Citations

AbstractBackgroundPharmacoepidemiologic studies assessing drug effectiveness for Alzheimer’s disease and related dementias (ADRD) are increasingly popular given the critical need for effective therapies for ADRD. To meet the urgent need for robust dementia ascertainment from real‐world data, we aimed to develop a novel algorithm for identifying incident and prevalent dementia in claims.MethodWe developed algorithm candidates by different timing/frequency of dementia diagnosis/treatment to identify dementia from inpatient/outpatient/prescription claims for 6,515 and 3,997 participants from Visits 5 (2011‐2013; mean age 75.8 (SD 5.3) years) and 6 (2016‐2017; mean age 79.8 (SD 4.8) years) of the ARIC cohort with ≥ 1‐year continuous Medicare Part A & B enrollment prior to each visit. We evaluated algorithm performance (sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV)) against the gold standard of the ARIC dementia classification based on an extensive battery of neurocognitive tests administered at each visit. We compared performance of the new algorithm with that of three existing algorithms (Jain, Bynum, Lee) and their relaxed forms (4‐year window, dementia diagnosis plus a depression diagnosis or dementia evaluation procedure, ignoring code position) to identify incident (n = 90 at V6) and prevalent dementia (n = 190 at V5; n = 160 at V6).ResultThe newly developed primary algorithm requires presence of a dementia diagnosis code followed by another diagnosis code within 1 year (under condition that the following non‐specific ICD‐9 diagnostic codes, 290.40, 290.41, 290.11, 290.3, should appear no more than once), or a subsequent dementia treatment prescription within 90 days (requiring Medicare Part D enrollment ≥ 6 months). The PPV of the new algorithm in the identification of incident dementia was PPV of 72.7%, with a specificity of 99.1%, outperforming existing algorithms. Its sensitivity of 38.7% and NPV of 96.2% were comparable to those achieved by existing algorithms. Sensitivity analysis restricting to ICD‐10 diagnostic codes increased the PPV and attenuated its sensitivity by 6%. Similar comparative performance was observed in the identification of prevalent dementia.ConclusionA novel algorithm for identifying dementia from Medicare claims, developed using linked ARIC‐Medicare data, outperforms previous algorithms and stands as a valuable tool in the assessment of ADRD drugs from real‐world data.

AbstractBackgroundAlzheimer’s disease (AD) is an age‐dependent neurodegenerative disorder with limited treatment options. As it progresses, synapse degeneration is the most important feature contributing to cognitive dysfunction. Mitochondria supply synapses with ATP for neurotransmitter release and vesicle recycling and buffer calcium concentrations. In AD, mitochondrial function is disrupted leading to energetic stress and synapse degeneration. We have identified a novel therapeutic strategy that blocks neurodegeneration and protects cognitive function in multiple mouse models of AD (amyloid and tau pathologies) via mild pharmacological inhibition of mitochondria complex I, which results in the activation of adaptive stress response and subsequent improvement of mitochondrial function.MethodAnalysis of mitochondrial morphology and synaptic density was done in the hippocampal CA1 tissue from APP/PS1 and non‐transgenic (NTG) mice treated with vehicle or mild complex I inhibitor CP2 for 14 months starting after the development of cognitive dysfunction and neurodegeneration. A serial block‐face scanning electron microscopy (SBF‐SEM) and three‐dimensional (3D) EM reconstructions were employed to determine the synaptic density and mitochondrial morphology and distribution associated with different dendritic spine types.ResultWe demonstrate that APP/PS1 mice have significantly reduced synaptic density in the hippocampus compared to the NTG littermates. CP2 treatment restores synaptic density to the levels observed in NTG mice evident by the increase in the number of synaptic densities visible in the electron micrographs. Mitochondrial morphology and association with synapses are currently being investigated.ConclusionOur data are consistent with previously conducted electrophysiology recording in acute brain slices from APP/PS1 and NTG mice treated with vehicle or CP2, demonstrating restoration of long‐term potentiation (LTP) after chronic CP2 treatment. Additionally, it suggests that 3D EM‐based assessment of synaptic density could serve as a surrogate marker for LTP and cognitive function useful for drug discovery.

