Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings. To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons. The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3–4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10

BACKGROUND AND OBJECTIVES:Cerebral adrenoleukodystrophy (cALD), the most severe clinical phenotype of X-linked adrenoleukodystrophy (X-ALD), is characterized by rapidly progressive, inflammatory destruction of the cerebral white matter. In adult patients, therapeutic options are limited to hematopoietic stem cell transplantation, which carries substantial treatment-related risks, necessitating careful and individualized clinical decision-making. Monitoring the progression of characteristic MRI changes provides a promising approach, both for guiding treatment and for serving as an outcome measure in interventional trials. Although the natural history of these MRI changes has been well described in childhood cALD, analogous data in adult patients remain scarce. METHODS:In this multicenter retrospective cohort study, we screened adult men with confirmed X-ALD at leukodystrophy centers in Leipzig, Amsterdam, and Boston between 2000 and 2025. Inclusion criteria required lesion progression on at least 2 high-quality MRI scans during a minimal untreated follow-up of 3 months. Volumes calculated from lesion masks were segmented using a 3D U-Net convolutional neural network followed by manual correction and compared with the disease-specific semiquantitative MRI Loes score. Gadolinium enhancement, primary lesion location, and serum neurofilament light chain (sNfL) levels, alongside demographic data, were evaluated as potential predictors of lesion progression. RESULTS:Of 578 individuals screened, 48 patients and 338 MRI scans were included in the analysis. Lesion progression followed an overall exponential growth rate of 3.4% per month (95% CI 2.6-4.2), with substantial interindividual variability (range 0.5-7.3). Growth rates were slower in lesions without contrast enhancement (0.9%/month vs 3.4%/month, p = 0.010) and varied depending on the initial lesion location. Increased sNfL concentrations (n = 37), a marker of neuroaxonal damage, were better explained by absolute lesion volume (mL) and lesion volume increase (mL/month; adjusted R2 = 0.669) than by semiquantitative Loes score measures (adjusted R2 = 0.488). DISCUSSION:In this comprehensive multicenter retrospective study on lesion evolution in adult cALD, we demonstrate that lesion growth follows an exponential trajectory, with considerable interindividual variability. Primary lesion location, contrast enhancement, and NfL levels emerge as potential predictors of lesion progression. This might support personalized treatment strategies for adults with cALD and guide clinical trial design in the future.

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder characterized by progressive white matter demyelination. Quantification of demyelinated white matter on MRI—typically expressed as the demyelination load—serves as a key imaging biomarker of disease burden, enabling objective monitoring beyond visual rating scales. However, current semi-automated pipelines are limited by manual interaction, pediatric brain variability, and differences in MRI acquisition. This study aimed to develop and validate a self-configuring convolutional neural network (CNN) for automated segmentation of demyelinated white matter in MLD and to compare its performance with a conventional semi-automated method across heterogeneous MRI datasets. An nnU-Net was trained on 189 3D T1- and axial T2-weighted scans from 35 MLD patients using visually controlled conventional masks as ground truth. Independent testing was performed on 130 scans (73 high-resolution 3D, 57 lower-resolution 2D T1-weighted) from 49 patients. Performance was assessed by Dice coefficient, Bland-Altman bias, correlation with Gross Motor Function Classification (GMFC-MLD), MLD MRI severity score, longitudinal consistency, and qualitative review of outliers. CNN-based segmentation showed strong spatial agreement with the reference method, with a median Dice coefficient of 0.82 for 3D T1-weighted scans and 0.75 for 2D scans. Volumetric bias was minimal on Bland-Altman analysis. CNN-derived demyelination load correlated significantly with motor impairment (rS = 0.38 for 3D and r = 0.56 for 2D; both p < 0.001) and showed a stronger association with the MLD MRI severity score than conventional segmentation (3D: rS = 0.48 vs. 0.28; 2D: rS = 0.83 vs. 0.29). Correlations with clinical status were slightly lower (CNN: rS = 0.38, p < 0.001; conventional: (rS = 0.26, p < 0.025)) Longitudinal analyses demonstrated stable, monotonic changes over time, and qualitative review revealed fewer boundary misclassifications. The nnU-Net enables fast, reproducible, and clinically meaningful segmentation of demyelinated white matter in MLD. It generalizes across MRI protocols, correlates with motor function, and offers a scalable tool for standardized biomarker extraction in clinical trials and other leukodystrophies.

