Citations

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

ImportanceAtrial fibrillation (AF) is the most common, chronic, cardiac arrythmia in older US adults. It is not known whether AF is independently associated with increased risk of retinal stroke (central retinal artery occlusion), a subtype of ischemic stroke that causes severely disabling visual loss in most cases and is a harbinger of further vascular events.ObjectiveTo determine whether there is an association between AF and retinal stroke.Design, Setting, and ParticipantsThis retrospective cohort study was performed between July 2023 and May 2024 using computerized inpatient, outpatient, emergency department, and skilled nursing facility claims files for a 5% sample of US fee-for-service Medicare beneficiaries aged 66 years and older between 2000 and 2020. Follow-up ended at death, conclusion of fee-for-service Medicare coverage, end of the study period, or loss to follow-up of 85% of the study cohort.ExposureAF, based on validated International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes.Main Outcomes and MeasuresThe primary end point was incident retinal stroke in the primary diagnostic position of a single claim in any venue of care. Secondary end points included retinal stroke in any position of a single claim, 1 positive control end point (cerebral ischemic stroke), and 4 negative control end points (central retinal vein occlusion, urinary tract infection, humeral fracture, and cataract). Unadjusted and adjusted hazard ratios (HRs) and rate differences were computed across matched and overlap-weighted cohorts with and without AF (defined as 1 inpatient claim or 2 outpatient claims within a 365-day period).ResultsIn total, 1 090 144 patients (591 400 female [54.3%]; mean [SD] age, 76.92 [7.09] years) were included in the study; 545 072 patients had AF and 545 072 were matched controls. The median (IQR) follow-up was 45 (18 to 90) months. In total, 1333 patients with AF (rate, 0.55 per 1000 person-years) and 1082 AF-free matched controls (rate, 0.50 per 1000 person-years) experienced retinal stroke. The cause-specific, adjusted HR of retinal stroke after overlap weighting was 1.14 (95% CI, 1.02 to 1.28; adjusted rate difference, 0.05 [95% CI, −0.01 to 0.11]). AF was associated with cerebral ischemic stroke (adjusted HR, 1.73 [95% CI, 1.69 to 1.76]; adjusted rate difference, 10.11 [95% CI, 9.72 to 10.49]). Of 4 prespecified negative control end points, AF was not associated with central retinal vein occlusion but was associated with urinary tract infection, cataract, and humeral fracture.Conclusions and RelevanceIn this cohort study of Medicare beneficiaries aged 66 years and older, AF was independently associated with retinal stroke. The magnitude of the association was small, and a contribution from residual, unmeasured confounding could not be excluded.

Background: Disparities in postoperative nausea and vomiting and its prophylaxis may exist based on race, ethnicity, and socioeconomic status. The objective was to evaluate whether patients from racial and ethnic minority groups and patients from lower socioeconomic status backgrounds received less appropriate postoperative nausea and vomiting prophylaxis and experienced higher rates of postoperative and postdischarge nausea and vomiting. Methods: This retrospective cohort study included 23,333 adults who underwent major surgeries (total knee arthroplasty, cholecystectomy, hysterectomy, and prostatectomy) from 2017 to 2022 in a single, multistate hospital system. Outcomes included prophylactic antiemetic administration according to consensus guidelines, as well as the occurrence of postoperative and postdischarge nausea and vomiting, with predictors being patient race and ethnicity, payor type, and community-level socioeconomic status. Results: About 45% (n = 10,407) of patients received guideline-recommended postoperative nausea and vomiting prophylaxis. Regression models showed statistically significant differences in appropriate postoperative nausea and vomiting prophylaxis by race and ethnicity, as well as community-level socioeconomic status, with Black (odds ratio, 0.76; 95% CI, 0.63 to 0.92) and Hispanic (odds ratio, 0.82; 95% CI, 0.70 to 0.96) patients having lower odds of receiving appropriate antiemetic prophylaxis compared to non-Hispanic White patients. Approximately 11% of patients (n = 2,522) experienced postoperative nausea and vomiting in the postanesthesia care unit, and about 19.5% of patients (n = 4,540) experienced postdischarge nausea and vomiting. No significant differences in postoperative nausea and vomiting were observed in the postanesthesia care unit among different groups; however, Black, Hispanic, other races and ethnicities, and patients with Medicaid had higher odds of postdischarge nausea and vomiting. Conclusions: The study identified differences in appropriate postoperative nausea and vomiting prophylaxis by race and ethnicity, as well as community-level socioeconomic status. There were no differences in postoperative nausea and vomiting by the predictors, but there were higher odds of postdischarge nausea and vomiting by race and ethnicity and payor. This study underscores the importance of data stratification in quality measures to identify disparities in perioperative care; it can lead to changes in perioperative anesthetic management. Further research should explore these associations in a broader cohort and address potential confounding sources.