AbstractRecent breakthrough findings in clinical trials on amyloid‐lowering therapies have led to the approval of these drugs for the treatment of amyloid‐ positive elderly individuals who show symptoms of mild cognitive impairment and mild dementia. The next frontier is the testing the efficacy of treatments for secondary prevention of AD dementia. Phase III trials in asymptomatic AD are already under way, raising a host of novel questions on the sequelae of trial participation such as the emotional and social repercussions of biomarker disclosure, understanding the risk of side effects and eventually weighing the risk‐benefit ratio of amyloid‐lowering treatment. In this session jointly organized by the Neuroimaging and Partnering with Research Participants PIAs, I will focus on the participants’ perspective on the role of imaging in outcomes and safety monitoring of preclinical interventional studies. I will outline the importance of a partnership between the study team and participants in the design and conduct of study procedures to ensure that they are both efficient and ethical.

AbstractBackgroundWe identified small molecule tricyclic pyrone compound CP2 as a mild mitochondrial complex I (MCI) inhibitor that induces neuroprotection in multiple mouse models of AD. One of the major concerns while targeting mitochondria is the production of reactive oxygen species (ROS). CP2 consists of two diastereoisomers, D1 and D2, with distinct activity and toxicity profiles. This study was designed to understand how structure of D1 and D2 affects their binding to MCI and the consequential impact on ROS production.MethodThe X‐ray crystallography and cryo‐electron microscopy (cryo‐EM) at global resolution of 3.25‐3.27Å were employed to identify the molecular structure of D1 and D2 and the D1 binding to the isolated ovine MCI. The assessment of the MCI inhibition and the extent of ROS generation were done in isolated MCI and human neuroblastoma MC65 cells using flow cytometry, a Seahorse extracellular flux analyzer, and the kinetic studies.ResultIn the closed conformation of MCI, D1 selectively binds to the deep Quinone‐site (Qd) but not to the shallow Q‐site (Qs), sharing the same binding pocket as rotenone. In the open MCI state, D1 exclusively binds to the Qs in contrast to rotenone, which binds Qd and Qs in both closed and open states. At the same concentrations, D1 inhibits respiration to a greater extent compared to D2 (5:1 ratio) and produces higher level of ROS.ConclusionCryo‐EM unambiguously identified binding of D1 to both the Qd and Qs sites, contingent upon the conformational state of MCI. In contrast to rotenone, D1 binds Qd only in the closed conformation during catalytic cycle, leading to mild inhibition. Superimposing X‐ray crystallography data of D1 and D2 onto cryo‐EM data suggests that the orientation of the methyl group in D2 induces a flatter conformation, resulting in lower binding affinity to MCI, which correlates with lower inhibition and toxicity compared to D1. At physiologically relevant concentrations, CP2 (D1:D2 = 1:1) demonstrates low MCI inhibition yielding negligible ROS levels. This observation provides new insight into the absence of toxicity associated with CP2 treatment in vivo, further highlighting feasibility for the development of safe and efficacious MCI inhibitors.