Amyloid-related imaging abnormalities (ARIA) on magnetic resonance imaging during treatment with amyloid beta–directed antibodies are well documented; however, detailed accounts of severe clinical presentations, although rare in occurrence, have not yet been well-described. We briefly describe 4 cases of radiographically severe and clinically serious ARIA. This case series presents the radiographic and clinical manifestations of severe ARIA events after aducanumab treatment from the EMBARK study. EMBARK (ClinicalTrials.gov identifier NCT04241068) was an open-label, multicenter, longitudinal, single-arm, Phase 3b study. EMBARK enrolled 1696 participants with Alzheimer’s disease who were previously enrolled in aducanumab trials (PRIME, EMERGE, ENGAGE, or EVOLVE). Participants received a monthly 10 mg/kg dose of aducanumab after an aducanumab treatment gap period imposed by the discontinuation of the aducanumab studies. The clinical history, management, and imaging findings of 4 selected severe and/or serious case reports of ARIAs in participants treated with aducanumab are presented. All of the participants carried the apolipoprotein E (ApoE) ε4 allele (3 were homozygous ApoE ε4 carriers). Possible risk factors were explored, and the clinical courses were delineated. These 4 cases were chosen to highlight key lessons on the monitoring and management of ARIAs. Observations from these select severe cases improve our understanding of the risk factors, symptoms, and management of ARIAs.

BACKGROUND:Cerebral amyloid angiopathy (CAA) is characterized by progressive cerebrovascular amyloid-beta deposition associated with hemorrhagic and nonhemorrhagic manifestations. Evidence of prior cerebral hemorrhage and CAA can have significant implications for treatment with some approved therapies. This study sought to estimate the proportion of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who have probable CAA by systematically applying Boston Criteria version 2.0. In addition, we sought to evaluate characteristics associated with probable CAA in this population. METHOD:Participants in ADNI with cognitive symptoms or deficits (at least one Clinical Dementia Rating-Sum of Boxes [CDR-SB] score of >0) with relevant imaging for CAA adjudication were included. 3D T1-weighted, fluid-attenuated inversion recovery (FLAIR) and T2* Gradient Echo magnetic resonance imaging (MRI) sequences were downloaded from the ADNI database. Blinded neuroradiologists evaluated brain MRIs to categorize participants as having no CAA, possible CAA, or probable CAA using the Boston Criteria version 2.0. A 10% sample was randomly selected to evaluate inter-reader variability. Baseline characteristics associated with probable CAA were assessed using univariate and multiple regression analyses. RESULT:828 participants met inclusion criteria (Figure 1): 30.8% had no CAA, 43.5% had possible CAA, and 25.7% had probable CAA. Among those with probable CAA, 46.9% had mild cognitive impairment and 44.6% had dementia; median CDR-SB score was 3 (IQR 1-5). Among age, sex, CDR-SB score, apolipoprotein E4 (APOE4) homozygosity, hypertension, and antithrombotic medication use, an exploratory multiple logistic regression identified older age, higher CDR-SB score, and APOE4 homozygosity as independently and significantly associated with probable CAA (p <0.05). High interobserver agreement was observed (inter-reader correlation >90%). Additional results will be presented. CONCLUSION:Systematic application of Boston Criteria version 2.0 using the ADNI database identified probable CAA in approximately 26% of participants with cognitive symptoms or deficits. Age, dementia severity, and APOE4 genotype may inform the likelihood of having CAA; however, probable CAA was identified in patients across the spectrum of cognitive impairment severity. These data underscore the value of rigorous assessment of CAA in patients with cognitive complaints broadly, and the need for research and clinical paradigms to meet the needs of such patients.

