Cerebral Amyloid Angiopathy Patients Research Articles

Finger-Like Projections in Lobar Haemorrhage on Early Magnetic Resonance Imaging Is Associated with Probable Cerebral Amyloid Angiopathy

Background: Recently, finger-like projections (FLP) and subarachnoid haemorrhage extension (SAHE) of lobar intracerebral haemorrhage (LH) on acute CT together with ApoE4 genotype have been used in a prediction model for histopathologically proven cerebral amyloid angiopathy (CAA). Our aim was to analyse FLP and SAHE on acute/early subacute magnetic resonance imaging (MRI) and to assess the association with probable CAA diagnosis according to modified Boston criteria. Methods: We retrospectively studied MRI scans (and CT if available) performed <7 days in a cohort of consecutive acute LH patients >55 years. Results: Forty-six patients (24 men and 22 women; mean age 73; 28 probable and 18 possible CAA patients) were analysed. Mean symptom onset-MRI delay was 1.3 days (including 26 patients with MRI <24 h). Both probable and possible CAA groups were comparable regarding age, sex, time MRI and CT performance, MRI field strength, and LH volume. On MRI, both FLP and SAHE were observed more frequently in probable than in possible CAA (FLP 43 vs. 6%, p = 0.0073; SAHE 79 vs. 44%, p = 0.027), and associated with larger LH volumes (FLP, p = 0.011; SAHE, p = 0.047). FLP was associated with earlier performed MRI (mean 0.3 vs. 1.75 days, p = 0.025). In the subgroup of 35 patients with available CT (performed a mean of 2.2 days before or after MRI), FLP presence on CT was observed more frequently in probable than in possible CAA (57 vs. 7%, p = 0.0039). Concordance of MRI and CT for FLP presence/absence was 89%. Conclusions: In acute LH patients, FLP and SAHE on acute/early subacute phase MRI are associated with probable CAA diagnosis. Larger LH volumes are associated with FLP and SAHE on MRI, and early performed MRI with FLP.

Impaired dynamic cerebral autoregulation in patients with cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) might disturb the sensitive mechanism of cerebral pressure autoregulation. This study examines whether dynamic cerebral autoregulation (CA) is impaired in the posterior or anterior circulation of CAA patients. Fifteen patients with known CAA on magnetic resonance imaging (MRI) and 14 age-matched controls were examined with transcranial Doppler. Dynamic CA was assessed in the middle (MCA) and posterior cerebral artery (PCA) via transfer function phase and gain during respiratory-induced 0.1 Hz oscillations of arterial pressure. Within the patient group, 4 patients showed additional microbleeds in the basal ganglia on the MRI performed within the study (pure CAA vs mixed microbleeds). PCA phase was significantly lower in patients compared with controls (p = 0.018), particularly in patients with pure CAA (p = 0.0034). MCA values showed a similar but non-significant trend towards lower phase in patients with pure CAA. Poorer phase was associated with a higher number of microbleeds on MRI (MCA r = −0.57, p = 0.027; PCA r = −0.52, p = 0.098) and superficial cortical siderosis (PCA: p = 0.0025). In conclusion, dynamic cerebral autoregulation is impaired in patients with CAA. The degree of impairment is associated with the extent of cerebral microbleeds.

Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers.

We investigated the frequency and clinical significance of amyloid β (Aβ) positivity on PET in patients with cerebral amyloid angiopathy (CAA). We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aβ positivity and investigated the effect of Aβ positivity on longitudinal cognitive decline. Among the 65 CAA patients, 43 (66.2%) showed Aβ PET positivity (Aβ+). Patients with Aβ+ CAA had more lobar microbleeds (median 9, interquartile range 2-41, vs. 3, 2-8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aβ- CAA had more lacunes (1, 0-2, vs. 0, 0-1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aβ+ patients (57.1%) than in Aβ- patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aβ positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models. Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aβ- on PET. Aβ positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aβ positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer's disease neuropathological changes.

