bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delirium diagnostic 2012 to 2021, contribution of CAM and clinical nurses of the geriatric consultation team in CIUSSS de l’Estrie‐CHUS
Authors: Lacombe Guy , Bel‐Maréchal Maria , Cowan Cathy Mc , Sabourin‐Tremblay Émilie , Poulin Véronique 
Published: December 2023

AbstractBackgroundTo evaluate the evolution of diagnostic of delirium following the introduction of CAM as a geriatric vital sign as part of The Specialized Approach to Senior Care (l’approche adaptée à la personne âgée, AAPA) in University Hospital CIUSSS de l’Estrie‐CHUS in 2014.MethodTraining on CAM and delirium was given in 2014. The nurses of the geriatric consultation team make recommendations/coaching to the treating teams during geriatric consultations. We analyze ICD‐10 data from > 65‐year‐olds hospitalized at the CHUS before (2012) and after (2016). A criteria base analysis of the files with diagnosis of delirium on the discharge letter or a geriatric consultation of November 2016 describes the considerations related to delirium.ResultOf the 32,000 hospitalizations at CHUS in 2016, 13,000 are over 65 years old and 1296 have a geriatric consultation. 2.2% in 2012 to 2.7% in 2016 had delirium according to the exit letter. That is 3% of 65‐75 year olds and 8% of those over 75. 102 consecutive files of geriatric nursing consultations from November 2016 are reviewed. 63 new diagnoses of delirium with an average of 3 recommendations from the AAPA to the treatment team.ConclusionDelirium remains under‐documented at release and improves little from 2012 to 2021. The modalities of use of the current tools remain insensitive. The support of geriatric consultation teams remains necessary to support the development of AAPA against delirium.
Self‐appraisal of cognitive performance in repeated daily digital assessments with amyloid and tau‐PET
Authors: Soberanes Daniel , Hsieh Stephanie , Molinare Cassidy , Weizenbaum Emma L , Jutten Roos J. , Vannini Patrizia , Dubbelman Mark A. , Gagliardi Geoffroy Pierre , Johnson Keith A. , Rentz Dorene M. , Sperling Reisa A. , Papp Kathryn V. , Amariglio Rebecca E. 
Published: December 2023

AbstractBackgroundLower self‐ratings of performance on single timepoint neuropsychological measures have been previously associated with elevated AD biomarkers, aligned with the notion of a period of heightened awareness of cognitive decline in preclinical AD. With the rise of digital tools, cognitive assessments can now be collected over multiple days to examine learning over repeated exposures, thought to be diminished in preclinical AD. However, it is unknown whether daily self‐appraisal of performance would mimic reduced learning observed in individuals with elevated biomarkers. In this study, we used the Boston Remote Assessment for Neurocognitive Health (BRANCH) platform to capture multi‐day learning curves and to analyze whether self‐evaluation of performance was associated with amyloid and tau PET in a sample of cognitively unimpaired older individuals.MethodOur sample consisted of 193 cognitively unimpaired individuals (mean age = 74.1, 64.8% female, 85.5% Caucasian) already enrolled in a longitudinal observational study who underwent PiB‐ and Flortaucipir‐PET. Using the BRANCH platform remotely, participants completed two paired associative learning tests with repeated stimuli on their own digital devices for 7 consecutive days. A self‐evaluation was prompted at the end of each assessment, asking participants to rate their performance from 0‐100. Multi‐day learning curve metrics for objective performance (obj‐MDLC) and self‐appraisal (subj‐MDLC) were calculated for each participant. We examined correlations between obj‐MDLC and subj‐MDLC and using linear mixed‐effects models investigated the relationship between MDLCs, global β‐amyloid (Aβ) and tau burden in entorhinal (ET) cortex.ResultObj‐MDLC was moderately correlated with the subj‐MDLC (r = 0.61, p < 0.001) and showed that, on average, participants under‐estimated their performance on the tasks. Both higher Aβ and higher ET tau were associated with a decreased obj‐MDLC (Day*Aβ = ‐0.08, p = 0.015; Day*ET = ‐0.06, p = 0.020) and subj‐MDLC (Day*Aβ = ‐0.09, p = 0.021; Day*ET = ‐0.09, p = 0.003).ConclusionParticipant’s self‐appraisal of their performance on the BRANCH tasks across days showed significant associations with tau and amyloid that were consistent with those seen with actual performance on the BRANCH tasks. These findings demonstrate that utilizing daily self‐appraisals, in addition to objective assessment, provides complementary information in early preclinical AD.
Associations Between Trauma, Cognition, and Depression in U.S. Older Adults: Findings from the Health and Retirement Study
Authors: Dong Fanghong , Britt Katherine Carroll , Hodgson Nancy A 
Published: December 2023