AbstractBackgroundSubjective cognitive concerns are common in functionally intact adults, potentially indicating future cognitive decline. Remote smartphone cognitive testing holds promise for objectively tracking cognition in individuals reporting complaints. In our initial exploration of the link between subjective cognitive complaints and digital clinical outcomes, we examined participants' self‐reported cognitive complaints' association with smartphone tests on memory and executive functioning.MethodsParticipants, without self‐reported MCI or dementia, were recruited from the UCSF Brain Healthy Registry (BHR) to complete cognitive tasks on their personal smartphone with the ALLFTD Mobile App. Participants also completed the 12‐item Everyday Cognition Screening Tool (ECog‐12), assessing subjective cognitive impairment, online as part of BHR. Average ECog‐12 scores, including Memory and Executive Functioning subdomains, were calculated. Correlations between scores from online ECog‐12 scores and app‐based smartphone tasks were examined. Regression analyses, adjusting for age, education, and sex, were performed to evaluate the relationship between ECog‐12 and smartphone tasks (Stroop & Flanker) measuring executive function and memory.ResultsOut of 2,283 invited BHR participants, 456 (mean age: 64.6 years (SD=11.8) and education: 16.3 years (SD=2.4)) completed smartphone tasks (81.1% completion rate). Age was negatively associated with executive functioning and memory tasks (β’s=‐0.51 to ‐0.54, p’s<0.05), while higher education correlated with better performance (β’s=0.10‐0.14, p’s<0.05). Sex was not significantly associated with performance on any task (β’s=‐0.04 to 0.09, p’s>0.05). Subjective cognitive concerns were linked to tasks of executive functioning (Stroop: β=‐0.18, p=0.002) and memory (β=‐0.14, p=0.02). Endorsement of executive functioning items on ECog‐12 associated with Stroop performance (β=‐0.16, p=0.005), and memory‐specific complaints were related to memory performance (β=‐0.1, p=0.09). The relationship with flanker scores was not significant (β=‐0.08, p=0.17). Similar patterns emerged with the online ECog‐12; online and app‐based scores are strongly correlated (β=0.75, p<0.05).ConclusionsIn this cognitively intact sample, subjective cognitive concerns were linked to poorer performance on ALLFTD Mobile App tasks assessing executive functioning and memory. These findings suggest that unsupervised remote smartphone testing merits further consideration to monitor cognition in individuals with subjective cognitive concerns. Subsequent studies in deeply phenotyped cohorts with follow‐up assessments are essential for understanding the clinical relevance of these results.

AbstractBackgroundGrowth Differentiation Factor 15 (GDF15) is a TGF‐beta superfamily protein upregulated during immune‐mediated stress responses. Peripheral GDF15 is linked to adverse aging across organ systems including the brain. Immune dysregulation is implicated in frontotemporal dementia (FTD) pathogenesis. We examined how plasma GDF15 levels associated with longitudinal cognitive and neurofilament light chain (NfL) trajectories in adults with FTD and controls. Furthermore, we tested the utility of GDF15 as a prognostic biomarker against common inflammatory proteins (CRP and IL6).Method231 adults with FTD (24.35% sporadic FTD syndromes; 19.19% MAPT; 19.56% GRN; 22.14% C9orf72 pathogenic carriers) and 40 normal controls from the ALLFTD Consortium completed longitudinal neuropsychological testing and a blood draw with plasma analyzed on SomaScan V4.0 (baseline only: GDF15, CRP, and IL6) and Simoa (longitudinal: NfL). CRP and IL6 were selected as control markers to test the specificity of GDF15. Linear mixed effects models separately examined longitudinal cognition (global, executive functioning, memory, and language z‐scores) and plasma NfL levels as a function of baseline plasma GDF15, time, and their interaction, controlling for baseline age, sex, and education. Parallel models were conducted for CRP and IL6.ResultIn the whole cohort, higher baseline plasma GDF15 levels associated with steeper global cognitive decline (b = ‐3.91, p = 0.0092) and NfL accumulation (b = 3.88, p = 0.00088) over time. When examining cognitive domains, we found GDF15 only associated with worse executive functioning trajectories (b = ‐3.19, p = 0.0021). In contrast, baseline levels of CRP and IL6 did not display statistically significant relationships with cognitive or NfL trajectories. Prognostic effects of GDF15 remained statistically significant when restricting analyses to those with FTD pathogenic variants (b = ‐2.98, p = 0.0054 [global cognition], b = 2.69, p = 0.0098 [NfL]).ConclusionAdults with FTD and higher baseline peripheral GDF15 levels exhibit accelerated cognitive decline and neurodegeneration. Our results support GDF15 as a potential prognosticator of adverse clinical outcomes in FTD and highlight the relevance of GDF15‐specific pathways in FTD progression. Plasma GDF15 may provide utility over commonly examined inflammatory proteins and further work to explore its clinical value is indicated.

