bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropsychiatric symptoms impact associations between plasma neurofilament light and cognition in individuals with Lewy body pathology, but not in Alzheimer’s disease.
Authors: Ortiz Gema , Weigand Alexandra J. , Cooper Shanna , Smirnov Denis S. , Salmon David P. , Galasko Douglas R. , Bangen Katherine J. , Thomas Kelsey R. 
Published: December 2022

AbstractBackgroundLewy body disease (LBD) is one of the most prevalent causes of dementia following Alzheimer’s disease (AD). Plasma neurofilament light chain (NfL) is a marker of neuroaxonal degeneration associated with cognitive decline in LBD, AD, and other neurodegenerative disorders. Neuropsychiatric symptoms are often present in both LBD and AD and can affect quality of life and cognitive performance. Therefore, we investigated whether the association between plasma NfL and cognition was moderated by the severity of neuropsychiatric symptoms in LBD and AD.MethodParticipants from the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center with data for the informant‐reported Neuropsychiatric Inventory (NPI), plasma NfL, and AD and/or LBD neuropathology at autopsy were included (n = 204). General linear models examined whether the influence of neuropsychiatric symptoms on the association between plasma NfL and cognition at the last assessment prior to death varied by neuropathology. Participants with LBD only (n = 22), LBD+AD (n = 59) and AD only (n = 123) were included. Covariates included: age, education, sex, APOE ε4 carrier status, cognitive classification (unimpaired, MCI, or dementia), and time from last assessment to death. Given similar patterns of results for the LBD and LBD+AD pathology groups, they were combined for the final analyses. The Dementia Rating Scale (DRS) was used as the cognitive outcome measure.ResultThe three‐way NfL x NPI x pathology interaction was significant (p = .019, η p 2 = .029). In the LBD+AD group, neuropsychiatric symptoms moderated the relationship between plasma NfL and DRS total score (p = .013, η p 2 = .084) such that higher NPI scores had a more negative association between NfL and DRS (total score as well as attention, initiative/perseveration, and memory subscales). Although there was an association between NfL and DRS total score in the AD‐only group, this was not moderated by NPI score (p = .460, η p 2 = .005).ConclusionThese results highlight the importance of considering neuropsychiatric symptoms when examining the relationship between NfL and cognition, particularly in patients with suspected LBD pathology. Neuropsychiatric symptoms differ in LBD and AD, so future work will examine whether specific symptoms that are more prevalent in LBD, such as apathy, are driving the observed relationships.
The pharmaceutical potential of AR‐65, a novel Alzheimer’s disease drug targeting the immunoproteasome
Authors: Park Ji Eun , Bhattarai Deepak , Park Yujin , Lee Min Jae , Son Sumin , Kim Dong‐Eun , Kim Kyung Bo 
Published: December 2022