AbstractBackgroundDespite the well‐known deleterious health effects of childhood and adulthood trauma and the aging of the global population, little is known about trauma experiences in older adults. Moreover, childhood trauma may beget adulthood trauma and alter life‐course trajectories of trauma exposure, and thus exhibit certain patterns in older adults. Using a national sample, this study aimed to (1) determine patterns of childhood and adulthood trauma, (2) examine their association with cognition and depression, and (3) investigate whether the association between trauma and depression is moderated by cognition.MethodData were from participants aged 60+ in the Health and Retirement Study in 2008 and 2012. Latent class analysis (LCA) was conducted to identify childhood and adulthood trauma patterns in 2008 (N = 6545). Depressive symptoms were measured by Center for Epidemiological Studies–Depression scale (CESD) and cognition was assessed by total cognition summary score (range 0‐35 and cognitive impairment defined as 8 or less) in both 2008 and 2012. The final sample size is 4684. Multiple regressions were conducted to examine cross‐sectional and longitudinal associations between trauma patterns, cognition, and depression, while moderation analyses were conducted to examine the moderating role of cognition, adjusting for age, gender, race, education, marital status, and body mass index.ResultParticipants had a mean age of 71.5(7.53) years, 58.4% female, and 85.7% White. A 3‐class LCA model was determined to be the best fit for the data with three patterns: (1) low trauma exposure (61.04%), (2) family life‐threatening events (20.07%) and (3) moderate trauma exposure (i.e., moderate probability of having experienced every type of trauma) (18.89%). Older adults experiencing family life‐threatening events or moderate trauma exposure have significantly worse cognition and higher depression. Furthermore, cognition moderated the association between trauma exposure and depression, especially for older adults who experienced family life‐threatening events.ConclusionFindings indicated significant associations between three distinct trauma patterns and depression, and the buffering role of cognition. Educating health professionals about trauma patterns, rather than only considering accumulation, could optimize targeted, integrated public health and clinical strategies to improve cognitive performance and decrease depression in vulnerable older adults who have experienced trauma.
Multi‐omic characterization of a novel FTD/ALS‐associated variant in ANXA11
Authors: Snyder Allison , Ryan Veronica , Qi Andy , Johnson Kory , Reed Xylena , Cookson Mark R , Ward Michael 
Published: December 2023

AbstractBackgroundMutations in Annexin A11 (ANXA11) disrupt its normal function and cause FTD/ALS spectrum disorders. Pathophysiologically, disease‐associated ANXA11 mutations alter its phase separation properties, resulting in ANXA11 aggregation, alterations in lysosomal‐RNA granule co‐trafficking, and TDP‐43 mislocalization. Multiple mutations in ANXA11 have been linked to FTD and ALS, but as genetic testing has become more accessible and affordable, additional variants of uncertain significance in in this and other genes have been identified. Determining whether these variants play causal roles in disease is a major challenge in the field.MethodWe identified a novel variant in ANXA11 (P93S) in a kindred that segregates with an FTD‐spectrum disorder with unusual radiographic features. We developed a pipeline to model ANXA11 variants in iPSC‐derived microglia and neurons, which scRNAseq analysis of human cortex revealed as the highest ANXA11 expressing cell types. Following differentiation, we characterized the proteomic, transcriptomic, and microscopy signature of the P93S variant compared to known pathogenic mutations in ANXA11.ResultMutant P93S ANXA11 expression in iPSC‐derived neurons resulted in increased ANXA11 fibrils and loss of nuclear TDP‐43. Proteomic analysis revealed disruption of multiple cellular pathways associated with neurodegenerative diseases.ConclusionOur iPSC neuron models of this variant recapitulate several hallmark pathological features of mutations in ANXA11 indicating that this novel ANXA11 P93S variant is likely pathogenic. Omic signatures of this variant provide additional evidence of pathogenicity. Importantly, the pipeline that we developed provides a proof‐of‐concept for future evaluation and adjudication of additional variants of uncertain significance across FTD/ALS associated genes.
Palmitoyl transferase zDHHCs: novel targets in Alzheimer’s disease
Authors: Fusco Salvatore , Natale Francesca , Spinelli Matteo , Gulisano Walter , Rinaudo Marco , Puzzo Daniela , Grassi Claudio 
Published: December 2023

