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Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk., (© 2024. The Author(s).)

Introduction: The advent of disease-modifying therapies for Alzheimer's disease (AD) has raised many questions and debates in the field as to the clinical benefits, risks, and costs of such therapies. The controversies have resulted in the perception that many clinicians are apprehensive about prescribing these medications to their patient populations. There also remains widespread uncertainty as to the economic impact, cost benefit ratio, and safety oversight for use of these medications in standard clinical care settings., Methods: To contextualize such issues, the present study compared anti-amyloid biologic therapy (lecanemab) to four commonly used biologic agents in other fields, including trastuzumab for breast cancer, bevacizumab for lung cancer, etanercept for rheumatoid arthritis, and ocrelizumab for multiple sclerosis., Results: The data presented demonstrate comparable costs, clinical benefits, and risks for these biologic agents in their disparate disease states., Discussion: These results provide context for the costs, clinical benefits, and safety regarding the mainstream use of anti-amyloid biologic agents for the prevention of cognitive loss. While the era of disease-modifying therapies for AD is now in its infancy, there is an expectation that these discoveries will be followed by improved therapies and combination treatments leading to greater efficacy in ameliorating the clinical trajectory of AD., Highlights: Anti-amyloid therapy costs are comparable to other commonly used biologics.Anti-amyloid therapy efficacy is comparable to other commonly used biologics.Anti-amyloid therapy safety is compatible with other commonly used biologics., Competing Interests: G.A. Jicha receives funding support from the National Institutes of Health, serves as a site investigator for ongoing clinical trials sponsored by AbbVie, Cassava, Cognition Therapeutics, Eisai, Eli Lilly, and Vivoryon, and has had travel funded by the Alzheimer's Association to participate in expert panel discussions. E.L. Abner receives funding support from the National Institutes of Health, has had travel funded by Ohio State University, and serves on a committee for the Alzheimer's Association. E.P. Coskun receives funding support from the National Institutes of Health and engages in contract research for ongoing clinical trials sponsored by Cognition Therapeutics, and Eisai. P.T. Nelson receives funding support from the National Institutes of Health. M.J. Huffmyer and T.C. Tucker have nothing to disclose. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The Medicare Medication Therapy Management (MTM) program has been available to eligible Medicare Part D beneficiaries since 2006, but research regarding program utilization and characterization is limited., Objective: To describe enrollee and MTM program characteristics in a national sample of Medicare fee-for-service (FFS) beneficiaries (2013 to 2016)., Methods: Using a 5% random sample of Medicare FFS beneficiaries, we conducted a descriptive time series analysis to examine annual MTM enrollment and describe the type of MTM criteria at enrollment (Center for Medicare and Medicaid Services [CMS] vs. expanded). We investigated the offer of Comprehensive Medication Review (CMR) along with CMR receipt status, and delivery characteristics, as well as frequencies of Target Medication Reviews (TMRs)., Result: Beneficiaries who met CMS enrollment criteria, compared to those eligible under expanded criteria, were significantly older, more likely to be of white race, more likely to be female, and had a significantly higher number of comorbidities. Of those meeting CMS criteria, the proportion receiving TMR increased from 95% in 2013% to 98.1% in 2016, and over 97% were offered a CMR. Although the proportion of beneficiaries offered a CMR was stable over the study period, the proportion who received a CMR increased from 17% in 2013% to 35.4% in 2016. Telephone CMR delivery was the most common method used (87.8% to 89.1% of CMRs over the study period). Over 95% of the CMRs were delivered by a pharmacist., Conclusion: During the years 2013 to 2016, enrollment in the MTM program increased, as did the proportion of enrollees receiving TMRs and CMRs. However, uptake remained low and the main factors driving participation remain unclear. Significant differences in demographic characteristics between beneficiaries enrolled under the CMS MTM enrollment criteria and the expanded criteria suggest the need to further investigate the optimal provision of such programs., Competing Interests: Disclosure The author declares no conflicts of interest or financial interests in any product or service mentioned in this article., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Common neuropathologies associated with dementia include Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. Participants (n = 29) had been autopsied and had antemortem CSF draws in a longitudinal cohort of older adults at the University of Kentucky AD Research Center. Cases were designated as LATE-NC + if they had LATE-NC stage > 1 (n = 9); the remaining 20 cases were designated LATE-NC-. This convenience sample of CSF specimens was analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry. Relative quantification was performed using Sciex software. Peptides referent to a total of 949 proteins were identified in the samples depleted of abundant proteins, and 820 different proteins were identified in the non-depleted samples. When the Bonferroni/false-discovery statistical correction was applied to account for having made multiple comparison tests, only 4 proteins showed differential expression (LATE-NC + vs LATE-NC-) in the non-depleted samples (RBP4, MIF, IGHG3, and ITM2B). Post hoc western blots confirmed that RBP4 expression was higher in the LATE-NC + cases at the group level. In summary, an exploratory assessment of proteomes of autopsy-confirmed LATE-NC and non-LATE-NC CSF did not demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was, however, an increase in RBP4 protein levels in CSF from LATE-NC cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field., Methods: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations., Results: Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection., Discussion: These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention., Highlights: Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Although gabapentin has been increasingly prescribed to older adults, the relation between gabapentin initiation and longer-term neurocognitive changes is not well understood. Thus, this study aimed to examine the association of gabapentin initiation with cognitive and motor function decline in older adult participants with cognitive impairment., Methods: A retrospective cohort study was conducted using the National Alzheimer's Coordinating Center Uniform Data Set (2005-March 2023). Participants with cognitive impairment at the visit of gabapentin initiation (i.e., index visit) were included. Using the incidence density sampling method, up to nine non-users were randomly selected for each initiator. Cognitive decline over 1 year was defined as any increase in Clinical Dementia Rating global score (CDR ® GLOB) or a 1-point increase in CDR ® sum of boxes (CDR ® SB). Functional status decline over 1 year was defined as at least a 3-point increase in the Functional Activities Questionnaire (FAQ) sum or a 0.3-point increase of mean of FAQ. Motoric decline over 1 year was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, joint stabilized inverse probability of treatment weights and censoring weights were used. Analyses compared index with index + 1 and index + 2 visits., Results: For the study of cognitive and functional status decline, we included 505 initiators (mean age [SD] 78.8 [7.4]; male = 45%) and 4545 non-users (79.2 [7.6]; 50.1%). For the study of motor decline, we included 353 initiators (78.3 [7.2]; 42.8%) and 3177 non-users (78.5 [7.4]; 48.1%). Gabapentin initiation was not statistically associated with decline on CDR ® GLOB, CDR ® SB, FAQ sum, or mean FAQ at the index + 1 or index + 2 visits. However, gabapentin initiation was significantly associated with increased odds of new falls at the index + 2 visit (odds ratio [95% confidence interval] 2.5 [1.3, 4.6])., Conclusions: Over 1 or 2 years of follow-up, gabapentin initiation was not associated with decline in cognitive or functional status but was associated with increased odds of falling among research participants with cognitive impairment., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete., Methods: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43., Results: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility., Discussion: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies., Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences., Methods: The National Alzheimer's Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit., Results: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups., Discussion: The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non-AD pathologies., Highlights: Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research-oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of T H 17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This T H 17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in T H 17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of T H 17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer's Disease Research Center (n = 91), the University of Kentucky Pathology Department (n = 31), and the University of Pittsburgh Pathology Department (n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 (r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1-3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., Competing Interests: CONFLICT OF INTEREST The authors declare no potential conflicts of interest.

