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Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses., (© 2024. The Author(s).)

Objective: We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS., Design: Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set., Settings: Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers., Participants: NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH., Measurements: Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU., Results: Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status., Conclusions: Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

A 2013 systematic review and Delphi consensus study identified 12 modifiable risk and protective factors for dementia, which were subsequently merged into the "LIfestyle for BRAin health" (LIBRA) score. We systematically evaluated whether LIBRA requires revision based on new evidence. To identify modifiable risk and protective factors suitable for dementia risk reduction, we combined an umbrella review of systematic reviews and meta-analyses with a two-round Delphi consensus study. The review of 608 unique primary studies and opinions of 18 experts prioritized six modifiable factors: hearing impairment, social contact, sleep, life course inequalities, atrial fibrillation, and psychological stress. Based on expert ranking, hearing impairment, social contact, and sleep were considered the most suitable candidates for inclusion in updated dementia risk scores. As such, the current study shows that dementia risk scores need systematic updates based on emerging evidence. Future studies will validate the updated LIBRA score in different cohorts. HIGHLIGHTS: An umbrella review was combined with opinions of 18 dementia experts. Various candidate targets for dementia risk reduction were identified. Experts prioritized hearing impairment, social contact, and sleep. Re-assessment of dementia risk scores is encouraged. Future work should evaluate the predictive validity of updated risk scores., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Spatial normalization-the process of mapping subject brain images to an average template brain-has evolved over the last 20+ years into a reliable method that facilitates the comparison of brain imaging results across patients, centers & modalities. While overall successful, sometimes, this automatic process yields suboptimal results, especially when dealing with brains with extensive neurodegeneration and atrophy patterns, or when high accuracy in specific regions is needed. Here we introduce WarpDrive, a novel tool for manual refinements of image alignment after automated registration. We show that the tool applied in a cohort of patients with Alzheimer's disease who underwent deep brain stimulation surgery helps create more accurate representations of the data as well as meaningful models to explain patient outcomes. The tool is built to handle any type of 3D imaging data, also allowing refinements in high-resolution imaging, including histology and multiple modalities to precisely aggregate multiple data sources together., 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. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.H. reports a relationship with Boston Scientific Corporation that includes: speaking and lecture fees. L.A. reports a relationship with Boston Scientific Corporation that includes: consulting or advisory. L.A. reports a relationship with Medtronic that includes: consulting or advisory. K.F. reports a relationship with Medtronic that includes: consulting or advisory. K.F. reports a relationship with Boston Scientific Corporation that includes: consulting or advisory. K.F. reports a relationship with Abbott that includes: funding grants. K.F. reports a relationship with Functional Neuromodulation that includes: funding grants. D.W. reports a relationship with Functional Neuromodulation that includes: funding grants. D.W. reports a relationship with Avid Lily that includes: funding grants. D.W. reports a relationship with Merck that includes: funding grants. D.W. reports a relationship with Jannsen that includes: consulting or advisory. D.W. reports a relationship with GE Healthcare that includes: consulting or advisory. D.W. reports a relationship with Biogen that includes: consulting or advisory. D.W. reports a relationship with Neuronix that includes: consulting or advisory. S.S. reports a relationship with Elsai that includes: consulting or advisory. S.S. reports a relationship with Lilly that includes: consulting or advisory. S.S. reports a relationship with Roche that includes: consulting or advisory. S.S. reports a relationship with Novartis that includes: consulting or advisory. S.S. reports a relationship with Biogen that includes: consulting or advisory. G.S. reports a relationship with NIH that includes: funding grants. M.S. reports a relationship with Allergan that includes: consulting or advisory. M.S. reports a relationship with Biogen that includes: consulting or advisory. M.S. reports a relationship with Roche that includes: consulting or advisory. M.S. reports a relationship with Cortexyme that includes: consulting or advisory. M.S. reports a relationship with Bracket that includes: consulting or advisory. M.S. reports a relationship with Brain Health Inc that includes: consulting or advisory. M.S. reports a relationship with uMethod Health that includes: consulting or advisory. C.L. reports a relationship with Functional Neuromodulation that includes: funding grants. C.L. reports a relationship with Avanir that includes: funding grants. C.L. reports a relationship with Eli Lily that includes: funding grants. C.L. reports a relationship with NFL Benefits Office that includes: funding grants. M.O. reports a relationship with NIH that includes: funding grants. M.O. reports a relationship with Tourette Association of America Grant that includes: funding grants. M.O. reports a relationship with Parkinson's Alliance that includes: funding grants. M.O. reports a relationship with Smallwood Foundation that includes: funding grants. M.O. reports a relationship with Parkinson's Foundation Medical Director that includes: consulting or advisory. M.O. reports a relationship with Books4Patients that includes: consulting or advisory. M.O. reports a relationship with American Academy of Neurology that includes: consulting or advisory. M.O. reports a relationship with Peerview that includes: consulting or advisory. M.O. reports a relationship with WebMD Medscape that includes: consulting or advisory. M.O. reports a relationship with Mededicus that includes: consulting or advisory. M.O. reports a relationship with Movement Disorders Society that includes: consulting or advisory. M.O. reports a relationship with Taylor and Francis that includes: consulting or advisory. M.O. reports a relationship with Demos that includes: consulting or advisory. M.O. reports a relationship with Robert Rose that includes: consulting or advisory. M.O. reports a relationship with Medtronic that includes: non-financial support. A.L. reports a relationship with Medtronic that includes: funding grants. A.L. reports a relationship with Functional Neuromodulation that includes: funding grants. A.L. reports a relationship with Medtronic that includes: consulting or advisory. A.L. reports a relationship with St. Jude that includes: consulting or advisory. A.L. reports a relationship with Boston Scientific that includes: consulting or advisory. A.L. has patent #US Patent 8346,365 licensed to Functional Neuromodulation., (Copyright © 2023. Published by Elsevier B.V.)