Cortical Superficial Siderosis Evolution.

Background and Purpose- We investigated cortical superficial siderosis (cSS) progression and its clinical relevance for incident lobar intracerebral hemorrhage (ICH) risk, in probable cerebral amyloid angiopathy presenting with neurological symptoms and without ICH at baseline. Methods- Consecutive patients meeting modified Boston criteria for probable cerebral amyloid angiopathy from a single-center cohort who underwent magnetic resonance imaging (MRI) at baseline and during follow-up were analyzed. cSS progression was assessed by comparison of the baseline and follow-up images. Patients were followed prospectively for incident symptomatic ICH. cSS progression and first-ever ICH risk were investigated in Cox proportional hazard models adjusting for confounders. Results- The cohort included 118 probable cerebral amyloid angiopathy patients: 72 (61%) presented with transient focal neurological episodes and 46 (39%) with cognitive complaints prompting the baseline MRI investigation. Fifty-two patients (44.1%) had cSS at baseline. During a median scan interval of 2.2 years (interquartile range, 1.2-4.4 years) between the baseline (ie, first) MRI and the latest MRI, cSS progression was detected in 33 (28%) patients. In multivariable logistic regression, baseline cSS presence (odds ratio, 4.04; 95% CI, 1.53-10.70; P=0.005), especially disseminated cSS (odds ratio, 9.12; 95% CI, 2.85-29.18; P<0.0001) and appearance of new lobar microbleeds (odds ratio, 4.24; 95% CI, 1.29-13.9; P=0.017) were independent predictors of cSS progression. For patients without an ICH during the interscan interval (n=105) and subsequent follow-up (median postfinal MRI time, 1.34; interquartile range, 0.3-3 years), cSS progression independently predicted increased symptomatic ICH risk (hazard ratio, 3.76; 95% CI, 1.37-10.35; P=0.010). Conclusions- Our results suggest that cSS evolution may be a useful biomarker for assessing disease progression and ICH risk in cerebral amyloid angiopathy patients and a candidate biomarker for clinical studies and trials.

Brain ApoA-I, ApoJ and ApoE Immunodetection in Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aβ) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aβ fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aβ deposits or without Aβ deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aβ accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aβ diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aβ pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aβ deposition within the brain.

Abstract WP555: Plasma Beta-Secretase 1 in Cerebral Amyloid Angiopathy

Backgrouds: Beta-secretase 1 (BACE1) is the rate-limiting enzyme in amyloidogenesis. We have recently reported that plasma BACE1 activity may predict Alzheimer’s disease as surrogate biomarkers, and BACE1 protein and activity levels are increased in cortical vessels from patients with cerebral amyloid angiopathy (CAA). However, little is known about the plasma BACE1 levels in CAA. Methods: A single-center prospective cohort of probable CAA patients admitted to Huashan Hospital from December 2014 to September 2017 were age, sex and education matched with elder adults from population-based Shanghai Aging Study cohort. We collected the clinical data, plasma and imaging markers. We measured plasma BACE1 concentration with our in house ELISA and BACE1 activity as we recently described. BACE1 concentration and activity were compared between CAA and controls and within CAA patients according to disease severity using generalized linear models. Results: There were 40 CAA patients with mean age of 73.3 years and 41 controls of 72.8 years. Compared with heathy controls, CAA patients showed a higher BACE1 protein concentration (5.44 [3.39, 9.17] ng/ml vs. 7.37 [5.38, 11.88] ng/ml, p=0.009), higher BACE1 activity (218.8±96.0 mFU/min vs. 285.7±119.4 mFU/min, p=0.007) and higher BACE1 activity per total plasma protein (6.99.0±3.07 mFU/min vs. 9.01±4.27 mFU/min, p=0.017), with no significant differences in BACE1 activity-to-concentration ratio (32.46 [20.11, 70.46] vs. 34.27 [17.23, 54.12], p=0.484). A cutoff value of BACE1 activity 252.6 mFU/min was determined to differentiate CAA from healthy elders with a sensitivity of 0.575 and a specificity of 0.683. For CAA patients, plasma BACE1 activity was higher in the severe group (total SVD score ≥4, n=10, 371.62±110.09 mFU/min) than in the mild group (total SVD score &lt;4, n=30, 257.04±109.61 mFU/min, p=0.012). No significant differences were found in CMBs&gt;10 vs. CMBs≤10 group (p=0.600). Conclusions: Plasma BACE1 concentration and activity are increased in CAA patients. Our results indicate that plasma BACE1 may be a promising biomarker for CAA diagnosis and have potential values in disease severity grading. A larger CAA cohort has been recruited to further validate the results.

