bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropsychiatric co‐morbidities and psychotropic medication use in Medicare beneficiaries with dementia
Authors: Johnson Kim G , Ford Cassie , Clark Amy G , Greiner Melissa , Lusk Jay , Perry Cody , O'Brien Richard , O'Brien Emily C 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms affect approximately 97% of patients with dementia. Prevalence of symptoms may be different dependent upon age, sex or race. Past studies report high rates of potentially inappropriate prescribing in the dementia population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort.MethodWe utilize Medicare claims and Medicare Part D prescription fill records in a cohort of 100% Medicare North and South Carolina fee‐for‐service beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia based on an ICD‐10‐CM diagnosis of dementia from an inpatient, outpatient, carrier, skilled nursing facility or home health claim, or a prescription claim for drug treatment between 1/1/2017 and 12/31/2017. We quantified neuropsychiatric diagnosis of anxiety, depression and psychosis using validated coding algorithms, searching inpatient, outpatient and physician 2017 claims. Demographic characteristics, including age, sex and race, as well as dual Medicare/Medicaid status were collected from the MSBF file for each individual. We search generic medication names in Medicare Part D claims for anti‐anxiety, antidepressant and antipsychotic medications to determine prescriptions filled during 2017.ResultProviders diagnosed anxiety and depression at higher rates in White patients; and psychosis at higher rates in Black patients. (P<0.001) Providers diagnosed female patients with depression, anxiety and psychosis at higher rates than males. (P<0.001) A provider diagnosis of anxiety, depression or psychosis is most prevalent in the age group 50‐59 and decreases with age to age 90+. Females with anxiety, depression and psychosis filled more anti‐anxiety and antidepressant medications than males. (P<0.001) Black and Other race patients filled more antipsychotic medications for anxiety and depression than White patients. (P<0.001)ConclusionOf concern is the high fill rate of anti‐anxiety (benzodiazepine) medications, especially in females. In patients with a neuropsychiatric diagnosis, consistently over half filled an antidepressant medication and over a quarter filled prescriptions for antipsychotics. These medications may have risks > benefits in this population and lack efficacy. As alternatives, non‐pharmacologic treatment with patient/caregiver education about expectations and psychosocial interventions show promise. Innovative community outreach and care delivery models incorporating these methods may help decrease levels of medication use.
Modeling the temporal evolution of plasma and PET Alzheimer’s disease biomarkers
Authors: Cogswell Petrice M , Lundt Emily S. , Therneau Terry M. , Graff‐Radford Jonathan , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Knopman David S. , Vemuri Prashanthi , Petersen Ronald C. , Jack Clifford R. 
Published: December 2023

AbstractBackgroundKnowledge of the temporal evolution among plasma Alzheimer’s biomarkers and PET will inform disease pathophysiology and appropriate implementation of plasma biomarkers (Therneau, NeuroImage 2021; Betthauser, Brain 2022). This study investigates the relative timing of progression of plasma p‐tau181, p‐tau217, GFAP, and amyloid PET on individual and population levels.MethodWe included 957 participants from the Mayo Clinic Study of Aging with clinical diagnoses of cognitively unimpaired (n = 732), MCI (n = 205), and Alzheimer’s clinical syndrome dementia (n = 20). An accelerated failure time (AFT) model was fit with amyloid (PiB) PET, plasma p‐tau217 (Meso Scale Discovery, Lilly), plasma p‐tau181, and GFAP (Simoa, Quanterix HD‐X) as quad‐variate endpoints, and sex, APOE genotype status, and education as covariates. The model output included a per subject adjustment or time‐shift for each biomarker indicating how much earlier or later it was estimated to progress relative to the average participant, the correlation (R) between adjustments for each pair of biomarkers, and the impact of covariates on each biomarker’s timing. Secondly, we estimated progression at a given age for selected cutpoints.ResultTemporal trajectories for each biomarker are shown in Figure 1. Individual‐level adjustments between plasma p‐tau217 and amyloid PET were highly correlated, R = 0.69(0.64‐0.74); how early or late an individual progressed on plasma p‐tau217 explained 48% of the variation in relative timing of amyloid PET progression. Associations of plasma p‐tau181 and GFAP with amyloid PET individual adjustments were moderate and low, respectively (Figure 2). Using the chosen cutpoints, the estimated order of biomarker progression was GFAP, amyloid PET, plasma p‐tau181, and plasma p‐tau217 (Figure 3).ConclusionOn the individual level, the strong association of the relative timing of progression of plasma p‐tau217 and amyloid PET supports that these processes are mechanistically related. The relatively lower associations of the timing of p‐tau181 and GFAP with amyloid PET likely reflect a lower biological association and greater measurement noise for p‐tau181. The individual adjustments, the primary output of this model, are independent of cutpoints. On the population level, relative timing of biomarker change is highly dependent on the cutpoints applied. This true for any analysis that employs cutpoints, regardless of the approach.