Background: The utility of neuropsychological measurements as forerunners of Alzheimer's Disease Dementia (AD) in individuals with normal cognition or mild cognitive impairment (MCI) is undeniable., Objectives: To assess the differential prognostic value of cognitive performance in older men versus women., Design: Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set., Settings: Data on older adults (≥60 years) were derived from 43 National Institute on Aging - funded Alzheimer's Disease Research Centers., Participants: 10,073 cognitively unimpaired (CU) older adults followed for 5.5±3.8 years and 3,925 participants with amnestic MCI monitored for 3.5±2.8 years., Measurements: The domains of episodic memory, verbal fluency, naming, attention, processing speed and executive function were assessed. Cox proportional hazards models examined associations between individual cognitive domains and AD incidence separately for each participant set. CU and MCI. These predictive models featured individual neuropsychological measures, sex, neuropsychological measure by sex interactions, as well as a number of crucial covariates., Results: Episodic memory and verbal fluency were differentially related to future AD among CU individuals, explaining a larger proportion of risk variance in women compared to men. On the other hand, naming, attention and executive function were differentially related to future AD among participants with MCI, accounting for a greater fraction of risk variance in men than women., Conclusion: Cognitive performance is differentially related to risk of progressing to AD in men versus women without dementia., Competing Interests: The authors declare that they have no conflict of interest.

Importance: Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis., Objective: To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders., Design, Setting, and Participants: This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023., Exposure: The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications., Main Outcomes and Measures: The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care., Results: A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response., Conclusions and Relevance: In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.

Introduction: Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections., Methods: We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study., Results: In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .011) and herpes simplex virus (p = .018) were individually associated with poorer MMSE performance (p = .011). A greater number of positive antibody tests among the five tested was associated with worse MMSE performance (p = .001)., Discussion: CMV, herpes simplex virus, and the global burden of multiple common infections were independently associated with poorer cognitive performance. Additional research that investigates whether the global burden of infection predicts cognitive decline and Alzheimer's disease biomarker changes is needed to confirm these findings., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: Among people with dementia, poor nutritional status has been associated with worse cognitive and functional decline, but few studies have examined its association with neuropsychiatric symptoms (NPS). We examined this topic in a population-based sample of persons with dementia., Design: Longitudinal, observational cohort study., Setting: Community., Participants: Two hundred ninety-two persons with dementia (71.9% Alzheimer's disease, 56.2% women) were followed up to 6 years., Measurements: We used a modified Mini-Nutritional Assessment (mMNA) and the Neuropsychiatric Inventory (NPI) to evaluate nutritional status and NPS, respectively. Individual linear mixed effects models examined the associations between time-varying mMNA total score or clinical categories (malnourishment, risk for malnourishment, or well-nourished) and NPI total score (excluding appetite domain) or NPI individual domain or cluster (e.g. psychosis) scores. Covariates tested were dementia onset age, type, and duration, medical comorbidities, sex, apolipoprotein E (APOE) genotype, and education., Results: Compared to the well-nourished, those at risk for malnourishment and those malnourished had higher total NPI scores [ b (95% CI) = 1.76 (0.04, 3.48) or 3.20 (0.62, 5.78), respectively], controlling for significant covariates. Higher mMNA total score (better nutritional status) was associated with lower total NPI [ b (95% CI) = -0.58 (-0.86, -0.29)] and lower domain scores for psychosis [ b (95% CI) = -0.08 (-0.16, .004)], depression [ b (95% CI = -0.11 (-0.16, -0.05], and apathy [ b (95% CI = -0.19 (-0.28, -0.11)]., Conclusions: Worse nutritional status is associated with more severe NPS. Dietary or behavioral interventions to prevent malnutrition may be beneficial for persons with dementia.