Valiltramiprosate (ALZ-801), an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 homozygotes with Early AD (Abushakra, 2024); the topline results being presented at this meeting (Power, 2025). While the primary clinical endpoint was not significant, hippocampal volume (HV, main imaging outcome) showed significant slowing of atrophy. This 78-week placebo-controlled study randomized 325 homozygotes (placebo, 265 mg BID), stratified by MCI/Mild AD. ADAS-Cog13 and CDR-SB were the primary and key secondary outcomes respectively, and DAD (disability assessment for dementia) was a secondary outcome. HV was the main imaging outcome, cortical thickness and whole brain volume (CT, WBV) were secondary. Analyses by disease stage were pre-specified using baseline severity as covariate in the MMRM model; drug-effect correlations utilized Spearman’s correlations. The pre-specified MCI subgroup (MMSE 27-30) included 125 subjects (58 placebo, 67 active); with balanced baseline characteristics except for cholinesterase-inhibitors (placebo 31%, active 19%). Imaging population included 54 placebo, 62 active subjects. The MCI subgroup vs placebo showed positive effects on ADAS-cog/DAD (nominal p <0.05), trend on CDR-SB ( p =0.053) with significant slowing of HV, CT and WBV atrophy vs placebo (26%, p =0.004; 35% p < 0.0001; 22%, p =0.027). In the active arm, change in HV correlated significantly with change in ADAS-Cog13 (r=-0.40, p <0.005), CDR-SB (r=-0.45, p <0.005), and DAD (r=0.33, p =0.018). For CT, the correlations were also significant: ADAS-Cog13 (r=-0.34, p =0.015), CDR-SB (r=-0.49, p < 0.005), and DAD (r=0.40, p <0.005). WBV treatment effect also correlated with the clinical outcomes ( p ≤ 0.01). These strong correlations between structural preservation and clinical benefits of valiltramiprosate at the MCI stage support its efficacy and are consistent with its proposed mechanism of inhibiting amyloid oligomer formation, thereby potentially protecting neurons from synaptic dysfunction and neurodegeneration. Given the accelerated neurodegeneration in APOE4/4 patients, these findings suggest that intervention at the early stages of AD when neuronal reserve is higher, may be critical for valiltramiprosate to exert meaningful clinical effects alongside preservation of brain structure and volume.

Amyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer’s disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV–cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months’ duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV–cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N 10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18–24 months (r = −0.40 to −0.44, p < 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm3 or ≥ 10

Cerebral amyloid angiopathy (CAA) is characterized by progressive cerebrovascular amyloid-beta deposition associated with hemorrhagic and nonhemorrhagic manifestations. Evidence of prior cerebral hemorrhage and CAA can have significant implications for treatment with some approved therapies. This study sought to estimate the proportion of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who have probable CAA by systematically applying Boston Criteria version 2.0. In addition, we sought to evaluate characteristics associated with probable CAA in this population. Participants in ADNI with cognitive symptoms or deficits (at least one Clinical Dementia Rating-Sum of Boxes [CDR-SB] score of >0) with relevant imaging for CAA adjudication were included. 3D T1-weighted, fluid-attenuated inversion recovery (FLAIR) and T2* Gradient Echo magnetic resonance imaging (MRI) sequences were downloaded from the ADNI database. Blinded neuroradiologists evaluated brain MRIs to categorize participants as having no CAA, possible CAA, or probable CAA using the Boston Criteria version 2.0. A 10% sample was randomly selected to evaluate inter-reader variability. Baseline characteristics associated with probable CAA were assessed using univariate and multiple regression analyses. 828 participants met inclusion criteria (Figure 1): 30.8% had no CAA, 43.5% had possible CAA, and 25.7% had probable CAA. Among those with probable CAA, 46.9% had mild cognitive impairment and 44.6% had dementia; median CDR-SB score was 3 (IQR 1-5). Among age, sex, CDR-SB score, apolipoprotein E4 ( APOE4 ) homozygosity, hypertension, and antithrombotic medication use, an exploratory multiple logistic regression identified older age, higher CDR-SB score, and APOE4 homozygosity as independently and significantly associated with probable CAA ( p <0.05). High interobserver agreement was observed (inter-reader correlation >90%). Additional results will be presented. Systematic application of Boston Criteria version 2.0 using the ADNI database identified probable CAA in approximately 26% of participants with cognitive symptoms or deficits. Age, dementia severity, and APOE4 genotype may inform the likelihood of having CAA; however, probable CAA was identified in patients across the spectrum of cognitive impairment severity. These data underscore the value of rigorous assessment of CAA in patients with cognitive complaints broadly, and the need for research and clinical paradigms to meet the needs of such patients.