Cognitive Decline Associated with Longitudinal Changes in 24‐h Ambulatory Blood Pressure Variability
Authors: Melgarejo Jesus D , Vatcheva Kristina P. , Mena Luis Javier , Chavez Carlos A , Silva Egle , Calmon Gustavo , Mavarez Rosa P. , Lee Joseph H. , Terwilliger Joseph D. , Maestre Gladys E. 
Published: December 2023

AbstractBackgroundCognitive decline has been associated with variability in blood pressure (BP). However, whether the increment of the BP variability during follow‐up precedes cognitive decline remains undocumented. We aimed this study to investigate cognitive decline in relation to longitudinal changes in 24‐h reading‐to‐reading BP variability.MethodsWe conducted an observational longitudinal study that included 717 dementia‐free participants from the Maracaibo Aging Study who underwent follow‐up assessment in both 24‐h ambulatory BP monitoring and cognitive tests between 1998 and 2015. Cognitive domains consisted of selective reminding tests (total, long‐term, short‐term, and recognition memory) and the Mini‐Mental State Examination (MMSE). Cognitive decline was a longitudinal decrease in cognitive scores. Participants underwent 24‐h ambulatory BP monitoring between 2‐4 times – with at least one‐year interval. Systolic and diastolic BP variability was studied during 24‐h and divided into daytime (from 06h00 to 23h00), and nighttime (23h00 to 06h00) periods. To account for BP level, we used variability independent of the mean (VIM) to compute systolic and diastolic BP variability. Other measures of BP variability included the nocturnal BP drop in comparison to the daytime BP level, which was estimated as the night‐to‐day ratio. Statistics included multivariate linear regression mixed models.ResultsOverall, the mean age was 65.6±7.36 years old and 66.5% (n = 447) of the participants were women. In mixed models, a decline in all memory domains was associated with greater variability in the 24‐h, daytime, and nighttime systolic BP during follow‐up, with an estimated decline in cognitive scores ranging from ‐0.2 to ‐0.04 points per unit increase in VIM systolic BP during follow‐up (P values ranged from 0.022 to 0.003). Decline in total, short‐term, and MMSE memory domains was associated with greater 24‐h and daytime diastolic BP variability (P≤0.015). A lower night‐to‐day dipping ratio during follow‐up increased the risk of cognitive decline, with a ‐5.8 to ‐1.6 decline in long‐term memory and MMSE scores; respectively (P≤0.037).ConclusionsCognitive decline associates with greater reading‐to‐reading 24‐h BP variability and lower falls in nocturnal BP over time. These findings might be indicative of deteriorated regulatory mechanisms to maintain steady BP levels as individuals age.
