Knopman, David S.

AbstractBackgroundPhysical and cognitive activities are associated with decreased risk of mild cognitive impairment and dementia. However, the longitudinal associations between physical and cognitive activities with trajectories of Alzheimer’s disease (AD) neuroimaging biomarkers among older adults free of dementia remain unclear.MethodWe conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants had information on physical and cognitive activity engagement in midlife (ages 30‐45 for participants aged 50‐69; ages 50‐65 for participants aged ≥ 70) and late‐life (12 months prior to baseline assessment), and AD biomarker assessments. We calculated linear mixed‐effect models to examine the association between baseline physical and cognitive activity composite scores for mid‐ and late‐life, and trajectories for individual yearly change in amyloid deposition (measured by PiB‐PET), tau burden (measured by Tau‐PET), regional glucose hypometabolism (measured by FDG‐PET), cortical thickness (measured by MRI), and white matter hyper intensities (WMH, measured by FLAIR‐MRI). The models were adjusted for age, sex, and APOE ɛ4 carrier status.ResultThe sample included 2755 persons (52% males; 2462 cognitively unimpaired, 293 with MCI). The mean [SD] age was 72.7 [9.8] years; 774 participants were APOE ɛ4 carriers. Although, overall, participants showed an increase in amyloid deposition, tau burden, WMH, and a decrease in glucose metabolism and cortical thickness over time, those with higher late‐life physical activity experienced less pronounced increase in Tau‐PET SUVR over time [estimate for late‐life physical activity with time interaction: ‐0.002; 95% CI ‐0.004, ‐0.000; p = 0.034]. In addition, participants with higher cognitive activities in midlife [est. for midlife cognitive activity with time interaction: 0.001; 95% CI 0.000, 0.003; p = 0.026] and late‐life [est. for late‐life cognitive activity with time interaction 0.002; 95% CI 0.001, 0.003; p = 0.005] had less pronounced decrease in FDG‐PET SUVR over time. There were no further significant interactions.ConclusionPreliminary findings suggest significant associations between 1) late‐life physical activity and less tauopathy, and 2) cognitive activities in mid‐ and late‐life with less synaptic dysfunction over time. Further research is needed to validate study findings.

AbstractBackgroundTAR DNA‐binding protein 43 (TDP‐43) mislocalization is present in over 50% of patients with frontotemporal dementia and about 20% of patients with Alzheimer’s disease, but there is still an unmet need for clinical trials targeting sporadic TDP‐43 pathology in patients with dementia. The semantic variant of primary progressive aphasia (svPPA) is highly predictive of frontotemporal lobar degeneration with TDP‐43 mislocalization (FTLD‐TDP) and presents an ideal cohort in which to explore therapeutics with potential benefit across the spectrum of TDP‐43 pathology. Oxidative stress promotes mislocalization of TDP‐43 in neurons and may be a viable therapeutic target in svPPA and other FTLD‐TDP disorders. Verdiperstat is a potent, oral, CNS penetrant, myeloperoxidase inhibitor that reduces production of oxidative species from microglia. The Veri‐T trial (NCT05184569) explores the therapeutic potential of verdiperstat and is the first clinical trial to focus on patients suffering from svPPA.MethodsVeri‐T is a multisite, phase 1, randomized, double‐blind, placebo‐controlled trial. N = 64 participants with svPPA will be randomized 3:1 to oral verdiperstat (titrated to a dose of 600mg BID) or placebo for 6 months of double‐blind therapy. Neuropsychological assessments, plasma, CSF, and volumetric brain imaging are collected prior to and upon conclusion of treatment. Recruitment is ongoing at 5 ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) research network clinical centers.ResultsThe primary objective is to determine the safety and tolerability of verdiperstat in svPPA. The secondary objective is to determine the pharmacokinetic profile of verdiperstat in this cohort. Exploratory endpoints are focused on identifying potential pharmacodynamic effects and identifying endpoints for future efficacy trials including plasma myeloperoxidase activity, CSF biomarkers of glial activity (chitinase‐family proteins), neurodegeneration (neurofilament light chain), and unbiased CSF proteomics (Somalogics), as well volumetric MRI changes unique to svPPA, and cognitive and language impairments measured using the ALLFTD Mobile App.ConclusionThe Veri‐T trial examines the safety, tolerability and pharmacokinetic properties of verdiperstat in svPPA, and explores novel pharmacodynamic biomarkers and outcome measures that could be employed in future efficacy studies. Veri‐T is the first multicenter clinical trial of a potentially disease modifying agent for svPPA, and the first to leverage resources of the ALLFTD network.

