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Structural inequality, the uneven distribution of resources and opportunities, influences health outcomes. However, the biological embedding of structural inequality in aging and dementia, especially among underrepresented populations, is unclear. We examined the association between structural inequality (country-level and state-level Gini indices) and brain volume and connectivity in 2,135 healthy controls, and individuals with Alzheimer's disease and frontotemporal lobe degeneration from Latin America and the United States. Greater structural inequality was linked to reduced brain volume and connectivity, with stronger effects in Latin America, especially in the temporo-cerebellar, fronto-thalamic and hippocampal regions. In the United States, milder effects were observed in the insular-cingular and temporal areas. Results were more pronounced in Alzheimer's disease and were independent of age, sex, education, cognition and other confounding factors. The findings highlight the critical role of structural inequality in aging and dementia, emphasizing the biological embedding of macrosocial factors and the need for targeted interventions in underserved populations., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diagnosis of sports-related concussion (SRC) primarily relies on an athlete's self-report of injury and associated symptoms. Social pressures and attitudes surrounding SRC influence athlete reporting behavior. Unfortunately, underreporting of SRC symptoms is an issue among adolescent athletes. Nondisclosure of SRC symptoms may lead to premature return-to-play and potential persistent symptoms. This scoping review summarizes prevailing theories that explain SRC symptom reporting intent and behavior among adolescent athletes. Literature was reviewed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension for Scoping Review guidelines. Inter-rater reliability was calculated at each stage. Thirty-four articles published between 2013-2024 were included. Inter-rater reliability was fair to perfect across all review stages. Of the 16 unique theories described, the Theory of Reasoned Action/Theory of Planned Behavior (TRA/TPB) was the most frequently cited theory explaining SRC symptom reporting behavior. Although the TRA/TPB framework was useful when predicting SRC symptom reporting intent, it did not adequately predict reporting behavior, consistent with the broader health behavior literature which has established that intention is not a good predictor of behavior. In light of these findings, new frameworks must be considered that consider neurodevelopmental, cognitive, and cultural factors, as these may be more useful for understanding SRC symptom reporting behavior in adolescence.

Background: Dementia poses a significant burden on healthcare systems. Early identification of individuals at risk for cognitive decline is crucial. The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results., Methods: This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline., Results: Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm; p = 0.037). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14, 95% CI = 1.01-1.30, p = 0.035). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline., Conclusions: This study suggests that OCT-derived macular GCIPL thickness may be a valuable biomarker for identifying individuals at risk of cognitive decline. Our findings highlight GCIPL as a potentially more sensitive marker compared to RNFL thickness for detecting early neurodegenerative changes., Trial Registration Number and Name of the Trial Registry: National Healthcare Group Domain-Specific Review Board (NHG DSRB) reference numbers DSRB Ref: 2018/01368. Name of the trial: Harmonisation project., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the National Healthcare Group Domain-Specific Review Board (NHG DSRB reference number 2018/01098 and 2010/00017). The study adhered to the tenets of the Declaration of Helsinki and its later amendments. Study coordinators obtained written informed consent from all participants or legal representatives before their study inclusion. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Psychotropic medication (PM) use in behavioral-variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD., Methods: We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART)., Results: We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants., Discussion: Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated., Highlights: We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: With the increased use of computer-based tests in clinical and research settings, assessing retest reliability and reliable change of NIH Toolbox-Cognition Battery (NIHTB-CB) and Cogstate Brief Battery (Cogstate) is essential. Previous studies used mostly White samples, but Black/African Americans (B/AAs) must be included in this research to ensure reliability., Method: Participants were B/AA consensus-confirmed healthy controls (HCs) (n = 49) or mild cognitive impairment (MCI) (n = 34) adults 60-85 years that completed NIHTB-CB and Cogstate for laptop at two timepoints within 4 months. Intraclass correlations, the Bland-Altman method, t -tests, and the Pearson correlation coefficient were used. Cut scores indicating reliable change provided., Results: NIHTB-CB composite reliability ranged from .81 to .93 (95% CIs [.37-.96]). The Fluid Composite demonstrated a significant difference between timepoints and was less consistent than the Crystallized Composite. Subtests were less consistent for MCIs (ICCs = .01-.89, CIs [-1.00-.95]) than for HCs (ICCs = .69-.93, CIs [.46-.92]). A moderate correlation was found for MCIs between timepoints and performance on the Total Composite ( r = -.40, p = .03), Fluid Composite ( r = -.38, p = .03), and Pattern Comparison Processing Speed ( r = -.47, p = .006).On Cogstate, HCs had lower reliability (ICCs = .47-.76, CIs [.05-.86]) than MCIs (ICCs = .65-.89, CIs [.29-.95]). Identification reaction time significantly improved between testing timepoints across samples., Conclusions: The NIHTB-CB and Cogstate for laptop show promise for use in research with B/AAs and were reasonably stable up to 4 months. Still, differences were found between those with MCI and HCs. It is recommended that race and cognitive status be considered when using these measures.

