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The overall goal of the Alzheimers Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA-approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNIs promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer the clinical trial of the future focusing on demographic inclusivity. HIGHLIGHTS: The Alzheimers Disease Neuroimaging Initiative (ADNI) introduced a novel model for public-private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimers disease. ADNI generated and disseminated vital data for designing AD clinical trials.

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.

INTRODUCTION: The Alzheimers Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimers disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment. METHODS: URPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board). RESULTS: As of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4s ≥ 50% URP representation goal for new enrollees but may not represent final enrollment. DISCUSSION: Findings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity. HIGHLIGHTS: The Alzheimers Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.

Benjamin Griffin,1 Andrew Walkden,1,2 Arthur Okonkwo,1,2 Leon Au,1,2 Arun Brahma,1,2 Fiona Carley1,2 1Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 2School of Medical Sciences, University of Manchester, Manchester, UKCorrespondence: Andrew WalkdenManchester Royal Eye Hospital, Oxford Road, M13 9WL Tel +44 7792153269Email walkdenandrew@gmail.comPurpose: To investigate the frequencies, trends, and in vitro drug susceptibilities of the causative pathogens in corneal transplant microbial infections in Manchester Royal Eye Hospital.Methods: Corneal scrape results recorded by the microbiology service between 2004 and 2015 were extracted from an established database. This microbiological data was matched with a separate database of all corneal transplant procedures performed in our centre over this time period. Patient records were examined to collect specific patient data and to confirm the diagnosis of microbial keratitis.Results: A total of 1508 grafts had been performed at our centre in this period. 72 episodes of graft microbial keratitis were identified from 66 eyes that had undergone keratoplasty procedures. Mean age was 56, and 51% of subjects were male. Ninety-three percent of microbial keratitis episodes occurred in penetrating keratoplasty procedures and 6% in deep anterior lamellar keratoplasty procedures. No endothelial grafts presented with infections throughout this time period. Of the 79 organisms identified, 73% were gram positive, 23% gram negative and 4% fungi. With regard to gram-positive organisms, vancomycin and gentamicin showed 100% and 91% susceptibility, respectively. Ofloxacin had a resistance rate of 13.7%. In terms of gram-negative organisms, gentamicin and chloramphenicol showed 100% sensitivity, with cefuroxime showing 69%. Resistance rates were less than 15% in all tested gram-negative antimicrobials.Conclusion: This paper describes the largest collection of corneal transplant infections identified within the UK. This finding may aid clinicians in predicting possible causative organisms for microbial keratitis and aid antibiotic choice.Keywords: cornea, transplant, infection, graft, microbial keratitis

Dementia prevention in Africa is critically underexplored, despite the continents high prevalence of modifiable risk factors. With a predominantly young and middle-aged population, Africa presents a prime opportunity to implement evidence-based strategies that could significantly reduce future dementia cases and mitigate its economic impact. The multinational Africa-FINGERS program offers an innovative solution, pioneering culturally sensitive, multidomain interventions tailored to the unique challenges of the region.  Leveraging insights from landmark global studies such as Worldwide-FINGERS and Alzheimers Disease Neuroimaging Initiative, the program employs a multideterminant precision prevention framework, grounded in community based systems dynamics. Africa-FINGERS further integrates cutting-edge state-of-the-art multimodal biomarker evaluations tailored to regional contexts, with the goal of advancing brain health and establishing a global standard for dementia prevention. This groundbreaking initiative highlights the potential for scalableand sustainable interventions, thus is poised to transform dementia risk reduction efforts across the continent. HIGHLIGHTS: Dementia rates are escalating in Africa, largely due to longer life spans and increased prevalence of modifiable risk factors. Yet, few regional interventions have directly targeted lifestyle factors to reduce dementia risk. The multinational Africa-FINGERS study will address this gap by adapting the successful FINGERS lifestyle intervention to African populations. Africa-FINGERS will pioneer a culturally informed, multidomain dementia risk reduction intervention in the African region through feasibility dementia prevention trials in rural and urban sites across Kenya and Nigeria in the first instance, enrolling 600 at-risk adults (≥ 50 years). The program adopts participatory research methods to develop culturally appropriate interventions and build infrastructure to evaluate dementia biomarkers from ante and post mortem samples. A cost-effectiveness analysis will be conducted to guide the strategic implementation of Africa-FINGERS into regional health systems. The Africa-FINGERS strategy aligns with the Worldwide-FINGERS framework and integrates the global Alzheimers Disease Neuroimaging Initiative approach, emphasizing multimodal analysis.

