INTRODUCTION:Intermittent hypoxemia (IH) is common in preterm infants and linked to brain injury. S100B is a glial-derived protein that rises early after neural injury and can be measured noninvasively in urine. We evaluated the relationship between IH burden and urinary S100B in preterm infants of ≤32 weeks' gestation. METHODS:Preterm infants of ≤32 weeks' gestation were prospectively enrolled. Oxygen saturation was continuously monitored, and IH profiles were quantified using validated algorithms. Urine S100B was measured by ultrasensitive immunoassay and normalized for urinary creatinine. Infants with severe intraventricular hemorrhage were excluded. Weighted Spearman correlations examined associations between IH metrics and urinary S100B, overall and by gestational age subgroups. RESULTS:Twenty-one infants contributed 53 urine samples. Higher urinary S100B correlated with greater IH frequency, percent time in hypoxemia, longer event duration, and lower nadir saturations (all p < 0.05). Short events showed the strongest correlations for frequency (ρ = 0.49) and percent time (ρ = 0.51), while longer events correlated most strongly with nadir (ρ = -0.69). Extremely preterm infants demonstrated stronger associations for nadir and duration; very preterm infants only for event severity. S100B increased stepwise across IH burden tertiles. CONCLUSIONS:Urinary S100B increases with IH burden, with patterns varying by gestational age and event duration. Urinary S100B may provide an early, noninvasive biomarker of IH-related brain injury in preterm infants.

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer’s disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a cerebrovascular atlas confirmed that ARIA-associated TEMRAs are transcriptionally “addressed” for vascular engagement. Together, these findings identify a peripheral immune signature linking metabolic reprogramming, clonal CD8+ expansion, and altered intercellular communication to ARIA, with implications for biomarker development and risk mitigation pending validation in larger cohorts. Johnson et al. link ARIA, a complication of anti-amyloid therapy, to clonal expansion of cytotoxic CD8 + T cells with glycolytic reprogramming and vascular trafficking potential, with implications for biomarker development and risk mitigation.

INTRODUCTION:Intermittent hypoxemia (IH) frequently occurs in preterm infants and is increasingly linked to adverse outcomes. We previously demonstrated a relationship between IH and S100B, a brain injury biomarker. Here, we assess these relationships with glial fibrillary acidic protein (GFAP), a protein released following astrocyte injury. METHODS:Infants ≤ 32 weeks' gestation were prospectively enrolled. Oxygen saturation was continuously monitored. IH metrics were quantified using validated algorithms using multiple SpO₂ thresholds. Urine was collected at multiple time points, and GFAP concentrations were measured using an ultrasensitive immunoassay. Infants with severe intraventricular hemorrhage were excluded. Associations between IH metrics and urinary GFAP were examined using weighted Spearman correlation analyses (ρ). RESULTS:Twenty-nine infants contributed 71 urine samples with a median of 2.4 samples per infant [IQR 1.0-4.0] collected at a median postnatal age of 36.0 days [IQR 24.0-45.3]. Higher GFAP concentrations were associated with greater IH burden, including greater percent time in hypoxemia (ρ=0.45-0.47), increased IH frequency (ρ=0.42-0.44), longer IH duration (ρ=0.47-0.48), and lower nadir (ρ= -0.42 to -0.44), all p < 0.001. When stratified by gestational age, extremely preterm infants (<28 weeks gestational age) demonstrated strong relationships between GFAP and IH events of both short (<1 min) and longer (≥1 min) duration, whereas very preterm infants (28-31 weeks gestational age) showed significant associations primarily with longer IH events. CONCLUSIONS:Urinary GFAP levels increase with greater IH exposure in preterm infants. Together with our prior findings for S100B, these results suggest that GFAP represents another astroglial biomarker associated with IH-related brain injury and may provide both mechanistic insight and a noninvasive tool for detecting early brain injury in this vulnerable population.