A novel sociodemographically‐neutral speech analysis algorithm to detect cognitive impairment in a Spanish population
Authors: Gabirondo Peru , Coca Alberto , Kaser Alyssa , Schaffert Jeffrey , Cullum Munro , Raboso Javier Jiménez , Guardia Pablo , Lacritz Laura 
Published: December 2023

AbstractBackgroundEarly detection of mild cognitive impairment (MCI) and dementia is crucial for initiation of care. Brief, cost‐effective cognitive screening instruments are needed to identify individuals who require further evaluation. This study presents preliminary data on a new screening technology using automated recordings analysis software in a Spanish population.MethodData were collected from 148 Spanish‐speakings in Spain (MAge = 74.4, MEducation = 12.93, 43.3% males), clinically diagnosed as cognitively normal (CN, n = 78) or impaired (MCI, n = 49; all‐cause dementia, n = 21). Participants were recorded performing four language tasks [Animal fluency, alternating fluency (sports and fruits), phonemic “F” fluency and Cookie Theft Description]. Recordings were processed via text‐transcription and digital‐signal processing techniques to capture neuropsychological variables and audio characteristics. A training sample of 103 subjects with similar demographics (age, sex, education) across groups was used to develop an algorithm to detect cognitive impairment. The features of each task and of speech were used separately to develop five algorithms to compute scores between 0 and 1, and a final algorithm was constructed from these using repeated cross‐validation. Of the 45 remaining original participants, an age‐balanced subset of 28 subjects was used to test the algorithm. General linear modeling was used to quantify demographic biases in the data and in the predicted logistically‐transformed algorithm scores.ResultMean logit algorithm scores were significantly different across groups in both test/training samples (p<1e‐3). Sex‐bias in the test dataset (psex = 1.3e‐5) was reduced by predicted logit scores (psex = 0.01); other demographic variables were not significant across samples (page = 0.31→0.21; peducatiom = 0.69→0.58; pmultilingualism = 0.74→0.32). The final algorithm in test/training samples obtained an AUC of 0.908/0.956, with overall accuracy of 89%/89%, sensitivity of 0.85/0.95, and specificity of 0.92/0.83 in discriminating CN and impaired groups.ConclusionThese findings provide initial support for the utility of this automated speech analysis algorithm as a screening tool for cognitive impairment that does not explicitly use memory tests. Further research is needed to validate algorithm in other languages and cultures.
Adult‐ and childhood onset dementias: related causes and related solutions?
Authors: Barthelson Karissa , Lardelli Michael , Hemsley Kim M 
Published: December 2023

AbstractBackgroundThe endo‐lysosomal pathway (ELP) of cells is central to their importation of nutrients and for recycling of cellular components. Much genetic evidence supports the importance of dysfunction of the ELP in Alzheimer’s disease (AD). However, AD is a complex disorder and how AD‐associated genetic variation affects ELP function is unclear. Sanfilippo syndrome childhood dementia is a consequence of extreme ELP dysfunction, where inherited recessive mutations result in the ELP’s inability to properly catabolise a particular polysaccharide. Unlike AD, Sanfilippo is genetically simple. All the causative genes have been identified and the biochemical consequences of their mutations are understood. Animal models of Sanfilippo are considered excellent models of the human disease. Using zebrafish as a model organism, we are dissecting shared disease mechanisms between these two dementia subtypes.MethodZebrafish models of both (early‐onset familial) AD and Sanfilippo syndrome were generated using CRISPR‐Cas9‐based approaches. The brain transcriptomes (RNA‐seq) and metabolomes (metabolomics/fluxomics) of both models are compared within single zebrafish families. Spatial working memory in both models is assessed using a Y‐maze.ResultPreliminary brain transcriptome analyses have identified changes‐in‐common to both oxidative phosphorylation and ribosome gene expression in both AD and Sanfilippo model zebrafish. Metabolomics and behavioural analyses of these models are ongoing.ConclusionNeurodegeneration in Sanfilippo syndrome and Alzheimer’s disease may share common mechanisms that are amenable to common therapeutic approaches.