There is greater interest in amyloid biomarker for the diagnosis of Alzheimer disease (AD) with the recent Food and Drug Administration approval of amyloid-targeted therapy. The goal of this study was to assess the clinical utility of amyloid positron emission tomography (PET) in clinically ambiguous cases of cognitive impairment by examining outcomes of patients enrolled in the Imaging Dementia-Evidence of Amyloid Scanning study at 2 academic institutions. Of the 112 patients in the study, 66.1% (n=74) of patients had a positive amyloid PET scan, and 33.96% (n=38) had a negative amyloid PET scan. Lower cognitive test scores were predictive of positive amyloid PET scan ( P =0.001). Eighty-two percent (92/112) of the patients were seen for follow-up. Of the 30 patients with negative amyloid PET scan results, 90% had a diagnosis of non-AD etiology after receiving the negative results, suggesting a negative amyloid scan can be used to rule out AD diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aβ deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aβ 42 , Aβ 40 , total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aβ 42 /Aβ 40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aβ 42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aβ 42 /Aβ 40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring., 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 © 2023 Manolopoulos, Delgado-Peraza, Mustapic, Pucha, Nogueras-Ortiz, Daskalopoulos, Knight, Leoutsakos, Oh, Lyketsos and Kapogiannis.)

The recent advances in creating pluripotent stem cells from somatic cells and differentiating them into a variety of cell types is allowing us to study them without the caveats associated with disease-related changes. We generated induced Pluripotent Stem Cells (iPSCs) from eight Alzheimer's disease (AD) patients and six controls and used lentiviral delivery to differentiate them into excitatory glutamatergic neurons. We then performed RNA sequencing on these neurons and compared the Alzheimer's and control transcriptomes. We found that 621 genes show differences in expression levels at adjusted p < 0.05 between the case and control derived neurons. These genes show significant overlap and directional concordance with genes reported from a single-cell transcriptome study of AD patients; they include five genes implicated in AD from genome-wide association studies and they appear to be part of a larger functional network as indicated by an excess of interactions between them observed in the protein-protein interaction database STRING. Exploratory analysis with Uniform Manifold Approximation and Projection (UMAP) suggests distinct clusters of patients, based on gene expression, who may be clinically different. Our research outcomes will enable the precise identification of distinct biological subtypes among individuals with Alzheimer's disease, facilitating the implementation of tailored precision medicine strategies.

We investigated costs of delivering the Tailored Activity Program (TAP) and cost savings from two perspectives (health sector and societal) for people living with dementia (PLWD) and their caregivers (dyads) compared to attention control (AC) using data from a randomized controlled trial. The evaluation assessed intervention delivery costs and caregiver reported health care utilization. The total intervention cost of TAP was $1707/dyad versus $864/dyad for AC, and total costs over 6 months for TAP dyads as compared to AC were $1299 (CI: -$10,496, $7898) less from the healthcare perspective, and $761 (CI: -$10,133, $8611) less from the societal perspective. TAP cost savings are driven by lower use of healthcare services among participating dyads, but further analyses with larger samples is warranted to confirm its financial impact.