BACKGROUND: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery. METHODS: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014-2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported. FINDINGS: Of 2032 subjects (age: mean = 41.4-years, range = 17-89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p

Background and objectivesTraumatic spinal cord injury (SCI) remains a devastating condition with no proven effective treatment options available. In a prior single-arm study of patients with thoracic complete SCI (INSPIRE; ClinicalTrials.gov, NCT02138110), acute implantation of an investigational bioresorbable polymer scaffold (Neuro-Spinal Scaffold [NSS]) appeared to be safe through 24 months postimplantation and was associated with an American Spinal Injury Association Impairment Scale (AIS) conversion rate that exceeded historical controls. Here, we evaluated whether NSS implantation demonstrates probable benefit for safety and neurological recovery in patients with thoracic complete SCI vs standard-of-care spine surgery.MethodsINSPIRE 2.0 was a randomized, controlled, parallel, multicenter study conducted at Level I trauma centers in the United States (ClinicalTrials.gov, NCT03762655; funded by InVivo Therapeutics Corporation). Patients with AIS grade A, thoracic (T2-T12), nonpenetrating SCI requiring spine surgery ≤7 days postinjury were randomized (1:1, computer-generated allocation) to undergo NSS implantation or spine surgery alone (control group). Patients and follow-up International Standards for Neurological Classification of SCI assessors were blinded. A predefined study success criterion required the proportion of patients with improvement of ≥1 AIS grade at 6 months postsurgery (primary endpoint) to be ≥20% higher in the NSS group than in the control group.ResultsTarget enrollment was reached (N = 20) with 10 patients randomized and analyzed in each group. At 6 months postsurgery, an improvement in the AIS grade was reported in 2 NSS patients (20%; both to AIS C) and 3 control group patients (30%; to AIS B [n = 2] or AIS C [n = 1]). No serious or unanticipated adverse device effects were reported. The study was closed to further follow-up because of not meeting its primary endpoint.ConclusionIn this small group of patients with thoracic complete (AIS A) SCI, implantation of an intraparenchymal bioresorbable scaffold did not produce probable clinical benefit. However, this study provides evidence that surgical intervention in an injured spinal cord parenchyma may be performed safely.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimers Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's-related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14-16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

OBJECTIVE: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization After Significant Head Injury (CRASH) prognostic models for mortality and outcome after traumatic brain injury (TBI) were developed using data from 1984 to 2004. This study examined IMPACT and CRASH model performances in a contemporary cohort of US patients. METHODS: The prospective 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years 2014-2018) enrolled subjects aged ≥ 17 years who presented to level I trauma centers and received head CT within 24 hours of TBI. Data were extracted from the subjects who met the model criteria (for IMPACT, Glasgow Coma Scale [GCS] score 3-12 with 6-month Glasgow Outcome Scale-Extended [GOSE] data [n = 441]; for CRASH, GCS score 3-14 with 2-week mortality data and 6-month GOSE data [n = 831]). Analyses were conducted in the overall cohort and stratified on the basis of TBI severity (severe/moderate/mild TBI defined as GCS score 3-8/9-12/13-14), age (17-64 years or ≥ 65 years), and the 5 top enrolling sites. Unfavorable outcome was defined as GOSE score 1-4. Original IMPACT and CRASH model coefficients were applied, and model performances were assessed by calibration (intercept [< 0 indicated overprediction; > 0 indicated underprediction] and slope) and discrimination (c-statistic). RESULTS: Overall, the IMPACT models overpredicted mortality (intercept -0.79 [95% CI -1.05 to -0.53], slope 1.37 [1.05-1.69]) and acceptably predicted unfavorable outcome (intercept 0.07 [-0.14 to 0.29], slope 1.19 [0.96-1.42]), with good discrimination (c-statistics 0.84 and 0.83, respectively). The CRASH models overpredicted mortality (intercept -1.06 [-1.36 to -0.75], slope 0.96 [0.79-1.14]) and unfavorable outcome (intercept -0.60 [-0.78 to -0.41], slope 1.20 [1.03-1.37]), with good discrimination (c-statistics 0.92 and 0.88, respectively). IMPACT overpredicted mortality and acceptably predicted unfavorable outcome in the severe and moderate TBI subgroups, with good discrimination (c-statistic ≥ 0.81). CRASH overpredicted mortality in the severe and moderate TBI subgroups and acceptably predicted mortality in the mild TBI subgroup, with good discrimination (c-statistic ≥ 0.86); unfavorable outcome was overpredicted in the severe and mild TBI subgroups with adequate discrimination (c-statistic ≥ 0.78), whereas calibration was nonlinear in the moderate TBI subgroup. In subjects ≥ 65 years of age, the models performed variably (IMPACT-mortality, intercept 0.28, slope 0.68, and c-statistic 0.68; CRASH-unfavorable outcome, intercept -0.97, slope 1.32, and c-statistic 0.88; nonlinear calibration for IMPACT-unfavorable outcome and CRASH-mortality). Model performance differences were observed across the top enrolling sites for mortality and unfavorable outcome. CONCLUSIONS: The IMPACT and CRASH models adequately discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to update prognostic models to incorporate contemporary changes in TBI management and case-mix. Investigations to elucidate the relationships between increased survival, outcome, treatment intensity, and site-specific practices will be relevant to improve models in specific TBI subpopulations (e.g., older adults), which may benefit from the inclusion of blood-based biomarkers, neuroimaging features, and treatment data.

BackgroundPrior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples.MethodsThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included.ResultsData collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators.ConclusionThe pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.