Background: Posterior Cortical Atrophy (PCA) is a clinical syndrome characterized by progressive visuospatial and visuoperceptual impairment. As the neurodegenerative disease progresses, patients lose independent functioning due to the worsening of initial symptoms and development of symptoms in other cognitive domains. The timeline of clinical progression is variable across patients, and the field currently lacks robust methods for prognostication. Here, evaluated the utility of MRI-based cortical atrophy as a predictor of longitudinal clinical decline in a sample of PCA patients., Methods: PCA patients were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit PCA Program. All patients had cortical thickness estimates from baseline MRI scans, which were used to predict longitudinal change in clinical impairment assessed by the CDR Sum-of-Boxes (CDR-SB) score. Multivariable linear regression was used to estimate the magnitude of cortical atrophy in PCA patients relative to a group of amyloid-negative cognitively unimpaired participants. Linear mixed-effects models were used to test hypotheses about the utility of baseline cortical atrophy for predicting longitudinal clinical decline., Results: Data acquired from 34 PCA patients (mean age = 65.41 ± 7.90, 71% females) and 24 controls (mean age = 67.34 ± 4.93, 50% females) were analyzed. 62% of the PCA patients were classified as having mild cognitive impairment (CDR 0.5) at baseline, with the rest having mild dementia (CDR 1). Each patient had at least one clinical follow-up, with the mean duration of 2.78 ± 1.62 years. Relative to controls, PCA patients showed prominent baseline atrophy in the posterior cortical regions, with the largest effect size observed in the visual network of the cerebral cortex. Cortical atrophy localized to the dorsal attention network, which supports higher-order visuospatial function, selectively predicted the rate of subsequent clinical decline., Conclusions: These results demonstrate the utility of a snapshot measure of cortical atrophy of the dorsal attention network for predicting the rate of subsequent clinical decline in PCA. If replicated, this topographically-specific MRI-based biomarker could be useful as a clinical prognostication tool that facilitates personalized care planning., Competing Interests: Declarations. Ethics approval and consent to participate: The study design and protocol were approved by the Mass General Brigham Institutional Review Boards for human research. Each participant and their informant gave written informed consent in accordance with the Mass General Brigham Human Subjects Research Committee guidelines. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: We investigated whether early life exposure to state-level structural sexism influenced late-life memory trajectories among United Staes (U.S.) -born women and men and determined whether associations differed between racialized groups., Methods: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; N = 2314) and Health and Retirement Study (HRS; N = 18,631). State-level structural sexism was measured via U.S. census and administrative data and linked to participants in each study by birth year and state., Results: Exposure to greater structural sexism was associated with lower baseline memory performance among WHICAP women and HRS men and faster memory decline among women in both studies. Women born in the state with the highest structural sexism showed memory decline like that of those who were 9 years older. Structural sexism-baseline memory associations were stronger among Black women than White women., Discussion: Early life exposure to structural sexism negatively impacts late-life memory trajectories among women., Highlights: A longitudinal measure captured state-level structural sexism from 1900 to 1960. Exposure to structural sexism was associated with worse late-life memory outcomes. Associations were strongest among women for memory decline. The negative impact on memory performance was stronger among Black women. Lowering structural sexism may, in turn, reduce memory decline among women., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Placental growth factor (PlGF) may regulate cerebrovascular permeability. We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment., Methods: MarkVCID consortium participants ≥55 years old with plasma PlGF and brain MRI were included. We tested cross-sectionally whether FW mediated the associations between PlGF and WMH, or PlGF and cognition, measured using the Clinical Dementia Rating (CDR) scale and an executive function (EF) composite (Uniform Data Set version 3 [UDS3]-EF)., Results: For 370 participants (mean age 72), a higher PlGF was associated with higher FW, higher WMH, and higher CDR, but not UDS3-EF. Higher FW was associated with higher WMH, higher CDR, and lower UDS3-EF. FW explained 26% of the association between PlGF and CDR and 73% of the association between PlGF and WMH., Discussion: Elevated PlGF may contribute to WMH and cognitive impairment through white matter FW accumulation., Clinical Trial Registration: NCT06284213 HIGHLIGHTS: PlGF is a promising blood-based biomarker for vascular cognitive impairment. In MarkVCID, higher PlGF was associated with accumulated white matter FW on MRI. FW mediated the association between higher PlGF and MRI-visible white matter injury. FW mediated the association between PlGF and worse CDR scale. PlGF may contribute to cognitive dysfunction via accumulated interstitial fluid., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The role of oxytocin-related genes in social-cognitive function has been previously established, but structural brain mechanisms underlying this link remain poorly understood. Utilizing a substantial dataset from the UK Biobank (N ≈ 30,000), this research determined associations between variations in ten single nucleotide polymorphisms (SNPs) within three oxytocin pathway genes (i.e., the oxytocin/neurophysin I prepropetide gene, the cluster of differentiation 38 glycoprotein gene, the oxytocin receptor gene) and whole-brain gray matter volume. Carriers of the AA or AG genotypes of the oxytocin receptor gene rs237851 SNP exhibited significantly larger hippocampal volume than carriers of the GG genotype. These results support the link between variations in the oxytocin receptor gene and hippocampal structure, with possible impact on social-cognitive function such as social recognition memory., Competing Interests: Conflict of interest The authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: The term rapid progressive dementia (RPD) may be applied to patients who develop dementia within 1 year or complete incapacitation within 2 years of the first symptom of impairment. However, in select cases, cognitive impairment may emerge abruptly, with symptoms evolving across hours or days. We sought to determine the frequency, etiologies, and factors that associated with ultra-RPD., Methods: Ultra-RPD was defined as persistent dementia (global Clinical Dementia Rating ®  ≥ 1), developing within 7 days of initial symptoms. Patients with ultra-RPD were identified via case review of patients enrolled in a prospective study of RPD at two tertiary care centers (February 2016-September 2023) followed by a systematic review of multiple English-language databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (completed January 2024)., Results: Three of 188 patients with RPD enrolled in our prospective series met the proposed definition for ultra-RPD (frequency = 1.6%). Systematic review yielded 57 additional cases from 47 publications (60 total cases). Ultra-RPD was attributed to vascular (40%), toxic/metabolic (22%), autoimmune/inflammatory (20%), and iatrogenic/structural (12%) causes. Lesions within the Papez circuit were detected in 52/59 (88%) of patients on neuroimaging. Twelve patients (20%) had potentially treatable causes of ultra-RPD., Discussion: Patients with ultra-RPD were rarely encountered in our prospective series, representing < 2% of cases of RPD, and rarely reported in the extant literature. The evaluation of patients with ultra-RPD should prioritize testing for vascular, toxic/metabolic, and autoimmune/inflammatory conditions that affect neuroanatomical structures or networks critical for memory formation and retrieval., Competing Interests: Declarations. Conflicts of interest: Yoav D Piura reports no conflicts of interest relevant to the manuscript. Nick Corriveau-Lecavalier reports no conflicts of interest relevant to the manuscript. Abd Moain Abu Dabrh reports no conflicts of interest relevant to the manuscript. Michael D Geschwind reports no conflicts of interest relevant to the manuscript. Tara Brigham reports no conflicts of interest relevant to the manuscript. Gregory S Day reports no conflicts of interest relevant to the manuscript. Ethical approval: The experimental procedure was approved by the ethics committee of Washington University School of Medicine and Mayo Clinic and complied with the ethical standards of the Declaration of Helsinki. Consent to participate: Informed consent was obtained from all individual participants or legal guardians included in the study., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

State of the Art: Semantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition., Methodology: We selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery - Recognition, Naming, Semantic associations - pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task's performance were conducted with a Voxel-based morphometry approach using CAT12., Results: svPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces' recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with grey matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS)., Conclusion: Our results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Older age is associated with poorer ability to accurately infer mental states, but some mental states are more complex than others. Sarcasm is a complex mental state because the literal and intended meaning of a speaker's words are in opposition. Individuals must rely on additional cues (e.g., facial expressions, intonation) for accurate inference. We hypothesized that understanding of sarcastic versus sincere exchanges would be more sensitive to age-related difficulty in mental state understanding., Methods: We examined accuracy at identifying sarcasm among 263 adults (ages 18-90 years) using videos of social interactions in The Awareness of Social Inference Test. Hypotheses were tested using a logistic linear mixed effects model predicting correct/incorrect trial-level responses. To characterize why sarcasm differed with age, we measured 2 abilities commonly implicated in mental state understanding: facial emotion recognition and cognitive performance., Results: Sarcasm understanding declined with age, whereas understanding of sincere exchanges did not. Both better emotion recognition and cognitive performance related to better understanding of sarcastic but not sincere exchanges. Only cognitive performance showed an age-related effect such that the cognitive performance among the oldest participants facilitated their understanding of both sarcastic and sincere exchanges., Discussion: We showed that individual variation related to age and social and cognitive performance is more pronounced when the use of multiple mental state cues is more (sarcasm) or less (sincerity) necessary for accurate understanding of social interactions. Naturalistic paradigms involving multiple mental state cues can address important questions about how older adults make decisions in the real world., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP)., Methods: This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4 , and interval between LP and death., Results: The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs., Discussion: This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes., Classification of Evidence: This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

