Citations

AbstractBackgroundStructural variants range from simple loss or gain of genetic material to complex events that restructure entire chromosomes. This heterogeneity coupled with variant size greater than sequencing read‐length makes structural variant mapping from short‐read sequencing data difficult and error‐prone. Consequently, the role of structural variants is poorly explored in many phenotypes, including dementia.MethodWe used the GATK‐SV pipeline that combines four external structural variant mapping algorithms with machine‐learning to build high‐quality consensus structural variant calls. We applied GATK‐SV to short‐read whole‐genome sequencing data of 2,601 frontotemporal dementia‐amyotrophic lateral sclerosis spectrum (FTD/ALS) patients, 2,612 Lewy body dementia (LBD) patients, and 4,132 neurologically unaffected participants.ResultAfter stringent quality‐control, we performed genome‐wide association studies on 2,307 ALS/FTD patients versus 3,677 controls with 4,699 common structural variants and 2,355 LBD patients versus 3,700 controls with 4,889 common structural variants. In the FTD/ALS cohort, we identified well‐known risk variants at the C9orf72 (p‐value = 4.99×10‐18, OR = 14.47, 95% CI = 7.90–26.49) and MAPT loci (p‐value = 3.48×10‐6, OR = 0.77, 95% CI = 0.68–0.86) corroborating the ability of our pipeline to identify disease‐associated structural variants. Moreover, we discovered, replicated, and validated TPCN1 as a novel risk locus for LBD (p‐value = 9.18×10‐6, OR = 1.43, 95% CI = 1.22–1.67). Further, we identified rare exonic variants with known pathogenic or likely pathogenic effects, such as an SNCA gene duplication in LBD and a deletion of exons 1 and 2 in CHCHD10 in FTD/ALS. We additionally observed structural variants in regulatory regions, e.g. a deletion of a key PSEN2 enhancer, which resulted in an approximate 0.70 fold‐change in PSEN2 expression in LBD. Finally, we built an interactive web app where structural variants can be visualized and explored (https://ndru-ndrs-lng-nih.shinyapps.io/non_ad_dementias_sv_app/).ConclusionCommon and rare structural variants play a role in LBD and FTD/ALS. Our structural variant resource is publicly available and can be used to further explore the role of structural variants in LBD and FTD/ALS.

ObjectiveTo determine the characteristics of participants with amyloid‐related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).Methods142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β‐amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross‐sectional and longitudinal analyses evaluated potential ARIA‐related risk factors.ResultsEleven participants developed ARIA‐E, including 3 with mild symptoms. No ARIA‐E was reported under solanezumab while gantenerumab was associated with ARIA‐E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE‐ɛ4 carriers were more likely to develop ARIA‐E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA‐E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA‐E occurrence, all ARIA‐E participants were amyloid‐PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA‐H. Most ARIA‐E radiologically resolved after dose adjustment and developing ARIA‐E did not significantly increase odds of trial discontinuation. ARIA‐E was more frequently observed in the occipital lobe (90%). ARIA‐E severity was associated with age at time of ARIA‐E.InterpretationIn DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA‐E risk, with additional risk for individuals APOE‐ɛ4(+) or with microhemorrhage. ARIA‐E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.MethodThe DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.ResultEleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p‐value<0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR>0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=[1.0,30.4], p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value<0.05), rate of change (rho=0.78, p‐value<0.01), and baseline PiB‐PET (rho=0.68, p‐value<0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.ConclusionIn DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.

AbstractBackgroundAlzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.

AbstractBackgroundGantenerumab is a humanized anti‐amyloid‐beta monoclonal antibody in clinical development for the treatment of several stages of Alzheimer disease (AD). Gantenerumab was evaluated in a phase 2/3 clinical trial program designed to evaluate its efficacy in autosomal dominant AD based on a combination of clinical and biomarker evidence.MethodThe study enrolled both mutation carriers (n=69 with 3:1 randomization of treatment (n=52) vs placebo (n=17)) and non‐carriers (n=28, all on placebo) from 15 years before to 10 years after the expected age of onset inclusive. Patients were both asymptomatic (CDR 0 and MMSE >25) and symptomatic (CDR 0.5‐1 and MMSE >16). There were 41 asymptomatic and 28 symptomatic mutation carriers. The initial dose of gantenerumab was 225 mg monthly administered subcutaneously. The dose was titrated to 1200 mg/month following a protocol amendment based on the increased amyloid lowering seen at higher doses in the gantenerumab program in symptomatic AD. The treatment duration was a minimum of 4 years (range 48‐80 months). The primary outcome was change from baseline in the DIAN‐TU multivariate cognitive endpoint. Secondary clinical outcomes included the DIAN‐TU cognitive composite, Cogstate multivariate cognitive endpoint, CDR SB, and time to CDR progression of >0.5 points. Change from baseline in amyloid PET was the primary biomarker outcome. Other biomarker outcomes included MRI, tau PET, CSF amyloid, tau and phosphotau, and CSF and plasma neurofilament light (NfL). Safety outcomes including ARIA were compared between drug and placebo groups.ResultWe will report change from baseline on the DIAN‐TU multivariate cognitive endpoint, DIAN‐TU cognitive composite, CDR‐SB and other secondary efficacy endpoints. We expect significant lowering on amyloid PET with PIB and florbetapir based on the results from recent anti‐amyloid antibodies, including Gantenerumab, in sporadic AD. We will also present the results of change in other key imaging and fluid biomarkers. The frequency, duration, and severity of ARIA will be reported and compared with studies in sporadic AD.ConclusionThis clinical trial was designed to inform future for ADAD and will provide new insights on the role of amyloid reduction in both pre‐symptomatic and clinical AD.

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.

Abstract The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Abstract Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir‐based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter‐individual variability of the two tracers were compared using multivariate linear models both cross‐sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.