Introduction: This study examined the relationships between 13 novel blood-plasma biomarkers and dementia-related demographic and health factors in a cohort of 237 cognitively normal research volunteers whose average age was ≈82 years and who were 63% female., Methods: We regressed each biomarker on selected covariates to explore the associations between the biomarkers and selected factors to assess whether they may contribute to biomarker values. Post hoc sensitivity analyses were done with updated data and consistent variable sets for robustness and batch effects., Results: Biomarker concentrations were largely not associated with demographics or health conditions, but some expected associations (e.g., apolipoprotein E [APOE] status with amyloid beta [Aβ]42/Aβ40) were observed. Post hoc results remained similar to those of the main analysis., Discussion: The absence of strong associations between the biomarkers with age, gender, or medical conditions suggests that changes in these biomarkers, when observed, may be attributable to neuropathological changes., Highlights: Among N = 237 cognitively normal adults, we studied candidate Alzheimer's disease and related dementia (ADRD) plasma biomarkers. Biomarkers were largely not associated with demographic or health factors. Apolipoprotein E (APOE) status was associated with amyloid beta (Aβ)42/Aβ40 ratio. These results support hypotheses that plasma biomarkers are informative for ADRD., (© 2023 the Alzheimer's Association.)

Research suggests that farmer suicide rates are at least two-fold higher than the general population. In estimating rates, prior research considered suicide events among farmers together with farmworkers, fishing, and forestry occupations and included non-farming populations in the defined at-risk populations (i.e., denominators). In this study, we sought to define and differentiate farmer suicide decedents from other agricultural occupations, estimate U.S. farmer suicide rates, and evaluate rate time trends. Farmer suicide decedents were ascertained from the 36 states in the National Violent Death Reporting System (NVDRS) from 2003-2017 using NVDRS occupation data. Farmers were defined as persons responsible for day-to-day farm decisions and operations. An expert panel was convened to classify farmer occupations. Rates were calculated using Census of Agriculture-identified farmers as the rate denominator, and time trends were evaluated using regression. Due to a low number of female decedents, female farmer suicide rates were not estimated. We identified1,575 male farmer suicide decedents and 77 female farmer decedents from the NVDRS during the study period. Aggregated age-specific male farmer suicide rates were highest among farmers ages 65 years and older (22.0/100,000). Estimated suicide rates for male farmers were highest during 2003 (31.8/100,000) and lowest during 2005 (19.2/100,000). Trend analysis revealed a statistically significant 2.4% annual percent change (APC) in rates over the 15-year study period. Suicide rates among male farmers showed evidence of an increase from 2003-2017. Farmer suicide rates parallel the rates of the U.S. population; thus, farmer suicide remains a public health concern., Competing Interests: We have no conflicts of interest to disclose.