In at least some individuals who suffer a traumatic brain injury (TBI), there exists a risk of future neurodegenerative illness. This review focuses on the association between the brain-based paravascular drainage pathway known as the "glymphatic system" and TBI-related neurodegeneration. The glymphatic system is composed of cerebrospinal fluid (CSF) flowing into the brain parenchyma along paravascular spaces surrounding penetrating arterioles where it mixes with interstitial fluid (ISF) before being cleared along paravenous drainage pathways. Aquaporin-4 (AQP4) water channels on astrocytic end-feet appear essential for the functioning of this system. The current literature linking glymphatic system disruption and TBI-related neurodegeneration is largely based on murine models with existing human research focused on the need for biomarkers of glymphatic system function (e.g., neuroimaging modalities). Key findings from the existing literature include evidence of glymphatic system flow disruption following TBI, mechanisms of this decreased flow (i.e., AQP4 depolarization), and evidence of protein accumulation and deposition (e.g., amyloid β, tau). The same studies suggest that glymphatic dysfunction leads to subsequent neurodegeneration, cognitive decline, and/or behavioral change although replication in humans is needed. Identified emerging topics from the literature are as follows: link between TBI, sleep, and glymphatic system dysfunction; influence of glymphatic system disruption on TBI biomarkers; and development of novel treatments for glymphatic system disruption following TBI. Although a burgeoning field, more research is needed to elucidate the role of glymphatic system disruption in TBI-related neurodegeneration., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Cholinesterase inhibitors (CEIs) are prescribed for dementia to maintain or improve memory. Selective serotonin reuptake inhibitors (SSRIs) are also prescribed to manage psychiatric symptoms seen in dementia. What proportion of outpatients actually responds to these drugs is still unclear. Our objective was to investigate the responder rates of these medications in an outpatient setting using the electronic medical record (EMR). Methods: We used the Johns Hopkins EMR system to identify patients with dementia who were prescribed a CEI or SSRI for the first time between 2010 and 2021. Treatment effects were assessed through routinely documented clinical notes and free-text entries in which healthcare providers record clinical findings and impressions of patients. Responses were scored using a three-point Likert scale named the NOte-based evaluation method for Treatment Efficacy (NOTE) in addition to the Clinician's Interview-Based Impression of Change Plus caregiver input (CIBIC-plus), a seven-point Likert scale used in clinical trials. To validate NOTE, the relationships between NOTE and CIBIC-plus and between NOTE and change in MMSE (Mini-Mental State Examination) before and after medication were examined. Inter-rater reliability was evaluated using Krippendorff's alpha. The responder rates were calculated. Results: NOTE showed excellent inter-rater reliability and correlated well with CIBIC-plus and changes in MMSEs. Out of 115 CEI cases, 27.0% reported improvement and 34.8% reported stable symptoms in cognition; out of 225 SSRI cases, 69.3% reported an improvement in neuropsychiatric symptoms. Conclusion: NOTE showed high validity in measuring the pharmacotherapy effects based on unstructured clinical entries. Although our real-world observation included various types of dementia, the results were remarkably similar to what was reported in controlled clinical trials of Alzheimer's disease and its related neuropsychiatric symptoms., Competing Interests: KIO is a consultant for “AnatomyWorks” and “Corporate-M.” This arrangement is being managed by Johns Hopkins University in accordance with its conflict-of-interest policies. The remaining 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 © 2023 Chotiyanonta, Onda, Nowrangi, Li, Xu, Adams, Lyketsos, Zandi and Oishi.)

Objective: To examine whether associations between individual neuropsychiatric symptoms (NPS) and incident Alzheimer's dementia (AD) differ in men versus women., Methods: Data were acquired from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Two sets of older (≥ 60 years) participants were formed: one of cognitively unimpaired (CU) individuals, and one of participants with mild cognitive impairment (MCI). NPS were assessed using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models examined associations between individual NPS and AD incidence separately for each participant set. These models featured individual NPS, sex, NPS by sex interactions as well as a number of covariates., Results: The analysis involved 9,854 CU individuals followed for 5.5 ± 3.8 years and 6,369 participants with MCI followed for 3.8 ± 3.0 years. NPS were comparably associated with future AD in men and women with MCI. Regarding CU participants, the following significant sex by NPS interactions were noted: female sex moderated the risk conferred by moderate/severe apathy (HR = 7.36, 3.25-16.64) by 74%, mitigated the risk conferred by moderate/severe depression (HR = 3.61, 2.08-6.28) by 52%, and augmented the risks conferred by mild depression (HR = 1.00, 0.60-1.68) and agitation (HR = 0.81, 0.40-1.64) by 83% and 243%, respectively., Conclusions: Apathy, depression and agitation were differentially associated with incident AD in CU men and women. No individual NPS was associated with different risks of future AD in men versus women with MCI., (© 2022. The Author(s).)