Brain MRI segmentation is required for quantitative PET analysis, in order to derive regional uptake and calculate uptake ratio relative to reference regions. FreeSurfer has been a popular method but is being supplanted by faster and more robust AI-driven methods. The objective of this work is to confirm that the use of Clario’s novel AI segmentation method, whose impact was assessed towards various MRI endpoints, is also valid in the context of PET quantification. 507 subjects from ADNI were selected, including normal controls, subjective memory complainers, early/late MCI and AD subjects. Besides, 210 were selected with available test/re-test data. For each, a pair of good quality 3DT1 MRI and Amyloid PET scans were available. 3DT1 data were segmented with both FreeSurfer v6 (FS) and Clario’s AI method (AI), and registered to PET space for calculation of Standard Uptake Value (SUV) in a set of cortical regions (frontal, posterior cingulate, lateral parietal and lateral temporal) and reference regions (cerebellar grey and whole cerebellum). SUVR (ratio to reference region) was calculated for both. Results were also converted to Centiloid (CL) units. SUV and SUVR values were compared across segmentation methods via Bland-Altmann plots and correlated with Pearson’s coefficient. The ability to distinguish between disease severity stages was assessed by ROC analysis using global AUC. Finally, classification as amyloid (Aβ) positive or negative was assessed by setting a cut-off of 20.1 CL and looking at Cohen’s Kappa. SUV and SUVR values were highly and significantly correlated between FS and AI methods (r>0.99, p<0.001) and for test/re-test, for all regions investigated, with a difference that did not exceed 0.41% on average (SD<1.38%). Global AUC was comparable for both methods and for test/retest (average gAUC=0.62). Aβ classification was near-perfect across methods (κ=0.98) and between test/retest data (κ FS =0.97, κ AI =0.99). Comparing FreeSurfer and Clario’s AI-based MRI segmentation method, no impact was found on subsequent PET analyses and test/retest performance was equivalent. These results support the use of either method for PET quantification. For future trials, the AI method could either be used as the primary method, or as a back-up when traditional FS segmentation fails.

INTRODUCTION:Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors. METHODS:This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling. RESULTS:CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger. DISCUSSION:Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect. HIGHLIGHTS:Of the 1414 participants from the CHARIOT-PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.

