In vivo calibration of the T2* cardiovascular magnetic resonance method at 1.5 T for estimation of cardiac iron in a minipig model of transfusional iron overload.

BACKGROUND: Non-invasive estimation of the cardiac iron concentration (CIC) by T2* cardiovascular magnetic resonance (CMR) has been validated repeatedly and is in widespread clinical use. However, calibration data are limited, and mostly from post-mortem studies. In the present study, we performed an in vivo calibration in a dextran-iron loaded minipig model. METHODS: R2* (= 1/T2*) was assessed in vivo by 1.5 T CMR in the cardiac septum. Chemical CIC was assessed by inductively coupled plasma-optical emission spectroscopy in endomyocardial catheter biopsies (EMBs) from cardiac septum taken during follow up of 11 minipigs on dextran-iron loading, and also in full-wall biopsies from cardiac septum, taken post-mortem in another 16  minipigs, after completed iron loading. RESULTS: A strong correlation could be demonstrated between chemical CIC in 55 EMBs and parallel cardiac T2* (Spearman rank correlation coefficient 0.72, P < 0.001). Regression analysis led to [CIC] = (R2* - 17.16)/41.12 for the calibration equation with CIC in mg/g dry weight and R2* in Hz. An even stronger correlation was found, when chemical CIC was measured by full-wall biopsies from cardiac septum, taken immediately after euthanasia, in connection with the last CMR session after finished iron loading (Spearman rank correlation coefficient 0.95 (P < 0.001). Regression analysis led to the calibration equation [CIC] = (R2* - 17.2)/31.8. CONCLUSIONS: Calibration of cardiac T2* by EMBs is possible in the minipig model but is less accurate than by full-wall biopsies. Likely explanations are sampling error, variable content of non-iron containing tissue and smaller biopsies, when using catheter biopsies. The results further validate the CMR T2* technique for estimation of cardiac iron in conditions with iron overload and add to the limited calibration data published earlier.

Histological distribution pattern of hemosiderin deposition on the chorionic plate and fetal membrane of diffuse chorioamniotic hemosiderosis related to chronic abruption oligohydramnios sequence.

INTRODUCTION: Chronic abruption oligohydramnios sequence (CAOS) is histologically characterized by diffuse chorioamniotic hemosiderosis (DCH). However, the criteria for the histological evaluation of the extent of CAOS-related hemosiderin deposition (HD) of the membranes and the difference in HD between the chorionic plate (CP) and fetal membrane (FM) are not well studied. This case control study compared the degree and distribution pattern of HD on CP and FM to present the histological features of DCH and the criteria for histological evaluation. METHODS: From the medical records of Kyoto University Hospital (2010-2019), we selected 20 CAOS cases that were clinically diagnosed by Elliot's criteria. Twenty non-CAOS cases matched to the CAOS group by gestational age were selected as controls. We compared the clinical data and pathological features in the two groups. We performed iron staining in all the cases and analyzed HD in CP and FM according to the histological score (H-Score: 0-12), which was determined as the density (0-3) multiplied by the extent of staining (0-4). RESULTS: HD was found in 100% (20/20) of CAOS and 15% (3/20) of control cases. In both the FM and CP, CAOS cases showed a significantly higher HS than control cases (CAOS, HS = 4-12; Control, HS = 0-1, p < 0.0001). Three CAOS patients presented HD alone in the CP. The HS of the CP was significantly higher than that of the FM (p = 0.0003). DISCUSSION: CAOS presented DCH with HS ≥ 4. This study showed that the CP might be more suitable for evaluating DCH than the FM.

Spinal muscular atrophy type III complicated by spinal superficial siderosis: a case report with molecular and neuropathological findings.

Spinal muscular atrophy (SMA) is largely linked to deletion or mutation of the Survival motor neuron 1 (SMN1) gene located on chromosome 5q13. Type III (Kugelberg-Welander disease) is the mildest childhood form and patients may become ambulatory and have a normal life expectancy. We report the clinical history and morphological findings of a 55-year-old woman who began to experience motor problems at the age of two. She was never fully ambulatory, and her severe scoliosis required the insertion of surgical rod at age 19. Unexpectedly, around 35 years of age, she began to experience sensory symptoms best characterized as a myelo-radiculo-neuropathy with pain as the dominant symptom. Investigations never clarified the etiology of these symptoms. Molecular confirmation of SMA type III was done post-mortem. Neuropathological examination showed classic changes of lower motor neuron neurodegeneration, in line with those reported in the single molecularly confirmed case published so far, and with findings in rare cases reported prior to the discovery of the gene defect. A key autopsy finding was the presence of a severe superficial siderosis of the lower half of the spinal cord. In recent years, the concept of duropathy was put forward, associating superficial siderosis of the spinal cord with various spinal abnormalities, some of which were present in our patient. The presence of significant hemosiderin deposits in the spinal cord and sensory nerve roots with associated tissue and axonal damage provide a plausible explanation for the unexpected sensory symptomatology in this mild lower motor neurodegeneration.

Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice.

Mice homozygous for the human GRACILE syndrome mutation (Bcs1lc.A232G) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1lp.S78G), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FAs, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. SUMMARY STATEMENT: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.

Iron-Containing Abdominal Pathologies: Exploiting Magnetic Susceptibility Artifact on Dual-Echo Gradient-Echo Magnetic Resonance Imaging.

A multitude of pathologic entities involve abnormal iron deposition in the abdomen. These lesions demonstrate decreased signal on longer magnetic resonance sequences with longer echo time due to T2* effect. Dual-echo gradient-echo sequences demonstrate increased susceptibility artifact with longer echo sequences. In this article, the spectrum of iron-containing abdominal pathologies is illustrated, with their characteristic distributions. Included is a brief discussion of the physics of magnetic resonance imaging of iron-containing lesions.

Hemosiderin tubulopathy-induced acute kidney injury - A rare initial manifestation of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, infections, and thromboembolic complications. Renal abnormalities are rare which occur either due to hemolytic crisis or repeated thrombotic episodes involving small venules. Acute kidney injury (AKI) requiring hemodialysis due to toxic effects of hemoglobinuria, with a stable disease is exceptional. We describe a case of an elderly gentleman presenting with features of severe AKI requiring hemodialysis due to hemosiderin tubulotoxicity as the first manifestation of PNH. The diagnosis was challenging because of the rarity and unfamiliarity with this entity. The outcome was complete recovery of renal function with hemodialysis.

Cortical superficial siderosis and acute convexity subarachnoid hemorrhage in cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Acute convexity subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS) are neuroimaging markers of cerebral amyloid angiopathy (CAA) that may arise through similar mechanisms. The prevalence of cSS in patients with CAA presenting with acute cSAH versus lobar intracerebral hemorrhage (ICH) was compared and the physiopathology of cSS was explored by examining neuroimaging associations. METHODS: Data from 116 consecutive patients with probable CAA (mean age, 77.4 ± 7.3 years) presenting with acute cSAH (n = 45) or acute lobar ICH (n = 71) were retrospectively analyzed. Magnetic resonance imaging scans were analyzed for cSS and other imaging markers. The two groups' clinical and imaging data were compared and the associations between cSAH and cSS were explored. RESULTS: Patients with cSAH presented mostly with transient focal neurological episodes. The prevalence of cSS was higher amongst cSAH patients than amongst ICH patients (88.9% vs. 57.7%; P < 0.001). In multivariable logistic regression analysis, focal [odds ratio (OR) 6.73; 95% confidence interval (CI) 1.75-25.81; P = 0.005] and disseminated (OR 11.68; 95% CI 3.55-38.35; P < 0.001) cSS were independently associated with acute cSAH, whereas older age (OR 0.93; 95% CI 0.87-0.99; P = 0.025) and chronic lobar ICH count (OR 0.45; 95% CI 0.25-0.80; P = 0.007) were associated with acute lobar ICH. CONCLUSIONS: Amongst patients with CAA, cSS is independently associated with acute cSAH. These findings suggest that cSAH may be involved in the pathogenesis of the cSS observed in CAA. Longitudinal studies are warranted to assess this potential causal relationship.

Post-mortem study of the association between cardiac iron and fibrosis in transfusion dependent anaemia.