In addition to the memory disorders and global cognitive impairment that accompany neurodegenerative diseases, behavioral and psychological symptoms of dementia (BPSD) commonly impair quality of life and complicate clinical management. To investigate clinical-pathological correlations of BPSD, we analyzed data from autopsied participants from the community-based University of Kentucky Alzheimer's Disease Research Center longitudinal cohort (n = 368 research volunteers met inclusion criteria, average age at death 85.4 years). Data assessing BPSD were obtained approximately annually, including parameters for agitation, anxiety, apathy, appetite problems, delusions, depression, disinhibition, hallucinations, motor disturbance, and irritability. Each BPSD was scored on a severity scale (0-3) via the Neuropsychiatric Inventory Questionnaire (NPI-Q). Further, Clinical Dementia Rating (CDR)-Global and -Language evaluations (also scored on 0-3 scales) were used to indicate the degree of global cognitive and language impairment. The NPI-Q and CDR ratings were correlated with neuropathology findings at autopsy: Alzheimer's disease neuropathological changes (ADNC), neocortical and amygdala-only Lewy bodies (LBs), limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), primary age-related tauopathy (PART), hippocampal sclerosis, and cerebrovascular pathologies. Combinations of pathologies included the quadruple misfolding proteinopathy (QMP) phenotype with co-occurring ADNC, neocortical LBs, and LATE-NC. Statistical models were used to estimate the associations between BPSD subtypes and pathologic patterns. Individuals with severe ADNC (particularly those with Braak NFT stage VI) had more BPSD, and the QMP phenotype was associated with the highest mean number of BPSD symptoms: > 8 different BPSD subtypes per individual. Disinhibition and language problems were common in persons with severe ADNC but were not specific to any pathology. "Pure" LATE-NC was associated with global cognitive impairment, apathy, and motor disturbance, but again, these were not specific associations. In summary, Braak NFT stage VI ADNC was strongly associated with BPSD, but no tested BPSD subtype was a robust indicator of any particular "pure" or mixed pathological combination., (© 2023. The Author(s).)

Background: Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer's Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD., Methods: Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations., Results: Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications., Conclusion: The evaluation of modifications to MTM recommendations demonstrated that pharmacists' initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations., Trial Registration: Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016., (© 2023. The Author(s).)

Background: As opioid prescriptions have risen, there has also been an increase in opioid use disorder (OUD) and its adverse outcomes. Accurate and complete epidemiologic surveillance of OUD, to inform prevention strategies, presents challenges. The objective of this study was to ascertain prevalence of OUD using two methods to identify OUD in electronic health records (EHR): applying natural language processing (NLP) for text mining of unstructured clinical notes and using ICD-10-CM diagnostic codes., Methods: Data were drawn from EHR records for hospital and emergency department patient visits to a large regional academic medical center from 2017 to 2019. International Classification of Disease, 10th Edition, Clinic Modification (ICD-10-CM) discharge codes were extracted for each visit. To develop the rule-based NLP algorithm, a stepwise process was used. First, a small sample of visits from 2017 was used to develop initial dictionaries. Next, EHR corresponding to 30,124 visits from 2018 were used to develop and evaluate the rule-based algorithm. A random sample of the results were manually reviewed to identify and address shortcomings in the algorithm, and to estimate sensitivity and specificity of the two methods of ascertainment. Last, the final algorithm was then applied to 29,212 visits from 2019 to estimate OUD prevalence., Results: While there was substantial overlap in the identified records (n = 1,381 [59.2 %]), overall n = 2,332 unique visits were identified. Of the total unique visits, 430 (18.4 %) were identified only by ICD-10-CM codes, and 521 (22.3 %) were identified only by NLP. The prevalence of visits with evidence of an OUD diagnosis in this sample, ascertained using only ICD-10-CM codes, was 1,811/29,212 (6.1 %). Including the additional 521 visits identified only by NLP, the estimated prevalence of OUD is 2,332/29,212 (7.9 %), an increase of 29.5 % compared to the use of ICD-10-CM codes alone. The estimated sensitivity and specificity of the NLP-based OUD classification were 81.8 % and 97.5 %, respectively, relative to gold-standard manual review by an expert addiction medicine physician., Conclusion: NLP-based algorithms can automate data extraction and identify evidence of opioid use disorder from unstructured electronic healthcare records. The most complete ascertainment of OUD in EHR was combined NLP with ICD-10-CM codes. NLP should be considered for epidemiological studies involving EHR data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Co-occurrence of beta amyloid (Aβ) and white matter hyperintensities (WMHs) increase the risk of dementia and both are considered biomarkers of preclinical dementia. Moderation and mediation modeling were used to define the interplay between global and regional Aβ and WMHs measures in relation to executive function (EF) and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 clinically normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI 2). The moderation regression analysis showed additive effects of Aβ and WMHs over baseline memory and EF scores ( p = 0.401 and 0.061, respectively) and synergistic effects over follow-up EF ( p < 0.05). Through mediation analysis, the data presented demonstrate that WMHs effects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. These findings suggest that Aβ and WMHs contribute to baseline cognition independently while WMHs volumes exert effects on baseline cognitive performance directly and through influences on Aβ accumulation.