INTRODUCTION:Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear. METHODS:We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPPSAA knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks). RESULTS:Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and reduced cortical TNF-α without altering amyloid beta (Aβ) accumulation. DISCUSSION:HAPPSAA mice recapitulate female-predominant non-cognitive AD features, including sleep fragmentation and circadian instability preceding memory deficits. Sleep improved within weeks of MW151 treatment without Aβ reductions, implicating neuroinflammatory signaling as a rapid, modifiable driver of AD-related sleep disruption.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with significant neurological morbidity. In current practice, there are limited pharmacological interventions to reduce the neurologic and functional deficits after SAH. The current study tests a novel therapy designed to reduce neuroinflammatory responses and improve functional outcomes in a clinically relevant murine model of SAH. The effect of MW189, an anti-inflammatory small molecule investigational drug, was tested in a murine model of SAH induced by endovascular filament perforation. Male C57BL/6 J mice (10–12 weeks old) were treated with MW189 at a dose of 5 mg/kg in 100 µl 0.9

This report outlines the workflow, challenges, and key roles involved in operationalizing a complex, disruptive, acute clinical trial protocol requiring multidisciplinary collaboration. Yale University School of Medicine and the Neuroscience Intensive Care Unit (NICU) at Yale New Haven Hospital (YNHH) leverage interdisciplinary collaboration to successfully enroll patients into complex clinical trials, including the Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) trial (ClinicalTrials.gov identifier: NCT05020535). Successful execution of the BEACH trial relies on five key domains: ensuring patient safety, optimizing screening and enrollment, acquiring pharmacokinetics, identifying signals of efficacy, and adapting to operational challenges. These domains require precise coordination, communication, and adaptability within dynamic patient care environments. By streamlining workflows, all members of the care delivery team and the research team maximize efficiency and optimize patient enrollment while upholding the highest standards of ethical research and patient care. Implementation of the BEACH trial at the Yale research center exemplifies the critical role of interdisciplinary collaboration in clinical research. By integrating research into patient care, the team improves trial efficiency and contributes to innovative treatment strategies for intracerebral hemorrhage. Lessons learned can inform best practices for future acute trials and improve patient outcomes.

Alzheimer disease plasma biomarkers have emerged as minimally invasive, cost-effective tools for early diagnosis and disease monitoring yet their stability under common "real world" pre-analytical conditions remains incompletely characterized. We evaluated the stability of six plasma biomarkers, Aβ40, Aβ42, pTau181, pTau217, NfL, and glial fibrillary acidic protein (GFAP) using the Fujirebio Lumipulse G1200 platform. Plasma samples were initially collected from four healthy and cognitively unimpaired volunteers. Samples were stored under four conditions: room temperature (0-4 h), +4 °C (1-10 days), -20 °C (1-3 weeks), and -80 °C (4-8 weeks). In this pilot study, Aβ40 and Aβ42 remained generally stable. In contrast, pTau181 readings exhibited marked elevations in frozen samples, while pTau217 showed modest early fluctuations followed by significant decreases with prolonged storage. Next, we recruited 12 additional participants (six cognitively normal and six with mild cognitive impairment [MCI]), and their plasma samples were analyzed both fresh and after 4 weeks of storage at -80 °C. Among these participants, pTau181 readouts were significantly higher, and pTau217 were lower, in -80 °C frozen in comparison to never-frozen samples. These findings underscore the critical need for biomarker-specific sample workup and handling protocols and indicate that results for fresh plasma cannot be assumed to be the same as for frozen samples.

Four decades of the National Institute on Aging's sponsored research into Alzheimer's disease (AD) have resulted in symptomatic and mechanistic therapies, lifestyle interventions, increased understanding of genetic factors and protein misfolding, and descriptions of non-AD neuropathological entities that mimic AD clinical symptoms. This is an overview of contributions from one of the original ten Alzheimer Disease Research Centers (ADRCs), the University of Kentucky ADRC. We celebrate 40 years of helping the field to define early pathogenetic mechanisms underlying transitions from normal cognitive aging to impairment in our elderly community-based cohort, increased appreciation of the heterogeneity and multiple pathologies that characterize late-life dementia, strategies for therapeutic intervention, and novel statistical approaches. We also highlight our educational efforts to train the workforce of the future and our long-standing community outreach and partnerships. HIGHLIGHTS: The University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) is an experienced and collaborative center celebrating its 40th year of National Institute on Aging funding in 2025. Our long-standing community-based cohort of motivated older adult volunteers and strong neuropathology program support the rationale for our overarching theme: "Transitions from Normal to Late-Life Multi-Etiology Dementia." The UK-ADRC's focus on normal aging and early cognitive transitions has been central to elucidating pathogenic mechanisms underlying transitions from normal cognitive aging to impairment and defining the heterogeneity and multiple pathologies that characterize late-life dementia. UK-ADRC infrastructure and resources support and create new opportunities for innovative and inclusive research, clinical programs across the cognitive continuum, educational and training opportunities, and community and national partnerships.

White matter hyperintensities (WMH) are an MRI-based biomarker associated with aging, Alzheimer’s disease, and vascular dementia. Although the volume of WMH typically increases over time (growth) for individuals, WMH volume in some cases can also decrease (regress). This suggests the presence of active brain injury recovery mechanisms. Whether WMH regression reflects a true biological phenomenon or results from imaging artifacts or measurement errors, however, remains controversial. Here, we review published reports, following PRISMA search guidelines, describing or referring to WMH regression, the methods used to detect and quantitate regression, and proposed underlying mechanisms. Of 174 reviewed articles, 31 (26 original research studies and five case reports) were identified as directly related to WMH regression. Technical factors such as differences in longitudinal scan parameters, motion artifacts, and the interval between baseline and follow-up scans can affect WMH volume measurements. These factors may lead to inaccurate conclusions if appropriate controls are not employed. Although the use of standardized and systematic measurement protocols is essential, there is strong evidence indicating that WMH regression is a robust and biologically important phenomenon that may be influenced by clinical interventions. Further studies are needed to investigate WMH regression in relation to cerebrovascular risk mitigation and other therapeutic strategies.

OBJECTIVES:High-fat diet is well-known to contribute to systemic and central nervous system dysfunction and represents a modifiable risk factor for cognitive decline. A recent surge of new weight loss medications has demonstrated that caloric restriction by reduced overeating has been successful at mitigating peripheral markers of inflammation and metabolic dysfunction. However, less is known regarding such effects of dietary reversal within the brain. METHODS:Male mice received high-fat diet (HFD; 60%kCal fat) from 6 weeks of age (JAX #380050). At 14 weeks, half of the mice were reversed (Rev = 9) to a standard diet (14%kCal fat) while the other half (HFD = 10) remained on HFD for an additional 2 months. Weight, frailty, peripheral cytokines, and behavior were recorded at baseline and again at 1 and 2 months after dietary reversal. Mice were sacrificed at 22 weeks of age and terminal measures of brain neuroinflammation and metabolism were evaluated. RESULTS:In contrast to mice on continuous HFD, the mice in the Rev group lost weight, had lower frailty scores, preserved spatial discrimination, altered peripheral cytokine profiles, lower hippocampal GFAP, increased hippocampal MCP1 and IL4, improved hippocampal and midbrain insulin tone, and differentially altered TRIB3 in the hippocampus and midbrain. DISCUSSION:Early dietary reversal was effective at preventing the inflammatory, metabolic, and cognitive effects of sustained HFD with divergent effects on metabolic markers (TRIB3) depending on brain region.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7

BACKGROUND:Aneurysmal subarachnoid hemorrhage (aSAH) is a relatively uncommon but high mortality form of stroke that can result in long-lasting disability. A better understanding of key neuroinflammatory changes during the early phase (<72 h) may provide potential avenues of treatment. METHODS:In an attempt to understand these early changes, we recruited 7 aSAH patients for profiling of longitudinal plasma and cerebrospinal fluid (CSF) proteins at up to 72 h post injury. We additionally compared this to control plasma obtained previously from healthy elderly volunteers. Using the Alamar Biosciences NULISAseq platform, we obtained a comprehensive picture of early peripheral and central inflammatory changes after injury. RESULTS:This study demonstrated very early plasma changes across 107 inflammatory proteins, 22 of which showed significant correlations between plasma and CSF. Of these, CXCL12, IL-15, and SAA1 are detectably elevated <24 h in plasma, significantly correlated with CSF levels, and altered as a function of aSAH progression over time during this early phase. CONCLUSION:This study demonstrates the feasibility of measuring a large number of inflammatory proteins in CSF and plasma from aSAH patients soon after injury. Despite the small sample size and limitations of the control group, we identified several previously reported "hits" that may offer prognostic utility and/or therapeutic potential for aSAH patients: CXCL12, IL-15, and SAA1.