Abstract TMP109: Loss of Gray-White Contrast in Cerebral Amyloid Angiopathy: An in-vivo and Ex-Vivo Exploratory Approach

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) is associated with cortical and white matter atrophy. We hypothesized that changes in neural tissue signal properties could reflect microstructural alterations in diffusion, and hence demyelination. Methods: Two cohorts of non-demented CAA patients were examined (3T: 45 CAA patients vs 16 age-matched Healthy Controls [HC]; 1.5T: 66 CAA patients vs 18 matched HC), and dichotomized into moderate (3T: n=19; 1.5T: n=24) and severe CAA. FreeSurfer was employed to calculate gray and white (GW) matter signal intensities from a T1-weighted sequence, and their ratio was used to assess GW contrast. Two diffusion markers (fractional anisotropy [FA]; apparent diffusion coefficient [ADC]) were measured via Diffusion Weighted Imaging. In addition, brains of 13 deceased patients with CAA were scanned ex-vivo, sectioned, and stained using Luxol Fast Blue, to assess myelin content. GW ratio was calculated the same way as in the in-vivo cohorts. Results: CAA patients displayed loss of GW contrast, expressed by increased GW intensity ratio (3T: 0.802±0.01; 1.5T: 0.757±0.02), when compared to HC (3T: 0.789±0.01,p=0.003; 1.5T: 0.738±0.01,p&lt;0.0001). Patients with severe CAA showcased even lower GW contrast (3T: 0.806±0.01; 1.5T: 0.763±0.02) than patients with moderate CAA (3T: 0.797±0.01,p&lt;0.05; 1.5T: 0.745±0.02,p&lt;0.05) [ Fig ]. Moreover, loss of GW contrast within CAA correlated with lower FA (r=-0.30,p=0.049) and increased ADC (r=0.52,p&lt;0.0001). Within the ex-vivo CAA cohort, loss of GW contrast was highly linked to a decrease in underlying myelin concentration (p=0.0025). Conclusions: CAA patients consistently displayed lower GW contrast compared to HC. This loss of contrast became more pronounced with increased disease severity, and correlated with lower anisotropy and increased water diffusivity. Indeed, an ex-vivo CAA cohort revealed that loss of GW contrast corresponded to a decrease in myelin concentration.

Abstract TP575: Amyloid Accumulation Evaluated With Pib Pet in Patients With Cerebral Amyloid Angiopathy

