bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal grading is sensitive to changes in cognition in early MCI
Authors: Morrison Cassandra , Dadar Mahsa , Shafiee Neda , Collins Louis D 
Published: December 2022

AbstractBackgroundIncreased age and cognitive decline are both associated with changes in the hippocampus. These associations are often measured using hippocampal volume measurements and changes in episodic memory. Some studies have also observed a relationship between hippocampal volume and global cognition. However, these studies often only find associations in progressed stages of cognitive decline. This study examined (1) if hippocampal grading is associated with global cognition in cognitively normal controls (NC), early MCI (eMCI), late (lMCI), and Alzheimer’s disease (AD), and (2) whether these associations differ across diagnostic cohorts.MethodsParticipants for this study were selected from the Alzheimer’s Disease Neuroimaging Initiative. They were included if they completed baseline MRI scans and the Alzheimer’s disease Assessment Scale (ADAS‐13) and Clinical Dementia Rating – Sum of Boxes (CDR‐SB) cognitive tests. A total of 1620 older adults met the inclusion criteria and were included (495 CN, 262 eMCI, 545 lMCI, and 318 AD). Linear regressions examined the association between hippocampal grading and cognitive scores.ResultsLower global cognition (measured by increased ADAS‐13 scores) was associated with hippocampal grading scores in in NC, eMCI, lMCI and AD cohorts. Lower global cognition (measured by increased CDR‐SB scores) was associated with hippocampal grading scores in lMCI and AD, but not in eMCI or NC groups.ConclusionHippocampal grading was associated with changes in global cognition in healthy controls and in disease cohorts when there is sufficient dynamic range in the cognitive test. No correlation between CDR‐SB and NC was found because the NC group only had CDR‐SB scores of 0 and 1. Hippocampal grading may, thus, be a useful measure that is sensitive to progressive changes early in the disease course. Future research should determine if this method is associated with longitudinal changes in cognition.
Association of life‐course traumatic brain injury with the risk of dementia: a nationwide twin study
Authors: Zhang Lulu , Yang Wenzhe , Li Xuerui , Dove Abigail , Qi Xiuying , Pan Kuan‐Yu , Xu Weili 
Published: December 2022

AbstractBackgroundTraumatic brain injury (TBI) in late‐life has been related to dementia, but the impact of life‐course TBI on dementia remains unclear.We aimed to examine the association between TBI occurring at different ages and dementia, and to explore the role of cardiometabolic diseases (CMDs) and genetic and early‐life environmental factors in this association.MethodWithin the Swedish Twin Registry,35,312 dementia‐free twin individuals (mean age = 62.78±9.74 years, 53.95% female) were followed for up to 18 years.Life‐course TBI was ascertained from records in the SwedishNational Patient Registry (NPR) and divided into five age groups (≤39, 40‐49, 50‐59, 60‐69, and ≥70 years) according to age at TBI occurrence.Diagnoses of dementia and CMDs (including type 2 diabetes mellitus, heart disease, and stroke) were identified through the NPR and the Swedish Cause of Death Register.Generalized estimating equation (GEE) models were applied for the unmatched case‐control analysis among all individuals, and conditional logistic regression models were used for the co‐twin matched case‐control analysis in dementia‐discordant twin pairs.ResultOf all participants, 1,086 (3.1%) had TBI at baseline and 3,292 (9.3%)developed incident dementiaduring thefollow‐up.In multi‐adjustedGEE models, the odds ratio (OR, 95% confidence interval [CI]) of dementia was 1.27 (1.03–1.57) for TBI at any age, 0.86 (0.43–1.72)for TBI at ≤39 years, 1.33 (0.81‐2.19) for TBIat 40‐49 years,1.55 (1.04–2.31) for TBI at 50‐59 years, 1.68 (1.13–2.50) for TBI at 60‐69 years, and 0.91 (0.59–1.41) for TBI at ≥70 years. In joint effect analysis, the multi‐adjusted OR (95% CI) of dementia was 2.51 (1.60‐3.93) for those who had TBI between ages 50‐69 yearsand CMDscompared to those with neitherTBI nor CMDs. There was a statistically significant interaction between TBI occurring between ages50 and 69 years and CMDs on dementia (P<0.05). In multi‐adjusted conditional logistic regression, the TBI‐dementia association remained significant. The difference in ORs from the unmatched and co‐twin matched analyses was not statistically significant (P = 0.36).ConclusionTBI, especially occurring between ages 50‐69 years, is associated with an increased risk of dementia, and this risk is exacerbated among people with CMDs.Genetic and early‐life environmental factors may not account for the TBI‐dementia association.
Simulated communication skills training program effects using augmented reality with real‐time feedback: A randomized control study
Authors: Kobayashi Masaki , Iwamoto Miyuki , Une Saki , Kurazume Ryo , Nakazawa Atsushi , Honda Miwako 
Published: December 2022