ALZ-801 (valiltramiprosate) is an oral inhibitor of amyloid oligomer formation in development as a disease-modifying AD treatment, including a fully enrolled APOLLOE4 Phase 3 trial in 325 APOE4/4 homozygotes. A Phase 2 study is evaluating ALZ-801 effects on plasma biomarkers, brain volumes and cognitive outcomes in APOE4 carriers. Plasma p-tau 181 reduction over 104 weeks is primary endpoint. A study extension includes active treatment over additional 104 weeks for a total of 208 weeks (4 years). Long term analyses include plasma p-tau 181 , Aβ42/40, p-tau 217 , GFAP and other emerging biomarkers. Hippocampal volume and cognition are additional outcomes. This active study enrolled 84 APOE4 carriers (MMSE ≥22; positive CSF+ biomarkers) who receive ALZ-801 265 mg BID. CSF/plasma biomarkers were conducted at Dr. Blennow’s laboratory (Simoa, EuroImmun assays). MRIs analyzed by Clario at baseline, 52, 104, and in the long-term extension (LTE); cognitive and biomarker tests are every 26 weeks. Biomarkers are analyzed on observed cases, hippocampal volume (HV) and cognitive tests are analyzed by MMRM with two-sided p-values; with Spearman’s correlations of biomarker-clinical outcomes. Baseline mean age was 69 years, MMSE 26, 51% females, and 70% MCI; and 83 subjects had any post-treatment efficacy assessment. Total of 75 and 70 subjects completed 52 and 104 weeks. At 104 weeks, plasma p-tau 181 reduction was 31% (p=0.045), Aβ42 reduction was 4% (p=0.042). Hippocampal volume (HV) versus untreated matched subjects from ADNI showed ∼20% less atrophy (p<0.002). Immediate and delayed memory scores (Rey test) remained at baseline levels versus 21% decline in matched ADNI subjects (p<0.0001). Memory stabilization correlated with reduced HV atrophy (r= 0.44, p=0.0002). In the 66 ongoing LTE subjects, cognitive and HV ADNI comparisons and biomarker-cognitive correlations at 130 weeks will be reported. Most common TEAE was mild nausea, with no ARIA-E. Biomarker positive APOE4 carriers showed significant plasma p-tau 181 and Aβ42 effects, with promising HV effects that correlated with cognitive benefit. Sustained long term benefits on these outcomes over 2.5 years could support disease modification with a continued favorable safety profile of ALZ-801. Correlations of plasma biomarkers to long-term clinical and imaging outcomes provides valuable insights into ALZ-801 effects in AD.

Oral ALZ-801 (valiltramiprosate), a brain-penetrant agent that inhibits amyloid-oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer’s disease (AD). ALZ-801 effects on plasma AD biomarkers were evaluated in a 104-week Phase 2 study in APOE4-carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid-related imaging abnormalities (ARIA) in AD patients. Incidence of ARIA-H (microhemorrhages, MH; superficial siderosis, SS) and of ARIA-E (edema/effusion) was analyzed. This study enrolled 84 subjects (31 APOE4/4, 53 APOE3/4) MMSE ≥22 and CDR-G 0.5 or 1.0, with positive amyloid and CSF p-tau181 ≥60 pg/ml. Subjects received ALZ-801 at 265 mg BID over 104 weeks, with MRI at baseline, 52 and 104 weeks following a standardized protocol including 2D FLAIR and T2* Gradient Echo. Study allowed subjects with any number of MH, but ARIA-E and SS lesions >1cm were exclusionary. Data were evaluated centrally by Clario neuroradiologists for eligibility assessment and ARIA safety monitoring. The study’s primary outcome was plasma p-tau 181 reduction at 104 weeks. At baseline, mean age and MMSE were 69 years and 26 respectively, with 52% female and 70% MCI subjects. Of 84 enrolled, 83, 75 and 69 subjects had baseline, 52-week and 104-week MRI. Baseline MRIs showed >1 MH in 7/83 (8%), and 6/75 subjects (8%) with post-treatment MRI developed new MH, all asymptomatic. At baseline, 5 subjects had 1-4 MH, of whom 2 developed new MH (3-4); 1 subject had >10 MH and developed 29 new MH. 3 subjects developed de novo MH (1-3). There was no SS or ARIA-E. Study primary outcome was achieved with significant p-tau181 reduction (31%, p = 0.045) and 4% Aβ42 reduction (p = 0.042), with memory stabilization over 2 years (Hey, ADPD 2024). The Phase 2 APOE4-carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA-E. This 265 mg BID ALZ-801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ-801 in APOE4 carriers with Early AD.