Purpose: Cerebral amyloid angiopathy (CAA) is a disease with deposition of amyloid beta protein to meninges or intracerebral vessel walls. CAA is known as a cause of cerebral hemorrhage or subarachnoid hemorrhage occurring most frequently in the occipital lobe. CAA is usually accompanied with Alzheimer's disease, which shows specific pattern of amyloid accumulation. In this study we evaluated the distribution of the amyloid deposition in CAA patients using PIB-PET. Methods: Five patients, 3 males and 2 females, who developed cerebral hemorrhage or subarachnoid hemorrhage and clinically diagnosed as CAA were evaluated. Age of the patients was 28 - 74 years old. To detect amyloid accumulation, we injected 250-350mBq or 400-500mBq of [11C]PiB, followed by 60 minutes or 70 minutes dynamic scan using Eminence B PET camera (Shimadzu Corporation). Results: PIB accumulation was detected predominantly in the frontal lobe, parietal lobe, and lateral temporal lobe, but much less in the occipital lobe. The distribution of PIB accumulation was mostly similar to that in patients with Alzheimer disease. Little accumulation in the occipital lobe may reflect apparent effects of intracerebral hemorrhage. Conclusion: In most CAA patients, the examination by PIB-PET fails to detect amyloid deposition in the vessel walls of the occipital lobes. Instead, it more frequently reflect intracerebral amyloid deposition of accompanying Alzheimer's disease.

Abstract TP433: Structural, Molecular and Physiologic Alterations in Patients with Lobar Microbleeds

Background: Cerebral amyloid angiopathy (CAA) is diagnosed after a lobar intracerebral hemorrhage (L-ICH) but lobar microbleeds (LMB) are increasingly detected on MRIs of patients without L-ICH. We aimed to compare advanced imaging measures of structural brain damage, amyloid load, and cerebrovascular reactivity between CAA patients with L-ICH (CAA-ICH) and those with LMB (LMB-only). Methods: Standard MRI markers (LMB counts, cortical superficial siderosis [cSS], enlarged perivascular spaces [EPVS], white matter hyperintensity [WMH] patterns) and FreeSurfer based advanced volumetric analyses (calculated as percent of total intracranial volume) were obtained in 115 non-demented patients with either CAA-ICH or LMB-only. Pittsburgh compound B PET measures of amyloid deposition and fMRI measures of vascular reactivity (amplitude, time-to-peak, time-to-baseline) were also compared between the 2 groups. Results: LMB-only patients (n=37) presented with transient neurological symptoms or cognitive/gait complaints and stroke/neurodegenerative conditions were ruled out. Age, vascular risk factors, LMB counts, presence of cSS, EPVS counts and WMH patterns were not different between CAA-ICH and LMB-only (Table). Volume of WMH was significantly higher in CAA-ICH as compared to LMB-only patients in univariable and multivariable models (p=0.026). There was no difference in cortical thickness, WM volume, amyloid load/distribution and finally functional MRI markers of vascular reactivity between the two groups (Table). Conclusions: Our results indicate that measures of vascular physiology and amyloid load as well as structural damage of LMB-only patients are not different from CAA-ICH, except a lower WMH load. These data support the view that LMB-only patients represent a non-hemorrhagic stage of the disease and that they can be enrolled in clinical trials aimed at modifying the molecular/physiologic changes to reverse/prevent CAA progression.

Abstract WP140: The Effect of Age-related Gut Dysbiosis on Microglial Function in Cerebral Amyloid Angiopathy

The role of “gut-immune-brain axis” across our lifespan is well recognized as a biologic variable. As our populations age, so does the prevalence of age-related illnesses including stroke and its sequelae. We examined how manipulating the microbiome alters the natural history of cerebral amyloid angiopathy (CAA), a major cause of recurring brain hemorrhages, stroke, and cognitive decline. Microglial phenotype changes with aging and deficits in microglial phagocytosis lead to increased amyloid burden in animal models of Alzheimer’s but it is not known if this occurs in CAA. We hypothesize that age-related dysbiosis accelerates initiation and progression of CAA and this effect is mediated by failure of microglial amyloid phagocytosis (MAP). We have investigated the effects of dysbiosis on MAP and cognitive decline in wild-type (WT) and Tg2576 transgenic mice. Gut microbiomes were altered in pre- and post-symptomatic transgenic mice via fecal microbiota transfer (FMT) from young and aged WT mice. Cognitive decline and microglial phenotype were assessed using behavioral tests and flow cytometry. Function of microglia using in vitro primary and ex vivo sorted cultures from CAA mice were also examined. Our preliminary data shows: 1) An increased Firmicutes:Bacteroidetes ratio, indicative of an aging microbiome, occurred in young recipients given aged donor FMT; conversely, the ratio decreased in aged mice given young biome(P&lt;0.001, n=14); 2) Microglial phagocytosis was impaired in aged WT microglia (n=7/gp, P&lt;0.01); and 3) Motor strength in both young and aged WT mice after FMT (n=17/gp) were dependent on the age of the donor microbiome rather than the age of the host (P&lt;0.001). Our studies demonstrate an important role for the gut microbiome in modulating CAA pathogenesis and progression in the brain. Thus, manipulation of the gut microbiota could be an effective therapy to delay the onset and/or slow the progression of disease in CAA patients.