Background: Subjective memory complaints (SMC) are commonly studied in older adults and have been identified as potentially prodromal to dementia and Alzheimer's disease. Studies among younger adults from South America are lacking., Objective: To estimate the prevalence of SMC and the factors associated with it among Maule Cohort (MAUCO) participants., Methods: We performed a cross-sectional analysis to estimate the prevalence of SMC and investigated its associated factors from MAUCO baseline data (N = 6,687). Within groups defined by age (38-59, 60-74) and global cognition (Mini-Mental State Examination: ≥26, 25-22, ≤21), multinomial logistic regression models evaluated risk factors for SMC (Yes, Sometimes, No)., Results: Overall, SMC prevalence was 16.4%; 15.9% (95% CI 14.9-16.9%) among younger and 17.6% (15.8-19.4%) among older participants. Female sex, comorbidities, and bad/fair self-reported health status (SRHS) were generally associated with higher odds of SMC., Conclusion: Overall prevalence of SMC was 16%. Different factors were associated with the odds of SMC depending on age and global cognitive status. Future SMC studies should include sex-specific assessments, evaluate SRHS as a moderator of SMC reporting, and the influence of the SARS-CoV-2 pandemic on SMC reporting.

Introduction: Clinically, detection of disease-causing pathology associated with Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) is limited to magnetic resonance imaging and positron emission tomography scans, which are expensive and not widely accessible. Here, we assess angiogenic, inflammatory, and AD-related plasma biomarkers to determine their relationships with human post mortem neuropathology., Method: Plasma samples were analyzed using a digital immunoassay and pathological evaluation was performed by University of Kentucky Alzheimer's Disease Research Center neuropathologists. The association of plasma markers with neuropathology was estimated via proportional odds and logistic regressions adjusted for age., Results: Included cases (N = 90) showed increased tau/amyloid beta (Aβ)42 ratio, glial fibrillary acidic protein (GFAP), vascular endothelial growth factor A (VEGF-A), and placental growth factor (PlGF) were positively associated with higher level of AD neuropathological change, while higher Aβ42/Aβ40 ratio was inversely associated. Higher PlGF, VEGF-A, and interleukin 6 were inversely associated with chronic cerebrovascular disease, while Aβ42/Aβ40 ratio was positively associated., Discussion: Our results provide support for the continued study of plasma biomarkers as a clinical screening tool for AD and VCID pathology., (© 2022 the Alzheimer's Association.)

Background: Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood., Objective: Query data from a community-based autopsy series to assess pathologies that underlie UI., Methods: Included research subjects came to autopsy from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology., Results: Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p < 0.001). More women than men had a history of UI (p < 0.04), and women with UI had had more biological children than those without UI (p < 0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p < 0.001). The presence of LATE-NC (Stage > 1) was associated with UI with or without severe Alzheimer's disease neuropathologic changes and/or Lewy body pathology., Conclusion: In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC.

This study aimed to examine gabapentin utilization trends among older adults with different cognitive statuses and investigate concurrent medication use of potentially inappropriate medications. Data were extracted from the National Alzheimer's Coordinating Center Uniform Data Set (2006-2019). We estimated the yearly prevalence of gabapentin use, both overall and within subgroups defined by cognitive status (normal, mild cognitive impairment and dementia) and demographics (age and sex) for participants aged 65+. Additionally, we assessed the prevalence of concurrent use of gabapentin with opioids, combined opioids and benzodiazepine, antidepressant and antipsychotic. From 35 205 eligible older adults (mean age [SD]: 75.7 [7.0]; male: 43.1%), gabapentin use increased from 2006 to 2019 in both overall and every participant subgroup. About 10%-30% of gabapentin users reported to concurrently use opioids, and the concurrent use of gabapentin, opioid and benzodiazepine was up to 7.5% throughout the study period. The frequency of concurrent use with antipsychotics or antidepressants was higher in participants with dementia than those with normal cognition or those who were mildly cognitively impaired. Given increasing use among older adults, rigorous studies are needed to examine the safety of gabapentin in this population., (© 2022 British Pharmacological Society.)