AbstractBackgroundSeveral hypotheses exist regarding the neurologic substrate underlying visual hallucinations (VH) in Dementia with Lewy Bodies (DLB). Studies have suggested an association with regional cerebral hypometabolism in the primary visual or visual association cortices on FDG‐PET. We compared regional cerebral glucose metabolism and posterior cingulate island sign (CIS) ratios in DLB and in Mild Cognitive Impairment with Lewy Bodies (MCI‐LB) participants with (VH+) and without (VH‐) VH.MethodParticipants with clinically probable DLB or MCI‐LB and an FDG‐PET scan were identified from the Mayo ADRC database. Responses on the Visual Hallucinations and Delusions Questionnaire and Neuropsychiatric Inventory were used to assess presence or absence of VH. Standardized uptake value ratios (SUVr) were used to calculate regional cerebral glucose hypometabolism in the primary visual cortex (PVC), lateral occipital cortex (LOC), and whole occipital cortex (WOC). The CIS ratio was defined as posterior cingulate divided by the sum of the precuneus plus cuneus FDG‐PET uptake ratio.ResultTwo cohorts were identified (27 DLB and 18 MCI‐LB, 87% male). Eighteen DLB participants were VH+ and 9 were VH‐, whereas 5 MCI‐LB were VH+ and 13 were VH‐. There were no statistically significant differences in demographic (age, sex, education) and clinical features (MoCA, CDR, presence of other core DLB features, and UPDRS) between VH+ vs VH‐ in those with DLB, and between VH+ vs VH‐ in those with MCI‐LB. Similarly, there were no statistically significant differences in DLB between VH+ vs VH‐ in PVC (1.55±0.14 vs 1.58±0.15), LOC (1.22±0.16 vs 1.28±0.12), WOC (1.29±0.15 vs 1.34±0.11), or CIS ratio (1.16±0.08 vs 1.14±0.10), nor in MCI‐LB between VH+ vs VH‐ in PVC (1.68±0.19 vs 1.58±0.14), LOC (1.40±0.21 vs 1.32±0.14), WOC (1.45±0.20 vs 1.37±0.14), or CIS ratio (1.17±0.08 vs 1.19±0.10) (P>0.05 for all comparisons).ConclusionThese findings do not support a direct correlation between regional cerebral glucose metabolism and VH in DLB or MCI‐LB. Further work in DLB and MCI‐LB with larger numbers is warranted. Other neurologic substrates and mechanisms, such as REM sleep intrusions during wakefulness, neurotransmitter dysfunction, and disruption of functional connectivity across brain regions should be explored as contributors to VH in DLB.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.

AbstractBackgroundThe three most common genes responsible for the familial Frontotemporal Lobar Degeneration (f‐FTLD) are MAPT, GRN, and C9orf72, with the C9orf72 mutation being the most common cause of f‐FTLD. The ALLFTD Consortium targets to characterize f‐FTLD, including its preclinical stage, to prepare for clinical trials in FTLD. We sought to investigate the initial symptoms and clinical picture of f‐FTLD and compare them among the common pathogenic genes using longitudinal CDR® plus NACC FTLD.MethodWe longitudinally assessed the CDR® plus NACC FTLD among 292 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD caused by MAPT (n = 99), GRN (n = 67), or C9orf72 (n = 126) mutations, and described the detailed profiles of the CDR® plus NACC FTLD in the participants who developed Mild Behavioral and/or Cognitive Impairment (MBCI).ResultForty‐one participants (17 MAPT, 11 GRN, 13 C9orf72) developed MBCI during follow‐up visits . Age at the diagnosis of MBCI was 52.3±13.0 years (GRN 63.2±11.8, MAPT 43.5±8.6, C9orf72 54.7±10.7). Frequencies of abnormal rating on the eight CDR® plus NACC FTLD domains at the time of MBCI diagnosis were: “Memory” 44% (MAPT 47%, GRN 55%, C9orf72 31%); “Orientation” 7% (MAPT 6%, GRN 9%, C9orf72 8%); “Judgment and Problem Solving” 39% (MAPT 41%, GRN 55%, C9orf72 23%); “Community Affairs” 22% (MAPT 24%, GRN 18%, C9orf72 23%); “Home and Hobbies” 22% (MAPT 35%, GRN 0%, C9orf72 23%); “Personal Care” 0%; “Behavior/Comportment/Personality” 51% (MAPT 59%, GRN 55%, C9orf72 38%); “Language” 29% (MAPT 18%, GRN 55%, C9orf72 23%).ConclusionInitial symptoms and clinical picture of f‐FTLD in MBCI stage differ among responsible FTLD genes, which could be useful in detecting very early features of f‐FTLD in pathogenic mutation carriers.