Abstract 50: Interrelationship Between Lacunes and Cortical Microinfarcts in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is known for its hemorrhagic manifestations, but ischemic features of the disease are also recognized such as white matter hyperintensities (WMH). We aimed to investigate the interrelationship between two emerging ischemic markers related to CAA: lacunes and cortical microinfarcts (CMI). Methods: CMI were scored on MRIs using high resolution FLAIR, double inversion recovery and MEMPRAGE sequences, in prospectively enrolled patients with CAA. The presence, number, and topography of lacunes (deep vs. subcortical), cerebral microbleeds (CMB), cortical superficial siderosis (cSS), and enlarged perivascular spaces (EPVS) were identified. FreeSurfe r was used for volumetric analyses. The relationship of CMI and lacunes as well as the association of these lesions with other CAA-related markers were analyzed. Results: The cohort consisted of 122 nondemented probable CAA patients (mean age, 69.4±7.6 years, 73% men). Lacunes were present in 31 (25.4%) of the patients and all but 1 were located in subcortical as opposed to deep brain regions. Lacunes were not associated with age, sex, or vascular risk factors. CMI were found in 35 patients (28.7%). CMI were more common in patients with lacunes compared to patients without lacunes (51.6% vs. 20.9%, p=0.002) and this association remained significant in a multivariable model adjusting for age, sex and hypertension (odds ratio: 4.2, 95% CI: 1.75-10, p=0.001). WMH volume, EPVS, WM volume, cortical thickness, and hemorrhagic markers did not differ between patients with or without lacunes (p&gt;0.2 for all comparisons). CMI did not correlate with these markers except showing a positive association with presence/extent of cSS. Conclusion: Lacunes and CMI were common in CAA, and lacunes were more commonly found in subcortical WM as opposed to deep gray structures. Our study shows that CMI are more likely to occur in probable CAA patients with lacunes than without lacunes, suggesting that these two lesion types may be part of a common spectrum of small CAA-related ischemic infarcts. These pathologies did not correlate with markers of more widespread damage, however, suggesting that the mechanism for CAA-related infarcts is distinct from other more widespread effects of CAA.

Apolipoprotein E and clusterin inhibit the early phase of amyloid-\u03b2 aggregation in an in vitro model of cerebral amyloid angiopathy

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA.

Al18F-NODA Benzothiazole Derivatives as Imaging Agents for Cerebrovascular Amyloid in Cerebral Amyloid Angiopathy.

In this study, we synthesized four novel Al18/19F-labeled 2-phenylbenzothiazole derivatives conjugated to 1,4,7-triazacyclononane-1,4-diacetic acid via alkyl linkers and evaluated them as imaging agent targets to amyloid-β (Aβ) plaques deposited in the blood vessels of cerebral amyloid angiopathy (CAA) brain. The four ligands exhibited moderate-to-high binding ability to Aβ1–42 aggregates, of which complex 17 possessing the most potent affinity (Ki = 11.3 nM) was selected for further biological evaluations. In vitro fluorescent staining and in vitro autoradiography studies on brain sections from CAA patients proved that this ligand could label Aβ deposits in blood vessels selectively. In biodistribution study, [18F]17 can hardly penetrate the blood–brain barrier (brain2 min = 0.3% ID/g) and displayed a rapid blood washout rate (blood2 min/blood60 min = 25.2), which is favorable as CAA imaging agents. In conclusion, this Al18F-labeled 2-phenylbenzothiazole complex was developed and proved to be a promising CAA positron emission tomography agent.

Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy.

Background and Purpose- We aimed to explore the association between presence of cerebral cortical microinfarcts (CMIs) on magnetic resonance imaging and other small-vessel disease neuroimaging biomarkers in cerebral amyloid angiopathy (CAA) and to analyze the role of CMIs on individual cognitive domains and dementia conversion. Methods- Participants were recruited from an ongoing longitudinal research cohort of eligible CAA patients between March 2006 and October 2016. A total of 102 cases were included in the analysis that assessed the relationship of cortical CMIs to CAA neuroimaging markers. Ninety-five subjects had neuropsychological tests conducted within 1 month of magnetic resonance imaging scanning. Seventy-five nondemented CAA patients had cognitive evaluation data available during follow-up. Results- Among 102 patients enrolled, 40 patients had CMIs (39%) on magnetic resonance imaging. CMIs were uniformly distributed throughout the cortex without regional predilection ( P=0.971). The presence of CMIs was associated with lower total brain volume (odds ratio, 0.85; 95% CI, 0.74-0.98; P=0.025) and presence of cortical superficial siderosis (odds ratio, 2.66; 95% CI, 1.10-6.39; P=0.029). In 95 subjects with neuropsychological tests, presence of CMIs was associated with impaired executive function (β, -0.23; 95% CI, -0.44 to -0.02; P=0.036) and processing speed (β, -0.24; 95% CI, -0.45 to -0.04; P=0.020). Patients with CMIs had a higher cumulative dementia incidence compared with patients without CMIs ( P=0.043), whereas only baseline total brain volume (hazard ratio, 0.76; 95% CI, 0.62-0.92; P=0.006) independently predicted dementia conversion. Conclusions- Magnetic resonance imaging-detected CMIs in CAA correlated with greater overall disease burden. The presence of CMIs was associated with worse cognitive performance, whereas only total brain atrophy independently predicted dementia conversion.

Cerebral Amyloid Angiopathy With Vascular Iron Accumulation and Calcification.

Background and Purpose- Previous studies of symptomatic and asymptomatic hereditary cerebral amyloid angiopathy (CAA) patients offered the possibility to study the radiological manifestations of CAA in the early stages of the disease. Recently, a striped cortex, observable as hypointense lines perpendicular to the pial surface on T2*-weighted 7T magnetic resonance imaging (MRI), was detected in 40% of the symptomatic hereditary CAA patients. However, the origin of these MRI contrast changes is unknown. This study aimed at defining the underlying pathology associated with the in vivo observed striped pattern. Methods- Formalin-fixed postmortem brain material including the occipital lobe of 4 hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) cases and 6 sporadic CAA cases were selected from local neuropathology tissue collections. Depending on the availability of the material, intact hemispheres or brain slabs including the occipital lobe of these patients were screened for the presence of a striped cortex. Regions containing the striped cortex were then subjected to high-resolution 7T MRI and histopathologic examination. Results- We found 2 hereditary cerebral hemorrhage with amyloidosis-Dutch type cases and 1 sporadic CAA case with striped patterns in the occipital cortex resembling the in vivo signal. Histopathologic examination showed that the striped pattern in the cortex at 7T MRI is because of iron accumulation and calcification of penetrating arteries. The presence of both nonheme iron and calcification on penetrating arteries causes signal loss and hence the abnormal striped patterns in the cortical ribbon on T2*-weighted MRI. Conclusions- We identified iron accumulation and calcification of the vessel wall in hereditary cerebral hemorrhage with amyloidosis-Dutch type as the histopathologic correlates of the striped cortex observed on in vivo 7T MRI.