Background: Alzheimer's disease (AD) is characterized by cerebral amyloid plaques and neurofibrillary tangles and disruption of large-scale brain networks (LSBNs). Transcranial magnetic stimulation (TMS) has emerged as a potential non-invasive AD treatment that may serve as an adjunct therapy with FDA approved medications., Methods: We conducted a 10-subject open label, single site study evaluating the effect of functional connectivity-resting state functional MRI guided-approach to TMS targeting with dysfunctional LSBNs in subjects with biomarker-confirmed early-stage AD (https://clinicaltrials.gov/study/NCT05292222). Subjects underwent pre-post imaging and testing to assess connectivity dysfunction and cognition. All participants received intermittent theta burst stimulation [(iTBS), (80% motor threshold; 5 sessions per day; 5 days; 3 targets; 18,000 pulses/day)] over 2 weeks. Three Human Connectome Project (HCP) defined parcellations were targeted, with one common right temporal area G dorsal (RTGd) target across all subjects and two personalized., Results: We identified the following parcellations to be dysfunctional: RTGd, left area 8A ventral (L8Av), left area 8B lateral (L8BL), and left area 55b (L55b). There were no changes in these parcellations after treatment, but subjects showed improvement on the Repeatable Battery for the Assessment of Neuropsychological Status attention index (9.7; p  = 0.01). No subject dropped out of the treatment, though 3 participants were unable to tolerate the RTGd target due to facial twitching ( n  = 2) and anxiety ( n  = 1)., Conclusion: Accelerated iTBS protocol was well-tolerated and personalized target-based treatment is feasible in early-stage AD. Further sham-controlled clinical trials are necessary to determine if this is an effective adjunctive treatment in early-stage AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kashyap, Hanson, Gustafson, Barclay, Howe, Sherman, Hungs and Rosenbloom.)

Background: The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed., Objectives: To evaluate the MoCA as an outcome measure in PSP clinical trials., Methods: Cognitive data from 162 participants in the placebo arm of the Biogen PASSPORT study (NCT03068468) were analyzed using linear mixed-effects modeling (LMM) and repeated measures correlation., Results: There was a significant decline in the MoCA score over time of -1.4 (95% CI -0.84 to -1.97) points over a 48-week period ( p  < 0.0001). Small but significant changes ( p  < 0.01) were observed in all MoCA domains except abstraction. The MoCA correlated weakly with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) over time ( r rm  = 0.1, p  = 0.02) but exhibited a stronger correlation with the PSP Rating Scale (PSPRS) ( r rm  = -0.25, p  < 0.0001)., Conclusion: The MoCA appears to have limited sensitivity in capturing cognitive decline in PSP., Competing Interests: Unrelated to this study CS has provided scientific advisory for SwanBio Therapeutics and received research funding from Sanofi-Genzyme for a study of video oculography in late-onset GM2 gangliosidosis. His institution has received financial support from Sanofi-Genzyme, SwanBio therapeutics and Encora Therapeutics and previously from Biogen and Biohaven, for the conduct of clinical trials. He has received honoraria from the American Academy of Neurology and The International Parkinson and Movement Disorders Society. He has received grant support from the National Institutes of Health K23 NS118045. Unrelated to this study MD has funding from NIH NINDS K23NS121402 and has served as a consultant for Synergic Medical Technologies and Cognito Therapeutics. EB receives research funding from the NIA (K99AG073453) and Lewy Body Dementia Association. Unrelated to this study AP is supported by NIH/NINDS U01 NS102035 and NIH/NIA R44 AG080861. IG-C is funded by the Clinical Research Training Scholarship in FTD from the Holloway Family Fund of The Association for Frontotemporal Degeneration, the Bob Burros Family Memorial Fund of the American Brain Foundation, and the American Academy of Neurology. Unrelated to this study MT has participated in clinical trials funded by Janssen, Biogen, Avanex, Green Valley, UCB, Novo Nordisk, GSK, BMS, and Passage Bio, and has served as a consultant for Eisai, Lilly, and Novo Nordisk. Unrelated to this study AL has served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Krembil Brain Institute, Michael J. Fox Foundation, Parkinson Foundation, Parkinson Canada, and The Rossy Foundation; is serving as an expert witness in litigation related to paraquat and Parkinson’s disease, received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. Unrelated to this study MS has served as investigator on clinical trials sponsored by Sage Therapeutics, Biogen Inc., and BIA R&D. LG: Consultancies: AI Therapeutics, Amylyx, Apellis, Aprinoia, Ferrer, IQVIA, UCB, Woolsey. Advisory Boards: Amylyx, CurePSP (unpaid), Roche, Rossy Centre, Springer. Royalties: Rutgers University Press for single-author text, A Clinician’s Guide to PSP (2019). Copyright material licensing fees (via Rutgers University). Travel expenses: CurePSP. AW has research funding from NIA/NIH 1R01AG085029 and R44AG080861, from the Parkinson’s Foundation, has participated in clinical trials funded by Roche/Genentech, Biogen/Denali, Bial, Amylyx Pharmaceuticals, Ferrer, Ono Pharmaceuticals, and received consultant payments from Accordant, CVS/Caremark, Genentech, Amylyx Pharmaceuticals and Ono Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ibrahim, Isroff, Stephen, Iyer, Dale, Gunzler, Bayram, Xie, Pantelyat, Montaser-Kouhsari, Garcia-Cordero, Tartaglia, Lang, Swan, Boxer, Golbe and Wills.)

Script training is a speech-language intervention designed to promote fluent connected speech via repeated rehearsal of functional content. This type of treatment has proven beneficial for individuals with aphasia and apraxia of speech caused by stroke and, more recently, for individuals with primary progressive aphasia (PPA). In the largest study to-date evaluating the efficacy of script training in individuals with nonfluent/agrammatic primary progressive aphasia (nfvPPA; Henry et al., 2018), robust treatment effects were observed, with maintenance of gains up to one year post-treatment. However, outcomes were constrained to measures of script accuracy, intelligibility, and grammaticality, providing a limited view of potential treatment benefit to connected speech. The current study evaluated the utility of a broader set of connected speech measures for characterizing script training outcomes in 20 individuals with nfvPPA who were administered Video-Implemented Script Training for Aphasia (VISTA). Probes of trained and untrained script topics from pre- and post-treatment were transcribed, coded, and analyzed using Computerized Language ANalysis (CLAN, MacWhinney, 2000) to extract measures of fluency, grammar, and informativeness. Speech timing measures (e.g., articulation rate, mean pause duration) were derived from audio files. Participants demonstrated significant changes for trained topics from pre-to post-treatment in words per minute, fluency disruptions per hundred words, mean length of utterance in morphemes, grammatical complexity, and proportion of open to closed class words. Reductions were observed in mean and variability of syllable duration and mean pause duration, and speech to pause ratio increased. These findings lend additional support for script training as a means to promote fluency of connected speech in individuals with nfvPPA and illustrate the utility of automated and semi-automated measures for characterizing treatment effects following intervention., Competing Interests: Conflict of interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