Background: The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease., Objective: The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months., Methods: Baseline (n = 193) and 12-month (n = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable., Results: Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm., Conclusions: The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming., (© 2022. The Author(s).)

Introduction: Traumatic brain injury (TBI) may alter dementia progression, although co-occurring neuropsychiatric symptoms (NPS) have received less attention. Originally designed to evaluate behavioral disruption prior to dementia diagnosis, the mild behavioral impairment (MBI) construct relates NPS to underlying neural circuit disruptions, with probable relevance across the progression of neurodegenerative disease. Therefore, the MBI construct may represent a valuable tool to identify and evaluate related NPS both preceding diagnosis of all-cause dementia throughout the progression of disease, representing an important area of inquiry regarding TBI and dementia. This investigation sought to evaluate the effect of TBI on NPS related by the MBI construct in participants progressing from normal cognitive status to all-cause dementia., Methods: Using National Alzheimer's Coordinating Center data, individuals progressing from normal cognition to all-cause dementia (clinician diagnosed) over 7.6 ± 3.0 years were studied to estimate prevalence of MBI domains in 124 participants with prior TBI history (57 with loss of consciousness [LOC] <5 minutes, 22 with LOC >5 min, 45 unknown severity) compared to 822 without. MBI domain prevalence was evaluated (1) prior to dementia onset (including only time points preceding time at dementia diagnosis, as per MBI's original definition) and (2) throughout dementia progression (evaluating all available time points, including both before and after dementia diagnosis)., Results: More severe TBI (LOC >5 minutes) was associated with the social inappropriateness MBI domain (adjusted odds ratio = 4.034; P = 0.024) prior to dementia onset, and the abnormal perception/thought content domain looking across dementia progression (adjusted hazard ratio [HR adj ] = 3.703; P = 0.005). TBI (all severities) was associated with the decreased motivation domain looking throughout dementia progression (HR adj. = 1.546; P = 0.014)., Discussion: TBI history is associated with particular MBI profiles prior to onset and throughout progression of dementia. Understanding TBI's impact on inter-related NPS may help elucidate underlying neuropathology with implications for surveillance, detection, and treatment of behavioral concerns in aging TBI survivors., Highlights: The mild behavioral impairment (MBI) construct links related neuropsychiatric symptoms (NPS) by probable underlying neural network dysfunction.Traumatic brain injury (TBI) with loss of consciousness (LOC) > 5 minutes was associated with pre-dementia social inappropriateness.TBI was associated with decreased motivation looking across dementia progression.TBI with LOC > 5 minutes was associated with abnormal perception/thought content.The MBI construct may be useful for examining related NPS across dementia progression., Competing Interests: Dr. Cullum is the current Science Director of the Texas Alzheimer's Research & Care Consortium. Dr. Ismail has received fees for consultation and advisory work from Otsuka and Lundbeck. Dr. Lyketsos has received fees for consultation and advisory work from Astra‐Zeneca, Glaxo‐Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka, Servier, Astellas, Roche, Karuna, SVB Leerink, Maplight, Axsome, and Global Institute on Addictions as well as grant support from the National Institute of Mental Health, National Institute on Aging, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo‐Smith‐Kline, Eisai, Pfizer, Astra‐Zeneca, Lilly, Ortho‐McNeil, Bristol‐Myers, Novartis, National Football League, Elan, Functional Neuromodulation, and Bright Focus Foundation. The remaining authors declare no relevant 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.)