BACKGROUND: Heart failure related to cardiac siderosis remains a major cause of death in transfusion dependent anaemias. Replacement fibrosis has been reported as causative of heart failure in siderotic cardiomyopathy in historical reports, but these findings do not accord with the reversible nature of siderotic heart failure achievable with intensive iron chelation. METHODS: Ten whole human hearts (9 beta-thalassemia major, 1 sideroblastic anaemia) were examined for iron loading and fibrosis (replacement and interstitial). Five had died from heart failure, 4 had cardiac transplantation for heart failure, and 1 had no heart failure (death from a stroke). Heart samples iron content was measured using atomic emission spectroscopy. Interstitial fibrosis was quantified by computer using picrosirius red (PSR) staining and expressed as collagen volume fraction (CVF) with normal value for left ventricle <3%. RESULTS: The 9 hearts affected by heart failure had severe iron loading with very low T2* of 5.0 ± 2.0 ms (iron concentration 8.5 ± 7.0 mg/g dw) and diffuse granular myocardial iron deposition. In none of the 10 hearts was significant macroscopic replacement fibrosis present. In only 2 hearts was interstitial fibrosis present, but with low CVF: in one patient with no cardiac siderosis (death by stroke, CVF 5.9%) and in a heart failure patient (CVF 2%). In the remaining 8 patients, no interstitial fibrosis was seen despite all having severe cardiac siderosis and heart failure (CVF 1.86% ±0.87%). CONCLUSION: Replacement cardiac fibrosis was not seen in the 9 post-mortem hearts from patients with severe cardiac siderosis and heart failure leading to death or transplantation, which contrasts markedly to historical reports. Minor interstitial fibrosis was also unusual and very limited in extent. These findings accord with the potential for reversibility of heart failure seen in iron overload cardiomyopathy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00520559.

Zinc oxide nanoparticles hepatotoxicity: Histological and histochemical study.

Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal a high potential risk for human health with no information about hepatotoxicity that might be associated with their exposure. The present work was carried out to investigate the histological and histochemical alterations induced in the hepatic tissues by naked 35nm ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2mg/kg for 21days. Liver biopsies from all rats under study were subjected to histopathological examinations. In comparison with the control rats, the following histological and histochemical alterations were demonstrated in the hepatic tissues of rats exposed to ZnO NPs: sinusoidal dilatation, Kupffer cells hyperplasia, lobular and portal triads inflammatory cells infiltration, necrosis, hydropic degeneration, hepatocytes apoptosis, anisokaryosis, karyolysis, nuclear membrane irregularity, glycogen content depletion and hemosidrosis. The findings of the present work might indicate that ZnO NPs have potential oxidative stress in the hepatic tissues that may affect the function of the liver. More work is needed to elucidate the toxicity and pathogenesis of zinc oxide nanoparticles on the vital organs.

Comparison of 3 T and 1.5 T for T2* magnetic resonance of tissue iron.

BACKGROUND: T2* magnetic resonance of tissue iron concentration has improved the outcome of transfusion dependant anaemia patients. Clinical evaluation is performed at 1.5 T but scanners operating at 3 T are increasing in numbers. There is a paucity of data on the relative merits of iron quantification at 3 T vs 1.5 T. METHODS: A total of 104 transfusion dependent anaemia patients and 20 normal volunteers were prospectively recruited to undergo cardiac and liver T2* assessment at both 1.5 T and 3 T. Intra-observer, inter-observer and inter-study reproducibility analysis were performed on 20 randomly selected patients for cardiac and liver T2*. RESULTS: Association between heart and liver T2* at 1.5 T and 3 T was non-linear with good fit (R (2) = 0.954, p < 0.001 for heart white-blood (WB) imaging; R (2) = 0.931, p < 0.001 for heart black-blood (BB) imaging; R (2) = 0.993, p < 0.001 for liver imaging). R2* approximately doubled between 1.5 T and 3 T with linear fits for both heart and liver (94, 94 and 105 % respectively). Coefficients of variation for intra- and inter-observer reproducibility, as well as inter-study reproducibility trended to be less good at 3 T (3.5 to 6.5 %) than at 1.5 T (1.4 to 5.7 %) for both heart and liver T2*. Artefact scores for the heart were significantly worse with the 3 T BB sequence (median 4, IQR 2-5) compared with the 1.5 T BB sequence (4 [3-5], p = 0.007). CONCLUSION: Heart and liver T2* and R2* at 3 T show close association with 1.5 T values, but there were more artefacts at 3 T and trends to lower reproducibility causing difficulty in quantifying low T2* values with high tissue iron. Therefore T2* imaging at 1.5 T remains the gold standard for clinical practice. However, in centres where only 3 T is available, equivalent values at 1.5 T may be approximated by halving the 3 T tissue R2* with subsequent conversion to T2*.

Mugineic acid, active ingredient of wheat grass: an oral novel hexadentate iron chelator in iron overloaded diseases.