Background: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease., Objective: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol., Methods: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity., Results: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression., Conclusions: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking., Methods: A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L)., Results: Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature., Conclusions: Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function., Competing Interests: The authors declare they have no conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oh, Moga, Fardo and Abner.)

Objective: Visinin-like protein 1 (VILIP-1) is a neuron-specific calcium sensor protein rapidly released into blood after mild traumatic brain injury (mTBI) and may be a suitable biomarker for identification of sports-related concussion (SRC). The objective of the study is to test if quantification of a specific post-translationally modified (ubiquitinated) form of VILIP-1 (ubVILIP-1) from a fingerstick blood sample using a point of care (POC) lateral flow device (LFD) can be used to rapidly identify athletes with SRC., Design: Prospective cohort study., Setting: Side-line blood collection at football, soccer, and volleyball games/practices., Participants: Division I athletes with/without SRC., Main Outcome Measures: Blood ubVILIP-1 concentrations., Results: Data collected over 2 athletic seasons from non-SRC athletes (controls) show a small but statistically significant elevation of ubVILIP-1 over an individual season for male athletes (P = 0.02) dependent on sport (P = 0.014) and no significant changes in ubVILIP-1 levels between seasons. For SRC athletes, the data show ubVILIP-1 levels substantially increase above baseline as soon as 30 minutes postdiagnosis with peak concentrations and times postinjury that vary based on injury severity., Conclusion: Results of the study suggest quantification of blood ubVILIP-1 levels measured using an LFD may provide an objective identification of athletes with SRC, setting the stage for further study with a larger number of SRC patients., Competing Interests: M. Lovell holds an equity interest in Fawkes Diagnostics LLC, which has licensed the use of the LFD for detection of ubVILIP-1 (US Patent 9,482,675, Issued 11/1/16). The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: The pathologic substrates or neuroanatomic regions responsible for similarities in behavioral features seen in autism spectrum disorder and late-life dementia remain unknown. The present study examined the neuropathologic features of late-life dementia in research volunteers with and without antemortem behaviors characteristic of autism spectrum disorders., Methods: Antemortem cross-sectional assessment of autistic spectrum behaviors proximal to death in persons with diagnosis of mild cognitive impairment or dementia was completed using the Gilliam Autism Rating Scale, 2nd edition (GARS-2), followed by postmortem quantitative and semiquantitative neuropathologic assessment. All individuals who completed the GARS-2 prior to autopsy were included (n = 56) and we note that no participants had known diagnosis of autism spectrum disorder. The GARS-2 was used as an antemortem screening tool to stratify participants into two groups: "Autism Possible/Very Likely" or "Autism Unlikely." Data were analyzed using nonparametric statistics comparing location and scale to evaluate between-group differences in pathologic features., Results: Neurofibrillary tangles (NFT; p = 0.028) density and tau burden (p = 0.032) in the frontal region, the NFT density (p = 0.048) and neuritic plaque burden (p = 0.042), and the tau burden (p = 0.032) of the temporal region, were significantly different in scale between groups. For measures with significant group differences, the medians of the Autism Possible/Very Likely group were roughly equal to the 75th percentile of the Autism Unlikely group (i.e., the distributions were shifted to the right)., Discussion: This study links behaviors characteristic of autism to increased pathologic tau burden in the frontal and temporal lobes in persons with late-life dementia. Additional studies are needed to determine causal factors and treatment options for behaviors characteristic of autism behaviors in late-life dementias., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Cancer and Alzheimer's disease are common diseases in ageing populations. Previous research has reported a lower incidence of Alzheimer's disease-type (amnestic) dementia among individuals with a diagnosis of cancer. Both cancer and amnestic dementia are prevalent and potentially lethal clinical syndromes. The current study was conducted to investigate the association of cancer diagnosis with neuropathological and cognitive features of dementia. Data were analysed from longitudinally evaluated participants in a community-based cohort study of brain ageing who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. These data were linked to the Kentucky Cancer Registry, a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini-Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline. Included participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants, and a diagnosis of mild cognitive impairment or dementia was determined in 539 (68.7%). APOE ɛ4 allele dosage was lower among participants with cancer diagnosis compared to cancer-free participants overall (P = 0.0072); however, this association was not observed among those who were cognitively normal at baseline. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini-Mental State Examination scores evaluated 6 and ≤2 years ante-mortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP-43, α-synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials., Methods: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations., Results: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative., Conclusions: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution., (© 2022. The Author(s).)