AbstractBackgroundAnti‐amyloid immunotherapies modestly slow disease progression in early symptomatic AD; addition of other therapeutic modalities may be necessary to achieve larger treatment effects. Therapies that directly target tau can potentially produce substantial clinical benefit because the accumulation of insoluble tau protein is strongly correlated with the progression of AD. Which tau therapies are likely to be efficacious, whether or not to combine them with anti‐amyloid therapies, and which individuals are most likely to benefit are important unresolved questions that would require multiple parallel design trials to answer. Platform (umbrella) trials test multiple therapies in the same trial, allowing for substantial savings in time, cost and participant burden.MethodATP is a new NIH‐funded Phase 2 clinical trial platform that will be conducted as part of the AD Clinical Trials Consortium (ACTC) in partnership with industry and philanthropic groups. The goal is to investigate the effects of tau therapies on the biological hallmarks of AD including insoluble and soluble tau species, amyloid and other biomarkers of neurodegeneration. ATP will initially evaluate two tau therapies alone or in combination with an anti‐amyloid therapy. 900 participants with late preclinical or early prodromal AD (CDR 0 or 0.5) will be randomized to six arms for two years of blinded treatment, followed by an optional open label extension (Figure 1). At least 20 percent of participants will be from underrepresented groups. The primary endpoint is 18F MK6240 tau PET, with key secondary endpoints including plasma P‐tau and MTBR243‐tau, amyloid PET and clinical assessments (CDR‐SB, PACC5). Inclusion criteria are based on plasma P‐tau217, clinical status and regional 18F MK6240 uptake.ResultTwo tau therapies and an anti‐amyloid therapy have been chosen for inclusion in ATP and startup is underway. The final design, choice of therapies and design as well as plans for inclusion of additional tau therapies after the trial begins and other details will be presented.ConclusionThe ATP is a six arm factorial design platform trial that is planned to begin in late 2024 or early 2025 that will support efficient development of tau and combination therapies for early, sporadic AD.

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of age‐related dementia, and the presence of amyloid‐β (Aβ) plaques and tau‐containing neurofibrillary tangles is associated with the neurodegeneration and cognitive impairment in this incurable disease. Growing evidence shows that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in AD, and HDACs have been highlighted as a novel class of anti‐Alzheimer targets. Moreover, restoring Wnt/β‐catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy for AD. CI‐994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI‐994 can cross the blood‐brain barrier and is a cognitive enhancer.MethodWe evaluated the therapeutic potential of CI‐994 in human patient‐specific iPSC‐derived neurons and cerebral organoids with APOE ε4/ε4 genotype or carrying MAPT p.P301L mutation.ResultWe found that CI‐994 is not only a potent class I HDAC inhibitor but also a novel modulator of Wnt/β‐catenin signaling, and that activation of Wnt/β‐catenin signaling by CI‐994 is associated with elevated Wnt co‐receptor LRP6 protein level. Moreover, CI‐994 increased synaptic protein levels, enhanced spontaneous synaptic firing and network formation, and decreased tau phosphorylation in iPSC‐derived neurons. Finally, CI‐994 significantly increased histone acetylation, activated Wnt/β‐catenin signaling, and decreased Aβ production and tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids.ConclusionOur findings indicate that CI‐994 is a novel potential therapeutic candidate for AD.

AbstractBackgroundThe earliest cognitive manifestations of asymptomatic and prodromal familial frontotemporal dementia (f‐FTD) mutation carriers are still being characterized. Patients with symptomatic FTD are known to be error prone, particularly on tasks of executive function, but little is known about the frequency or predictive utility of these errors in the earliest stages of f‐FTD. The current study compared error rates on executive functioning tasks in controls and asymptomatic and prodromal mutation carriers and investigated whether errors predict worsening clinical status as follow up.MethodThis study included 90 participants (mean age = 48.57, SD = 13.30; 51.1% female; 86.67% white) with pathogenic FTD mutations (C9orf72, n = 45; GRN, n = 30; or MAPT, n = 15) who were asymptomatic or prodromal (Clinical Dementia Rating plus FTLD; CDR®+NACC‐FTLD ≤ 0.5). Propensity score matching identified (CDR®+NACC‐FTLD = 0) who did not carry pathogenic mutation but were matched on age, education, and sex. Regressions were used to compare controls and mutation carriers on error scores (rule violations and/or repetitions) from three executive functioning tasks: design fluency, lexical fluency, and Stroop inhibition. Mutation carriers with longitudinal data within 1.5 years were binarized as stable (n = 35) or progressors (n = 13) based on whether their CDR®+NACC‐FTLD sum of boxes score was worse at follow up (mean follow up = 1.07 years). Regressions were fit to evaluate the relationship between baseline error scores and group (i.e., stable vs. progressor).ResultMutation carriers committed significantly more errors than controls on the Stroop task (β = 0.67, p = 0.03) and lexical fluency (repetitions: β = 0.27, p = 0.02). The groups did not significantly differ in errors on the remaining tasks. A greater number of Stroop errors predicted mutation carriers who progressed at follow up (β = 1.04, p<0.001). When introducing the primary outcome from each task as a covariate (e.g., correct responses), the fluency task (repetitions: β = 0.10, p = 0.03) and Stroop task (errors: β = 0.82, p<0.001) were significantly associated with progression.ConclusionErrors on executive tasks may be early cognitive features in familial FTD. Importantly, errors were uniquely predictive above and beyond total scores. Research in larger samples will enable investigations of genetic differences in error rates.