AbstractBackgroundPreviously, we reported that inhibition of the immunoproteasome (iP), which is upregulated in reactive glial cells near amyloid‐β (Aβ) deposits in the brains of patients with Alzheimer’s disease (AD), leads to improved cognitive function in an AD mouse model of Aβ amyloidosis (Tg2576) via suppression of microglia‐mediated inflammation, independent of Aβ accumulation.MethodHere, we investigated the pharmaceutical properties of our lead iP inhibitor (AR‐65), a macrocyclic peptide epoxyketone, selected based on in vitro and cellulo iP inhibitory activities and cell‐based anti‐inflammatory efficacy. Specifically, the metabolic stability of AR‐65 was assessed using pooled human liver microsomes. In addition, the flux rate of AR‐65 was measured to evaluate the permeability across Caco‐2 monolayers over‐expressing ABCB1 and ABCG2, two major efflux drug transporters present in the human brain.ResultThe macrocyclic AR‐65 displayed improved metabolic stability (6‐fold increased half‐life), permeability, and solubility (in an injectable pharmaceutical buffer system with no cyclodextrin) compared to the FDA‐approved linear peptide epoxyketone proteasome inhibitor, carfilzomib (Kyprolis®). Finally, pilot PK studies performed using ICR mice confirmed that AR‐65 is metabolically more stable than carfilzomib and can cross the blood‐brain barrier to inhibit the brain iP.ConclusionTaken together, the results suggest that AR‐65 may hold great potential to be further investigated in clinical settings.
Interest in and perceived benefits and risks of Alzheimer’s disease clinical and biomarker results disclosure among diverse participants and care partners
Authors: Feldman Sara J , Lesniak Mary , Milliken Marie , Sadaghiyani Shima , Roberts J. Scott , Hampstead Benjamin M. , Rahman‐Filipiak Annalise 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) biomarker disclosure is a potential avenue for tailoring person‐centered care for patients and families and targeting known health disparities. However, disclosure cannot take a one‐size‐fits‐all approach. It is critical to understand whether older adults with and without cognitive impairment (i.e., mild cognitive impairment (MCI)) and their care partners are interested in engaging in biomarker disclosure, and what perceived benefits and risks exist, as a function of race, social determinants, and clinical status.Method57 participant‐care partner dyads [participants: 56.1% female; 36.8% Black, 74.3±5.98 years, 42.1% with MCI; partners: 79.0% female; 33.3% Black, 66.9±10.9 years] completed a semi‐structured interview assessing demographic factors, healthcare access, economic stability, social support, and perspectives on AD biomarker disclosure. Fisher’s exact tests were used to assess participant and partner characteristics associated with interest in, and perceived benefits and risks of the participant engaging in results disclosure. Differences in participant and care partner responses were evaluated using two‐sample t‐tests.ResultWhen asked to select the main benefit and disadvantage of knowing AD risk (out of 9 benefits and 10 disadvantages), participants and partners described varied benefits. Participants and partners both endorsed having the opportunity to engage in Alzheimer’s disease treatments and/or clinical trials (23.2% v. 29.8%), followed by having the opportunity to inform long‐term care plans (14.3% v. 17.5%) and learning more about the participants’ health (12.5% v. 15.8%) as primary motivators for engaging in biomarker disclosure. In contrast, the majority of participants (80.8%) and partners (82.1%) endorsed no perceived disadvantages of learning the participants’ biomarker information for risk of dementia‐Alzheimer’s Type. Nearly all dyads endorsed moderate to strong interest in cognitive test results (96.5% participants; 93.0% partners), structural neuroimaging (94.8%; 89.4%), genotyping (94.8%; 87.7%) and protein biomarker disclosure (98.3%; 87.7%). Interest was not associated with diagnosis, race, or social determinants of health.ConclusionParticipants and care partners endorse almost universal interest, varied benefits and few disadvantages of learning the participant’s AD biomarker results. Pre‐disclosure education and decisional‐capacity assessment are needed to ensure informed decision‐making. Further data on how social determinants may influence motivations for, reactions to, and risks of AD biomarker disclosure are needed.
African Americans' intentions to share their Alzheimer’s preclinical biomarker results with loved ones in a hypothetical vignette: the importance of support persons
Authors: Ketchum Fred B , Erickson Claire M , Chin Nathaniel A. , Gleason Carey E. , Clark Lindsay R. 
Published: December 2022

AbstractBackgroundLiterature on factors influencing the decision to enroll in Alzheimer’s biomarker research increasingly indicates that study partners are important to this decision. Limited research suggests participants are comfortable sharing their biomarker results within close relationships in the context of clinical trials. It is unknown how participants feel about sharing results in non‐clinical trial studies, which may be similar to future clinical settings in which risk information may be shared without an available clinical trial. Our objective was to understand whether and why prospective participants in preclinical AD biomarker studies intend to share their results. Because most preclinical biomarker research lacks adequate representation of African American and other racially and ethnically minoritized individuals, we focus our analysis on African Americans.MethodsWe enrolled African Americans (N = 145) between 46‐85 years of age from the Wisconsin Alzheimer’s Disease Research Center Clinical Core or the Wisconsin Registry for Alzheimer’s Prevention. After hearing a vignette describing a hypothetical biomarker research study, participants indicated how likely they would be to share their biomarker results with loved ones using a 5‐point Likert scale, and then provided open‐ended responses. Using qualitative content analysis, we identified themes that motivated and discouraged sharing results.Results72% of participants were either ‘very’ or ‘extremely’ willing to share their biomarker results with loved ones. The most common reasons motivating sharing results were so that their loved ones could support them and they could prepare together; so that their loved ones could monitor participants and understand cognitive changes they might experience; and to share important information about health. 16% would share the information selectively, and 12% were ‘not at all’ or ‘a little’ willing to share, for reasons including to avoid worrying their loved ones or concern about being treated differently.ConclusionMost participants wanted to share their biomarker results within close relationships. Increased understanding of motivations for sharing results may enable stronger support for both sides of this dyad. This in turn may suggest ways to increase participation in biomarker research and inform future research aimed at preparing to translate testing and disclosure into clinical practice, particularly among African Americans.
Participant education and preparedness in learning personal β‐amyloid PET results: Preliminary findings from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Erickson Claire M , Jonaitis Erin M. , Basche Kristin E , Chin Nathaniel A. , Johnson Sterling C. , Clark Lindsay R. 
Published: December 2022