Introduction: To generalize safety and efficacy findings, it is essential that diverse populations are well represented in Alzheimer's disease (AD) drug trials. In this review, we aimed to investigate participant diversity in disease-modifying AD trials over time, and the frequencies of participant eligibility criteria., Methods: A systematic review was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records., Results: In the 101 included AD trials, participants were predominantly White (median percentage: 94.7%, interquartile range: 81.0-96.7%); and this percentage showed no significant increase or decrease over time (2001-2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific Mini-Mental State Examination scores (90.1%; no significant increase/decrease over time) may have led to a disproportionate exclusion of ethnoracially diverse individuals., Discussion: Ethnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations are provided to broaden eligibility criteria., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Falls are a major public health problem affecting millions of older adults each year. Little is known about FRID prescribing behaviors after injurious falls occur. The primary objective of this study was to investigate whether an injurious fall is associated with being prescribed a new FRID., Methods: We conducted a cross-sectional analysis using data from the National Ambulatory Medical Care Survey (2016). We included visits from patients age ≥ 65 years and classified visits based on presence of an injurious fall. The outcome of interest was prescription of new FRID between those with and without an injurious fall. Multivariable logistic regression weighted for sampling and adjusted for demographics, health history and other medications was used. Age and Alzheimer's disease were examined as potential effect measure modifiers. Odds ratios and 95% confidence intervals were reported. Bayes factor upper bounds were also reported to quantify whether the data were better predicted by the null hypothesis or the alternative hypothesis., Results: The sample included 239,016,482 ambulatory care visits. 5,095,734 (2.1%) of the visits were related to an injurious fall. An injurious fall was associated with a non-statistically significant increase in odds of at least one new FRID prescription: adjusted OR = 1.6 (95% CI 0.6, 4.0). However, there was non-statistically significant evidence that the association depended on patient age, with OR = 2.6 (95% CI 0.9, 7.4) for ages 65-74 versus OR = 0.4 (95% CI 0.1, 1.6) for ages ≥ 75. In addition to age, Alzheimer's disease was also identified as a statistically significant effect measure modifier, but stratum specific estimates were not determined due to small sample sizes., Conclusions: Ambulatory care visits involving an injurious fall showed a non-statistically significant increase in odds of generating a new FRID prescription, but this association may depend on age., (© 2022. The Author(s).)

Background: Similarities exist in behavioral expression of autism spectrum disorder (ASD) and Alzheimer's disease and related dementias (ADRD). The purpose of this study was to assess presence of behavioral and psychiatric symptoms of dementia (BPSD) and ASD-like behaviors in adults with ADRD., Methods: Using a cross-sectional design, data from University of Kentucky Alzheimer's Disease Center participant cohort were used. Hierarchical linear regression was used to assess (1) the relationship between ASD-like behaviors (measured by the Gilliam Autism Rating Scale-Second Edition, GARS-2) and BPSD measured by the Neuropsychiatric Inventory (NPI), and (2) the relationship between ASD-like behaviors and dementia severity (measured by the Clinical Dementia Rating [CDR] sum of boxes), when controlling for BPSD., Results: Complete data were available for 142 participants. Using α of 0.05, analyses identified ASD behaviors were significantly associated with BPSD severity ratings ( r  = 0.47; p  < 0.001) and dementia severity ( r  = 0.46; p  < 0.001). GARS-2 explained 6.1% ( p  < 0.001) of variance in CDR sum of boxes when controlling for NPI and other covariates., Discussion: There is significant overlap in behaviors characteristic of ASD and BPSD as assessed by the NPI and GARS-2, despite the use of these instruments in disparate developmental vs. aging settings. ASD behaviors appear to not be solely present in early childhood as a manifestation of ASD but are also present in older adults with neurodegenerative cognitive impairment. Such associations warrant additional research into causation, assessment, and behavioral interventions to further enable new therapeutic approaches targeting ASD behaviors across the lifespan.