The extent to which the neural systems underlying semantic processes degrade with advanced age remains unresolved, which motivated the current study of neural activation on functional magnetic resonance imaging (fMRI) during semantic judgments of associated vs. unassociated, semantic vs. rhyme, and abstract vs. rhyme word pairs. Thirty-eight older adults, 55-85 years of age, performed semantic association decision tasks in a mixed event-related block fMRI paradigm involving binary judgments as to whether word pairs were related (i.e., semantically associated). As hypothesized, significantly greater activation was evident during processing of associated (vs. unassociated) word pairs in cortical areas implicated in semantic processing, including the angular gyrus, temporal cortex, and inferior frontal cortex. Cortical areas showed greater activation to unassociated (vs. associated) word pairs, primarily within a large occipital cluster. Greater activation was evident in cortical areas when response to semantic vs. phonemic word pairs. Contrasting activation during abstract vs. concrete semantic processing revealed areas of co-activation to both semantic classes, and areas that had greater response to either abstract or concrete word pairs. Neural activation across conditions did not vary as a function of greater age, indicating only minimal age-associated perturbation in neural activation during semantic processing. Therefore, the response of the semantic hubs, semantic control, and secondary association areas appear to be largely preserved with advanced age among older adults exhibiting successful cognitive aging. These findings may provide a useful clinical contrast if compared to activation among adults experiencing cognitive decline due Alzheimer's, frontal-temporal dementia, and other neurodegenerative diseases., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Oxytocin (OT) is a crucial modulator of social cognition and behavior. Previous work primarily examined effects of acute intranasal oxytocin administration (IN-OT) in younger males on isolated brain regions. Not well understood are (i) chronic IN-OT effects, (ii) in older adults, (iii) on large-scale brain networks, representative of OT's wider-ranging brain mechanisms. To address these research gaps, 60 generally healthy older adults (mean age = 70.12 years, range = 55-83) were randomly assigned to self-administer either IN-OT or placebo twice daily via nasal spray over four weeks. Chronic IN-OT reduced resting-state functional connectivity (rs-FC) of both the right insula and the left middle cingulate cortex with the salience network but enhanced rs-FC of the left medial prefrontal cortex with the default mode network as well as the left thalamus with the basal ganglia-thalamus network. No significant chronic IN-OT effects were observed for between-network rs-FC. However, chronic IN-OT increased selective rs-FC of the basal ganglia-thalamus network with the salience network and the default mode network, indicative of more specialized, efficient communication between these networks. Directly comparing chronic vs. acute IN-OT, reduced rs-FC of the right insula with the salience network and between the default mode network and the basal ganglia-thalamus network, and greater selective rs-FC of the salience network with the default mode network and the basal ganglia-thalamus network, were more pronounced after chronic than acute IN-OT. Our results delineate the modulatory role of IN-OT on large-scale brain networks among older adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Postoperative cognitive recovery is deeply important to patients and perioperative clinicians. Despite decades of data on "postoperative cognitive decline" (POCD), a research diagnosis based on objective cognitive test performance, perspectives on subjective cognitive complaints (SCC) after modern surgery/anesthesia have not been systematically collected or studied despite their recent inclusion in the 2018 redefinition of "postoperative neurocognitive disorder." The authors describe the alignment between SCC anecdotes and the research diagnosis of POCD, contextualizing these findings using recent literature within and outside anesthesiology. This article prepares anesthesiologists to discuss what is, and is not, known about subjective cognitive recovery after surgery/anesthesia., Competing Interests: Disclosure Ms L.Y. Li has no disclosures to report. Dr A.M. Staffaroni reports receiving research support from the National Institute on Aging, United States (NIA) of the National Institutes of Health (NIH), Bluefield Project to Cure FTD, the Alzheimer's Association, United States the Larry L. Hillblom Foundation, United States the Association for Frontotemporal Degeneration, United States the ALS Association, United States and the Rainwater Charitable Foundation, United States; and consulting for Alector Inc, Eli Lilly and Company/Prevail Therapeutics, Passage Bio Inc, and Takeda Pharmaceutical Company; and receiving licensing fees as a coinventor of smartphone cognitive tests. Dr E.L. Whitlock reports receiving research support from the NIA of the NIH., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hypertension is a major risk factor for both stroke and cognitive impairment, but it is unclear whether it may specifically affect post-stroke cognitive impairment. We assessed the effect of hypertension and/or stroke on brain injury, cognitive outcome, and the brain transcriptomic profile. C57BL/6J mice (n = 117; 3-5 mo.) received s.c. infusion of either saline or angiotensin II followed by sham surgery or photothrombotic stroke targeting the prefrontal cortex seven days later. Cognitive function was assessed with the Barnes maze and RNA sequencing was used to quantify transcriptomic changes in the brain. Angiotensin II treatment produced spontaneous hemorrhaging after stroke. In the Barnes maze, hypertensive mice that received stroke surgery had an increased escape latency compared to other groups (day 3: hypertensive + stroke = 166.6 ± 6.0 s vs. hypertensive + sham = 122.8 ± 13.8 s vs. normotensive + stroke = 139.9 ± 10.1 s vs. normotensive + sham = 101.9 ± 16.7 s), consistent with impaired cognition. RNA sequencing revealed >1500 differentially expressed genes related to neuroinflammation in hypertensive + stroke vs. normotensive + stroke, which included genes associated with apoptosis, microRNAs, autophagy, anti-cognitive biomarkers and Wnt signaling. Overall, we show that the combination of hypertension and stroke resulted in greater learning impairment and brain injury., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: More than one-fourth of older adults with cognitive impairment (CI) live alone; these individuals often lack support for medication management and face a high risk of adverse drug events. We characterized the frequency and types of high-risk medications used by older adults with CI living alone and, for context, compared patterns with those in older adults with CI living with others., Methods: This was a cross-sectional study of National Health and Aging Trends Study (NHATS) data and Medicare claims (2015-2017). We ascertained cognitive status from NHATS and medication use with Part D claims. We compared high-risk medication use (those with adverse cognitive effects or low tolerance for misuse) among older adults with CI living alone versus living with others using logistic regression models adjusted for demographic/clinical factors., Results: The unweighted sample included 1569 older adults with CI, of whom 491 (weighted national estimate, 31%) were living alone. In the living-alone group, the mean age was 79.9 years and 66% were female, 64% reported managing medications on their own without difficulty, 14% reported managing medications on their own with difficulty, and 18% received total support with medication management. Older adults with CI living alone used a median of 5 medications (IQR, 3-8), 16% took ≥10 medications, and 46% took ≥1 high-risk medication (anticholinergic/sedating: 24%; opioid: 13%; anticoagulant: 10%; sulfonylurea: 10%; insulin: 9%). Compared with those living with others, the use of high-risk medications was similar (p > 0.05 for unadjusted/adjusted comparisons). Those living alone were more likely both to take at least one high-risk medication and not receive help with medication management: 34% in those living alone versus 23% living with others (p < 0.05 for unadjusted/adjusted comparisons)., Conclusions: Older adults with CI living alone use many medications; nearly half use high-risk medications. Our findings can inform medication optimization interventions supporting this vulnerable population., (© 2024 The American Geriatrics Society.)

Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features., Competing Interests: Competing interests The authors declare the following competing interests: Jonathan D. Rohrer: received a grant from Bluefield Project Alzheimer’s Association and receives consulting fees from Novartis, Wave Life Sciences, Prevail, Alector, Aviado Bio, Takeda, Arkuda therapeutics, and Denali Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Peak-width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD., Methods: We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID-1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders., Results: Higher PSMD was associated with lower general cognition in MarkVCID-1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], -0.8 [-1.2, -0.4], P < 0.001). These findings were replicated in independent samples. Furthermore, PSMD explained cognitive status above and beyond white matter hyperintensities., Discussion: Our biological validation work supports the pursuit of larger clinical validation studies evaluating PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia., Highlights: Peak-width of skeletonized mean diffusivity (PSMD) is a novel small vessel disease neuroimaging biomarker. A prior instrumental validation study demonstrated that PSMD is a robust biomarker. This biological validation study shows that high PSMD relates to worse cognition. PSMD explains cognitive function above and beyond white matter hyperintensities. Future clinical validation will assess PSMD as a vascular contribution to cognitive impairment and dementia biomarker in clinical trials., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Amyloid-PET quantification through the tracer-independent Centiloid (CL) scale has emerged as an essential tool for the accurate measurement of amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. The AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context-of-use recommendations for the CL scale. Compared to histopathology, visual reads, and cerebrospinal fluid, CL quantification accurately reflects the amount of AD pathology. With high certainty, a CL value below 10 excludes the presence of Aβ pathology, while a value above 30 corresponds well with pathological amounts. Values falling in between these two cutoffs ("intermediate range") are related to an increased risk of disease progression. Together, CL quantification is a valuable adjunct to visual assessments of amyloid-PET images. An abnormal amyloid biomarker assessment is a key criterion to determine eligibility for anti-amyloid disease-modifying therapies, and amyloid-PET quantification can add further value by precisely monitoring amyloid clearance, and hence guiding patient management decisions. HIGHLIGHTS: Centiloid (CL) quantification robustly reflects of the amount of Aβ pathology. CL < 10/CL > 30 reflects Aβ-negativity/positivity thresholds with high certainty. CL quantification is a valuable adjunct to visual assessments of amyloid-PET. CL quantification can support trial design and treatment management. CL quantification could support the identification of early or emerging Aβ pathology., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Frontotemporal dementia (FTD) is one of the leading causes of young-onset dementia before age 65, typically manifesting as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). Although FTD affects all populations across the globe, knowledge regarding the pathophysiology and genetics derives primarily from studies conducted in North America and Western Europe. Globally, biomedical research for FTD is hindered by variable access to diagnosis, discussed in this group's earlier article, and by reduced access to expertise, funding, and infrastructure. This perspective paper was produced by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) and discusses the field's current status on the cross-cultural aspects of basic and translational research in FTD (including that focused on epidemiology, genetics, biomarkers, and treatment). It subsequently provides a summary of gaps and needs to address the disparities and advance global FTD biomedical research., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: In a nested case-control study, we examined how cerebral perfusion relates to cognitive status and amyloid in the oldest-old (i.e., 90 years of age and older)., Methods: Study participants included 113 dementia-free older adults (76 cognitively normal [CN]; 37 cognitively impaired, no dementia [CIND]) from the 90+ Study (mean age = 92.9, SD = 2.4). We quantified regional perfusion from arterial spin labeling-MRI (magnetic resonance imaging) and amyloid deposition from florbetapir-positron emission tomography (PET) in a region comprising the posterior cingulate and precuneus (PCC+PCu), and additionally quantified perfusion in other regions important for cognitive decline (medial temporal lobe, inferior parietal lobe, and orbitofrontal cortex)., Results: Participants with CIND displayed lower perfusion in the PCC+PCu relative to participants who were CN, but there was no statistically significant difference between the groups in amyloid burden in this region. In addition, participants with CIND exhibited lower inferior parietal and higher orbitofrontal perfusion., Discussion: Cerebral perfusion is related to cognitive status in the oldest-old independent of amyloidosis., Highlights: Cerebral perfusion and amyloid positron emission tomography (PET) were measured in older adults: 90 years of age and older. Perfusion but not amyloid differed between cognitively impaired and normal groups. Frontal and parietal regions linked to cognitive decline had altered perfusion. Perfusion is related to cognitive status in the oldest-old independent of amyloid., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline., Methods: Data from 9414 individuals from eight Dutch cohorts were included (Ø  age-range: 57-93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random-effects meta-analyses., Results: A higher endothelial dysfunction composite score was cross-sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled β-range: -0.04, -0.02). We found no association with change in cognition over time., Discussion: This comprehensive two-step, individual participant data (IPD) meta-analysis showed a small, consistent cross-sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association., Highlights: Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two-step, individual participant data (IPD) meta-analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Efforts to prevent dementia can benefit from precision interventions delivered to the right population at the right time; that is, when the potential to reduce risk is the highest. Young adults (aged 18-39 years) are a neglected population in dementia research and policy making despite being highly exposed to several known modifiable risk factors. The risk and protective factors that have the biggest effect on dementia outcomes in young adulthood, and how these associations differ across regions and groups, still remain unclear. To address these uncertainties, the Next Generation Brain Health team convened a multidisciplinary expert group representing 15 nations across six continents. We identified several high-priority modifiable factors in young adulthood and devised five key recommendations for promoting brain health, ranging from individual to policy levels. Increasing research and policy focus on brain health across the life course, inclusive of younger populations, is the next crucial step in the efforts to prevent dementia at the global level., Competing Interests: Declaration of interests KD declares support from The Netherlands Organization for Health Research and Development (1051003210004). EG-V declares support from National Institute on Aging (NIA; K23AG061276), Alzheimer’s Association, and Massachusetts General Hospital Executive Committee on Research. EG-V (VarMed Management), TGH-J (Cogstate), and BDJ (Alzheimer’s Association) declare consulting fees. KD participates on the Member Advisory Board of the National Dementia Strategy 2021–30 for the Dutch Ministry of Public Health, Welfare and Sport. BDJ participated on the Data Safety Monitoring Board and Advisory Board for Eisai. FA (GBHI); BDJ (Society for Epidemiologic Research); and LC, LK, and LIM (Alzheimer’s Association) declare support for attending meetings or travel, or both. LC declares leadership or fiduciary roles in WHO Guideline Development Group for clinical management of post-COVID-19 condition and the World Young Leaders in Dementia. WDD declares a leadership or fiduciary role in the Global Observatory of Long-Term Care; KD in the Member Expert Advisory Panel of Alzheimer Europe; and BDJ in the American Journal of Epidemiology and Society for Epidemiologic Research. WDD declares grants or contracts from BrainLat (BL-SRGP2021-03), Oregon Health Authority (interagency agreement numbers 171319, 181511, 18488, and 179517), American Nurses Foundation, NIA (P30 AG024978-18), Better with Age Initiative of the Portland State University Foundation, GBHI, Alzheimer’s Association (GBHI ALZ UK-20-640170), and Health Resources and Services Administration (U1Q53044). BDJ declares grant funding from NIA; and LIM from GBHI, Alzheimer’s Association, and The Atlantic Institute. WDD (GBHI), BDJ (Yale University and NIA), and LR (Eli Lilly) declare payment or honoraria. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer's Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations., Objective: To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states., Evidence Review: PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms "biomarker" OR "amyloid" OR "tau" OR "neurodegeneration" OR "preclinical" OR "CSF" OR "PET" OR "plasma" AND "Alzheimer's disease." The references of relevant articles were also searched., Findings: In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease., Conclusions and Relevance: The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

