Jack, Clifford R.

AbstractBackgroundDementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α‐synuclein aggregations, but many DLB cases show significant Alzheimer’s disease (AD) pathology in the form of β‐amyloid and tau. Our first objective was to investigate the effect of AD co‐pathology on functional network failure in DLB. Secondly, we studied how the distribution of tau relates to functional connectivity in DLB.MethodTwenty‐three DLB, 23 age‐ and sex‐matched AD, and 90 cognitively unimpaired (CU) participants underwent AV1451 tau‐PET, Pittsburgh compound‐B (PiB) PET, and resting state (rs)‐fMRI scans. The rs‐fMRI data were used to calculate the Network Failure Quotient (NFQ), a marker of functional network failure within the default mode network. The NFQ was then correlated with overall cortical tau standardized uptake value ratio (SUVr). The strength of inter‐regional functional connectivity was assessed using the Schaefer100 atlas. Tau‐PET covariance was measured as the correlation in AV1451 SUVr between any two regions across participants. The association between region‐to‐region functional connectivity and tau‐PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot‐ and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot‐ and coldspots.ResultOverall higher cortical tau‐PET uptake correlated with higher NFQ (i.e. greater functional network failure) in DLB who were PiB+ (N=14, ρ=0.60, p=0.02), but not in DLB who were PiB‐ (N=9, ρ=‐0.06, p=0.87). Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB, independent of PiB status. Higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher AV1451 SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory‐motor cortex) was related to lower AV1451 SUVr in the target region.ConclusionGreater tau burden in DLB patients with β‐amyloid co‐pathology is associated with an AD‐like functional network failure. As previously demonstrated within the AD spectrum, functional connectivity may contribute to the spreading of tau across the brain also in DLB.

AbstractBackgroundHearing impairment is associated with cognitive decline but whether it is a cause or marker is unknown. We investigated the association of hearing impairment with brain volumes and 8‐year cognitive decline. Because the superior temporal gyrus (STG) is the location of the primary auditory cortex, we stratified results by STG volume to investigate if the association of hearing and cognition differed among participants with and without evidence of possible hearing‐related brain atrophy.MethodWe used data from 1195 community‐dwelling adults (72‐94 years, 61% female, 36% black) from the Atherosclerosis Risk in Communities Study. A composite cognitive score was created from 10 neuropsychological tests administered at 3 study visits spanning 8 years (2011‐13 to 2018‐19). Brain volumes were calculated from structural magnetic resonance imaging scans for 6 regions of interest. Pure tone air conduction hearing thresholds (frequencies 0.5‐4 kHz) were obtained in 2016‐17 and averaged, with better‐ear hearing impairment defined as an average >25 dB. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes, adjusting for intracranial volume, demographic and clinical covariates. We estimated differences in annual rates of cognitive change by hearing impairment status adjusting for demographic and clinical covariates using linear mixed models; results were stratified by intracranial volume‐adjusted STG volume (below vs. equal to or greater than the median value).ResultThe mean STG volume difference comparing hearing impairment to normal hearing was ‐0.121 standard deviations (SD) (95% CI: ‐0.213, ‐0.028). Overall, the difference in the rate of cognitive decline associated with hearing impairment was ‐0.014 SD (‐0.023, ‐0.005). Hearing was more strongly associated with cognitive decline among participants with smaller STG volumes; rate difference, ‐0.014 SD (‐0.027, ‐0.002) compared to ‐0.008 (‐0.022, 0.006) for participants with larger STG volumes.ConclusionHearing impairment was associated with smaller brain volumes in the primary auditory region, but not with other regions. Our stratified analysis suggests that hearing treatment might be an important possible strategy to delay cognitive decline, even among participants with hearing‐related brain atrophy. Furthermore, the adverse cognitive effects of hearing impairment could potentially be mitigated if early hearing treatment can prevent STG atrophy.

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.

Background and purposeCerebral microbleeds (MB) and superficial siderosis (SS) are frequent neuroimaging findings in patients with logopenic progressive aphasia (LPA), often with frontal lobe predilection. Cerebral amyloid angiopathy (CAA) is hypothesized to be the major pathologic determinant of MB/SS in these patients; however, neuroimaging‐pathologic data are limited.MethodsAll patients who had been prospectively recruited by the Neurodegenerative Research Group at the Mayo Clinic (Rochester, MN) between 2010 and 2015 and met the following inclusion criteria were included: (i) received an antemortem LPA diagnosis, (ii) had a gradient‐recalled echo T2*‐weighted magnetic resonance imaging (MRI) performed, (iii) died and completed a brain autopsy. Demographic, genetic, neuroimaging, and clinical and pathologic characteristics were compared between patients with/without MB/SS. Two‐tailed Fisher exact and Wilcoxon rank sum tests were used for comparison of categorical and continuous variables, respectively.ResultsThirteen patients met inclusion criteria, six (46%) had MB/SS on MRI. Moderate/severe CAA was associated with the presence of MB/SS (p = 0.029). As expected, MB/SS most frequently involved the frontal lobes, followed by the parietal lobes. No clear associations were found between regional MB/SS distribution and regional distribution of CAA or hypometabolism on [18F]‐fluorodeoxyglucose–positron emission tomography. There was some evidence for a regional association between MB/SS and uptake on Pittsburgh compound B, although not in all patients. No formal statistical analyses to assess topographic relationships were performed due to the small sample size.ConclusionsThe presence of MB/SS is a strong indicator of underlying moderate/severe CAA in LPA, although the biological mechanisms underlying the topographic distribution of MB/SS remain unclear.

AbstractThe mechanisms through which tau and amyloid-beta (Aβ) accumulate in the brain of Alzheimer’s disease patients may differ but both are related to neuronal networks. We examined such mechanisms on neuroimaging in 58 participants with atypical Alzheimer’s disease (posterior cortical atrophy or logopenic progressive aphasia). Participants underwent Aβ-PET, longitudinal tau-PET, structural MRI and resting-state functional MRI, which was analyzed with graph theory. Regions with high levels of Aβ were more likely to be functional hubs, with a high number of functional connections important for resilience to cascading network failures. Regions with high levels of tau were more likely to have low clustering coefficients and degrees, suggesting a lack of trophic support or vulnerability to local network failures. Regions strongly functionally connected to the disease epicenters were more likely to have higher levels of tau and, less strongly, of Aβ. The regional rate of tau accumulation was associated with tau levels in functionally connected regions, in support of tau accumulation in a functional network. This study elucidates the relations of tau and Aβ to functional connectivity metrics in atypical Alzheimer’s disease, strengthening the hypothesis that the spread of the 2 proteins is driven by different biological mechanisms related to functional networks.