A framework for translating tauopathy therapeutics: Drug discovery to clinical trials.

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players.

Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration. Design, Setting, and Participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses. Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts). Main Outcomes and Measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume. Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (ß = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (ß = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (ß = -0.74 [95% CI, -1.35 to -0.13]; P = .04). Conclusions and Relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Cavum Septum Pellucidum in Former American Football Players: Findings From the DIAGNOSE CTE Research Project.

Background and Objectives: Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI. This study examines CSP in living former American football players, investigating its association with RHI exposure, traumatic encephalopathy syndrome (TES) diagnosis, and provisional levels of certainty for CTE pathology. Methods: Data from the DIAGNOSE CTE Research Project were used to compare the presence and ratio of CSP in former American football players (n = 175), consisting of former college (n = 58) and former professional players (n = 117), and asymptomatic unexposed controls without RHI exposure (n = 55). We further evaluated potential associations between CSP measures and cumulative head impact index (CHII) measures (frequency, linear acceleration, and rotational force), a TES diagnosis (yes/no), and a provisional level of certainty for CTE pathology (suggestive, possible, and probable). Results: Former American football players exhibited a higher CSP presence and ratio than unexposed asymptomatic controls. Among player subgroups, professional players showed a greater CSP ratio than former college players and unexposed asymptomatic controls. Among all football players, CHII rotational forces correlated with an increased CSP ratio. No significant associations were found between CSP measures and diagnosis of TES or provisional levels of certainty for CTE pathology. Discussion: This study confirms previous findings, highlighting a greater prevalence of CSP and a greater CSP ratio in former American football players compared with unexposed asymptomatic controls. In addition, former professional players showed a greater CSP ratio than college players. Moreover, the relationship between estimates of CHII rotational forces and CSP measures suggests that cumulative frequency and strength of rotational forces experienced in football are associated with CSP. However, CSP does not directly correlate with TES diagnosis or provisional levels of certainty for CTE, indicating that it may be a consequence of RHI associated with rotational forces. Further research, especially longitudinal studies, is needed for confirmation and to explore changes over time.

Single-nucleus multiome analysis of human cerebellum in Alzheimer's disease-related dementia.

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.

Identification of Parkinson's disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data.

Parkinson's disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (≥5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals' phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/α-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3, FYN, BECN1, APOA1, NEDD4, and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Care partner-informed meaningful change thresholds for the Clinical Dementia Rating-Sum of Boxes for trials of early Alzheimer's disease.

INTRODUCTION: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials. METHODS: Anchor-based analyses were conducted to evaluate MWPC on the CDR-SB in early AD (Tauriel; NCT03289143) using Caregiver Global Impression of Change in memory or daily activities. RESULTS: Across time points and anchors, mean CDR-SB changes associated with the "somewhat worse" category ranged from 1.50 to 2.12 in early AD, 1.07 to 2.06 in mild cognitive impairment-AD, and 1.79 to 2.25 in mild AD. DISCUSSION: The proposed ranges are appropriate to define meaningful progression on the CDR-SB in similar cohorts and support the interpretation of treatment benefit through MWPC analyses. Thresholds should be calibrated to the context of use; lower/higher thresholds may be applicable in studies of earlier/later disease over shorter/longer durations. HIGHLIGHTS: Within-patient CDR-SB change thresholds are provided using caregiver-rated anchors. 1.5 to 2.5 points may be an appropriate range in early AD trials of similar durations. Cumulative distribution function plots illustrate the benefit of a given treatment. When selecting thresholds, the target population and study design should be considered.

Characterizing Neurobehavioral Dysregulation Among Former American Football Players: Findings From the DIAGNOSE CTE Research Project.

OBJECTIVE: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses. METHODS: Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles. RESULTS: Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%). CONCLUSIONS: These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD.

Scenarios for the long-term efficacy of amyloid-targeting therapies in the context of the natural history of Alzheimer's disease.

INTRODUCTION: Recent clinical trials of amyloid beta (Aß)-targeting therapies in Alzheimer's disease (AD) have demonstrated a clinical benefit over 18 months, but their long-term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long-term scenarios. METHODS: Results from recent phase 3 trials of Aß-targeting antibodies were integrated with an estimate of the long-term patient-level natural history trajectory of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score to explore realistic long-term efficacy scenarios. RESULTS: Three distinct long-term efficacy scenarios were examined, ranging from conservative to optimistic. These extrapolations of positive phase 3 trials suggested treatments delayed onset of severe dementia by 0.3 to 0.6 years (conservative), 1.1 to 1.9 years (intermediate), and 2.0 to 4.2 years (optimistic). DISCUSSION: Our study provides a common language for long-term impact of disease-modifying treatments. Our work calls for studies with longer follow-up and results from early intervention trials to provide a comprehensive assessment of these therapies' true long-term impact. HIGHLIGHTS: We present long-term scenarios of the efficacy of AD therapies. In this framework, scenarios are defined relative to the natural history of AD. Long-term projections with different levels of optimism can be compared. It provides a common language for expressing beliefs about long-term efficacy.