Task-based functional Magnetic Resonance Imaging (tb-fMRI) leverages blood oxygenation to measure the brain's response to external stimuli. A lack of tb-fMRI equipment standardization is the well-recognized challenge when deploying this promising approach in multi-center clinical trials. We sought to implement and characterize visual task-based brain activation as an exploratory measurement in TRAILBLAZER-ALZ 6 (NCT05738486), a multicenter, randomized, double-blind, Phase 3b study of donanemab in adults with early symptomatic AD and confirmed amyloid pathology. A total of 41 3 Tesla scanners were qualified for tb-fMRI, including 9 sites with established hardware (e.g. MR compatible Liquid Crystal Displays / goggles and triggering devices) and 32 sites lacking hardware (de novo) where a video-capable projector and an MRI coil mirror were provided. A 4-minute visual task (alternating 30s blocks of flashing annulus and crosshair) was disseminated either via a paradigm (established) or as a video (de novo) . fMRI acquisition was an interleaved gradient recalled echo planar (GRE-EPI) sequence with TR(repetition time)/TE(echo time)= 3000ms/30ms, voxel size = 3x3x4mm 3 , and 35 slices. fMRI data was pre-processed and spatially normalized to brain atlas space using a validated Clario pipeline. Processed fMRI data was input to a general linear model (GLM) with outlier regression. Brain activation for each scan was quantified as the mean T-score and Blood Oxygenation Level Dependent (BOLD) contrast within a pre-specified region of interest (ROI) of atlas-space occipital subregions. Task-based fMRI data was acquired from 799 participants ( n established = 192, n de novo = 607). Brain activation within the entire ROI was significant across all participants for mean T-score ( t > 7, p < 0.0001) and BOLD contrast value ( t > 6.4, p < 0.0001). At the group-level, participants scanned on established equipment had significantly higher BOLD contrast values relative to de novo sites (two-tailed p < 0.03), but mean T-scores were not significantly different. Task-based fMRI is viable in multi-center clinical trials. Novice sites can be trained to utilize off-the-shelf components and generate analyzable data. Variance due to fMRI equipment capabilities appears to impact the magnitude of ROI activation more than its significance level.

Abstract Background Gaucher disease type 1 (GD1) is a rare autosomal recessive disorder characterized by hepatosplenomegaly, thrombocytopenia, and disabling bone manifestations that require regular MRI monitoring to assess disease progression and treatment responses. Velaglucerase alfa therapy results in long-term improvements in hematologic and visceral manifestations, but more real-world data on its impact on bone manifestations are needed. The EIROS study aimed to address this knowledge gap by using MRI data collected in daily practice in France to assess the impact of velaglucerase alfa on GD1 bone disease. Methods Patients with GD1 and bone MRI data from around the time of velaglucerase alfa initiation were eligible for inclusion. All MRIs collected retrospectively from treatment initiation and prospectively to the end of follow-up (12 months) were analyzed centrally by a blinded expert radiologist to evaluate bone infiltration using the Bone Marrow Burden (BMB) score and a qualitative method (scored for the spine and femur: stable, improved or worsened). Abdominal MRIs were also centrally analyzed to assess hepatosplenomegaly. Reports from bone MRIs, X-rays, and abdominal ultrasounds made by local radiologists were also collected. Clinical (acute and chronic bone pain) and biological parameters were analyzed from medical records. Results MRI data were available for 20 patients from 9 hospital centers: 6 treatment-naive patients and 14 patients who switched to velaglucerase alfa from another GD treatment. Readable MRIs for BMB scoring were only available for 7 patients for the spine and 1 patient for the femur. Qualitative assessments, performed for 18 patients, revealed stability in spine and femur infiltration in 100.0% and 84.6% of treatment-switched patients (n = 13), respectively, and improvements in 80.0% and 60.0% of treatment-naive patients, respectively; no worsening of bone infiltration was observed. Liver, spleen and hematologic parameters improved in treatment-naive patients and remained stable in treatment-switched patients. Conclusions This study provided real-world evidence suggesting the long-term effectiveness of velaglucerase alfa treatment in GD1, including bone manifestations. The data indicate that if MRI assessment by a radiologist with experience of GD bone manifestations is not possible, a simplified qualitative assessment provides sufficient evidence in clinical practice for monitoring bone disease progression and treatment response.