Iron chelation therapies are required for the treatment of iron overloaded patients; nonetheless, their side effects are also well known. We have evaluated iron-chelating activity of wheat grass extract (WHE) and its purified compound, mugineic acid in murine model with phenylhydrazine (PHZ) and dextran induced acute and chronic iron overload conditions. PHZ and dextran treatment induced acute and chronic iron overload condition in mice, respectively, as indicated by increased serum and tissue iron in both cases. Iron overload was also accompanied with haemosiderosis in tissues (liver and spleen). These PHZ and dextran -: treated mice were orally treated with either crude WHE or purified mugineic acid. The efficacy of mugineic acid and WHE was compared with the potent oral iron chelator ICL670 (Exjade). PHZ and dextran treatment followed by oral administration of WHE or mugineic acid significantly checked the rise of serum/plasma levels of iron as well as tissue iron and also, haemosiderosis in tissues. The results are highly comparable with known iron chelator ICL670. WHE and purified mugineic acid, both seem to have significant prospect to be the cheap, non-toxic, hexadentate and oral therapeutic agents to prevent or alleviate toxic iron overload in patients.

Correlation between Heart, Liver and Pancreas Hemosiderosis Measured by MRI T2* among Thalassemia Major Patients from Iran.

INTRODUCTION: Major thalassemia patients need lifelong transfusions. The consequence of these repeated transfusions is iron accumulation in different organs. The main aim of the present study was to investigate the correlation between heart, liver and pancreas hemosiderosis in thalassemic patients from Iran. METHODS: This cross-sectional study was conducted on 164 major thalassemia patients at Zafar Adult Thalassemia Center, a referral thalassemia center in Tehran, Iran, from May to November 2014.  All patients were on regular blood transfusion at 2-4 week intervals to keep their hemoglobin at a level of 7-9 gr/dL before each transfusion. Demographic data were gathered from patients' history. MRI T2* of liver, heart and pancreas were performed for all patients. RESULTS: There were a moderate correlation between pancreatic T2* and cardiac T2* relaxation times (r = 0.42, P < 0.001), a moderate correlation between T2* of pancreas and liver (r = 0.41, P < 0.001), and a weak correlation between T2* relaxation times of heart and liver (r = 0.31, P < 0.001). CONCLUSION: Poor correlation between liver and heart, as well as a weak to moderate correlation between pancreas and liver T2* relaxation times indicate that relying on liver MRI T2* to predict the exact condition of pancreas or heart iron overload might not be a reliable approach in thalassemia major patients. Our findings suggest the advantage of using pancreas and heart MRI T2* as a non-invasive method for estimation of iron overload instead of relying on liver MRI T2*.

Decreased VEGF Level Is Associated with Elevated Ferritin Concentration in Bronchoalveolar Lavage Fluid of Children with Interstitial Lung Diseases.

BACKGROUND: A decreased level of vascular endothelial growth factor (VEGF) was previously described in bronchoalveolar lavage fluid (BALF) of adults with interstitial lung diseases (ILD) due to bronchial epithelial cell apoptosis and its proteolytic degradation. Elevated intrapulmonary ferritin was produced by alveolar cells that promoted oxidative injury in such patients. OBJECTIVES: In this study, we analyzed the concentrations of VEGF and ferritin in BALF samples of ILD children and studied the relationship between their levels and the degree of inflammation. METHODS: BALF and serum concentration of VEGF as well as ferritin and albumin in BALF samples were measured using enzyme-linked immunosorbent assay in children with idiopathic interstitial pneumonia (n = 16), hypersensitivity pneumonitis (n = 11) and idiopathic pulmonary hemosiderosis (n = 3). Twenty-four age- and gender-matched subjects with suspicious foreign body aspiration served as a control group. RESULTS: VEGF per albumin levels in BALF were significantly decreased in ILD children compared to controls (1,075 [784-1,415] pg/mg albumin vs. 2,741 [1,131-4,660] pg/mg albumin, p = 0.0008). These values showed a significant negative correlation with inflammatory markers of total immune cell count in BALF (r = -0.411, p = 0.002) and serum C-reactive protein (r = -0.367, p = 0.006). Although serum VEGF was augmented in ILD children versus controls, no difference was observed among the ILD groups. In addition, BALF ferritin/albumin level (688 [188-1,571] ng/mg albumin vs. 256 [178-350] ng/mg albumin, p = 0.022) was significantly higher than normal in ILD individuals, especially in idiopathic pulmonary hemosiderosis. CONCLUSION: Depressed VEGF and increased ferritin in BALF may reflect the severity of chronic pulmonary inflammation in altered respiratory epithelium of childhood ILD.

Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a key role in the management of thalassemia major patients, but few data are available in pediatric population. This study aims at a retrospective multiparametric CMR assessment of myocardial iron overload, function, and fibrosis in a cohort of pediatric thalassemia major patients. METHODS AND RESULTS: We studied 107 pediatric thalassemia major patients (61 boys, median age 14.4 years). Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. All scans were performed without sedation. The 21.4% of the patients showed a significant myocardial iron overload correlated with lower compliance to chelation therapy (P<0.013). Serum ferritin ≥2000 ng/mL and liver iron concentration ≥14 mg/g/dw were detected as the best threshold for predicting cardiac iron overload (P=0.001 and P<0.0001, respectively). A homogeneous pattern of myocardial iron overload was associated with a negative cardiac remodeling and significant higher liver iron concentration (P<0.0001). Myocardial fibrosis by late gadolinium enhancement was detected in 15.8% of the patients (youngest children 13 years old). It was correlated with significant lower heart T2* values (P=0.022) and negative cardiac remodeling indexes. A pathological magnetic resonance imaging liver iron concentration was found in the 77.6% of the patients. CONCLUSIONS: Cardiac damage detectable by a multiparametric CMR approach can occur early in thalassemia major patients. So, the first T2* CMR assessment should be performed as early as feasible without sedation to tailor the chelation treatment. Conversely, late gadolinium enhancement CMR should be postponed in the teenager age.

Iron oxides in human spleen.

Iron is an essential element for fundamental cell functions and a catalyst for chemical reactions. Three samples extracted from the human spleen were investigated by scanning (SEM) and transmission electron microscopy (TEM), Mössbauer spectrometry (MS), and SQUID magnetometry. The sample with diagnosis of hemosiderosis (H) differs from that referring to hereditary spherocytosis and the reference sample. SEM reveals iron-rich micrometer-sized aggregate of various structures-tiny fibrils in hereditary spherocytosis sample and no fibrils in hemochromatosis. Hematite and magnetite particles from 2 to 6 µm in TEM with diffraction in all samples were shown. The SQUID magnetometry shows different amount of diamagnetic, paramagnetic and ferrimagnetic structures in the tissues. The MS results indicate contribution of ferromagnetically split sextets for all investigated samples. Their occurrence indicates that at least part of the sample is magnetically ordered below the critical temperature. The iron accumulation process is different in hereditary spherocytosis and hemosiderosis. This fact may be the reason of different iron crystallization.

Frequency and appearance of hemosiderin depositions after aneurysmal subarachnoid hemorrhage treated by endovascular therapy.

INTRODUCTION: It is still unclear how often subarachnoid hemorrhage (SAH) leads to chronic hemosiderin depositions. In this study, we aimed to determine the frequency of chronic hemosiderin depositions after aneurysmal SAH in patients who did not undergo surgery. Furthermore, we analyzed typical MRI patterns of chronic SAH and sought to obtain information on the temporal course of MRI signal changes. METHODS: We retrospectively analyzed 90 patients who had undergone endovascular treatment for acute aneurysmal SAH. In all patients, initial CT studies and at least one T2*-weighted MRI obtained 6 months or later after SAH were analyzed for the presence and anatomical distribution of SAH or chronic hemosiderin depositions. In total, 185 T2*-weighted MRI studies obtained between 2 days and 148 months after SAH were evaluated (mean follow-up 30.2 months). RESULTS: On MRI studies obtained later than 6 months after SAH, subpial hemosiderin depositions were found in 50 patients (55.5%). Most frequent localizations were the parenchyma adjacent to the frontal and parietal sulci and the insular cisterns. While the appearance of hemosiderin depositions was dynamic within the first 3 months, no changes were found during subsequent follow-up. MR signal changes were not only conclusive with subarachnoid hemosiderin depositions but in many cases also resembled those that have been associated with cortical hemosiderosis. CONCLUSIONS: T2*-weighted MRI is an effective means of diagnosing prior SAH. Our study suggests that chronic hemosiderin depositions can be found in a considerable number of patients after a single event of subarachnoid hemorrhage.

Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes.

OBJECTIVE: To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH). METHODS: MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, ≤3 sulci; disseminates, ≥4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype. RESULTS: Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE ε2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE ε4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE ε2 (but not APOE ε4) (odds ratio 5.83; 95% confidence interval 1.49-22.82, p = 0.011). CONCLUSIONS: This neuropathologically defined CAA cohort suggests that CSS and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms.