Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk.

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.

Short- and long-term safety of discontinuing chronic opioid therapy among older adults with Alzheimer's disease and related dementia.

BACKGROUND: Limited evidence exists on the short- and long-term safety of discontinuing versus continuing chronic opioid therapy (COT) among patients with Alzheimer's disease and related dementias (ADRD). METHODS: This cohort study was conducted among 162,677 older residents with ADRD and receipt of COT using a 100% Medicare nursing home sample. Discontinuation of COT was defined as no opioid refills for ≥90 days. Primary outcomes were rates of pain-related hospitalisation, pain-related emergency department visit, injury, opioid use disorder (OUD) and opioid overdose (OD) measured by diagnosis codes at quarterly intervals during 1- and 2-year follow-ups. Poisson regression models were fit using generalised estimating equations with inverse probability of treatment weights to model quarterly outcome rates between residents who discontinued versus continued COT. RESULTS: The study sample consisted of 218,040 resident episodes with COT; of these episodes, 180,916 residents (83%) continued COT, whereas 37,124 residents (17%) subsequently discontinued COT. Discontinuing (vs. continuing) COT was associated with higher rates of all outcomes in the first quarter, but these associations attenuated over time. The adjusted rates of injury, OUD and OD were 0, 69 and 60% lower at the 1-year follow-up and 11, 81 and 79% lower at the 2-year follow-up, respectively, for residents who discontinued versus continued COT, with no difference in the adjusted rates of pain-related hospitalisations or emergency department visits. CONCLUSIONS: The rates of adverse outcomes were higher in the first quarter but lower or non-differential at 1-year and 2-year follow-ups between COT discontinuers versus continuers among older residents with ADRD.

Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study.

INTRODUCTION: Little is known about the heterogeneous treatment effects of metformin on dementia risk in people with type 2 diabetes (T2D). METHODS: Participants (≥ 50 years) with T2D and normal cognition at baseline were identified from the National Alzheimer's Coordinating Center database (2005-2021). We applied a doubly robust learning approach to estimate risk differences (RD) with a 95% confidence interval (CI) for dementia risk between metformin use and no use in the overall population and subgroups identified through a decision tree model. RESULTS: Among 1393 participants, 104 developed dementia over a 4-year median follow-up. Metformin was significantly associated with a lower risk of dementia in the overall population (RD, -3.2%; 95% CI, -6.2% to -0.2%). We identified four subgroups with varied risks for dementia, defined by neuropsychiatric disorders, non-steroidal anti-inflammatory drugs, and antidepressant use. DISCUSSION: Metformin use was significantly associated with a lower risk of dementia in individuals with T2D, with significant variability among subgroups.

Pain intensity, physical function, and depressive symptoms associated with discontinuing long-term opioid therapy in older adults with Alzheimer's disease and related dementias.

INTRODUCTION: Limited evidence exists on the associations of discontinuing versus continuing long-term opioid therapy (LTOT) with pain intensity, physical function, and depression among patients with Alzheimer's disease and related dementias (ADRD). METHODS: A cohort study among 138,059 older residents with mild-to-moderate ADRD and receipt of LTOT was conducted using a 100% Medicare nursing home sample. Discontinuation of LTOT was defined as no opioid refills for ≥ 60 days. Outcomes were worsening pain, physical function, and depression from baseline to quarterly assessments during 1- and 2-year follow-ups. RESULTS: The adjusted odds of worsening pain and depressive symptoms were 29% and 5% lower at the 1-year follow-up and 35% and 9% lower at the 2-year follow-up for residents who discontinued versus continued LTOT, with no difference in physical function. DISCUSSION: Discontinuing LTOT was associated with lower short- and long-term worsening pain and depressive symptoms than continuing LTOT among older residents with ADRD. HIGHLIGHTS: Discontinuing long-term opioid therapy (LTOT) was associated with lower short- and long-term worsening pain. Discontinuing LTOT was related to lower short- and long-term worsening depression. Discontinuing LTOT was not associated with short- and long-term physical function.

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. METHODS: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016-2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all-cause dementia. RESULTS: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, -2.5%; 95% CI, -3.0% to -2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from -4.3% (-5.5 to -3.2) to -0.9% (-1.9 to 0.2). DISCUSSION: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all-cause dementia, but the association varied among different subgroups. HIGHLIGHTS: New users of sodium-glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all-cause dementia as compared to those of sulfonylureas. The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease. A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults.

Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the "stimulus" portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the "probe" portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the "stimulus" screen. Widespread bilateral whole-brain activation was observed when activation patterns of the "probe" contrast were subtracted from the "stimulus" contrast. Conversely, the subtraction of "stimulus" from "probe" was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function.

Meta-analysis of age-related cognitive decline reveals a novel locus for the attention domain and implicates a COVID-19-related gene for global cognitive function.

INTRODUCTION: Cognitive abilities have substantial heritability throughout life, as shown by twin- and population-based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains. METHODS: We conducted a meta-analysis on 3045 individuals aged ≥65, derived from three population-based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene-based and functional bioinformatics analyses. RESULTS: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E-09) and global cognitive function (p = 1.84E-08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E-08), near RASEF. Gene-based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS-CoV-2, to be associated with the decline in global cognitive function (p = 4.28E-07). DISCUSSION: Domain-specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains. HIGHLIGHTS: rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS-CoV-2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains.

Air pollution and dementia in older adults in the Ginkgo Evaluation of Memory Study.

INTRODUCTION: Growing evidence implicates air pollution as a risk factor for dementia, but prior work is limited by challenges in diagnostic accuracy and assessing exposures in the decades prior to disease development. We evaluated the impact of long-term fine particulate matter (PM2.5 ) exposures on incident dementia (all-cause, Alzheimer's disease [AD], and vascular dementia [VaD]) in older adults. METHODS: A panel of neurologists adjudicated dementia cases based on extensive neuropsychological testing and magnetic resonance imaging. We applied validated fine-scale air pollutant models to reconstructed residential histories to assess exposures. RESULTS: An interquartile range increase in 20-year PM2.5 was associated with a 20% higher risk of dementia (95% confidence interval [CI]: 5%, 37%) and an increased risk of mixed VaD/AD but not AD alone. DISCUSSION: Our findings suggest that air pollutant exposures over decades contribute to dementia and that effects of current exposures may be experienced years into the future.

Early prediction of Alzheimer's disease and related dementias using real-world electronic health records.

INTRODUCTION: This study aims to explore machine learning (ML) methods for early prediction of Alzheimer's disease (AD) and related dementias (ADRD) using the real-world electronic health records (EHRs). METHODS: A total of 23,835 ADRD and 1,038,643 control patients were identified from the OneFlorida+ Research Consortium. Two ML methods were used to develop the prediction models. Both knowledge-driven and data-driven approaches were explored. Four computable phenotyping algorithms were tested. RESULTS: The gradient boosting tree (GBT) models trained with the data-driven approach achieved the best area under the curve (AUC) scores of 0.939, 0.906, 0.884, and 0.854 for early prediction of ADRD 0, 1, 3, or 5 years before diagnosis, respectively. A number of important clinical and sociodemographic factors were identified. DISCUSSION: We tested various settings and showed the predictive ability of using ML approaches for early prediction of ADRD with EHRs. The models can help identify high-risk individuals for early informed preventive or prognostic clinical decisions.

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults.

Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65-88 underwent 3 T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values<.05). Binary logistic regressions also adjusting for total intracranial volume revealed left DLPFC surface area that significantly predicted the probability of being in the higher performing group (P = 0.017). The left DLPFC BOLD signal and surface area were not significantly associated and did not significantly interact to predict group membership (P values>.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.

Agreement of Minimum Data Set 3.0 depression and behavioral symptoms with clinical diagnosis in a nursing home.

OBJECTIVES: While the Minimum Data Set (MDS) 3.0 has adopted Patient Health Questionnaire (PHQ)-9 to screen for depression and rephrased language for behavioral symptoms among nursing home residents, it remains unclear how well the assessment data agree with medical records. DESIGN: Using a retrospective review of MDS 3.0 linked to medical records between October 2010 and November 2017, we included residents with at least one quarterly or short-term (day 30 or day 60) MDS 3.0 assessment of depression PHQ-9 (n = 446) or behavioral symptoms (n = 460). For each resident of each cohort, we randomly selected an eligible MDS 3.0 depression and behavioral symptom assessment and compared against the respective medical diagnoses recorded within 30 days before the MDS 3.0 assessment. RESULTS: Percent agreement was high for depression (90.1%) and behavioral symptoms (89.3%). Negative agreement was high for depression (94.8%) and behavioral symptoms (94.3%), while positive agreement was low for both conditions (4.3% and 10.9%). CONCLUSION: MDS 3.0 depression and behavioral symptoms had high overall and negative agreement, but low positive agreement with clinician diagnoses. MDS 3.0 data may be useful in ruling out depression and behavioral symptoms. Confirmation of the findings in a representative sample of nursing homes is warranted.

Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.

INTRODUCTION: Amyloid beta (Aß) oligomers are one of the most toxic structural forms of the Aß protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aß oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aß oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aß oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aß oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aß oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.

High density lipoprotein and its apolipoprotein-defined subspecies and risk of dementia.

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology.

Brain health INnovation Diplomacy: a model binding diverse disciplines to manage the promise and perils of technological innovation.

