeds (CoMBs) in the neocortex, were compared between the groups. Considerable HA was observed in the ALS group compared to the control group. The incidence of HMIs and HMBs was low and comparable in the ALS and control groups. Moreover, the frequency of CoMIs and CoMBs in the neocortex was relatively comparable in the two groups. This post-mortem observation of HA is an additional argument in favor of the link between ALS and FTLD. Furthermore, both ALS and FTLD share a low vascular risk profile.

Comparison of Post-mortem 7.0-Tesla Magnetic Resonance Imaging of the Brains of Alzheimer Patients with and without Cerebral Amyloid Angiopathy

Purpose: The influence of cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD) remains unexplored. The present post-mortem study investigated possible differences in the degree of hippocampal atrophy (HA) between AD patients with and without CAA using 7.0-tesla magnetic resonance imaging (MRI). Also, the incidence of the hippocampal cortical micro-infarcts (HCoMIs) and hippocampal cortical micro-bleeds (HCoMBs) is compared to those in the neocortex. Methods: The examined post-mortem brains included 30 AD-CAA cases and 20 AD without CAA cases. The samples of the hippocampus were evaluated on the most representative coronal section with T2 and T2* MRI sequences. The average degree of HA was determined in both groups. The incidences of HCoMIs and HCoMBs, along with the frequency of CoMIs and CoMBs in the neocortex were compared in both groups: AD-with CAA and AD without CAA cases. Results: No significant differences were observed in the degree of HA and the incidence of hippocampal micro-infarcts (HMIs) and hippocampal micro-bleeds (HMBs) between the AD-CAA and the AD brains in contrast to the higher incidence of these cerebrovascular lesions in the neocortex of AD-CAA brains. The incidence of CoMIs and CoMBs in the neocortex showed similarity to that in the hippocampus of AD patients without CAA. Conclusions: CAA does not influence the degree of HA and the incidence of micro-infarcts (MIs) and micro-bleeds (MBs) in the hippocampus, in contrast to the high contribution of the latter with CAA in the neocortex. The hippocampus seems to be more spared from cerebrovascular involvement than the other parts of the brain.