Objectives: As epidemiological studies become longer and larger, the field needs novel graphical methods to visualize complex longitudinal data. The aim of this study was to present the Slinkyplot, a longitudinal crosstabulation, to illustrate patterns of antidepressant use in a large prospective cohort of older adults with mild cognitive impairment., Methods: Data from the National Alzheimer's Coordinating Center are used to track switches between different states and types of antidepressant use. A Slinkyplot is populated with rows representing the state of medication use at each timepoint and columns representing the state at each subsequent visit., Results: The constructed Slinkyplots display the common practice of switching on and off different antidepressants over time, with citalopram, sertraline, and bupropion most commonly used followed by switching to another SSRI or SNRI as second-line treatment., Conclusions: Slinkyplots are an innovative graphical means of visualizing complex patterns of transitions between different states over time for large longitudinal studies., (© 2022 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Background and Objectives : To explore whether specific Neuropsychiatric Symptoms (NPS) are related to worse performance in particular cognitive domains. Materials and Methods : A cross-sectional analysis of the baseline evaluations of older (≥60 years), cognitively unimpaired (CU) participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set was performed. Data were derived from 43 Alzheimer's Disease Research Centers. Cognitively impaired individuals, participants with psychiatric disorders and/or under treatment with antipsychotic, anxiolytic, sedative, or hypnotic agents were excluded. NPS were assessed using the Neuropsychiatric Inventory Questionnaire. The association of NPS with participants' performance on episodic memory, semantic memory, language, attention, processing speed and executive function was analysed using an adjusted (considering important demographic and medical factors) multivariate general linear model. Results : A total of 7179 CU, older, predominantly female, Caucasian, and well-educated participants were included in the present analysis. Among them, 1856 individuals had one or more NPS. Our analysis revealed that moderate/severe anxiety was related to worse performance on semantic memory, attention and executive function, the presence of hallucinations was linked to worse processing speed and executive function scores, while the presence of elation/euphoria and aberrant motor behaviour were associated with poorer attention and language performance, respectively. In the context of a secondary, exploratory analysis, the presence of moderate/severe delusions was related to worse processing speed and executive function performance. Conclusions : The relationship between specific NPS and worse performance in particular cognitive domains could inform the formulation of individualized preventive strategies directed to the ''fortification'' of specific cognitive functions in CU individuals with NPS.

Aiming to examine whether specific motor signs are associated with worse performance in specific cognitive domains among cognitively unimpaired (CU) individuals, we performed a cross-sectional analysis of data from the baseline evaluations of older, CU participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. In total, 8149 CU (≥60 years) participants were included. Of these, 905 individuals scored ≥ 2 on at least one of the motor domains of the Unified Parkinson's Disease Rating Scale part III (UPDRSIII). Cognitively impaired individuals, participants with psychiatric disorders and/or under treatment with antipsychotic, anxiolytic, sedative or hypnotic agents were excluded. Nine motor signs were examined: hypophonia, masked facies, resting tremor, action/postural tremor, rigidity, bradykinesia, impaired chair rise, impaired posture/gait and postural instability. Their association with performance on episodic memory, semantic memory, language, attention, processing speed or executive function was assessed using crude and adjusted linear regression models. Individuals with impaired chair rise had worse episodic memory, semantic memory, processing speed and executive function, while those with bradykinesia had worse language, processing speed and executive function. Sensitivity analyses, by excluding participants with cerebrovascular disease or PD, or other Parkinsonism, produced similar results with the exception of the relationship between bradykinesia and language performance.