AbstractBackgroundNormative models (NM) of brain metrics based on large, diverse populations offer novel strategies to detect individual brain abnormalities. To create an age‐dependent statistical model of brain microstructure over the human lifespan, we built the largest multi‐site NM of white matter (WM) diffusion tensor imaging (DTI) metrics based on 54,591 subjects. We used state‐of‐the‐art tools to adjust for site‐dependent effects.MethodWe used Hierarchical Bayesian Regression (HBR) to determine the age trajectory and lifespan centile curves (ages 3‐100 years) by merging data from different sections of the lifespan. We analyzed 19 international public datasets with the ENIGMA‐DTI protocol. Mean fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AxD, RD) were extracted for 21 bilateral ROIs from the JHU‐WM atlas and the whole WM skeleton. Regressions were run with each metric per ROI as a function of age and sex, and the DTI protocol as the batch effect (37 protocols). Z‐scores were derived for 81 patients with Alzheimer’s disease (AD; mean age: 77y±8.4, 46M/35F) and 225 MCI participants (mean age: 75.1y±8.1, 127M/98F) and extreme deviations (Z>|2|) were quantified for each condition. ROI‐wise areas under the ROC curve were calculated to determine the classification accuracy of the Z‐scores.ResultThe average FA for the overall WM skeleton reached its peak value at 27 years, with minima for MD, RD and AxD at 47, 42 and 54 years, respectively. We found extreme FA deviations (Z>2) for MCI (AUC=0.67) and AD (AUC=0.66) in the genu of the corpus callosum, extreme RD deviations (Z<2) in the tapetum (AUC=0.73) and Extreme AxD deviations (Z>2) for MCI in the superior longitudinal fasciculus (AUC=0.65). See Figures 1 & 2.ConclusionNM of brain microstructure with HBR yielded lifespan trajectories for widely‐used DTI metrics. By pooling large scale multi‐site dMRI to create a statistical reference, single subject deviations are detectable across the lifespan for AD and MCI. These NM will be publicly available to the research community.

AbstractBackgroundPlasma Aβ42/40 and p‐tau217 can predict amyloid positivity in cross‐sectional studies. However, it is unclear how plasma biomarkers perform longitudinally, which is important to inform their utility in tracking disease progression. The goal of this study is to describe temporal evolutions of plasma Aβ42/40 and ptau217 ratio (p‐tau217r) measured via mass spectrometry, p‐tau217 measured via an immunoassay, and amyloid PET.MethodsWe included participants in the Mayo Clinic Study of Aging with amyloid PET (PiB) and plasma Aβ42/40 + ptau217r (mass spectrometry, C2N) and/or p‐tau217 (Lilly, MSD). We fit a joint non‐linear mixed effects model with Aβ42/40, p‐tau217r, p‐tau217 (Lilly), and amyloid PET as outcomes and age, sex, APOE ε4 carriership and education as covariates. The model included a per‐participant adjustment (time‐shift) for each biomarker indicating how much earlier or later in time the biomarker was estimated to progress relative to the average participant, a correlation (R) between adjustments for each pair of biomarkers, and the impact of covariates on each biomarker’s timing.ResultsThe study included 1459 participants, age 77 (10) years, 44% female, 82% cognitively unimpaired. Mean (SD) years of followup was 5.6(3.0) years for mass spectrometry plasma measures, 2.5(0.7) years for p‐tau217 (Lilly), and 4.6(3.3) for amyloid PET. Model fits are shown for each biomarker, with greater variability in serial measurements for plasma than PET (Figure 1). Individual adjustments between each of the plasma biomarkers and amyloid PET were highly correlated: p‐tau217r, R=0.73 (95%CI: 0.67, 0.78); p‐tau217 (Lilly), R=0.66 (0.62, 0.7); Aβ42/40, R=0.6 (0.52, 0.68) (Figure 2). The p‐tau217r and Aβ42/40 individual adjustments were modestly correlated, R=0.39 (0.28, 0.49). APOE ε4 carriership had the strongest covariate effect on all biomarkers, e.g. p‐tau217r progression 9.4 (6.7, 12) years earlier (Figure 3).ConclusionsPlasma Aβ42/40 and p‐tau217 measured with currently available assays may both be amenable to longitudinal modeling, although the degree of variability in Aβ42/40 over time may pose challenges. Findings suggest that both plasma Aβ42/40 and p‐tau217r may provide information regarding an individual’s timing of progression on amyloid PET; lower correlations with each other than amyloid PET suggests that each analyte may provide complimentary information.