AbstractBackgroundRemote assessment tools offer significant promise for aiding early detection of cognitive impairment. Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). We examined the diagnostic accuracy of the SLS and a MTD composite (SLS max span, SLS trials 1–5 total correct, SLS delay correct, [Symbols correct item response time*‐1]) for amnestic mild cognitive impairment (aMCI). We also explored diagnostic accuracy for a broader group that included individuals with possible MCI (pMCI; see Figure 1).MethodsParticipants were recruited from the Mayo Clinic Study of Aging for this ancillary remote study. 226 were cognitively unimpaired (CU; concordant CU diagnosis by 3 independent raters). Fifty‐six participants had possible MCI (at least 1 of 3 raters indicated MCI) and 16 had a consensus diagnosis of aMCI. Primary outcome variables were SLS sum of trials, AVLT sum of trials, Symbols correct items response time, and MTD composite. Mean difference analyses used linear model ANOVAs (alpha = .05). Receiver operating characteristic (ROC) curves were applied; we derived optimal cutoff scores based on the Youden index method.ResultsBoth aMCI and possible MCI groups showed significantly lower performance than the CU group on SLS (Hedge’s g aMCI = ‐1.72, pMCI = ‐1.04), Symbols (Hedge’s g aMCI = 1.38, pMCI = 0.64), and MTD composite (Hedge’s g aMCI = ‐1.89, pMCI = ‐1.09); see Tables 1 and 2 (all p‘s<.01 even when additionally covarying age, education, sex). Total area under the curve was high for differentiating of CU vs. aMCI (MTD Composite = 0.91, SLS = 0.91) and acceptable for CU vs. pMCI (MTD Composite = 0.77, SLS = 0.77); see Table 2. Consistent with our flexible platform, a variety of device types were used to complete remote testing (32% smartphone, 12% tablet, 56% PC).ConclusionsMTD and the SLS show high diagnostic accuracy for aMCI. MTD is a flexible, brief, and easy‐to‐use remote cognitive assessment tool with great potential for scalable use in future studies seeking to maximize inclusion of individuals with aMCI in clinical trials or for cognitive screening in clinical settings.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.Methods248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50–69, 70–79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).ResultsSession completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p = .69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).ConclusionsThough the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.

AbstractBackgroundSlow walking speed is associated with numerous negative health outcomes including global cognitive decline.1 More detailed gait analysis can differentiate among different dementia subtypes,10 but the predictive power of baseline gait metrics for domain‐specific cognitive decline needs further characterization.MethodWe conducted a follow up study on 534 participants of the Mayo Clinic Study of Aging who underwent evaluations every 15 months (median follow‐up = 5.4 years). We analyzed quantitative gait metrics, acquired with a pressure‐sensing walkway (GAITRite® instrument), and cognitive scores using a linear mixed effects model to identify correlations between z‐scored baseline gait metrics (cadence, swing time, stance time, velocity, double support time (DST), stride length, stride length standard deviation (SD), stride time SD, swing time SD, stance time SD, DST SD) and cognitive domain z‐scores (memory, attention, language, visuospatial, global) at baseline and over time. Models controlled for age, sex, and probable REM sleep behavior disorder at baseline.ResultThe table includes both baseline associations and difference in slopes (Δ), relative to the average person, in cognitive domains. These slopes ranged from about ‐0.05 for visuospatial to ‐0.12 for attention.ConclusionIncreased gait velocity and stride length are associated with less severe domain‐specific and global cognitive decline while increased swing time SD and DST are associated with more severe rates of decline in some domains. These findings suggest that baseline gait characteristics could be a helpful predictor of future cognitive changes.References:1. Savica R, Wennberg AMV, Hagen C, et al. Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. Journal of Alzheimer's disease : JAD. 2017;55(2):559. doi:10.3233/JAD‐1606972. Mc Ardle R, del Din S, Galna B, Thomas A, Rochester L. Differentiating dementia disease subtypes with gait analysis: feasibility of wearable sensors? Gait & Posture. 2020;76:372–376. doi:10.1016/j.gaitpost.2019.12.028