Changes in neuronal inhibition have been implicated in age-related declines in sensorimotor performance. While indirect evidence suggests that inhibitory mechanisms are also involved in rhythm entrainment, this association has not been tested. Using magnetic resonance spectroscopy, we tested the association between dorsomedial frontal GABA+/H2O concentrations and musical rhythm production in healthy younger (n = 14; 18-35) and older (n = 12; 55-79) adults, hypothesizing that lower GABA+/H2O concentrations would be associated with increased timing error, particularly on more difficult exercises, and intra-individual variability (quantified via mean successive squared difference (MSSD)). Rhythm learning exercises were presented in order of complexity. Linear mixed effects modeling revealed GABA+/H2O-by-exercise number interaction (β = -0.59, p = 0.006) such that participants with lower GABA+/H2O showed greater performance decrement with increasing exercise difficulty. GABA+/H2O trended toward an inverse association with MSSD (β = -0.25, p = 0.089), such that higher GABA+/H2O was associated with lower variability in performance. Older age was associated with increased absolute timing error (β = 0.66, p < 0.001) and greater MSSD (β = 0.86, p = 0.012). However, there was no evidence for age group differences in GABA+/H2O-performance relationships. This finding suggests that GABAergic neuronal inhibition may be important in musical rhythm production across age groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The behavioral variant of frontotemporal dementia (bvFTD) includes symptoms that reflect altered pursuit of rewards, including food, alcohol, and money. Little is known, however, about how these reward changes relate to atrophy and functional connectivity within reward-related regions. The goal of this study was to examine the structural and functional correlates of valence perception for olfactory rewards in 24 patients with bvFTD. Regression analysis of resting-state brain functional connectivity indicated that more positive valence ratings of olfactory stimuli were predicted by ventral pallidum connectivity to other reward circuit regions, particularly functional connectivity between ventral pallidum and bilateral anterior cingulate cortex/ventromedial prefrontal cortex. Structural analysis showed that atrophy of the anterior cingulate cortex was also significantly associated with perceiving stimuli as more rewarding. Finally, there was a significant interaction between ventral pallidum connectivity and atrophy of the anterior cingulate cortex. More specifically, the ventral pallidum connectivity had a greater effect on the positive perception of olfactory stimuli in the setting of low anterior cingulate cortex volume. These findings indicate that atrophy and functional connectivity within reward-relevant regions exert independent and interacting effects on the perception of pleasantness in bvFTD, potentially due to changes in hedonic "liking" signals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo MRS. However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T 2 changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T 2 and age in a large, multi-site cohort., Methods: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ y old (n = 101 total). We collected PRESS data at eight TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T 2 ., Results: Older age was correlated with shorter T 2 for tNAA 2.0 , tCr 3.0 , tCr 3.9 , tCho, and tissue water (CSO and PCC), as well as mI and Glx (PCC only); r s  = -0.22 to -0.63, all p < 0.05, false discovery rate (FDR)-corrected. These associations largely remained statistically significant when controlling for cortical atrophy. By region, T 2 values were longer in the CSO for tNAA 2.0 , tCr 3.9 , Glx, and tissue water and longer in the PCC for tCho and mI. T 2 did not differ by region for tCr 3.0 ., Conclusion: These findings underscore the importance of considering metabolite T 2 differences with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T 2 values instead of relying on uniform default values., (© 2024 International Society for Magnetic Resonance in Medicine.)

The locus coeruleus (LC) is among the first brain structures impacted by Alzheimer's disease (AD), and noradrenergic denervation may contribute to early neurovascular dysfunction in AD. Mechanistic links between the LC and cerebral perfusion have been demonstrated in rodents, but there have been no similar studies in aging humans. Community-dwelling older adults with no history of stroke or dementia (N=66) underwent structural (T1-MPRAGE; T1-FSE) and perfusion (resting pCASL) MRI. Plasma AD biomarkers levels were evaluated for Aβ42/40 ratio (n=56) and pTau181 (n=60). Higher rostral LC structural MRI contrast was associated with lower perfusion in entorhinal and limbic regions but higher perfusion in lateral and medial orbitofrontal cortices. Relationships between LC structure and regional cerebral perfusion were attenuated in older adults with higher plasma pTau levels and lower plasma Aβ42/40 ratios. Previously unstudied links between LC structure and cerebral perfusion are detectible in older adults using MRI and are attenuated in those showing greater AD pathophysiologic change, suggesting an uncoupling of LC-cerebral perfusion relationships in older adults with aggregating AD-related pathophysiology., Competing Interests: Disclosure statement The authors confirm that no conflicts of interest exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cognitive aging has become a public health concern as the mean age of the population is ever-increasing. It is a naturalistic and common process of degenerative and compensatory changes that may result in neurocognitive disorders. While heterogeneous, cognitive aging mostly affects executive functions that may be associated with functional losses during activities of daily living. Cognition-oriented treatments like cognitive training and transcranial direct current stimulation (tDCS) have garnered considerable attention in the past few decades while the exact picture regarding their efficacy in healthy older adults has not been determined yet. The present paper aimed to evaluate the effects of a 3-month intervention of tDCS over the dorsolateral prefrontal cortex (DLPFC) with multimodal cognitive training on the Stroop test and Trail Making Tests A and B performance. One hundred and ninety-three healthy older adults from 2 sites were administered repeated sessions of active/sham tDCS with cognitive training. Baseline, post-intervention, and 1-year performance results between groups were compared using multiple linear regressions. Active tDCS resulted in better Stroop test performance at post-intervention (p = 0.033) but not at 1-year follow-up while no differences between groups were observed in Trail Making Tests A & B performance. The present results may correspond to a modest improvement in conflict monitoring, potentially due to modulation of prefrontal regions, without changing shifting performance. Further investigation is warranted to draw an interference regarding the subdomain-specific impact of repeated tDCS with multimodal cognitive training on executive functions., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Introduction: Subjective visual impairment (VI) is related to cognition in cognitively unimpaired (CU) older adults, mild cognitive impairment (MCI) patients, and Alzheimer's disease (AD) patients. The utility of subjective VI as an indicator for domain-specific cognitive impairment is unknown., Methods: We used the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25 item) and a neuropsychological battery to assess the relationship between subjective VI and domain-specific cognitive performance in CU older adults ( N  = 58) and MCI patients ( N  = 16)., Results: The CU group showed a positive relationship between subjective VI and visuospatial performance. CU older adults at high risk for AD demonstrated a unique relationship between subjective VI and attention, processing speed, and executive function. Peripheral vision was related to domain-specific performance in the patient group., Discussion: Subjective VI complaints may indicate potential for domain-specific cognitive decline in visuospatial performance, executive function, processing speed, and attention in older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dubois, Sergio, Mozdbar, Price, Stradtman, Thompson, Snyder and Alber.)

Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts ( n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.

Background: Western countries have provided reference values (RV) for Alzheimer's disease (AD) plasma biomarkers, but there are not available in Sub-Saharan African populations., Objective: We provide preliminary RV for AD and other plasma biomarkers including amyloid- β (Aβ42/40), phosphorylated tau-181 and 217 (p-tau181, p-tau217), neurofilament light (Nfl), glial fibrillary acidic protein (GFAP), interleukin 1b and 10 (IL-1b and IL-10) and tumor necrosis factor α (TNFα) in Congolese adults with and without dementia., Methods: 85 adults (40 healthy and 45 dementia) over 50 years old were included. Blood samples were provided for plasma AD biomarkers Aβ42/40 and p-tau181, p-tau217; Nfl and GFAP; IL-1b and IL-10 and TNFα analyzed using SIMOA. Linear and logistic regressions were conducted to evaluate differences in biomarkers by age and gender and neurological status, and for the prediction of dementia status by each individual biomarker. RV were those that optimized sensitivity and specificity based on Youden's index., Results: In this sample of 85 adults, 45 (53%) had dementia, 38 (45%) were male, overall mean age was 73.2 (SD 7.6) years with 8.3 (5.4) years of education. There were no significant differences in age, gender, and education based on neurological status. Biomarker concentrations did not significantly differ by age except for p-tau181 and GFAP and did not differ by sex. Preliminary normal value cutoffs of various plasma in pg./mL were 0.061 for Aβ42/40, 4.50 for p-tau 181, 0.008 for p-tau 217, 36.5 for Nfl, 176 for GFAP, 1.16 for TNFa, 0.011 for IL-1b, and 0.38 for IL-10. All AUCs ranged between 0.64-0.74. P-tau 217 [0.72 (95% CI: 0.59, 0.84)] followed by GFAP [0.72 (95% CI: 0.61, 0.83)], and Nfl [0.73 (95% CI: 0.62, 0.84)] had the highest AUC compared to other plasma biomarkers., Conclusion: This study provides RV which could be of preliminary utility to facilitate the screening, clinical diagnostic adjudication, and classification, of dementia in Congolese adults., Competing Interests: AJ was employed by ALZpath, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ikanga, Jean, Medina, Patel, Schwinne, Epenge, Gikelekele, Tshengele, Kavugho, Mampunza, Mananga, Teunissen, Stringer, Rojas, Chan, Lario Lago, Kramer, Boxer, Jeromin, Gross and Alonso.)

A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABA A potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABA A receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.

Background: Subjective cognitive concerns (SCC) may be among the earliest clinical symptoms of dementia. There is growing interest in applying mobile app-based cognitive assessment to remotely screen for cognitive status in preclinical dementia, but the relationship between SCC and relevant mobile assessment metrics is uncertain., Objective: We characterized the relationship between SCC and adherence, satisfaction, and performance on mobile-app assessments in cognitively unimpaired older adults., Methods: Participants (N=122, Mage=69.85, Meducation=16.52, %female=66.7, %White=86.2) completed 8 assessment days using Mobile Monitoring of Cognitive Change (M2C2), an app-based testing platform, with brief daily sessions within morning, afternoon, and evening time windows (24 total testing sessions). M2C2 includes digital working memory, processing speed, and episodic memory tasks. Participants provided feedback about their satisfaction and motivation related to M2C2 upon study completion. SCC was assessed using the Cognitive Function Instrument (CFI). Regression analyses evaluated the association between SCC and adherence, satisfaction, and performance on M2C2, controlling for age, sex, depression, and loneliness. Linear-mixed effects models evaluated whether SCC predicted M2C2 subtest performance over the 8-day testing period, controlling for covariates., Results: SCC was not associated with app satisfaction or protocol motivation, but it was significantly associated with lower rates of protocol adherence (ß=-0.197, p=.037, 95% CI -0.647, -0.021). Higher SCC endorsement significantly predicted worse overall episodic memory performance (ß=-0.200, p = .020, 95% CI -0.020, -0.002), but not working memory or processing speed. There was a main effect of SCC on working memory performance at day 1 (Est=-1.047, SE=0.47, p=0.031) and a significant interaction between SCC and working memory over the 8-day period (Est=0.048, SE=0.02, p=0.031), such that SCC was associated with initially worse, then progressively better working memory performance., Conclusions: SCCs are associated with worse overall memory performance on mobile-app assessments, patterns of cognitive inefficiency (variable working memory) and mildly diminished adherence across an 8-day assessment period. Findings suggest that mobile app assessments may be sensitive to subtle cognitive changes, with important implications for early detection and treatment for individuals at risk for dementia.