AbstractBackgroundWhile communication with dementia patients is challenging, known educational methods to improve communication skill for medical professionals are lacking. Our study aimed to assess the efficacy of simulated communication skills training for nursing students using augmented reality (AR) with real‐time feedback.MethodsThis is a randomized control study. Twenty‐five nursing students enrolled and learned standardized multimodal comprehensive care communication skills through a self‐learning material, which includes pathophysiology and clinical manifestations of dementia. Subsequently, participants were randomly assigned to one of the two learning systems—AR training or conventional nursing mannequin training. Each group had the training intervention to change the clothes of mannequins for one hour. The mannequin of the AR group was a superimposed computer graphic of an elderly woman’s face which reacted to participants' communication. Further, the communication skills of gaze and voice were evaluated by artificial intelligence (AI) and feedbacked to the participants’ head‐mounted display in real‐time. The conventional training group had the self‐training with nursing mannequins. All participants performed basic nursing care, including changing clothes and bed bath, to simulated patients before and after the training intervention, which were video‐recorded by an eye‐tracking camera and a fixed camera, then the videos were analyzed the communication skills by AI. Additionally, participants' empathy to patients was evaluated by the Jefferson Scale of Empathy‐Health Professions Students Version (JSPE‐HSP). The primary outcome was the proportion of time spent in eye contact during the care to simulated patients. The secondary outcome was the empathy score of JSPE‐HSP.ResultsAfter the training intervention, the proportion of time spent in eye contact in the AR training group significantly increased than the conventional training group (eye contact 13.6% versus 4.4%, P<0.05). Moreover, the JSPE‐HSP score increased from pre‐training to post‐training in the AR training group, whereas it decreased in the conventional training group [Mean (SD): 9.1 (6.6) versus ‐1.3 (3.8), P<0.01].ConclusionsThe simulated communication skills training for nursing students using augmented reality with real‐time feedback was associated with increased interactive communication skills to simulated patients and the empathy to patients.
Optimizing cCOG, a web‐based tool, to detect dementia with Lewy Bodies.
Authors: van Gils Aniek M. , van de Beek Marleen , van Unnik Annemartijn , Tolonen Antti , Handgraaf Dédé , van Leeuwenstijn Mardou , Lötjönen Jyrki , van der Flier Wiesje M. , Lemstra Afina W. , Meester Hanneke F.M. Rhodius‐ 
Published: December 2022