AbstractBackgroundEarlier detection of Alzheimer’s disease (AD) coupled with improved accessibility of testing means more adults may learn their biomarker results. To reduce potential negative psychosocial impacts and promote autonomy to act on the AD risk information to make lifestyle and advanced care planning changes, it is imperative that individuals understand the meaning of their results. The Wisconsin Registry for Alzheimer’s Prevention is disclosing β‐amyloid (Aβ) PiB‐PET results to a subsample of cognitively unimpaired older adult participants and assessing the impact of Aβ‐PET disclosure on psychological well‐being, health behaviors, and long‐term planning.MethodPrior to learning Aβ‐PET results, participants (n = 64,age = 71.4±4.6) engaged in an education session. Participants were assessed on their baseline knowledge of AD and meaning of Aβ‐PET results utilizing a 15‐question quiz with multiple choice and true/false questions. Next, participants were guided through a 20‐minute interactive presentation describing AD and potential Aβ‐PET results. The same quiz was administered again to ensure adequate understanding. We assessed within‐person differences on pre‐ and post‐education quiz scores using paired t‐tests. The Views and Perceptions of Amyloid Imaging questionnaire surveyed reasons participants wanted to learn their Aβ‐PET results. Upon study completion, participants provided feedback on their experience and satisfaction with different elements of the education session.ResultThe most common reasons participants reported wanting to learn their Aβ‐PET results included to contribute to AD research (88.9% very‐extremely important) and to inform potential preventative measures (85.2% very‐extremely important). Post‐education quiz scores were on average two points higher than baseline scores (t = 10.2, df = 62, p<0.0001). Of those that have completed 6‐month follow‐up, over 90% agreed they understood the meaning of elevated and non‐elevated results and 73% agreed the educational materials were useful.ConclusionEven in this highly educated and research‐involved group, an education session improved knowledge about AD risk and amyloid PET results. As research further elucidates the relationship between preclinical biomarker accumulation and AD dementia risk, it will be important to effectively communicate findings with individuals who learn their AD biomarker results. Returning results can promote transparency and potentially goodwill with participants. However, responsible return of results must incorporate intentional efforts to ensure understanding of such information.
Special Circumstances: Agitation with Dementia in Emergency Departments
Authors: Rosenberg Paul B. 
Published: December 2022