The p38 mitogen-activated protein kinase has a well-characterized role in modulation of inflammatory processes throughout the body. In the central nervous system, p38 is primarily studied within neurons and microglia, most commonly in the context of neurological insult. The present study was designed to determine its function in astrocytes during non-pathological aging. We generated a conditional knockout model in which a tamoxifen-inducible Aldh1l1 promoter drives Cre recombinase expression in mice with exon 1 of the p38α gene flanked by loxP sites. Knockout of astrocyte p38α was achieved via tamoxifen administration in young sexually mature mice at 3–4 months old. Animals were subsequently aged to 21–24 months prior to performing electrophysiological, immunohistochemical, and biochemical analyses. We found that early loss of astrocyte p38α was associated with a reduction in hippocampal neuroinflammation and concomitant enhancement of synaptic strength in aged female mice. In subsequent experiments in younger animals, the knockout reduced peripheral GFAP levels and increased non-synaptic mitochondrial uncoupling. These findings indicate that astrocyte p38α has wide-ranging effects on brain metabolism, inflammation, and synaptic function during the course of normal aging, including release of GFAP from the central nervous system to the periphery. Follow-up studies exploring the role of astrocyte p38α in various age-associated neuropathological contexts are warranted.

INTRODUCTION:In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field. METHODS:During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic. RESULTS:The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de-risk clinical pipeline, and (4) centralize data management. DISCUSSION:In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To finally address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified four X-chromosome-wide significant loci (P ≤ 1.7 × 10−6). Two signals locate in theFRMPD4andDMDgenes, while the two others are more than 300 kb away from the closest protein coding genesNLGN4XandGRIA3. Overall, this XWAS found no common genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in “pure” models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies. Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses. Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured. Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies (i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting.

The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta-amyloid and tau. Recent clinical trial readouts implicate a variety of non-amyloid/non-tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13-14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs. Participants also discussed the current definition of therapies that target underlying AD pathophysiology, what endpoints best define what is considered a meaningful change beyond the current approved definition for clinical efficacy, and how the recent NANT findings should inform the development of future guidelines for AD classification and personalized treatment strategies. Highlights:The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government to review the current state of non-beta amyloid and non-tau (NANT) targets on underlying Alzheimer's disease (AD) pathophysiology.The totality of scientific and clinical evidence supports the hypothesis that emerging NANT targets play a role in cognitive decline and neurodegeneration in AD. New biomarkers based on NANT targets must be globally developed and implemented with specific consideration of fluid biomarkers as a cost-effective clinical option, to ensure better, more equitable treatment options for AD.

Finite Markov chains with absorbing states are popular tools for analyzing longitudinal data with categorical responses. The one step transition probabilities can be defined in terms of fixed and random effects but it is difficult to estimate these effects due to many unknown parameters. In this article we propose a three-step estimation method. In the first step the fixed effects are estimated by using a marginal likelihood function, in the second step the random effects are estimated after substituting the estimated fixed effects into a joint likelihood function defined as a h-likelihood, and in the third step the covariance matrix for the vector of random effects is estimated using the Hessian matrix for this likelihood function. An application involving an analysis of longitudinal cognitive data is used to illustrate the method.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue ( n = 408) and single nucleus RNAseq ( n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM , and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.

IntroductionWe evaluated the relationship between plasma levels of transactive response DNA binding protein of 43 kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. MethodsPlasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). ResultsNegative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. DiscussionPlasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification. HIGHLIGHTSPlasma transactive response DNA binding protein of 43 kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.