AbstractBackgroundDiagnosing dementia with Lewy bodies (DLB) is challenging due to overlapping clinical and cognitive presentation with Alzheimer’s disease (AD). Web‐based cognitive and clinical assessments could aid by providing remote and easily accessible diagnostic tools. In this study, we adapted a web‐based cognitive test tool, cCOG, by adding a visuospatial test and a brief clinical survey and assessed its ability to differentiate between DLB and AD.MethodWe included 110 patients (67±7 years, 44% female, MMSE 26±4; n = 30 DLB, n = 32 AD dementia and n = 48 controls with subjective cognitive decline (SCD)). All completed cCOG, comprising six cognitive subtasks assessing memory functioning, reaction time, executive functioning, a visuospatial task, and a brief survey addressing seven self‐reported DLB core features and suggestive autonomic features. First, we compared cCOG cognitive tasks to traditional neuropsychological tasks for all diagnostic groups and clinical questions to validated assessments of clinical features in DLB only. Then, we studied the performance of cCOG cognitive tasks and clinical questions, separately and combined, in differentiating diagnostic groups.ResultcCOG cognitive tasks and clinical survey had moderate to strong correlations to standard neuropsychological testing (.61≤ rs
≤ .77) and to validated assessments of clinical features (.41≤ rs ≤ .65), except for fluctuations and REM‐sleep behavior disorder (RBD) (rs= .32 and rs= .10). cCOG cognitive tasks only, resulted in a diagnostic accuracy of 0.70 [95% CI 0.61‐0.78]. Full cCOG, including both cognitive tasks and brief survey had a diagnostic accuracy of 0.82 [95% CI 0.73‐0.89], with good discrimination of DLB versus AD/controls (acc 0.90 [0.83‐0.95]) and DLB versus AD (acc 0.87 [0.76‐0.95]).ConclusionWe illustrated that cCOG aids in distinguishing DLB and AD patients by using remote assessment of cognition and clinical features. Our findings pave the way to a funneled, harmonized diagnostic process among memory clinics and eventually to a more timely and accurate diagnosis of DLB and AD.
Polygenic determinants of White Matter Hyperintensities and sex‐specific genetic profiles in the Alzheimer’s continuum
Authors: Genius Patricia , Rodríguez‐Fernández Blanca , Operto Grégory , Falcon Carles , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Esteller Manel , Guigó Roderic , Zetterberg Henrik , Blennow Kaj , Sudre Carole H , Suárez‐Calvet Marc , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia 
Published: December 2022

AbstractBackgroundRecent genetic association studies suggested the polygenic contribution to white matter hyperintensities (WMH). The aim of this study was to provide a genetic characterization of WMH in middle‐aged cognitively unimpaired individuals at higher risk of Alzheimer’s disease (AD) by investigating whether the genetic predisposition to specific complex diseases is associated with WMH and whether these effects are sex‐specific and dependent on core AD CSF biomarker levels.MethodA total of 497 cognitively unimpaired middle‐aged participants at risk of AD were included (63.2% of women). A subgroup of 288 individuals also had available information on CSF biomarkers measured using the Elecsys ® and the exploratory Roche NeuroToolKit immunoassays. We classified individuals in groups defined by their biomarker profile (A/T framework). Genetic predisposition was calculated through polygenic risk scores (PRS), estimated from the most recent genome‐wide association meta‐analyses for cerebrovascular/vascular, neurodegenerative, and AD‐related biomarkers. WMH volumes were quantified through fluid‐attenuated inversion recovery (FLAIR) images obtained from magnetic resonance scans. We used non‐parametric Spearman’s rank tests to assess the association between global WMH volumes and PRSs (nominal p‐value < 0.05). Models stratified by sex and A/T group were assessed to discern WMH sex‐specific genetic differences and to discriminate genetic profiles associated with WMH in the earliest stages of the Alzheimer’s continuum.
ResultGenetic predisposition to small vessel disease was positively correlated with volumes of WMH only in women [Figure 1]. Furthermore, only for A+T‐ individuals, we found that genetic predisposition to higher CSF interleukin 6 levels and cerebral infarction was positively correlated with WMH volumes. Moreover, genetic predisposition to abnormal CSF p‐tau levels and AD was negatively correlated with volumes of WMH. We did not find significant results neither in A+T+ nor in A‐T‐ individuals.ConclusionSex differences were found suggesting better genetic predictability of cerebrovascular‐PRSs to assess WMH in women. Results by A/T group suggested that asymptomatic individuals that are amyloid‐β‐positive but tau‐negative (A+T‐) have several differential genetic patterns associated with WMH that were not significant in the other groups. Overall, these findings may lead to sex differences and different biological mechanisms affecting WMH in the Alzheimer's continuum.
The assessment of ubiquitin C‐terminal hydrolase‐1 (UCH‐L1) in patients with Alzheimer’s disease
Authors: Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Mroczko Piotr , Borawska Renata , Doroszkiewicz Julia , Litman‐Zawadzka Ala , Arslan Daria , Slowik Agnieszka 
Published: December 2022