Background/Objectives: Gaucher disease type 1 (GD1) is characterized by hepatosplenomegaly, thrombocytopenia, and disabling bone manifestations requiring regular MRI monitoring. The EIROS study assessed the real-world impact of velaglucerase alfa on GD1 bone disease, using MRI data collected in French clinical practice. Methods: MRIs collected retrospectively from treatment initiation and prospectively during follow-up (12-months) were analyzed centrally by a blinded expert radiologist to evaluate bone infiltration using the Bone Marrow Burden (BMB) score and a qualitative method (stable, improved or worsened for the spine and femur). Abdominal MRIs were also centrally analyzed to assess hepatosplenomegaly. Bone manifestations, hepatosplenomegaly, and hematologic parameters were analyzed from medical records. Results: MRI data were available for 20 patients: 6 treatment-naive patients and 14 patients who switched to velaglucerase alfa from another GD treatment. Interpretable MRIs for BMB scoring were available for seven patients for the spine and one patient for the femur. Qualitative assessments (n = 18) revealed stability in spine and femur infiltration in 100.0% and 84.6% of treatment-switched patients (n = 13), respectively, and improvements in 80.0% and 60.0% of treatment-naive patients (n = 5), respectively; no worsening of bone infiltration was observed. Liver, spleen, and hematologic parameters improved in treatment-naive patients and remained stable in treatment-switched patients. Conclusions: The qualitative real-world data support findings from clinical trials suggesting the long-term effectiveness of velaglucerase alfa on GD1 bone manifestations. When MRI assessment by radiologists with experience of GD is not possible, a simplified qualitative assessment may be sufficient in clinical practice for monitoring bone disease progression and treatment response.

Abstract INTRODUCTION Anti‐amyloid‐β (Aβ) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti‐Aβ mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti‐amyloid‐induced amyloid‐related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti‐Aβ mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA‐edema (ARIA‐E) that can assess severity on a 3‐ or 5‐point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3‐point Severity Scale of ARIA‐E (SSAE‐3) and the 5‐point Severity Scale of ARIA‐E (SSAE‐5), respectively. METHODS MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA‐E were selected to read all cases independently. One rater was then chosen for a second read to assess intra‐reader reproducibility. RESULTS The three raters had high agreement in identifying and grading ARIA‐E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter‐ and intra‐reader comparisons for SSAE‐3 and SSAE‐5 were 0.79 (0.70–1.00), 0.94 (0.94–1.00), 0.73 (0.66–1.00), and 0.90 (0.90–1.00), respectively. DISCUSSION Our study suggests that SSAE‐3 and SSAE‐5 are valid ARIA‐E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti‐Aβ mAbs as a treatment option for people living with Alzheimer's disease. Highlights A simple rating scale is needed to rate severity of amyloid‐related imaging abnormalities–edema (ARIA‐E) in both research and clinical settings. The 3‐ and 5‐point Severity Scales of ARIA‐E (SSAE‐3/‐5) have good inter‐ and intra‐reader agreement. The SSAE‐3/‐5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large‐scale use in routine clinical practice, which may help support the expansion of anti‐amyloid antibodies as treatment options for AD.