Classifying Alzheimer's Disease Neuropathology Using Clinical and MRI Measurements.

Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.

Alzheimer's Disease: Combination Therapies and Clinical Trials for Combination Therapy Development.

Alzheimer's disease (AD) is a complex multifaceted disease. Recently approved anti-amyloid monoclonal antibodies slow disease progression by approximately 30%, and combination therapy appears necessary to prevent the onset of AD or produce greater slowing of cognitive and functional decline. Combination therapies may address core features, non-specific co-pathology commonly occurring in patients with AD (e.g., inflammation), or non-AD pathologies that may co-occur with AD (e.g., α-synuclein). Combination therapies may be advanced through co-development of more than one new molecular entity or through add-on strategies including an approved agent plus a new molecular entity. Addressing add-on combination therapy is currently urgent since patients on anti-amyloid monoclonal antibodies may be included in clinical trials for experimental agents. Phase 1 information must be generated for each agent in combination drug development. Phase 2 and Phase 3 of add-on therapies may contrast the new molecular entity, the approved agent as standard of care, and the combination. More complex development programs including standard or modified combinatorial designs are required for co-development of two or more new molecular entities. Biomarkers are markedly affected by anti-amyloid monoclonal antibodies, and these effects must be anticipated in add-on trials. Examining target engagement biomarkers and comparing the magnitude and sequence of biomarker changes in those receiving more than one therapy, compared with those on monotherapy, may be informative. Using network-based medicine approaches, computational strategies may identify rational combinations using disease and drug effect network mapping.

Improving Fecal Immunochemical Test Collection for Colorectal Cancer Screening During the COVID-19 Pandemic.

Background: Colonoscopy is a first-line method for colorectal cancer (CRC) screening. However, cost-effective noninvasive tests, such as high-sensitivity guaiac-based fecal occult blood test (gFOBT) and fecal immunochemical test (FIT), are also used. The COVID-19 pandemic had a substantial negative impact on CRC screening rates. The James A. Haley Veterans Affairs Hospital (JAHVAH) continued socially distant CRC screening using FITs, but encountered inefficiencies due to high rates of incorrectly collected FIT samples. A quality improvement (QI) project was conducted to increase correctly collected and testable FIT kits upon initial laboratory submission. Observations: The ambulatory QI project sought out root causes for incorrectly returned FITs and proposed Plan-Do-Study-Act (PDSA) cycles based on a series of approved action plans. A multidisciplinary team of laboratory, nursing, administrative, and primary care staff worked together to discover 6 major root causes. Our multipronged PDSA cycle attempted to set up redundant patient reminders, centralize the FIT dispersal process, and make the patient-FIT interface more user-friendly. All PDSA solutions were implemented over 4 months. Lack of collection date was the most common reason for incorrectly returned FIT kits and the focus of PDSA improvements. The rate of FITs with missing collection dates dropped from 24% prior to PDSA to 14% in April 2021. The rate of correctly returned FIT kits rose from 38% before the project to 72% afterwards, surpassing the 20% improvement goal. Conclusions: FIT is a useful method for CRC screening that can be particularly helpful when in-person visits are limited, as seen during the COVID-19 pandemic. The increase in demand for FITs during the pandemic revealed process deficiencies and gave JAHVAH an opportunity to improve workflow.

Generating real-world evidence in Alzheimer's disease: Considerations for establishing a core dataset.

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings.

Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.

Abnormal calcium signaling is a central pathological component of Alzheimer's disease (AD). Here, we describe the identification of a class of compounds called ReS19-T, which are able to restore calcium homeostasis in cell-based models of tau pathology. Aberrant tau accumulation leads to uncontrolled activation of store-operated calcium channels (SOCCs) by remodeling septin filaments at the cell cortex. Binding of ReS19-T to septins restores filament assembly in the disease state and restrains calcium entry through SOCCs. In amyloid-ß and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-ß and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.

p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial.

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders: A Review.