Background: White matter hyperintensities (WMH), associated with both dementia risk and progression, can individually progress, remain stable, or even regress influencing cognitive decline related to specific cerebrovascular-risks. This study details the development and validation of a registration protocol to assess regional, within-subject, longitudinal WMH changes (ΔWMH) that is currently lacking in the field., New Method: 3D-FLAIR images (baseline and one-year-visit) were used for protocol development and validation. The method was validated by assessing the correlation between forward and reverse longitudinal registration, and between summated regional progression-regression volumes and Global ΔWMH. The clinical relevance of growth-regression ΔWMH were explored in relation to an executive function test., Results: MRI scans for 79 participants (73.5 ± 8.8 years) were used in this study. Global ΔWMH vs. summated regional progression-regression volumes were highly associated (r2 = 0.90; p-value < 0.001). Bi-directional registration validated the registration method (r2 = 0.999; p-value < 0.001). Growth and regression, but not overall ΔWMH, were associated with one-year declines in performance on Trial-Making-Test-B., Comparison With Existing Method(s): This method presents a unique registration protocol for maximum tissue alignment, demonstrating three distinct patterns of longitudinal within-subject ΔWMH (stable, growth and regression)., Conclusions: These data detail the development and validation of a registration protocol for use in assessing within-subject, voxel-level alterations in WMH volume. The methods developed for registration and intensity correction of longitudinal within-subject FLAIR images allow regional and within-lesion characterization of longitudinal ΔWMH. Assessing the impact of associated cerebrovascular-risks and longitudinal clinical changes in relation to dynamic regional ΔWMH is needed in future studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The factors associated with chronic opioid therapy (COT) in patients with HIV is understudied. Using Medicaid data (2002-2009), this retrospective cohort study examines COT in beneficiaries with HIV who initiated standard combination anti-retroviral therapy (cART). We used generalized estimating equations on logistic regression models with backward selection to identify significant predictors of COT initiation. COT was initiated among 1014 out of 9615 beneficiaries with HIV (male: 10.4%; female: 10.7%). Those with older age, any malignancy, Hepatitis C infection, back pain, arthritis, neuropathy pain, substance use disorder, polypharmacy, (use of) benzodiazepines, gabapentinoids, antidepressants, and prior opioid therapies were positively associated with COT. In sex-stratified analyses, multiple predictors were shared between male and female beneficiaries; however, chronic obstructive pulmonary disease, liver disease, any malignancy, and antipsychotic therapy were unique to female beneficiaries. Comorbidities and polypharmacy were important predictors of COT in Medicaid beneficiaries with HIV who initiated cART., (© 2021. The Author(s).)

BACKGROUND In this scoping review, we identified and reviewed 23 original articles from the PubMed database that investigated the relationship between nonacute opioid use (NOU) and cardiovascular outcomes. METHODS AND RESULTS We defined NOU to include both long-term opioid therapy and opioid use disorder. We summarized the association between NOU and 5 classes of cardiovascular disease, including infective endocarditis, coronary heart disease (including myocardial infarction), congestive heart failure, cardiac arrythmia (including cardiac arrest), and stroke. The most commonly studied outcomes were coronary heart disease and infective endocarditis. There was generally consistent evidence of a positive association between community prevalence of injection drug use (with opioids being the most commonly injected type of drug) and community prevalence of infective endocarditis, and between (primarily medically indicated) NOU and myocardial infarction. There was less consensus about the relationship between NOU and congestive heart failure, cardiac arrhythmia, and stroke. CONCLUSIONS There is a dearth of high-quality evidence on the relationship between NOU and cardiovascular disease. Innovative approaches to the assessment of opioid exposure over extended periods of time will be required to address this need.

Finite Markov chains are useful tools for studying transitions among health states; these chains can be complex consisting of a mix of transient and absorbing states. The transition probabilities, which are often affected by covariates, can be difficult to estimate due to the presence of many covariates and/or a subset of transitions that are rarely observed. The purpose of this article is to show how to estimate the effect of a subset of covariates of interest after adjusting for the presence of multiple other covariates by applying multidimensional dimension reduction to the latter. The case in which transitions within each row of the one-step transition probability matrix are estimated by multinomial logistic regression is discussed in detail. Dimension reduction for the adjustment covariates involves estimating the effect of the covariates by a product of matrices iteratively; at each iteration one matrix in the product is fixed while the second is estimated using either standard software or nonlinear estimation, depending on which of the matrices in the product is fixed. The algorithm is illustrated by an application where the effect of at least one Apolipoprotein-E (APOE) gene ϵ 4 allele on transition probability is estimated in a Markov Chain that includes adjustment for eight covariates and focuses on transitions from normal cognition to several forms of mild cognitive impairment, with possible absorption into dementia. Data were drawn from annual cognitive assessments of 649 participants enrolled in the BRAiNS cohort at the University of Kentucky's Alzheimer's Disease Research Center., (© 2021 John Wiley & Sons, Ltd.)

Spinal cord injuries can abolish both motor and sensory function throughout the body. Spontaneous recovery after injury is limited and can vary substantially between individuals. Despite an abundance of therapeutic approaches that have shown promise in preclinical models, there is currently a lack of effective treatment strategies that have been translated to restore function after spinal cord injury (SCI) in the human population. We hypothesized that sex and genetic background of injured individuals could impact how they respond to treatment strategies, presenting a barrier to translating therapies that are not tailored to the individual. One gene of particular interest is APOE , which has been extensively studied in the brain because of its allele-specific influences on synaptic plasticity, metabolism, inflammation, and neurodegeneration. Despite its prominence as a therapeutic target in brain injury and disease, little is known about how it influences neural plasticity and repair processes in the spinal cord. Using humanized mice, we examined how the ε3 and ε4 alleles of APOE influence the efficacy of therapeutic intermittent hypoxia (IH) in inducing spinally-mediated plasticity after cervical SCI (cSCI). IH is sufficient to enhance plasticity and restore motor function after experimental SCI in genetically similar rodent populations, but its effect in human subjects is more variable (Golder and Mitchell, 2005; Hayes et al., 2014). Our results demonstrate that both sex and APOE genotype determine the extent of respiratory motor plasticity that is elicited by IH, highlighting the importance of considering these clinically relevant variables when translating therapeutic approaches for the SCI community., (Copyright © 2021 Strattan et al.)