An optimized integrated functional genomics toolkit identifies novel role of SORL1 in microglia
Authors: Sher Falak 
Published: December 2023

AbstractBackgroundRecent genome wide association studies implicated microglia in the pathophysiology of neurodegeneration; however, the translation of these genetic discoveries is hindered by the current lack of a robust human microglia in vitro model system and standardized protocols for functional genomics assessment. Though microglia differentiated from human induced pluripotent stem cells (iMG) could be a promising cellular model, the available differentiation protocols are variable, lengthy and give inefficient, mixed yields, limiting our ability to utilize modern gene editing tools (e.g., CRISPR‐Cas9) in this model for elucidating the functional consequences of disease relevant genes and variants.MethodsIn order to streamline microglia functional genomics, we optimized a highly efficient protocol to differentiate human induced pluripotent stem cells into iMG in two easy steps, offering a significant improvement in purity and time requirement for iMG production. We validated this iMG model system in a robust way through a comprehensive single cell RNA‐sequencing (scRNA‐Seq) study, mass spectrometry‐based proteomics and microglial functional assays. In addition, the iMG differentiation protocol includes sequential iMG harvesting and cell freezing steps, that will allow the researchers to scale up the production of iMG for high‐throughput assays. Furthermore, the toolkit also includes a drug inducible CRISPR‐ON/OFF approach in our newly established microglia model system that enables the investigation of gene function in a temporal fashion. All the data generated as part of the comprehensive validation is publicly available in the form of a searchable online platform (https://jasonchungngo.shinyapps.io/IPSC-derived-Microglia/).ResultsWe used this newly developed integrated microglia functional genomics toolkit, along with human primary microglia freshly purified from dorsolateral prefrontal cortex (DLPFC), to investigate the thus far unidentified role of SORL1, an AD associated gene, in microglia. By combining state‐of‐the art (e.g. single cell RNA‐Seq, proteomics and focused CRISPR‐Cas9 screen) and standard (immunohistochemistry on postmortem human aged brain tissues) approaches we established the molecular mechanisms by which SORL1 shapes the functional phenotypes of human microglia. Most interestingly, we have found divergent roles for SORL1 in microglia when compared to neurons.ConclusionsOur findings highlight the importance of cell type specific functional genomics of susceptibility genes in AD.
NEUROPROTECTIVE EFFECT OF PALIPERIDONE IN LPS INDUCED ANIMAL MODEL OF AD
Authors: Thakur Smriti , Sandhu Rajender , Deshmukh Rahul Renukadas 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is a progressive neurological condition, that impairs cognition and memory. Extracellular beta‐amyloid plaques and intracellular neurofibrillary tangle formation are the two hallmarks while cognitive decline, neurotransmitter deficit, neuroinflammation, mitochondrial dysfunction, decreased cerebral glucose uptake, and oxidative stress has been known to contribute to the pathogenesis of AD. The present study was designed to investigate the neuroprotective potential of Paliperidone on intracerebroventricular (i.c.v.) Lipopolysaccharide‐induced experimental dementia of Alzheimer’s type.MethodLPS was administered by the i.c.v route on 1st day of the study in rats. Paliperidone was administered (1mg/Kg and 2mg/kg/day i.p) from the 1st to 21st day in LPS‐infused rats. Morris water maze, open‐field test, and object recognition parameters were used to assess learning, memory, behavioral changes and locomotor activity in rats. LPS infusion rapidly causes neuroinflammation and oxidative‐nitrosative stress.ResultThese markers were determined in the cortical and hippocampal brain regions of rats. While paliperidone treatment attenuates the LPS‐induced behavioral and biochemical abnormalities in rats by reducing levels of Malondialdehyde (MDA), reduced glutathione (GSH), and increasing levels of catalase. The neurodegeneration in Hippocampus and cortex regions was observed through histopathological examination. The observed cognitive improvement following paliperidone in LPStreated rats may be due to its antioxidant and anti‐inflammatory activity and restoration of cholinergic functions.ConclusionOur results suggest the therapeutic potential of paliperidone in cognitive disorders such as AD. However, more investigations are required to evaluate the potential of paliperidone in boosting memory and cognition and preventing neuronal damage.