AbstractBackgroundWe previously demonstrated that Alzheimer’s disease (AD) patients ≥70 y/o tend to have smaller medial temporal volumes in the presence of relatively less medial temporal 18F‐flortaucipir‐PET uptake compared to young AD patients. TAR DNA‐binding protein 43 (TDP‐43) is frequently found in the brains of AD patients and is associated with old age and medial temporal atrophy. In this study, we aimed to determine whether TDP‐43 could be contributing to the mismatch between medial temporal volumes and flortaucipir‐PET uptake in older AD patients.MethodWe identified 77 participants (median age at death 79 years [range: 51‐99]) who had been enrolled into the Mayo Clinic Alzheimer’s Disease Research Center or Neurodegenerative Research Group (NRG), had undergone flortaucipir‐PET and volumetric MRI scans close to death, and autopsy confirmed AD neuropathological changes, as well as TDP‐43 assessments. Grey matter volumes and flortaucipir standard uptake value ratios (SUVRs) were calculated for hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. We used bivariate‐response linear regression modelling, adjusting for Braak neurofibrillary tangle stage, to estimate the effect of TDP‐43 and age on gray matter volume and flortaucipir uptake, and tested whether TDP‐43 effect sizes varied according to age.ResultAfter accounting for Braak stage, older individuals tended to have significantly lower flortaucipir uptake across regions and lower hippocampal and entorhinal cortex (ERC) volumes. TDP‐43 was associated with reduced hippocampus and ERC volumes but was unrelated to flortaucipir SUVRs (Figure 1). Notably, the TDP‐43 effect size for the hippocampus and ERC was largely consistent across age, i.e., at any age, TDP‐43‐positive participants had significantly smaller hippocampal (∼12% decrease) and ERC (13% decrease) volumes than TDP‐43‐negative participants. However, at older ages, the mean volumes in the whole cohort and, more evidently, in those with dementia moved closer towards the mean of those with TDP‐43 (Figure 1), likely attributable to the increasing frequency of TDP‐43 with age.ConclusionTDP‐43 is a major contributor to the mismatch between flortaucipir uptake and medial temporal lobe volumes in older AD patients where lower medial temporal regional volumes are observed in the presence of less flortaucipir uptake.

AbstractBackgroundTDP‐43 is a nuclear RNA‐binding protein involved in various neurodegenerative diseases, including Alzheimer’s Disease (AD), and normal aging. It strongly affects cognition and memory loss in AD. Concomitant TDP‐43 pathology increases the likelihood of being cognitively impaired at death.MethodMayo Clinic has amassed a large database with 1072 study participants with known TDP‐43 pathology status, who were prospectively recruited and followed in the Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Group. All underwent neurologic, genetic, and neuropathologic evaluations. Amygdala sections immunostained with antibodies against TDP‐43 were screened for TDP‐43‐immunoreactive inclusions and successively staged using the Josephs staging scheme. The frequency of TDP‐43 pathology by age at death was estimated using logistic regression with age modelled using a restricted cubic spline. Models were fit for all cases including the subset of 581 cases with dementia.ResultOur cohort was predominantly White (99%) with median age at death of 87 years (IQR: 80‐92) and relatively even sex distribution (52% female). About 55% had Braak stage V‐VI and 61% had Thal amyloid phase ≥3. Fifty‐two percent met criteria for intermediate‐high probability AD. TDP‐43‐immunoreactivity (TDP‐43+) was detected in 44% with median TDP‐43 stage of 3 (IQR: 1‐5), and in 54% with a median stage of 3 (IQR: 2‐5) in those with dementia. TDP‐43+ frequency increased approximately linearly with age at death. At 70 years at death, an estimated 30% (95% CI: 25–35) of the cohort was TDP‐43+ versus 33% (CI: 27–40) of those with dementia. By 90 years at death, 49% (CI: 45–52) of the overall cohort and 68% (CI:62‐73) of those with dementia were TDP‐43+.ConclusionThe results from our large cohort confirm that TDP‐43 pathology frequency increases in elderly White study participants with age of death, independent of cognitive status. Furthermore, TDP‐43 pathology frequency increases to a greater degree with age in those with dementia. Given the clear links between TDP‐43 and impaired cognition, the contribution of TDP‐43 to an individual’s cognitive impairment is likely to increase with age; a dynamic with significant public health consequences given our aging population.