Cortical Microinfarcts on 3T Magnetic Resonance Imaging in Cerebral Amyloid Angiopathy

Background and Purpose- Cerebral microinfarcts are small ischemic lesions that are found in cerebral amyloid angiopathy (CAA) patients at autopsy. The current study aimed to detect cortical microinfarcts (CMI) on in vivo 3 Tesla (3T) magnetic resonance imaging (MRI) in CAA patients, to study the progression of CMI over a 1-year period, and to correlate CMI with markers of CAA-related vascular brain injury and cognitive functioning. Methods- Thirty-five CAA patients (mean age, 74.2±7.6 years), 13 Alzheimer disease (AD) patients (67.0±5.8 years), and 26 healthy controls (67.2±9.5 years) participated in the study. All participants underwent a standardized clinical and neuropsychological assessment as well as 3T MRI. CMI were rated according to standardized criteria. Results- CMI were present in significantly more CAA patients (57.1%; median number: 1, range 1-9) than in Alzheimer disease (7.7%) or in healthy controls (11.5%; P<0.001). Incident CMI were observed after a 1-year follow-up. CMI did not correlate with any other MRI marker of CAA nor with cognitive function. Conclusions- In vivo CMI are a frequent finding on 3T MRI in CAA patients, and incident CMI are observable after 1-year follow-up. CMI can be regarded as a new MRI marker of CAA, potentially distinct from other well-established markers. Future larger cohort studies with longitudinal follow-up are needed to elucidate the relationship between CMI and possible causes and clinical outcomes in CAA.

Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features

Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ42 levels, and more severe amyloid load on FBB-PET.

FV4. Comparing whole-brain susceptibility patterns in patients with Alzheimers disease and cerebral amyloid angiopathy: A QSM study

Background Evidence exists, that cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) partially share pathophysiological pathways, including the accumulation of amyloid in the vessels’ walls and vascular damage (Charidimou et al., 2017). Further hints are the similar distribution of Amyloid b in PET studies (Johnson et al., 2007) and the presence of microbleeds in both AD and CAA (Cordonnier and Flier, 2011). Iron accumulation has been proposed as a marker of neural degeneration (Ward et al., 2014) and its global distribution can be assessed in vivo using quantitative susceptibility mapping (QSM) in magnetic resonance imaging (MRI) (Acosta-Cabronero et al., 2017). Using QSM, we aim to compare the magnetostatic distribution patterns of CAA and AD patients. Methods 25 patients affected by CAA, 25 AD patients and 25 community-dwelling elderly adults underwent high-resolution MRI at 3T (1.0 × 1.0 × 2.0 mm). After QSM reconstruction, whole brain analysis, will be performed using FSL (Jenkinson et al., 2012) to compare susceptibility maps between groups. Sex, age and educational level will be set as nuisance variables, while clusters will be considered significant when p(FEW) Hypothesis We expect to observe partially overlapping patterns in the magnetostatic distribution of CAA and AD patients, and additionally suppose to find group differences, such as the prevalence of occipital iron accumulation in CAA patients. In this case, a disease specific QSM-pattern could be suggested as a complementary diagnostic tool. Results will be available before end of the year.

PB4. In vivo analysis of hippocampal vascularization patterns in patients with cerebral amyloid angiopathy – A 7T time-of-flight MR-angiography study