The impact of neuropsychiatric symptoms in in PSP. An overview of quality of life and functionality
Authors: Morales‐Rivero Alonso , Khoja Abeer , Cordero Indira Ruth Garcia , Couto Blas , Monteiro Marta , Tsang Michelle , Antwi Jeffrey , Sasitharan Johnathan , Bhakta Puja , Alwazan Batoul , Kovacs Gabor G. , Fox Susan , Tang‐Wai David F. , Lang Anthony E , Tartaglia Carmela 
Published: December 2023

AbstractBackgroundProgressive supranuclear paralysis (PSP) is an atypical parkinsonian disorder associated with oculomotor features, motor disturbances, postural instability along with cognitive problems and neuropsychiatric symptoms. Functional impairment and quality of life (QOL) are often related to the motor symptoms. Our aim was to investigate the contribution of neuropsychiatric symptoms such as depression, anxiety and sleep disturbance to functionality and QOL.MethodWe used data from 69 patients meeting criteria for probable PSP from the Rossy PSP Centre. Neuropsychiatric symptoms, severity and functionality were examined using validated rating scales including the Hamilton Anxiety Rating Scale (HAM‐A) for anxiety, Geriatric Depression Scale (GDS) for depression, Epworth sleepiness scale (ESS) for sleep and Neuropsychiatry Inventory (NPI) total scores. To examine function, we used the Schwab and England Activities of Daily Living Scale (SEADL), severity of disease we used PSP rating scale and for QOL the (EQ‐5D‐5L). Cognition was examined using the Montreal Cognitive Assessment (MOCA). We investigated the relationships between neuropsychiatric symptoms and function and QOL using Pearson correlations controlling for multiple comparisons with false discovery test.ResultIn our sample (37.7% female, mean age 71.2+/‐ 6.5) 26.9% had depression, 13% had anxiety, 97.3% had scores compatible with cognitive impairment. Mean QOL‐EQ‐5D‐5L score was 50.4 +/‐ 25.3, mean PSP‐RS 39.5 +/‐ 12.7. Subgroups were made for QOL and functionality analysis. We found negative correlations between SEADL and HAM‐A (r ‐0.32 p = 0.01), and GDS (r ‐0.32 p = 0.01); between QOL‐EQ‐5D‐5L and GDS (r‐0.51 p = 0.014) and HAM‐A (r‐0.49 p = 0.014). Positive correlations were found between SEADL and QOL‐EQ‐5D‐5L (r = 0.61 p = 0.005) and between PSP‐RS and ESS (r 0.35 p = 0.004). The SEADL and PSP‐RS were negatively correlated (r‐0.39 p = 0.002).ConclusionConsistent with apriori hypotheses we found anxiety, depression and PSP‐RS are related to function as measured by the SEADL and quality of life of PSP patients. Sleep disturbance was related to PSP‐RS. These results emphasize the importance of comprehensive evaluations to better capture the multi‐faceted impairments seen in PSP that have a meaningful impact on the patient’s life.
A new home‐based cognitive test using phone calls in mild cognitive impairment
Authors: Hong Yun Jeong , Lee Kyung Won 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) is a risk group of dementia. Despite of plethora of hospital‐based neuropsychological tests, assessment tools that can be performed at home to detect cognitive progression are lacking. We thought that a home‐based cognitive test (HCT) is useful for regular cognitive monitoring without visiting the hospital. Our study aimed to validate the HCT by assessing relationships with existing hospital‐based neuropsychological tests scores.MethodThis pilot study was conducted in a university‐affiliated dementia clinic from July 2019 to December 2021. We had developed a new HCT that can be examined using phone calls without visiting the hospital. The newly developed HCT is composed of 20 questions (score ranges 0‐30), a higher score indicates better general cognition. Participants with MCI were enrolled and underwent regular HCT during 6 months. Brain MRI, plasma amyloid, baseline and endpoint neuropsychological tests, and assessment for clinical progression were performed. Associations between HCT scores and in‐person neuropsychological tests were investigated. We additionally assessed whether the HCT scores are correlated with Alzheimer’s disease (AD)‐related biomarkers including plasma amyloid values and regional brain volumes. To assess relevance, partial correlation coefficient adjusted by age, sex, and education was performed.ResultHCT had good intraclass correlation coefficient values (test‐retest Cronbach’s alpha 0.839 & inter‐rater reliability Cronbach’s alpha 0.627). Totally 38 participants were enrolled and 32 completed the endpoint evaluations at 6 months. Seven participants progressed to mild dementia. Baseline HCT score showed good correlations with Mini‐Mental State Examination (MMSE) score, verbal memory delayed recall scores, and stroop test scores after adjustment for age, sex, and education. However, HCT scores did not show significant associations with AD‐biomarkers. MCI with higher risk of progression (APOE4 carrier or positivity in plasma amyloid values) showed numerical trends of faster HCT declines compared with MCI with lower risk of progression, although it did not reach statistical significance (p>0.05).ConclusionWe demonstrated good reliability and correlations of the newly developed HCT with existing in‐person neuropsychological tests. It also showed good applicability on the elderly with MCI. Hence, HCT could be a promising and alternative option to monitor cognitive declines without visiting the hospital.