Objectives: Persons living with dementia (PLWD), particularly those with higher levels of functional impairment, are at increased risk of hospitalization and higher hospital-associated health care costs. Our objective was to provide a nuanced description of reasons for hospitalizations over a 12-month period among community-living persons with dementia taking part in a dementia care coordination study using caregiver-reported data and to describe how reasons varied by disease stage., Design: Retrospective descriptive analysis of pooled data from 2 concurrent studies of PLWD receiving the MIND at Home dementia care coordination program., Setting and Participants: Four hundred ninety-four community-dwelling PLWD with a family caregiver in the Greater Baltimore and Central Maryland region, 2015‒2019., Methods: PLWD sociodemographic, clinical, functional, cognitive, and behavioral characteristics were assessed during an in-home baseline visit. Caregiver-reported hospitalizations and primary reasons for events were recorded every 4.5 months by research staff and by memory care coordinators during program delivery for a 12-month period. Hospitalization event data were subsequently reviewed, reconciled, and coded by a trained investigator., Results: One hundred seventy PLWD (34.4%) had at least 1 hospitalization within 12 months of enrollment, with 316 separate events. The most common primary reason for hospitalization according to caregivers was infection (22.4%), falls (16.5%), and cardiovascular/pulmonary (12.4%). Top reasons for hospitalization were falls among persons with mild and moderate functional impairment (17.7% and 21.9% respectively) and infection among PLWD with severe impairment (30.3%)., Conclusions and Implications: Infections and falls were the most common caregiver-reported reasons for hospitalization in PLWD receiving dementia care coordination. Reasons for hospitalization varied based on severity of functional impairment. Greater understanding of reasons for hospitalization among PLWD receiving dementia care management interventions, from multiple important perspectives, may help programs more effectively address and prevent hospitalization., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: There is a limited understanding of the cognitive and psychiatric sequelae of COVID-19 during the post-acute phase, particularly among racially and ethnically diverse patients., Objective: We sought to prospectively characterize cognition, mental health symptoms, and functioning approximately four months after an initial diagnosis of COVID-19 in a racially and ethnically diverse group of patients., Methods: Approximately four months after COVID-19 diagnosis, patients in the Johns Hopkins Post-Acute COVID-19 Team Pulmonary Clinic underwent a clinical telephone-based assessment of cognition, depression, anxiety, trauma, and function., Results: Most Johns Hopkins Post-Acute COVID-19 Team patients assessed were women (59%) and members of racial/ethnic minority groups (65%). Of 82 patients, 67% demonstrated ≥1 abnormally low cognitive score. Patients requiring intensive care unit (ICU) stays displayed greater breadth and severity of impairment than those requiring less intensive treatment. Processing speed (35%), verbal fluency (26%-32%), learning (27%), and memory (27%) were most commonly impaired. Among all patients, 35% had moderate symptoms of depression (23%), anxiety (15%), or functional decline (15%); 25% of ICU patients reported trauma-related distress. Neuropsychiatric symptoms and functional decline did not differ by post-ICU versus non-ICU status and were unrelated to global cognitive composite scores., Conclusions: At approximately 4 months after acute illness, cognitive dysfunction, emotional distress, and functional decline were common among a diverse clinical sample of COVID-19 survivors varying in acute illness severity. Patients requiring ICU stays demonstrated greater breadth and severity of cognitive impairment than those requiring less intensive treatment. Findings help extend our understanding of the nature, severity, and potential duration of neuropsychiatric morbidity after COVID-19 and point to the need for longitudinal assessment of cognitive and mental health outcomes among COVID-19 survivors of different demographic backgrounds and illness characteristics., (Copyright © 2021 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field., (© 2022. Springer Nature Limited.)

The hallmarks of Alzheimer's disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a "liquid biopsy" for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ 42 , p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ 42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ 42 -laden NDEVs may be an adaptive mechanism in AD.

Dementia-related behavioral and psychology symptoms (BPSD) are undertreated and have negative consequences. However, families do not have access to disease information, tailored problem-solving  and effective management strategies, and with COVID-19, are more socially isolated and distressed. To address this dementia care gap, we describe a Phase III efficacy trial testing an online platform, WeCareAdvisor, and design modifications necessitated by COVID-19. WeCareAdvisor provides caregivers with disease information, daily tips, and a systematic approach for describing behaviors, investigating underlying causes, creating tailored strategies, and evaluating their effectiveness (DICE). The trial will enroll 326 caregivers nationwide, randomly assign them to immediately receive WeCareAdvisor (treatment), or a 3-month waitlist (control) and evaluate short (1- and 3-month) and long-term (6-month) outcomes for caregiver distress with and confidence managing BPSD, and BPSD occurrences. We will also evaluate utilization patterns with different prompting conditions: high-intensity (telephone and email reminders), low-intensity (email reminders), or no reminders to use WeCareAdvisor. COVID-19 necessitated design modifications resulting in greater inclusivity of caregivers from diverse races, ethnicities, and geographic areas. Key modifications include shifting from in-home, in-person interviewing to telephone; adjusting tool functionality from operating on a grant-funded iPad to caregivers' personal internet-capable devices; and expanding recruitment from one metropolitan area to nationwide. Study modifications necessitated by COVID-19 facilitate national outreach, easier tool adoption, and enable more diverse caregivers to participate. This study addresses a critical dementia care need, and design modifications may shorten timeline from efficacy testing to commercialization., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) 2021.)

Improving the prevention, detection, and treatment of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced "shared") for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials., Competing Interests: The authors declare no conflicts.

Objectives: While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium., Methods: Patients 65 years old or older (N = 199) who were undergoing hip fracture repair and enrolled in the study "A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients" completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aβ) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau) 181 ., Results: For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR = 1.13, 95%CI = 1.02-1.25). Both CSF Aβ42/t-tau (β = -1.52, 95%CI = -2.1 to -0.05) and Aβ42/p-tau 181 (β = -0.29, 95%CI = -0.48 to -0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers., Conclusions: In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome., (Copyright © 2021 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed., Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019., Results: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies., Discussion: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied-at multiple international centres-58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation-including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear-were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)