AbstractBackgroundAlzheimer's disease is a debilitating disease that leads to a disability of the patient and it is therefore interesting not only from a medical but also from a legal point of view. Despite progress in studies on pathological mechanisms underlying the Alzheimer's disease (AD) still remains incurable. One of the mechanisms responsible for the oligomerization / aggregation of misfolded or damaged proteins in AD may be dysfunction of the ubiquitin‐proteasome system (UPS), including the highly abundant neuronal enzyme ubiquitin carboxyl‐terminal hydrolase L1 (UCHL‐1). UCHL‐1 is involved in the regulation of proteasomal degradation of damaged proteins. The presence of UCH‐L1 was found in neurofibrillary tangles in the AD brain. The aim of the present study was to measure UCHL1 levels in the cerebrospinal fluid (CSF) patients with AD and evaluate a relationship between concentrations of UCHL1 and classical neurochemical dementia biomarkers.MethodThe concentrations of UCHL‐1 and classical AD biomarkers were measured in 30 subjects, including AD patients and individuals from control group by means of multiplexing assay.ResultThe CSF concentration of UCHL‐1 was significantly higher in AD group in comparison with cognitively normal individuals. Additionally, in the whole study group levels of UCHL‐1 correlated negatively with decreased concentration of Aβ 1‐42, MMSE. Furthermore, the significant relationship between UCHL‐1 and tau proteins was also revealed.ConclusionThe study suggest a potential role of UCHL‐1 protein in the pathology of AD and its potential usefulness as a candidate biomarker of AD, but these investigations need to be further confirmed.
Sex modifies the association between hippocampal blood flow and episodic memory in cognitively unimpaired individuals
Authors: Brugulat‐Serrat Anna , Cobigo Yann , Fonseca Corrina S. , Tsuei Torie , Goldberger Lauren , Rosen Howard J. , Kramer Joel H. , Elahi Fanny M , Staffaroni Adam M. , Casaletto Kaitlin B 
Published: December 2022

AbstractBackgroundCerebral blood flow (CBF) is disrupted in Alzheimer’s disease (AD) and associated with worse cognition, including episodic memory performance. Sex differences have been noted in both CBF and memory performance in AD; women demonstrate higher global CBF and memory performance than men. However, the effect of sex on the association between CBF and memory performance has not been explored. This study examined whether there were sex differences in the association between memory performance and CBF in AD‐related regions in typically aging older adults.MethodThe study included 119 functionally intact (CDR=0) older adults from the UCSF Hillblom Aging Network (mean age 74.9 (5.7), 51.2% females) who completed a cognitive assessment with brain MRI including T1‐weighted and arterial spin labeling (ASL) in hippocampal and precentral gyrus (as control) regions. Episodic memory was assessed by the California Verbal Learning Test and Benson figure delayed recall. Mean Z‐scores estimated a memory composite score. Memory composites were the dependent variable in regression models testing the interaction between regional ASL and sex as predictors, and age, education, APOE‐ε4, hippocampal volume, and vascular burden composite as covariates.ResultThere were no significant sex differences in levels of hippocampal CBF, but females performed better on the memory composite (p<0.001) than males after adjustment for age and education. We found that sex modified the association between hippocampal CBF and memory performance (figure 1) (p=0.04). Specifically, the positive association between hippocampal CBF and memory performances was stronger in men compared to women. This interaction remained significant after further adjusting for APOE‐ε4, hippocampal volume, and vascular burden. There was no significant sex by CBF interaction on memory performance when examining precentral CBF (p=0.79).ConclusionOur result suggests that sex modifies the association between memory performance and perfusion in brain regions vulnerable to pathological changes in preclinical AD. Specifically, greater hippocampal CBF is positively associated with memory performance in men but not women. Men may benefit more from increased blood flow, possibly reflecting vascular integrity, in hippocampal regions in memory performance than women. This work highlights mechanisms that may be differentially vulnerable by sex differences and inform risk for neurodegenerative diseases.
Sildenafil (Viagra) is a candidate drug for Alzheimer’s disease
Authors: Cheng Feixiong , Fang Jiansong , Zhang Pengyue , Zhou Yadi , Chiang Chien‐Wei , Tan Juan , Hou Yuan , Cummings Jeffrey 
Published: December 2022

