Sex Differences in Prescription Patterns and Medication Adherence to Guideline-directed Medical Therapy Among Patients with Ischemic Stroke.

Background: Ischemic stroke is a leading cause of death and disability. Society guidelines recommend pharmacotherapies for secondary stroke prevention. However, the role of sex differences in prescription and adherence to guideline-directed medical therapies (GDMT) after ischemic stroke remains understudied. The aim of this study was to examine sex differences in prescription and adherence to GDMT at 1-year after ischemic stroke in a cohort of commercially insured patients. Methods: Using the Truven Health MarketScan database from 2016-2020, we identified patients admitted with ischemic stroke. GDMT was defined as any statin, antihypertensive, and anticoagulant prescription within 30-days after discharge. Medication adherence was estimated using the proportion of days covered (PDC) at 1-year. PDC <0.80 was used to define non-adherence. A multivariable model adjusting for covariates was performed to identify the factors associated with non-adherence at 1-year. This analysis was restricted to new users of GDMT. Results: Among 155220 patients admitted with acute ischemic stroke during the study period, 15,919 met the inclusion criteria. The mean age was 55.7 years, and 7,701 (48.3%) were women. Women were less likely prescribed statins (58.0% vs 71.8%), and antihypertensives (27.7% vs 41.8%). In this subset of patients with atrial flutter/fibrillation, women were also less likely prescribed anticoagulants (41.2% vs 45.0%). Women were more likely to be non-adherent (i.e., PDC <0.80) to statins (47.3% vs 41.6%, P<0.0001), antihypertensives (33.3% vs 32.2%, P=0.005), and the combination of both (49.6% vs 45.0%, P=0.003). On multivariable analysis, women were likely to be non-adherent to GDMT at 1-year (odds ratio 1.23, 95% confidence interval 1.08-1.41). Conclusions: In this real-world analysis of commercially insured patients with ischemic stroke, women were less likely initiated on GDMT within 30 days after discharge. Women were more likely to be non-adherent to statins and antihypertensive agents at 1-year. Future efforts and novel interventions are needed to understand the reasons and minimize these disparities.

Perspectives on the clinical use of anti-amyloid therapy for the treatment of Alzheimer's disease: Insights from the fields of cancer, rheumatology, and neurology.

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.

Cancer research provides a model for advancing clinical trials in dementia in the era of disease-modifying Alzheimer's-type dementia therapies.

Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy's side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on "health-span" rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on "dementia worry" strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than "magic bullet") clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

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.

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.

Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

BACKGROUND AND PURPOSE: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. METHODS: Study participants from a University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aß42/Aß40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. RESULTS: CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. CONCLUSION: These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aß40, Aß42, Aß42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. DISCUSSION: Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. HIGHLIGHTS: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aß40, Aß42, Aß42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.

Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

Background and Purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. Methods: Study participants from a University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aß42/Aß40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. Results: CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. Conclusion: These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

Early Hippocampal Atrophy Is an Important Signal for Clinicians but Not Necessarily a Harbinger of Alzheimer Disease.

Dementia is one of the most formidable health care challenges we face today. Fortunately, there is new hope for patients and clinicians because we are on the verge of anti-ß-amyloid (Aß) therapies to slow disease progression in Alzheimer disease (AD). But these new therapies are far from curative, and many challenges remain related to confounding pathologic processes and mixed disease states. These challenges are only beginning to be addressed in regard to the use of antemortem biomarkers.

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.

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.

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.

White matter hyperintensities influence distal cortical ß-amyloid accumulation in default mode network pathways.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid ß (Aß) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. METHODS: Regional standard uptake value ratios (SUVr) from Aß-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aß-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. RESULTS: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p = .011). CONCLUSION: The findings suggest that the relation between Aß in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aß and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Feasibility of Telehealth Occupational Therapy for Behavioral Symptoms of Adults With Dementia: Randomized Controlled Trial.

IMPORTANCE: Supporting community residency of adults with Alzheimer's disease (AD) is a critical public health initiative. Occupational therapy can contribute to this goal. OBJECTIVE: To assess the feasibility of a novel telehealth intervention to support occupational engagement in community-residing people with AD. DESIGN: Single-blind, three-arm, parallel, randomized controlled trial. SETTING: Occupational therapy delivered through telehealth in participants' homes. PARTICIPANTS: People with AD who reside in the community with behavioral symptoms and their care partners (dyads). INTERVENTIONS: (1) HARMONY (Helping older Adults cReate & Manage OccupatioNs successfully), a telehealth intervention that applies principles of individualized guided discovery with environmental cueing for caregivers of persons with AD to promote activity participation and manage behavioral symptoms; (2) standardized training regarding the use of a sensory-based approach in dementia care; and (3) a control, including home safety education and weekly monitoring of behaviors. OUTCOMES AND MEASURES: Feasibility was assessed as the primary outcome measured by completion of at least 75% of the telehealth sessions. Secondary outcomes included change in functional activity performance and neuropsychiatric behavioral symptoms. RESULTS: Twenty-eight dyads participated. The intervention was feasible, with high adherence to weekly visits (M number of visits = 5.4 for HARMONY, 4.9 for standardized training, and 4.6 for control), with high participant retention in the intervention arms. HARMONY demonstrated promise in improving patient performance and behavioral symptoms. CONCLUSIONS AND RELEVANCE: HARMONY is feasibly delivered through telehealth service and has a positive effect on occupational performance and behavioral symptoms of AD. Additional studies are needed to explore effectiveness in a broader population. What This Article Adds: Use of HARMONY for community-residing adults with AD is feasible and has promise for improving functional activity performance and behavioral symptoms, as well as caregiver satisfaction.

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.

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.

Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions.

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

When Alzheimer's is LATE: Why Does it Matter?

Recent therapeutic advances provide heightened motivation for accurate diagnosis of the underlying biologic causes of dementia. This review focuses on the importance of clinical recognition of limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE affects approximately one-quarter of older adults and produces an amnestic syndrome that is commonly mistaken for Alzheimer's disease (AD). Although AD and LATE often co-occur in the same patients, these diseases differ in the protein aggregates driving neuropathology (Aß amyloid/tau vs TDP-43). This review discusses signs and symptoms, relevant diagnostic testing, and potential treatment implications for LATE that may be helpful for physicians, patients, and families. ANN NEUROL 2023;94:211-222.

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.