BACKGROUND: Brain health diplomacy aims to influence the global policy environment for brain health (i.e. dementia, depression, and other mind/brain disorders) and bridges the disciplines of global brain health, international affairs, management, law, and economics. Determinants of brain health include educational attainment, diet, access to health care, physical activity, social support, and environmental exposures, as well as chronic brain disorders and treatment. Global challenges associated with these determinants include large-scale conflicts and consequent mass migration, chemical contaminants, air quality, socioeconomic status, climate change, and global population aging. Given the rapidly advancing technological innovations impacting brain health, it is paramount to optimize the benefits and mitigate the drawbacks of such technologies. OBJECTIVE: We propose a working model of Brain health INnovation Diplomacy (BIND). METHODS: We prepared a selective review using literature searches of studies pertaining to brain health technological innovation and diplomacy. RESULTS: BIND aims to improve global brain health outcomes by leveraging technological innovation, entrepreneurship, and innovation diplomacy. It acknowledges the key role that technology, entrepreneurship, and digitization play and will increasingly play in the future of brain health for individuals and societies alike. It strengthens the positive role of novel solutions, recognizes and works to manage both real and potential risks of digital platforms. It is recognition of the political, ethical, cultural, and economic influences that brain health technological innovation and entrepreneurship can have. CONCLUSIONS: By creating a framework for BIND, we can use this to ensure a systematic model for the use of technology to optimize brain health.

Development of a transcallosal tractography template and its application to dementia.

Understanding the architecture of transcallosal connections would allow for more specific assessments of neurodegeneration across many fields of neuroscience, neurology, and psychiatry. To map these connections, we conducted probabilistic tractography in 100 Human Connectome Project subjects in 32 cortical areas using novel post-processing algorithms to create a spatially precise Trancallosal Tract Template (TCATT). We found robust transcallosal tracts in all 32 regions, and a topographical analysis in the corpus callosum largely agreed with well-established subdivisions of the corpus callosum. We then obtained diffusion MRI data from a cohort of patients with Alzheimer's disease (AD) and another with progressive supranuclear palsy (PSP) and used a two-compartment model to calculate free-water corrected fractional anisotropy (FAT) and free-water (FW) within the TCATT. These metrics were used to determine between-group differences and to determine which subset of tracts was best associated with cognitive function (Montreal Cognitive Assessment (MoCA)). In AD, we found robust between-group differences in FW (31/32 TCATT tracts) in the absence of between-group differences in FAT. FW in the inferior temporal gyrus TCATT tract was most associated with MoCA scores in AD. In PSP, there were widespread differences in both FAT and FW, and MoCA was predicted by FAT in the inferior frontal pars triangularis, preSMA, and medial frontal gyrus TCATT tracts as well as FW in the inferior frontal pars opercularis TCATT tract. The TCATT improves spatial localization of corpus callosum measurements to enhance the evaluation of treatment effects, as well as the monitoring of brain microstructure in relation to cognitive dysfunction and disease progression. Here, we have shown its direct relevance in capturing between-group differences and associating it with the MoCA in AD and PSP.

Exploratory study of sport-related concussion effects on peripheral micro-RNA expression.

OBJECTIVE: Explore changes in micro-RNA (miRNA) expression in blood after sport-related concussion (SRC) in collegiate athletes. METHODS: Twenty-seven collegiate athletes (~41% male, ~75% white, age 18.8 ± 0.8 years) provided both baseline and post-SRC blood samples. Serum was analyzed for expression of miR-153-3p (n = 27), miR-223-3p (n = 23), miR-26a-5p (n = 26), miR-423-3p (n = 23), and miR-let-7a-5p (n = 23) at both time points via quantitative polymerase chain reaction (qPCR). Nonparametric analyses were used to compare miRNA expression changes between baseline and SRC and to evaluate associations with clinical outcomes (symptom severity, cognition, balance, and oculomotor function, and clinical recovery time). RESULTS: Participants manifested a significant increase in miRNA expression following SRC for miR153-3p (Z = -2.180, p = .029, 59% of the participants increased post-SRC), miR223-3p (Z = -1.998, p = .046, 70% increased), and miR-let-7a-5p (Z = -2.190, p = .029, 65% increased). There were no statistically significant associations between changes in miRNA expression and clinical test scores, acute symptom severity, or clinical recovery time. CONCLUSION: MiR-153-3p, miR-223-3p, and miR-let-7a-5p were significantly upregulated acutely following SRC in male and female collegiate athletes compared to baseline levels, though several athletes demonstrated no change or a decrease in expression. The biological mechanisms and functional implications of the increased expression of these circulating miRNA are unclear and require more research, as does their relevance to clinical outcomes.

Community perceptions related to brain donation: Evidence for intervention.

INTRODUCTION: Research progress on neurocognitive disorders requires donation of both healthy and diseased brains. Here, we describe attitudes toward brain donation among a large community sample in Florida. METHODS: HealthStreet, a community engagement program at the University of Florida, used community health workers to assess community attitudes toward research participation, including brain donation. RESULTS: Over 60% of people, primarily Caucasian and employed, indicated that they would be likely or somewhat likely to donate their brain for research. Those who would be willing to donate were also more likely to be willing to participate in other research studies and to have participated in research. DISCUSSION: Brain donation will add to the science of disorders of aging, including accurate diagnoses and validation of in vivo biomarkers. Increasing willingness to donate is a first step toward donation. Community populations are willing; community health workers can educate others about the need for this initiative in communities.