AbstractBackgroundThe hypothesis that accumulation of amyloid‐beta protein and consequent tau pathology represents the main cause of Alzheimer’s disease (AD) has dominated the field for more than 2 decades; yet, anti‐tau or anti‐amyloid selective drug discovery approaches have lack of clinical benefits for AD patients. We posited that systematic identification of underlying AD‐related endophenotype modules shared by amyloid and tau may provide a foundation for generating predictive models to characterize pathogenesis and therapeutic development for AD.MethodIn this study, we developed an endophenotype network‐based methodology for in silico drug repurposing in AD. Specifically, we proposed an integrated network‐based framework by incorporating systems pharmacology and network medicine strategies to identify candidate drugs for AD. We further evaluated the drug‐AD outcomes by analyzing 7.23 million U.S. commercially insured individuals and investigated the drug’s mechanism‐of‐action using AD patient‐induced pluripotent stem cells (iPSC)‐derived neuron models.ResultUsing an endophenotype disease module‐based methodology for Alzheimer’s disease (AD) drug repurposing, we identified sildenafil as a potential disease risk modifier. Based on retrospective case‐control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25‐0.39, P<1.0´10−8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho‐tau expression in AD patient iPSC‐derived neurons, supporting mechanistically its potential beneficial effect in Alzheimer’s disease.ConclusionWe identified sildenafil (Viagra) as potential treatment of AD; yet, the association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.
CSF proteins involved in neuroplasticity are associated with altered whole brain connectivity in prodromal AD
Authors: de Leeuw Diederick Martijn , Dicks Ellen , Barkhof Frederik , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2022

AbstractBackgroundIndividuals with prodromal Alzheimer’s Disease (AD) and higher gray matter connectivity measures show slower decline, suggesting resilience to AD. However, the precise biological processes underlying preserved brain connections remains unclear. Here, we studied this question using cerebrospinal fluid (CSF) proteomics.MethodFrom the ADNI we selected 78 individuals with MCI and abnormal CSF amyloid (i.e., prodromal AD) and 34 with normal cognition and normal CSF amyloid levels for whom MRI and CSF proteomic data was available. For each T1 MRI scan we constructed gray matter networks using an automated pipeline (Tijms, Series et al. 2012) and calculated degree, connectivity density, clustering, path length and small‐world measures (i.e. gamma, lambda and small world coefficient). Linear models were used to test associations between each connectivity measure and CSF protein levels while correcting for age and gender. Proteins showing associations of p < 0.1 were selected to find groups of proteins that are associated with biological processes according to Gene Ontology (GO). Proteomic profiles for each connectivity measure were compared to investigate overlap. Finally, we tested for enrichment of potential upstream drivers with the Enrichr tool.ResultIn total, 115 proteins were associated with altered connectivity in prodromal AD subjects (figure 1). The majority of proteins (n = 93, 80%) showed higher levels with stronger (i.e., resilient) brain networks characterized by increased degree, connectivity density, clustering, path length, gamma, lambda or small world coefficient values. In controls, 80 of these 93 proteins showed an opposite relationship, with lower levels relating to higher values for these connectivity measures, which suggests that increased levels in prodromal AD may indicate a compensatory mechanism to maintain strong brain connectivity. According to a pathway analysis in GO, these proteins associated with stronger brain networks were mainly involved in neuroplasticity pathways. A subsequent Enrichr analysis suggested involvement of upstream divers SUZ12 and REST, which are known to regulate neuroplasticity processes.ConclusionWe observed that higher CSF levels of neuroplasticity associated proteins were associated with higher brain connectivity values in prodromal AD, suggesting that plasticity mechanisms may play a role in resilience to AD pathology.