Importance: Neuropsychiatric syndromes (NPSs) are common in neurodegenerative disorders (NDDs); compromise the quality of life of patients and their care partners; and are associated with faster disease progression, earlier need for nursing home care, and poorer quality of life. Advances in translational pharmacology, clinical trial design and conduct, and understanding of the pathobiology of NDDs are bringing new therapies to clinical care. Observations: Consensus definitions have evolved for psychosis, agitation, apathy, depression, and disinhibition in NDDs. Psychosocial interventions may reduce mild behavioral symptoms in patients with NDD, and pharmacotherapy is available for NPSs in NDDs. Brexpiprazole is approved for treatment of agitation associated with Alzheimer disease dementia, and pimavanserin is approved for treatment of delusions and hallucinations associated with psychosis of Parkinson disease. Trials are being conducted across several of the NDDs, and a variety of mechanisms of action are being assessed for their effect on NPSs. Conclusions and Relevance: Detection and characterization of NPSs in patients with NDDs is the foundation for excellent care. New definitions for NPSs in NDDs may inform choices regarding clinical trial populations and translate into clinical practice. Psychosocial and pharmacologic therapies may reduce behavioral symptoms and improve quality of life for patients and caregivers. Approved agents may establish regulatory precedents, demonstrate successful trial strategies, and provide the foundation for further advances in treatment development.

Montreal Cognitive Assessment (MoCA) XpressO: Validation of a digital self-administered cognitive prescreening tool.

BACKGROUND: The need for cognitive testing is increasing with the aging population and the advent of new Alzheimer disease therapies. To respond to the increased demand, the XpressO was developed as a self-administered digital cognitive prescreening tool that will help distinguish between populations of subjective and objective cognitive impairment according to the Montreal Cognitive Assessment (MoCA). METHODS: This is a prospective validation study. XpressO is composed of tasks that assess memory and executive functions. It is validated compared to the digital MoCA as a gold standard. Out of 118 participants screened from the MoCA Clinic and a family practice clinic, 88 met inclusion criteria, two participants had missing data due to incomplete tasks, 86 participants were included in the analysis; the mean age was 70.34 years. A logistic regression model was built, and its accuracy was evaluated by the sensitivity, specificity, and Area Under the Curve (AUC) of the Receiver Operating Characteristic. RESULTS: Analysis showed strong correlation between (1) XpressO memory tasks scores and the MoCA Memory Index Score (p-values < 0.001), and between (2) XpressO sub-test scores and MoCA total score (p-values < 0.005). The AUC for predicting MoCA performance is 0.845. To classify individuals with normal and abnormal MoCA scores, two threshold values were introduced for the total XpressO scores: sensitivity of 91% at a cutoff of 72, specificity of 90% at a cutoff of 42, and an undetermined range in between. CONCLUSION: XpressO demonstrated high AUC, high sensitivity and specificity to predict cognitive performance compared to the digital MoCA. It may provide efficient cognitive prescreening by identifying individuals who would benefit from further clinical assessments, potentially reducing waiting times and high burden on healthcare clinics.

Alzheimer's disease drug development pipeline: 2024.

INTRODUCTION: New therapies to prevent or delay the onset of symptoms, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed. METHODS: We interrogated clinicaltrials.gov including all clinical trials assessing pharmaceutical therapies for AD active in on January 1, 2024. We used the Common Alzheimer's Disease Research Ontology (CADRO) to classify the targets of therapies in the pipeline. RESULTS: There are 164 trials assessing 127 drugs across the 2024 AD pipeline. There were 48 trials in Phase 3 testing 32 drugs, 90 trials in Phase 2 assessing 81 drugs, and 26 trials in Phase 1 testing 25 agents. Of the 164 trials, 34% (N = 56) assess disease-modifying biological agents, 41% (N = 68) test disease-modifying small molecule drugs, 10% (N = 17) evaluate cognitive enhancing agents, and 14% (N = 23) test drugs for the treatment of neuropsychiatric symptoms. DISCUSSION: Compared to the 2023 pipeline, there are fewer trials (164 vs. 187), fewer drugs (127 vs. 141), fewer new chemical entities (88 vs. 101), and a similar number of repurposed agents (39 vs. 40). Highlights: In the 2024 Alzheimer's disease drug development pipeline, there are 164 clinical trials assessing 127 drugs.The 2024 Alzheimer's disease drug development pipeline has contracted compared to the 2023 Alzheimer pipeline with fewer trials, fewer drugs, and fewer new chemical entities.Drugs in the Alzheimer's disease drug development pipeline target a wide array of targets; the most common processes targeted include neurotransmitter receptors, inflammation, amyloid, and synaptic plasticity.The total development time for a potential Alzheimer's disease therapy to progress from nonclinical studies to FDA review is approximately 13 years.

Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.