AbstractBackgroundOlder persons presenting to the emergency department (ED) with agitation have a high prevalence of cognitive impairment which may not have been previously diagnosed.. Agitation in the ED may have many causes, one of the most prominent of which is delirium which occurs in 8–10% of older persons in the ED, and is often not diagnosed till hospital admission . The recently developed IPA algorithm for diagnosis and management of agitation in dementia is applicable to the ED environment particularly as it applies to delirium.MethodThis abstract describes the application of the IPA algorithm to the ED settingResultsOne of the major challenges of agitation management in the ED is taking a history, particularly for patients coming from a LTC environment. LTC staff can readily describe the index episode of agitation, but what is often missing is understanding the timeframe of agitation, including provoking and mitigating factors and any history of prior episodes and their causes. This makes it difficult to know if cognitive impairment is chronic or acute, the hallmark of delirium. A systematic approach to diagnosis and management is required. EDs are making increased use of well‐validated delirium screening assessments such as the Confusion Assessment Method (CAM). Other useful tools for management of delirium in the ED include ADEPT and the Delirium Triage Screen (DTS).Nonpharmacologic strategies have an important role in treatment of agitated patients in the ED. Interventions to prevent or reduce delirium in acute care environments are becoming increasingly effective: a recent Cochrane review supported the effectiveness of interventions including re‐orientation (including use of familiar objects), cognitive stimulation, sleep hygiene, attention to nutrition and hydration, oxygenation, medication review, assessment of mood, and bowel and bladder care. EDs increasingly incorporate these interventions into routine care including the use of delirium‐focused order sets and deployment of geriatric management teams which have been shown to reduce 30‐day ED readmission rates.ConclusionFurther studies should integrate diagnostic workflows and algorithms for behavioral interventions developed for both agitation and delirium management in the ED.
Plasma NfL predicts default mode network functional connectivity in older adults at higher risk for Alzheimer’s disease
Authors: Jung Youjin , Counts Scott E. , Hampstead Benjamin M. , Damoiseaux Jessica S. 
Published: December 2022

AbstractBackgroundNeurofilament light (NfL) is a measure of neuronal damage and has the potential as a monitoring and prognostic biomarker of Alzheimer’s disease (AD) (Mattsson et al., 2019). Likewise, alterations in default mode network (DMN) functional connectivity (FC) may predict AD progression (Jones et al., 2016). Here, we investigated the relationship between plasma NfL levels and DMN FC along the continuum of AD, and explored whether APOE ε4 status influenced this relationship.MethodResting‐state functional MRI data and blood samples were available for 103 older adults (17 with AD dementia, age: 69.2±6.9; m/f: 8/9; CDR: 0.7±0.3; and 86 without dementia (includes amnestic MCI and control), age: 71.7±7.4; m/f: 21/65; CDR: 0.3±0.2). Plasma NfL was measured using a single‐molecule array (Simoa) assay. We calculated DMN FC using 32 high consensus DMN ROIs from Dworetsky et al. (2021). DMN FC was defined as the average correlation between the mean time‐series of three ROIs labeled as posterior cingulate cortex and those of all the other ROIs. Participants’ APOE status was defined as APOE ε4 carriers (ε3/ε4 or ε4/ε4) and noncarriers (ε3/ε3). Multiple regression was run with DMN FC as the outcome variable, plasma NfL as the predictor, and age and sex as covariates.ResultPlasma NfL levels were higher in those with dementia compared to those without dementia (t = 4.4608, p = 0.0002) but did not differ between amnestic MCI and control (t = 1.6116, p = 0.1130). Across all participants, plasma NfL did not predict DMN FC (Β = 0.0045, p = 0.4830). However, higher plasma NfL was marginally associated with higher DMN FC in those with dementia (Β = 0.0045, p = 0.0657) but not in those without dementia (Β = 0.0021, p = 0.3160). Moreover, in those without dementia, higher plasma NfL predicted higher DMN FC in APOE ε4 carriers (Β = 0.0079, p = 0.0312) but not in APOE ε4 noncarriers (Β = 0.0023, p = 0.4871).ConclusionOur results indicate that the increase of DMN FC, seen at early stages of AD (Damoiseaux et al., 2012), is significantly associated with more neuronal damage in APOE ε4 carriers without dementia.
Using biological pathways in Machine Learning methods for Alzheimer’s disease risk prediction
Authors: Rowe Thomas , Leonenko Ganna , Williams Julie , Holmans Peter , Ivanov Dobril , Escott‐Price Valentina 
Published: December 2022