AbstractBackgroundUnderstanding the relationship between AβPET and AβCSF biomarkers will define their potential utility in Aβ treatment. Few longitudinal or neuropathological comparisons have been reported. We assessed the relationship of AβPET and AβCSF biomarkers in a large community cohort.MethodParticipants 50+ years with coincident AβPET and AβCSF biomarkers (pTau181/Aβ42, n=505, and Aβ42/40, n=54) were included. Of these participants, a subgroup was identified that had neuropathology data (n=47) of which many had longitudinal AβPET and CSF testing. The relationships of AβPET and CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in those with autopsy data. Analyses were performed using AβPET Meta‐ROI and AβPET early‐Aβ‐deposition ROIs (ROIs with early Aβ deposition: fusiform, angular, inferior temporal, middle temporal, middle occipital, and calcarine).ResultIn biomarker tests performed at the same time, more participants were AβPET+ and CSF‐ than AβPET‐ and CSF+ using Meta‐ROI AβPET. This discordance occurred more frequently when using early‐Aβ‐deposition regions (Figure 1). Of 47 participants with autopsy data, 35 had Thal stage ≥1. The sensitivity for earliest detection of cortical Aβ neuropathology by AβPET was 89% (31/35) and by CSF was 66%, (23/35). Eight of these 35 had positive AβPET findings and negative coincident CSF tests at the first time tested. Of these, 5/8 were Meta‐ROI and early AβPET ROI positive. The other 3/8 were only positive on early‐Aβ AβPET ROIs. Four of the 8 with negative CSF and positive AβPET had subsequent testing and 2/4 became positive on CSF tests after 1.5 years while 2/4 continued to be negative on subsequent testing.ConclusionAβPET is more sensitive for detection of early cortical Aβ deposition than CSF biomarkers in cross‐sectional or autopsy data. While the assessment of AβPET by standard Meta‐ROI AβPET methods showed cortical Aβ deposition occurring when not indicated by CSF biomarkers, AβPET ROIs for early Aβ deposition detected additional participants that were AβPET positive and AβCSF negative. These findings have implications for detecting early Aβ neuropathology among CU participants in Aβ prevention trials when robust detection is needed. Further work is needed to compare Aβ plasma biomarkers and AβPET using these methods.

AbstractBackgroundNormative models (NM) of brain metrics based on large, diverse populations offer novel strategies to detect individual brain abnormalities. To create an age‐dependent statistical model of brain microstructure over the human lifespan, we built the largest multi‐site NM of white matter (WM) diffusion tensor imaging (DTI) metrics based on 54,591 subjects. We used state‐of‐the‐art tools to adjust for site‐dependent effects.MethodWe used Hierarchical Bayesian Regression (HBR) to determine the age trajectory and lifespan centile curves (ages 3‐100 years) by merging data from different sections of the lifespan. We analyzed 19 international public datasets with the ENIGMA‐DTI protocol. Mean fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AxD, RD) were extracted for 21 bilateral ROIs from the JHU‐WM atlas and the whole WM skeleton. Regressions were run with each metric per ROI as a function of age and sex, and the DTI protocol as the batch effect (37 protocols). Z‐scores were derived for 81 patients with Alzheimer’s disease (AD; mean age: 77y±8.4, 46M/35F) and 225 MCI participants (mean age: 75.1y±8.1, 127M/98F) and extreme deviations (Z>|2|) were quantified for each condition. ROI‐wise areas under the ROC curve were calculated to determine the classification accuracy of the Z‐scores.ResultThe average FA for the overall WM skeleton reached its peak value at 27 years, with minima for MD, RD and AxD at 47, 42 and 54 years, respectively. We found extreme FA deviations (Z>2) for MCI (AUC=0.67) and AD (AUC=0.66) in the genu of the corpus callosum, extreme RD deviations (Z<2) in the tapetum (AUC=0.73) and Extreme AxD deviations (Z>2) for MCI in the superior longitudinal fasciculus (AUC=0.65). See Figures 1 & 2.ConclusionNM of brain microstructure with HBR yielded lifespan trajectories for widely‐used DTI metrics. By pooling large scale multi‐site dMRI to create a statistical reference, single subject deviations are detectable across the lifespan for AD and MCI. These NM will be publicly available to the research community.

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.