Clifford, David B.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

ABSTRACT Objective The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Methods Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post‐contrast gadolinium enhancement resolution at 6 months post‐treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow‐up. Results Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39–55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2–3) and 4 (IQR 2.5–6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A 1 ), 36 (17.8%) received corticosteroids < 4 weeks (B 1 ), 21 (10.4%) received corticosteroids plus sarcoidosis‐directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non‐sarcoidosis‐directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 1 27/106 (25.5%), B 1 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal–Wallis p = 0.69 and 0.63, respectively) after median follow‐up of 46.5 months (IQR 18–91.3). Interpretation Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P &amp;lt; .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P &amp;lt; .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

AbstractINTRODUCTIONIncreasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double‐blind phase 3 DIAN‐TU‐001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab.METHODSWe used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker.RESULTSLC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid‐no‐change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid‐reduction class exhibited reductions in the annual decline rates compared to the amyloid‐growth class across multiple biomarker, clinical, and cognitive outcomes.DISCUSSIONLC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials.Highlights We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid‐reduction class exhibited remarkably better outcomes compared to the amyloid‐growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

AbstractBackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β‐amyloid protein important in the pathogenesis of Alzheimer’s disease (AD). Three previous 18‐month double‐blind placebo‐controlled trials of low‐dose solanezumab in late‐onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly‐inherited mutation‐associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation‐carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 – 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double‐blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN‐MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale‐Revised, the Digit Symbol Substitution Test total score from the WAIS‐R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN‐MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β‐amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre‐specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti‐amyloid therapy in sporadic AD.