AbstractBackgroundRecent genome‐wide studies have identified over 70 risk loci for late onset Alzheimer’s Disease (AD) (Kunkle et al. 2019, Bellenguez et el. 2021, Wightman et al. 2021). Analysis in this study focused on developing Machine Learning (ML) models to predict AD risk from genetic data. We compared the prediction accuracy of ML to polygenic risk scores (PRS) using SNPs in disease‐associated biological pathways.MethodWe used the Genetic and Environmental Risk for Alzheimer’s Disease consortium dataset (Harold et al. 2009). SNPs were selected from the AD associated pathways in Kunkle et al. 2019. Two decision tree‐based ML algorithms were used, Random Forests (RFs) and Gradient Boosting (GB). The prediction ability of these methods was compared to Polygenic Risk Score (PRS). RFs and GB models were developed using the Python library sklearn. These were trained and tested using 5‐fold cross‐validation. Clumping and thresholding (CT), as implemented in PLINK, was used to generate PRS, with logistic regression used for prediction. CT PRS was compared to the PRS generated by the PRS‐CS method (Ge, T., Chen, CY., Ni, Y. et al).ResultInitial results demonstrate that PRS, PRS‐CS and ML perform similarly for pathway specific analysis (AUC∼69%) when pathways include APOE.ConclusionSubsequent analyses will compare the performance of the methods when APOE SNPs are removed from the pathways, and in multivariate analyses modelling multiple pathway effects simultaneously.
Processing of acoustically degraded emotional prosody in primary progressive aphasia and Alzheimer’s disease
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Russell Lucy L , Warren Jason D , Hardy Chris JD 
Published: December 2022

AbstractBackgroundAccurately interpreting a speaker’s nonverbal emotional vocal signals (their prosody) is often essential for successful communication. In the noisy conditions of daily life, this presents the brain with a difficult computational challenge that may be vulnerable to neurodegenerative pathologies. However, processing of acoustically degraded prosody has not been studied in these diseases.MethodHere we addressed this issue in patients representing all major syndromes of primary progressive aphasia (N = 33) and Alzheimer’s disease (N = 18) versus healthy age‐matched controls (N = 24). As a model paradigm for the degraded ‘noisy’ speech signals of everyday life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on recognition of three canonical prosodic emotions (anger, surprise, sadness) at three noise‐vocoding levels.ResultCompared with healthy controls, all patient groups were impaired recognising prosodic emotions (particularly anger) in clear speech, while patients with Alzheimer’s disease showed a disproportionate cost for recognition of the noise‐vocoded emotion of sadness.ConclusionOur findings open a window on a dimension of emotional communication that has been relatively overlooked in dementia, and suggest a novel candidate paradigm for investigating and quantifying this systematically.
Special Circumstances of Persons with Dementia and Agitation in Hospice Care.
Authors: Mintzer Jacobo E 
Published: December 2022

AbstractBackgroundApproximately 45% of patients with dementia will experience agitation in the last stages of disease. Furthermore, approximately 35% of patients in the late stages of their lives will present agitation despite being treated with lorazepam, morphine, and atypical antipsychotics. Since agitation is particularly prevalent in hospice care, we estimate that at least 45% of the subjects with dementia in hospice care, or approximately 80,000 individuals a year, will die suffering from symptoms of agitation.MethodsDifferences between agitation in dementia at different stages of the disease were evaluated.ResultsAgitation in patients with dementia in the moderate stages of the disease requires the correction of the medical condition that could contribute to the presence of agitation. In hospice care eligible patients with agitation and dementia, these conditions are often untreatable and/or side effects associated with treatment could be more deleterious than the presence of agitation. In the treatment of hospice care eligible patients with agitation and dementia, the main concern is to control symptoms and improve patient’s comfort level while preserving alertness and controlling pain and other symptoms frequently present in terminal patients, including nausea and dyspnea, rather than to uncover and treat the potential underlying cause(s) of the syndrome. In addition, several distinct physiological processes develop both in the CNS and in the periphery during the last few weeks of an individual’s life, including changes in tissue concentrations of glucose, lactate, pyruvate, ATP, ADP, AMP, and phosphocreatine (reflecting brain energy metabolism changes observed during the process of dying and after cardiopulmonary resuscitation).ConclusionSymptoms of agitation in moderate demented patients appear to be biologically and symptomatically different than symptoms of agitation in hospice care eligible patients with dementia. Therefore, the hospice care eligible patients with agitation and dementia need to be better studied and treatments tailored to these specific conditions should be developed.