AbstractBackgroundThe Progressive Supranuclear Palsy Quality of Life (PSP‐QoL) scale is a 45‐question participant‐completed questionnaire used to evaluate physical and cognitive task difficulties. Participants enrolled in the ALLFTD research program are asked to complete this questionnaire annually during their study visits.MethodPSP‐QoL responses were analyzed at baseline visits. Our analysis focused on responses to the overall satisfaction of life (range 0‐100, with 0 being extremely dissatisfied and 100 being extremely satisfied) relative to disease severity (CDR®+NACC‐FTLD global scores) and as a function of clinical phenotypes. A Kruskal‐Wallis test was used to compare overall satisfaction ratings against CDR®+NACC‐FTLD global score.Result788 PSP‐QoL survey responses were analyzed (participant mean age 55.3 ±15 years, 50.5% female). Analysis included responses from 372 (47.2%) asymptomatic participants (CN; CDR®+NACC‐FTLD = 0), 140 prodromal (17.8%) CDR®+NACC‐FTLD = 0.5, 160 (20.3%) CDR®+NACC‐FTLD = 1, 106 (13.5%) CDR®+NACC‐FTLD 2, and 10 (1.3%) CDR®+NACC‐FTLD = 3. All symptomatic groups were similar in PSP‐QOL overall satisfaction of life rating: (mean overall satisfaction CDR®+NACC‐FTLD = 0.5: 74.5 (SD 22.5); CDR®+NACC‐FTLD = 1: 74.1 (SD 24.7) and CDR®+NACC‐FTLD = 2/3: 74.1 (SD 25.8)), but these differed from asymptomatic (cognitively normal): (mean 83.7, (SD 14.6); p<0.0001). Similarly, when including the CN group and symptomatic phenotype groups, a statistically significant difference in ratings was seen: mean overall satisfaction CN = 83.7 (SD 14.7), MCI = 78.3 (SD 16.6), PPA = 71.6 (SD 26.9), PSP = 66.3 (SD 28.2), bvFTD = 76.8 (SD 23.8), and other = 70.6 (SD 23.2). However, even after removing the CN group, a difference amongst symptomatic phenotypes remained (p = 0.036).ConclusionMean overall life satisfaction as measured by the PSP QoL questionnaire was lower in all symptomatic compared to clinically normal participants, regardless of disease severity or phenotype. Further longitudinal analyses are needed to better understand how clinical progression impacts overall satisfaction of life.