The accumulation of neurofibrillary tangles contributes to a neurodegenerative cascade toward Alzheimer’s disease, of which altered cerebral metabolism is also a feature. 18F-Flortaucipir PET allows visualization of tau pathology in vivo, while MRI-based arterial spin labeling techniques assess metabolism via cerebral blood flow. We sought to characterize the within-subject relationship between tau burden and cerebral blood flow throughout the brain. 130 ADNI3 subject visits with concurrent MRI ASL and flortaucipir PET scans were selected from the database (http://adni.loni.ucla.edu) for analysis. ADNI PET core PVC values referencing inferior cerebellar cortex were used to index SUVR across the entire FreeSurfer parcellation, and ADNI MRI core regional CBF values were identified from an overlapping set of 71 FreeSurfer regions. Linear partial correlation coefficients were calculated for tau PET SUVR and CBF in each brain region, controlling for age and amyloid PET SUVR. Lasso logistic regression returned penalized maximum-likelihood fitted coefficients for a generalized linear model estimating meta-temporal tau SUVR from regional CBF; regions with non-zero coefficients in the sparsest model are reported. Following correction for age and amyloid load, significant within-subject partial correlations between tau PET uptake and ASL CBF were observed throughout the brain. The associations were strongest in amyloid positive subjects with MCI or AD. Correlation strength was regionally specific and strongly positive (marginal p < 0.005) in subcortical and early Braak regions, while strongly negative (marginal p < 0.005) across frontal and later Braak regions. The strongest tau burden associations were observed with hypermetabolism in hippocampus (p = 0.0005, partial r = 0.59), and hypometabolism in posterior cingulate gyrus (p = 0.0001, partial r = -0.63). Lasso regression revealed a subset of non-zero coefficients in the sparsest model including subcortical, temporal, parietal and frontal brain regions. Tau PET uptake is associated with a pattern of hypermetabolism in early Braak stages, and hypometabolism in later Braak stages. This suggests a dynamic relationship where tau accumulation and cerebral blood flow alterations colocalize, but the direction of the effect is regionally specific.

ALZ-801 is an oral inhibitor of amyloid oligomer formation in development as a disease-modifying Alzheimer’s treatment, including a Phase 3 trial in APOE4/4 homozygotes and a Phase 2 biomarker study in APOE4 carriers. We analyzed correlations between brain volume and cognitive effects of ALZ-801 after 1 year in the Phase 2 study. We previously reported that at 1-year timepoint, plasma p-tau 181 (primary outcome) was significantly reduced by 41% from baseline, and hippocampal volume (HV) showed ∼20% less atrophy compared to external matched controls. The study is conducted at 7 European sites and enrolled 84 APOE4 carriers (MMSE 22-30) with positive amyloid/tau biomarkers who receive ALZ-801 265 mg BID for 104 weeks. Primary outcome is plasma p-tau 181 at 104 weeks, and primary imaging outcome is hippocampal volume (HV) atrophy. Volumetric vMRI measures (baseline, 52 and 104 weeks) are performed by Clario, and MMSE conducted. A PK sub-study was conducted at 65 weeks (n = 23) with bioanalysis at DDS (UK) and non-compartmental PK analyzed by WinNonlin. Pearson correlations of MMSE changes to BSI changes of HV and lateral ventricle volume (LVV) were conducted, with two-sided p-values reported. At 52 and 65 weeks, changes of MMSE from baseline showed significant correlations to HV (r = 0.32 and 0.34; p<0.01, n = 66) and LVV changes (r = -0.42 and -0.44; p<0.001, n = 65). Correlations between DMMSE and DLVV were significant for both genders (range r = -0.54 to -0.42, p<0.02); correlations were observed for DHV in females (range r = 0.39-0.47; p<0.05) and males (range r = 0.26-0.23; p<0.18, ns). PK/PD analysis in 23 subjects showed trends (r = 0.21-0.16, ns) between decreased HV atrophy/LVV expansion and plasma AUC 24h of tramiprosate+3-SPA (active and primary metabolite). ALZ-801 exhibited favorable safety; main treatment-related adverse event was mild nausea. No ARIA-E was observed. Early AD subjects treated with ALZ-801 for 65 weeks in the Phase 2 biomarker study showed strong correlations between MMSE stability, HV reduction, and decreased ventricular enlargement in overall group, and by genders. The significant correlations between cognitive and brain volume effects support the clinical benefits of ALZ-801 in APOE4 carriers with early AD. Oral ALZ-801 showed favorable safety and no brain edema/ARIA-E.