Faculty Bibliography

Worldwide, over half of all individuals with dementia are undiagnosed. In the United States, racial, ethnic, and economic inequities mirror global findings, with higher rates of missed and delayed diagnosis and poorer diagnostic quality among minoritized and disadvantaged groups. For example, delayed diagnosis is more prevalent among people identifying as non-Hispanic Black or Latino than non-Hispanic White. Systematic efforts to improve detection can increase diagnosis rates; there is broad consensus that earlier detection and initiation of focused care and support services benefit both affected individuals and their loved ones. Systemic under-detection and its contributions to persistent population-level suffering underscore the importance of early detection of dementia as a key public health issue. Improving early detection calls for comprehensive, coordinated responses from local, regional, and national public health systems in partnership with health care delivery systems and community-based organizations. The Public Health Center of Excellence on Early Detection of Dementia (PHCOE on EDD), funded by the Centers for Disease Control and Prevention (CDC), is a national resource to promote understanding and implementation of evidence-based and evidence-informed public health strategy for early detection of dementia. We, together with the PHCOEs on Dementia Risk Reduction and Dementia Caregiving, and nearly four dozen state and local initiatives, seek to operationalize the priorities of the Building Our Largest Dementia Infrastructure for Alzheimer's Act and National Healthy Brain Initiative, established by federal legislation in 2018 and 2024. Our efforts support the CDC's mandate to build a national public health infrastructure for brain health and dementia.

Cardiovascular collapse and arrest in the periprocedural setting and intensive care unit differ from arrests in other contexts (such as out-of-hospital or hospital ward) because clinicians almost always witness the event, and the most likely precipitating cause may be known. In comparison to other settings, the response can be timelier and more focused on treating the underlying cause(s). Since many patients deteriorate over minutes to hours, clinicians can evaluate the patient expeditiously, generate a diagnosis, and initiate appropriate treatment more rapidly than in other arrest circumstances. This iteration of Perioperative Resuscitation and Life Support (PeRLS) employs Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology to review the most recent evidence on preventing and managing cardiac arrest during the perioperative period. Furthermore, many of the recommendations and algorithms may also be applicable to areas outside the operating room, such as the intensive care unit and emergency room.

BACKGROUND:In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p-tau217 as a potential biomarker for CTE p-tau pathology, and examined the concordance between plasma p-tau217 and Aβ pathology in an at-risk for CTE sample. METHOD/METHODS:The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p-tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p-tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p-tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4. RESULT/RESULTS:Sample characteristics are in Table 1. p-tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p-tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p = 0.001) but not when Aβ+ (n = 17) participants and those with kidney/liver disease (n = 5) were excluded. Aβ+ participants had the highest p-tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p-tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p-tau217 between 0.60-1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p-tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. CONCLUSION/CONCLUSIONS:Plasma p-tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p-tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p-tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p-tau assays.

[This corrects the article DOI: 10.3389/fnut.2021.748847.].

BACKGROUND:. However, the microstructural alterations driving these differences are unclear. Here, we assess associations of MK and KFA with neurite orientation dispersion and density imaging (NODDI) and magnetization transfer imaging (MTI) metrics, which provide a more specific characterization of tissue microstructure. METHOD/METHODS:(75 SCD) ages 55-88 were included in the analysis. Participants were defined as SCD if they endorsed problems with their memory and in the control group otherwise. Diffusion images were processed to obtain MK, Radial Kurtosis (RK), Axial Kurtosis (AK) and KFA from DKI and Neurite Density (ND) and Orientation Dispersion (OD), a marker of neurite organization, from NODDI. MTI was used to calculate the Magnetization Transfer Ratio (MTR), a marker of myelin and potentially amyloid aggregation. Mean metric values were calculated for bilateral amygdala (Figure 1). Between-group comparisons were conducted using Wilcoxon rank-sum tests, corrected for multiple testing. Associations between DKI, NODDI, and MTR metrics were examined using linear models corrected for age and sex. RESULT/RESULTS:SCD had lower KFA, higher MK, and higher RK in the right amygdala (Table 1). KFA had a weak negative correlation with ND, while MK and RK had strong positive correlations (Figure 2A-C). Only MK had a weak positive correlation with OD (Figure 2D-F). Neither KFA, MK, nor RK correlated with MTR (Figure 2G-I). CONCLUSION/CONCLUSIONS:DKI metrics are more sensitive to amygdala changes in SCD than NODDI metrics or MTR. Lower KFA, higher MK, and higher RK were associated with higher ND but not MTR, suggestive of dendritic or glial branching. Higher MK was additionally associated with higher OD, potentially indicating reduced neurite organization. Further analyses on the impact of these amygdala changes on SCD related neuropsychiatric symptoms are needed. References 1. Flaherty R, Sui YV, Li M, et al. Alzheimers Dement. 2024;20(S9):e093982. 2. Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1-25.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with intracranial stenosis-related large-vessel occlusion (ICAS-LVO) may experience better outcomes with stent placement compared with stand-alone mechanical thrombectomy (MT). This study evaluates the safety and clinical outcomes of self-expanding stents (SES) versus balloon-mounted stents (BMS) in patients with ICAS-LVO treated with MT and stent placement. MATERIALS AND METHODS/METHODS:This secondary analysis of the Registry of Emergent Large-Vessel Occlusion Due to Intracranial Stenosis, a multicenter observational study, included patients with ICAS-LVO from 25 stroke centers who underwent stent placement. Patients were stratified by stent type (SES or BMS). The primary end point was 90-day mRS = 0-2. Secondary outcomes included successful reperfusion, recurrent stroke, and infarct volume. Symptomatic intracranial hemorrhage was the primary safety outcome. Inverse probability-weighting was adjusted for confounders. RESULTS:= .001), particularly in patients without prestenting angioplasty (14% versus 1%). CONCLUSIONS:SES and BMS demonstrated comparable safety and clinical outcomes in patients with ICAS-LVO. However, SES were linked to higher rates of restenosis and recurrent strokes, potentially influenced by the absence of prestenting angioplasty. Further research is needed to refine stent-placement strategies in this population.