AbstractBackgroundMany treatments targeting frontotemporal lobar degeneration (FTLD) are in the developmental pipeline, but the rarity of the disease, coupled with the behavioral and motor features of FTLD, make it challenging to identify sufficient trial participants who can attend frequent in‐person visits. Decentralized clinical trial designs with remote evaluations are attractive alternatives but require validated tools for symptom tracking. Our previous cross‐sectional analyses showed that cognitive tasks deployed via the ALLFTD Mobile App are reliable and sensitive to early stages of disease. The current study seeks to evaluate whether unsupervised smartphone cognitive tests are sensitive to longitudinal changes that occur with increasing FTLD disease stage.MethodThe study included 194 participants (mean baseline age 54.30, SD = 15.66; mean education = 16.52, SD = 2.31; 55.2% women) who were asymptomatic (Clinical Dementia Rating plus FTLD (CDR®+NACC‐FTLD) = 0 [n = 109; 43 carriers of FTLD‐associated genetic variants]), prodromal (CDR®+NACC‐FTLD = 0.5 [n = 39]), or symptomatic (CDR®+NACC‐FTLD>0.5 [n = 46]) at baseline. Participants completed ALLFTD Mobile App smartphone versions of Stroop, flanker, and 2‐back tasks, as well as an adaptive associative memory task, every six months for up to two years. Linear‐mixed effects models investigated the effect of disease severity on cognitive trajectories by testing the interaction of baseline CDR®+NACC‐FTLD box score and time on smartphone test scores. Analyses were repeated in the subsample of asymptomatic/prodromal CDR®+NACC‐FTLD<1) familial FTLD mutation carriers (C9orf72, n = 27; MAPT, n = 16). All models controlled for age, education, and sex.ResultGreater baseline disease severity was associated with lower cognitive scores across all tasks (β range: ‐0.28 to ‐0.13; p’s < 0.001), and faster rates of decline on the memory and 2‐back tasks (β range: ‐0.15 to ‐0.07; p’s<0.04). When the sample was restricted to asymptomatic and prodromal individuals (CDR®+NACC FTLD<1), greater baseline disease severity was still associated with lower scores across most tasks (β range: ‐0.48 to ‐0.27; p’s<0.002; 2‐back: β = ‐0.19, p = 0.26). When the sample was restricted to asymptomatic/prodromal mutation carriers, disease severity remained associated with the memory and flanker tasks (β range: ‐0.85 to ‐0.45; p’s<0.01).ConclusionThis study provides initial evidence that longitudinal smartphone‐based cognitive measurements capture the accelerated cognitive worsening that accompanies increasing disease progression in FTLD.

AbstractBackgroundFrontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive changes to behavior, personality, language, and movement with onset typically before age 60. Currently, several potential FTD therapies are under investigation, underscoring the need for increased diversity in research participation. Two validated scores describe socioeconomic and geographic factors that may impact willingness to participate in research. The Area Deprivation Index (ADI) assesses socioeconomic disadvantages and captures social determinants of health. The Rural‐Urban Commuting Area Codes (RUCA) measures population density, urbanization, and daily commuting to determine individuals living in urban versus rural communities. FTDDR is a compliant, web‐based registry to facilitate FTD research. ADI and RUCA analyses of FTDDR participants can provide insight into current participants’ demographics and areas for recruitment prioritization.MethodFTDDR participants living in the United States were divided into two cohorts: (1‐FTDDR) enrolled in FTDDR only and (2‐ALLFTD) enrolled in FTDDR through ALLFTD, a longitudinal natural history study. ADI was calculated from self‐reported zip codes for 1392 participants in cohort 1 and 983 participants in cohort 2. RUCA scores were generated using self‐reported zip codes for 4565 participants from cohort 1 and 1174 participants from cohort 2.ResultADI analysis showed a low percentage (6.9% FTDDR, 5.7% ALLFTD) of participants lived in highly disadvantageous communities. 40.5% of FTDDR cohort and 49.3% of ALLFTD cohort lived in communities considered “low disadvantage,” suggesting they may have fewer socioeconomic risk factors or impediments to research participation. Most participants in both cohorts lived in urban areas (87.9% FTDDR, 85.8% ALLFD); only 3.2% of both cohorts lived in rural communities.ConclusionSocioeconomic and geographic factors may play a role in accurate diagnosis, access to medical centers, and ability to participate in research. ADI and RUCA analyses indicate that the majority of FTDDR participants, including those actively enrolled in FTD research, live in less disadvantageous neighborhoods and in urban areas, highlighting the need for outreach to more disadvantaged and rural communities. FTDDR prioritizing an engagement strategy to identify, recruit, and retain diverse individuals willing to participate in research could accelerate advancements in FTD research.