Exploratory Mass Spectrometry of Cerebrospinal Fluid from Persons with Autopsy-Confirmed LATE-NC.

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.

The Association of Gabapentin Initiation with Cognitive and Behavioral Changes in Older Adults with Cognitive Impairment: A Retrospective Cohort Study.

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.

Medicare Medication Therapy Management: beneficiary characteristics and utilization patterns in a national CMS Medicare fee-for-service sample (2013-2016).

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 (2013-2016). 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 (TMR). 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 2013-2016, 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.

Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance.

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.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

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: Aß, 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-, Aß/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.

Association of Physical Frailty and Cognitive Function in a Population-Based Cross-Sectional Study of American Older Adults.

INTRODUCTION: Cognitive impairment and frailty are prevalent in older persons. Physical frailty is associated with cognitive decline; however, the role of effect modifiers such as age, sex, race/ethnicity, and cognitive reserve is not well understood. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey (2011-2014) were obtained for participants aged ≥60 years. Complete availability of cognitive scores was an inclusion criterion. Physical frailty was defined by the presence of exhaustion, weakness, low body mass, and/or low physical activity, and categorized into three groups: robust (0 present), pre-frail (1-2 present), or frail (3-4 present). Four cognitive test scores were converted to z-scores, and global cognition (composite z-score) was calculated by averaging the four-individual z-scores. Multivariable linear regression models were fit to estimate the associations between frailty and cognitive function. Frailty was also evaluated as a risk factor for self-reported subjective memory complaint (SMC) using logistic regression. All models were adjusted for age, sex, race/ethnicity, education, alcohol use, income, marital status, diabetes, hypertension, and history of stroke. Effect measure modification analyses were conducted by age, sex, race/ethnicity, education, and occupational cognitive demand. RESULTS: The study population comprised 2,863 participants aged ≥60 years. 50.6% of the participants were categorized into robust, 43.2% pre-frail, and 6.2% frail. After adjusting for covariates, compared to robust participants, frail and prefrail participants had lower adjusted mean global cognitive z-scores, ß^ = -0.61, 95% CI: -0.83, -0.38 and ß^ = -0.21, 95% CI: -0.30, -0.12, respectively. Both prefrail and frail participants had higher odds of SMC compared to the robust participants. We did not see strong evidence that the association between frailty and cognition was modified by the factors we studied. DISCUSSION/CONCLUSION: Both pre-frailty and frailty were associated with lower cognitive performance and were more likely to report subjective memory complaints relative to persons without frailty. These findings provide additional evidence that physical frailty may serve as a prognostic factor for cognitive deterioration or dementia, and prevention of frailty may be an important public health strategy.

Different cohort, disparate results: Selection bias is a key factor in autopsy cohorts.

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.

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults.

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 TH17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This TH17 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 TH17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of TH17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection.

Child Mental Health Services Access and Efficacy Post-Disaster: A Scoping Review.

INTRODUCTION: The increased threat of natural disasters makes understanding the relationship between community resources and children's mental health critical. Mental health care efficacy and access are crucial to assessing the quality of community mental health care availability. OBJECTIVES: The primary objective of this scoping review is to investigate the relationship between children's mental health and community mental health resource efficacy and accessibility after a major disaster. METHODS: Conducted a systematic search to identify epidemiologic and health service utilization studies assessing the relationship between disasters and subsequent health service utilization amongst children and adolescents. RESULTS: The research returned 1682 potentially relevant studies and 31 articles were selected based on identified criteria from pre-selected databases. CONCLUSION: The studies conclude a gender and age-based disparity in access and efficiency of children's mental health services. The studies also identify the need for greater resource distribution and organizational structure.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

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.

Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC.

Background: 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. Methods: Participants were recruited from a longitudinal cohort of older adults at the University of Kentucky AD Research Center. A convenience sample of clinically obtained lumbar puncture cerebrospinal fluid (CSF) samples was analyzed from 29 older adults that had autopsy confirmation of the presence or absence of LATE-NC. Nine of the participants had autopsy-confirmed LATE-NC. Antemortem CSF specimens were 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 using an Eksigent Ekspert nanoLC 400 system in line with a Sciex 6600+ mass spectrometer. Protein identification was performed using Protein Pilot (Sciex, ver. 5) software, and relative quantification was performed using the SWATH processing microApp in PeakView and MarkerView software (Sciex), respectively. Following data analyses, additional studies were performed using western blots. Results: A total of 830 proteins were identified in the samples depleted of abundant proteins, and 730 proteins were identified in the non-depleted samples. Whereas some dementia-related proteins were detected (Aß peptide and α-synuclein protein), others were not (TDP-43, TMEM106B, and tau proteins). When the Bonferroni correction was applied to correct for multiple comparisons, only 4 proteins showed differential expression (LATE-NC vs non-LATE-NC) in the nondepleted samples (RBP4, MIF, IGHG3 and ITM2B), whereas none showed statistically different changes in the depleted samples. Post-hoc western blots confirmed that RBP4 expression was higher in the LATE-NC cases at the group level, but there was overlap between the levels of RBP4 in LATE-NC and non-LATE-NC cases. Conclusions: An exploratory assessment of CSF proteomes of autopsy-confirmed LATE-NC and non-LATE-NC cases from a community-based cohort failed to demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was intriguing increase in RBP4 protein levels in CSF from LATE-NC cases. This may provide clues about pathogenetic mechanisms in LATE-NC.

Prevalence and Factors Associated with Subjective Memory Complaint in a Semi-Rural Community in Chile.

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.

A neuropathologic feature of brain aging: multi-lumen vascular profiles.

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.

Farmer Suicides Among States Reporting Violent Deaths, 2003 - 2017.

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.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Neurodegenerative pathologies associated with behavioral and psychological symptoms of dementia in a community-based autopsy cohort.

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.

Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes.

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.

Acceptability of patient-centered, multi-disciplinary medication therapy management recommendations: results from the INCREASE randomized study.

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.

Amyloid-PET and White Matter Hyperintensities Have Independent Effects on Baseline Cognitive Function and Synergistic Effects on Longitudinal Executive Function.

Co-occurrence of beta amyloid (Aß) 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 Aß 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 Aß 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 Aß and WMHs contribute to baseline cognition independently while WMHs volumes exert effects on baseline cognitive performance directly and through influences on Aß accumulation.

Associations of potential ADRD plasma biomarkers in cognitively normal volunteers.

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 [Aß]42/Aß40) 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 (Aß)42/Aß40 ratio. These results support hypotheses that plasma biomarkers are informative for ADRD.