Background Hippocampal integrity is crucial for many cognitive functions (e.g. episodic memory) commonly affected in Alzheimer‘s dementia (AD). The hippocampus compared to several cortical areas seems to be less able to cope with oxidative stress as a result of e.g. hypoperfusion and anoxia (Duvernoy et al., 2005), which may rely on different hippocampal vascularization patterns based on the hippocampal arteries‘ origin from the posterior cerebral artery (PCA) or from both, PCA and anterior choroidal artery (AChA) (Marinkovic et al., 1992; Spallazzi et al., under review). There is considerable overlap between AD pathology and sporadic cerebral amyloid angiopathy (CAA), that is vascular s-amyloid deposition found throughout the whole brain also affecting the hippocampal arteries and leading to cognitive decline through several downstream pathologies comprising e.g. hypoperfusion, microbleeds or microinfarcts. Methods We performed high-resolution 7 Tesla (T) and 3 T magnetic resonance imaging (MRI) comprising time-of-flight (ToF) magnetic resonance angiography (MRA) (7 T) on so far 12 non-demented patients diagnosed to suffer from CAA according to Boston criteria (mean [SD] age 70.9 [6.40] years, 66.67% male) and 20 age-matched healthy controls (70.38 [4.868] years, 45% male). MRI was considered as a baseline. Furthermore, regional blood perfusion was measured using Arterial Spin Labelling (ASL) at 3 T MRI (Grade et al., 2015) and will be correlated to the vascularization patterns. Cognitive function was assessed at baseline and will be measured during at least two follow-ups to extract various composite scores adjusted for education. Conversion to dementia will be diagnosed according to standardized criteria. A hippocampal mask was created using FreeSurfer (Fischl et al., 1999) and adopted as an anatomical landmark to analyze 7T ToF MRA data. Hippocampal vessels as well as the different distribution patterns of the right and left hemispheres will be visually inspected and vascularization patterns will be classified using MeVisLab ( https://www.mevislab.de ). Hypothesis Based on the proposed hippocampal vascularization patterns we here hypothesize to find different CAA phenotypes characterized by two features, (i) the extent of CAA-related downstream pathologies, and (ii) the resilience against those downstream pathologies resulting in different slopes of cognitive decline as well as various dementia conversion rates. Thereby, higher hippocampal perfusion and less microbleeds or microinfarcts are expected to be found in hemispheres where PCA and AChA are both participating to hippocampal vascularisation. CAA patients displaying that hippocampal vascularization pattern are further hypothesized to reveal higher cognitive reserve mechanisms resulting in slower cognitive decline and lower dementia conversion rates.

Abstract WP415: Posterior Distribution of White Matter Damage Correlates to Visuospatial Impairment in Cerebral Amyloid Angiopathy

Introduction: Several studies have revealed that patients with cerebral amyloid angiopathy (CAA) have cognitive decline relating to MRI changes especially white matter damage (WMD). CAA showing preference for posterior regions was in accordance with visual cortex, however few focused on visuospatial function and its related imaging makers in CAA. Hypothesis: Severity and distribution of WMD correlate to visuospatial function in CAA patients. Methods: We enrolled non-demented probable CAA patients based on modified Boston criteria in a single hospital, and normal elder people from Shanghai Aging Study. CAA-related WMD included WMH volumes and brain network connection changes measured by regional mean fractional anisotropy (FA), and was evaluated from aspects of severity (mean FA and WMH volumes) and distribution pattern (posterior-anterior gradient). CAA patients completed a standard cognitive test battery for visuospatial function and others. The association of WMD and cognitive domains were analyzed by univariate regression model. Results: 28 non-demented CAA patients and 56 normal controls were enrolled. For WMD, CAA patients demonstrated prominently increased WMH volumes (3.89 mm 3 versus 28.84mm 3 , p&lt;0.001) and posterior-anterior gradient (-22% versus 17%, p=0.004), and decreased posterior mean FA (0.365 versus 0.350, p=0.037), without differences in global and anterior mean FA. For cognitive function in CAA patients, there was no association between severity of WMD and any cognitive domain. Only posterior-anterior gradient of regional FA (β=0.538, p=0.015) and WMH volumes (β=-0.599, p=0.005) significantly related to visuospatial function, which was not found in other domains. Conclusions: Posterior predisposition of decreased brain network connections and increased WMH volumes correlated to visuospatial impairment, which might help to understand the possible mechanism of cognitive decline in CAA patients.