Background: Failure to clear Aβ from the brain is partly responsible for Aβ brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aβ across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp). In AD, P-gp levels are reduced, which contributes to impaired Aβ brain clearance. However, the mechanism responsible for decreased P-gp levels is poorly understood and there are no strategies available to protect P-gp. We previously demonstrated in isolated brain capillaries ex vivo that human Aβ40 (hAβ40) triggers P-gp degradation by activating the ubiquitin-proteasome pathway. In this pathway, hAβ40 initiates P-gp ubiquitination, leading to internalization and proteasomal degradation of P-gp, which then results in decreased P-gp protein expression and transport activity levels. Here, we extend this line of research and present results from an in vivo study using a transgenic mouse model of AD (human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576)., Methods: In our study, hAPP mice were treated with vehicle, nocodazole (NCZ, microtubule inhibitor to block P-gp internalization), or a combination of NCZ and the P-gp inhibitor cyclosporin A (CSA). We determined P-gp protein expression and transport activity levels in isolated mouse brain capillaries and Aβ levels in plasma and brain tissue., Results: Treating hAPP mice with 5 mg/kg NCZ for 14 days increased P-gp levels to levels found in WT mice. Consistent with this, P-gp-mediated hAβ42 transport in brain capillaries was increased in NCZ-treated hAPP mice compared to untreated hAPP mice. Importantly, NCZ treatment significantly lowered hAβ40 and hAβ42 brain levels in hAPP mice, whereas hAβ40 and hAβ42 levels in plasma remained unchanged., Conclusions: These findings provide in vivo evidence that microtubule inhibition maintains P-gp protein expression and transport activity levels, which in turn helps to lower hAβ brain levels in hAPP mice. Thus, protecting P-gp at the blood-brain barrier may provide a novel therapeutic strategy for AD and other Aβ-based pathologies.

Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD)., Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats., Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ 42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding., Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms., Competing Interests: The authors declare no competing interests., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals., Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis., Methods: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed., Results: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters' frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n = 14) at baseline. Importantly, the converters' baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08)., Conclusion: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis.

Background: Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously., Objective: The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership., Methods: Data were drawn from autopsied longitudinally followed participants of two cohorts (total N = 1,346), community-based cohort at the University of Kentucky Alzheimer's Disease Research Center (n = 365) and National Alzheimer's Coordinating Center (n = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups., Results: GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline., Conclusion: Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer's Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositive cases based on age at death and extensive neuropathologic data. Although many of the brains had mixed pathologies, four discernible clusters were identified. Key differentiating features were age at death and the severity of comorbid Alzheimer's disease neuropathologic changes (ADNC), particularly neuritic amyloid plaque densities. Cluster 1 contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD-TDP), consistent with enrichment of frontotemporal dementia clinical phenotypes including appetite/eating problems, disinhibition and primary progressive aphasia (PPA). Cluster 2 consisted of elderly limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) subjects without severe neuritic amyloid plaques. Subjects in Cluster 2 had a relatively slow cognitive decline. Subjects in both Clusters 3 and 4 had severe ADNC + LATE-NC; however, Cluster 4 was distinguished by earlier disease onset, swifter disease course, more Lewy body pathology, less neocortical TDP-43 proteinopathy, and a suggestive trend in a subgroup analysis (n = 114) for increased C9orf72 risk SNP rs3849942 T allele (Fisher's exact test p value = 0.095). Overall, clusters enriched with neocortical TDP-43 proteinopathy (Clusters 1 and 2) tended to have lower levels of neuritic amyloid plaques, and those dying older (Clusters 2 and 3) had far less PPA or disinhibition, but more apathy. Indeed, 98% of subjects dying past age 85 years lacked clinical features of the frontotemporal dementia syndrome. Our study revealed discernible subtypes of LATE-NC and underscored the importance of age of death for differentiating FTLD-TDP and LATE-NC.

Importance: Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood., Objective: To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort., Design, Setting, and Participants: This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019., Main Outcomes and Measures: Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (≤13 points) ranges during the 12 years before death., Results: The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range., Conclusions and Relevance: Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid α-synuclein and TDP-43 with Alzheimer disease pathology (tau and Aβ) may complicate efforts to identify therapies to treat and prevent Alzheimer disease.

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)