INTRODUCTION/BACKGROUND:The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS:We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS:Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION/CONCLUSIONS:We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS/CONCLUSIONS:The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

OBJECTIVE:Distinctive differences in multiple sclerosis (MS) disease severity, progression, and mortality have been observed among different races. Social determinants of health (SDH) can contribute to such racial disparities. This study aims to: 1) compare Non-Hispanic White (NHW) and Black (Bl) persons with MS in terms of MS and SDH; 2) explore the impact of SDH-adjustment in the association between race and Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25-FW), 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT). METHODS:120 patients, self-identified as Bl (n = 60) or NHW (n = 60) persons, were included in this cross-sectional analysis from a prospectively enrolled cohort. We used parametric and non-parametric tests; logistic models were performed to select the most relevant SDH. Univariable linear regression models were used to explore differences in EDSS, T25-FW, 9-HPT, SDMT and models were adjusted for relevant SDH using propensity scores (PS). RESULTS:Significant racial disparities in adverse SDH were identified in Black persons with MS (BpwMS). BpwMS patients had a higher EDSS (β=0.66, p = 0.022), log-transformed T25-FW (β=0.16, p = 0.001), 9-HPT (β=2.89, p = 0.001) and lower SDMT (β=-5.97, p = 0.003); after PS-adjustment, associations were no longer significant except for T25-FW (β=0.13, p = 0.030) and the magnitude of all coefficients was reduced (EDSS: -27 %, T25-FW: -19 %, 9-HPT: -36 %, SDMT: -45 %). INTERPRETATION/CONCLUSIONS:More efforts are necessary to adequately address the SDH that distinguish Bl from NHW persons with MS; additional unknown or unmeasured variables, including biologic differences as well as other SDH, should be explored to elucidate the mechanisms behind worse MS outcomes in BpwMS.

While the physical manifestations of NF2-related schwannomatosis (NF2-SWN) have been well documented, there are a limited number of qualitative studies on health-related quality of life in NF2-SWN. The present study sought to explore the cumulative impact of symptoms, treatments, and healthcare on the quality of life of individuals with NF2-SWN. We interviewed 16 adolescent and adult patients with NF2-SWN enrolled in the INTUITT-NF2 clinical trial and 10 clinicians with NF2-SWN expertise from the United States, United Kingdom, and Australia. Analysis of patient and clinician interviews yielded five overall themes: (1) impacts on daily living, (2) impacts on life roles, (3) impacts on relationships and social integration, (4) impacts on psychological and emotional wellbeing, and (5) burden of treatment and healthcare. Multiple symptom areas contributed to impairments in quality of life across each theme. These findings reveal that quality of life in NF2-SWN is shaped not only by individual symptoms, but by their complex, cumulative impact-highlighting the urgent need for disease-specific tools and holistic care approaches that reflect the lived realities of patients across the lifespan.

Language comprehension involves the prediction of upcoming linguistic units across multiple timescales. However, how this prediction process is hierarchically implemented in the human brain remains unclear. Combining natural language processing (NLP) and functional magnetic resonance imaging (fMRI) in a narrative comprehension task, we first applied the group-based general linear model (gGLM) to identify the neural underpinnings associated with anticipating upcoming words and sentences. Our results revealed a cortical hierarchy supporting linguistic prediction, extending from the superior temporal cortices to the default mode network (DMN). Next, we investigated how the word and sentence levels interact by testing two rival hypotheses: the continuous updating hypothesis posits that higher-level regions are updated continuously as inputs unfold over time, while the sparse updating hypothesis states that higher-level regions are updated only at the boundaries of their preferred timescales. Using computational modeling and autocorrelation analysis, we found that the sparse model outperformed the continuous model, with updating occurred at the sentence boundaries. Together, our results extend evidence for linguistic prediction to longer timescales and elucidate the neurocomputational mechanisms of hierarchical information updating in the human brain.