Based on historic observations that children with reading disabilities were disproportionately both male and non-right-handed, and that early life insults of the left hemisphere were more frequent in boys and non-right-handed children, it was proposed that early focal neuronal injury disrupts typical patterns of motor hand and language dominance and in the process produces developmental dyslexia. To date, these theories remain controversial. We revisited these earliest theories in a contemporary manner, investigating demographics associated with reading disability, and in a subgroup with and without reading disability, compared structural imaging as well as patterns of activity during tasks of verb generation and non-word repetition using magnetoencephalography source imaging. In a large group of healthy aging adults (n = 282; average age 72.3), we assessed reading ability via the Adult Reading History Questionnaire and found that non-right-handedness and male sex significantly predicted endorsed reading disability. In a subset of participants from the larger cohort who endorsed reading disability (n = 14) and a group who denied reading disability (n = 22), we compared structural and functional imaging data. We failed to detect structural differences in volumetric brain morphometry analyses, however we observed decreased neural activity on magnetoencephalography within the reading disability group. The detected differences were largely restricted to left hemisphere ventral occipito-temporal and posterior-lateral temporal cortices, the visual word form area and middle temporal gyrus, regions implicated in developmental dyslexia. Moreover, these observed disruptions occurred in a focal, network-specific manner, preferentially disturbing the ventral/sight reading recognition pathway, resulting in a pattern of regional anomalous lateralization of function that distinguished the reading disability cohort from normal readers. Collectively, the results presented here align with old theories regarding the etiology of developmental dyslexia and highlight how results from investigating neurodevelopmental differences in healthy aging individuals can powerfully contribute towards our overall understanding of neurodevelopment and neurodiversity., Competing Interests: Declaration of competing interest ZAM reports no relevant disclosures. LBNH reports no relevant disclosures. VB reports no relevant disclosures. EM reports no relevant disclosures. WS reports no relevant disclosures. DM reports no relevant disclosures. RB reports no relevant disclosures. MLM reports no relevant disclosures. JD reports no relevant disclosures. CWP reports no relevant disclosures. IEA reports no relevant disclosures. JH reports no relevant disclosures. JHK reports no relevant disclosures. BLM reports serving on the Cambridge National Institute for Health Research Biomedical Research Centre advisory committee and its subunit, the Biomedical Research Unit in Dementia; serving as a board member for the American Brain Foundation; serving on John Douglas French Alzheimer's Foundation board of directors; serving on the Safely You board of directors; serving as scientific director for the Tau Consortium; serving as medical advisor for and receiving a grant from The Bluefield Project for Frontotemporal Dementia Research; serving as a consultant for Rainwater Charitable Foundation, Stanford Alzheimer's Disease Research Center, Buck Institute SAB, Larry L. Hillblom Foundation, University of Texas Center for Brain Health, University of Washington Alzheimer's Disease Research Center EAB, and Harvard University Alzheimer's Disease Research Center EAB; receiving royalties from Guilford Press, Cambridge University Press, Johns Hopkins Press, and Oxford University Press; serving as editor for Neurocase; serving as section editor for Frontiers in Neurology; and receiving grants P30 AG062422, P01 AG019724, R01 AG057234, and T32 AG023481 from the NIH. SSN reports no relevant disclosures. MLGT reports no relevant disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Postoperative delirium is a common complication in older adults, associated with poor outcomes, morbidity, mortality, and higher health care costs. Older age is a strong predictor of delirium. Intraoperative burst suppression on the electroencephalogram (EEG) has also been linked to postoperative delirium and poor neurocognitive outcomes., Methods: In this a secondary analysis of data from the Perioperative Anesthesia Neurocognitive Disorder Assessment-Geriatric (PANDA-G) observational study, the raw EEGs of 239 spine surgery patients were evaluated. Associations between delirium and age, device-generated burst suppression ratio, and visual detection of the raw EEG were compared., Results: Demographics and anesthesia durations were similar in patients with and without delirium. There was a higher incidence of burst suppression identified by analysis of the raw EEG in the delirium group than in the no delirium group (73.45% vs. 50.9%; P=0.001) which appeared to be driven largely by a higher incidence of burst suppression during maintenance of anesthesia (67.2% vs. 46.3%; P=0.004). Burst suppression was more strongly associated with delirium than with age; estimated linear regression coefficient for burst suppression 0.182 (SE: 0.057; P=0.002) and for age 0.009 (SE: 0.005; P=0.082). There was no significant interaction between burst suppression and age (-0.512; SE: 0.390; P=0.190). Compared with visual detection of burst suppression, the burst suppression ratio overestimated burst suppression at low values, and underestimated burst suppression at high values., Conclusion: Intraoperative burst suppression identified by visual analysis of the EEG was more strongly associated with delirium than age in older adults undergoing spine surgery. Further research is needed to determine the clinical importance of these findings., Competing Interests: O.L.B.C. participated as an investigator for the clinical trial OLIVER from Medtronic. M.K. and P.S.G. are co-inventors on several patents related to intraoperative EEG analysis owned by Columbia and TUM. P.S.G. is a co-founder of a company, Lantern Laboratories Inc., that has a license to build software and hardware for intraoperative monitoring. P.S.G. received funding from Merck Inc., for study on an unrelated topic. M.K. received funding from Masimo Corporation, Narcotrend-Gruppe, Medtronic GmbH, and Fresenius Kabi Deutschland GmbH for conducting EEG-based training for anesthesiologists. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Accurate Alzheimer's Disease (AD) progression prediction is essential for early intervention. The TADPOLE challenge, involving 92 algorithms, used multimodal biomarkers to predict future clinical diagnosis, cognition, and ventricular volume. The winning algorithm, FROG, utilized a Longitudinal-to-Cross-sectional (L2C) transformation to convert variable longitudinal histories into fixed-length feature vectors, which contrasted with most existing approaches that fitted models to entire longitudinal histories, e.g., AD Course Map (AD-Map) and minimal recurrent neural networks (MinimalRNN). The TADPOLE challenge only utilized the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. To evaluate FROG's generalizability, we trained it on the ADNI dataset and tested it on three external datasets covering 2,312 participants and 13,200 timepoints. We also introduced two FROG variants. One variant, L2C feedforward neural network (L2C-FNN), unified all XGBoost models used by the original FROG with an FNN. Across external datasets, L2C-FNN and AD-Map were the best for predicting cognition and ventricular volume. For clinical diagnosis prediction, L2C-FNN was the best, while AD-Map was the worst. L2C-FNN compared favorably with other approaches regardless of the number of observed timepoints, and when predicting from 0 to 6 years into the future, underscoring its potential for long-term dementia progression prediction. Pretrained ADNI models are publicly available: GITHUB&#95;LINK.

Brain age is a powerful marker of general brain health. Furthermore, brain age models are trained on large datasets, thus giving them a potential advantage in predicting specific outcomes - much like the success of finetuning large language models for specific applications. However, it is also well-accepted in machine learning that models trained to directly predict specific outcomes (i.e., direct models) often perform better than those trained on surrogate outcomes. Therefore, despite their much larger training data, it is unclear whether brain age models outperform direct models in predicting specific brain health outcomes. Here, we compare large-scale brain age models and direct models for predicting specific health outcomes in the context of Alzheimer's Disease (AD) dementia. Using anatomical T1 scans from three continents (N = 1,848), we find that direct models outperform brain age models without finetuning. Finetuned brain age models yielded similar performance as direct models, but importantly, did not outperform direct models although the brain age models were pretrained on 1000 times more data than the direct models: N = 53,542 vs N = 50. Overall, our results do not discount brain age as a useful marker of general brain health. However, in this era of large-scale brain age models, our results suggest that small-scale, targeted approaches for extracting specific brain health markers still hold significant value.