AbstractBackgroundGrowing evidence points to altered metabolic signals as a risk factor for Alzheimer’s disease (AD). The high fatty acid levels and brain insulin resistance (BIR) found in AD brains may impinge on protein S‐palmitoylation, which is a post‐translational modification critically involved in the regulation of neuronal protein localization and synaptic function. Our previous findings highlighted the critical role of aberrant palmitoylation in BIR‐dependent memory impairment (Spinelli et al., 2017).MethodWe analyzed both the expression of palmitoyl‐transferase enzymes (zDHHCs) in mouse AD brains and S‐palmitoylation levels of key proteins in human AD brains. We also tested the effect of chronic intranasal injection of the palmitoylation inhibitor 2‐bromopalmitate (2BP) on a large cohort of male and female 3xTg‐AD mice, starting from 3 months of age, by performing cognitive (novel object recognition and object displacement tests), electrophysiological (LTP), immunohistochemical (Abeta deposition) and molecular analyses (Abeta measurement by ELISA). Finally, we investigated the effects of lentiviral particles‐mediated zDHHC7 or zDHHC21 silencing in the hippocampus of 3xTg‐AD.ResultWe found increased levels of zDHHC7 and zDHHC21 in the hippocampus of 3xTg‐AD mice and aberrant palmitoylation of key enzymes triggering beta amyloid aggregation in human AD brains. 2BP delayed the onset of memory deficits in both male and female 3xTg‐AD mice. More importantly, 2BP significantly enhanced cognitive performances in 6‐, 9‐ and 12‐month‐old animals. Accordingly, electrophysiological analyses on hippocampal brain slices from 2BP‐treated 3xTg‐AD mice revealed greater long‐term potentiation at CA3‐CA1 synapses. In addition, both 2BP‐treated male and female mice showed lower Abeta deposition in hippocampus and a significant extension of lifespan. Finally, genetic inhibition of palmitoyl transferase zDHHC7 reverted the aberrant palmitoylation of proteins involved in synaptic plasticity and APP metabolism, and counteracted the onset of neurodegeneration and cognitive deficits in 3xTg‐AD mice.ConclusionThis is the first preclinical study on the effect of 2BP treatment on AD‐related cognitive decline. Our data indicate that aberrant palmitoylation plays a critical role in the onset and progression of AD and unveil the potential druggable role of zDHHC enzymes in dementia‐related neurodegenerative disorders.
Applying CVR, composite value ratio, to brain MRI volume and thickness as an atrophy biomarker for Alzheimer’s disease clinical trials
Authors: Saguer Isaac Llorente , Oxtoby Neil P 
Published: December 2023

AbstractBackgroundBiomarkers are key tools for clinical trials of putative therapeutics in Alzheimer’s Disease. Biomarkers with higher signal‐to‐noise ratio can improve the efficiency of drug development through reduced sample sizes and shorter trial durations. Image‐based biomarkers such as SUVR from PET and volumes from MRI have been used as secondary outcomes in many studies. Previously, we showed how our biomarker‐discovery algorithm CVR (combined value ratio) outperformed tau‐PET SUVR in clinical trial applications [Saguer et al., Alzheimer’s ∖& Dementia 2022]. Here, we apply the same methodology to brain volumes and cortical thickness, which are both cheaper than PET and routinely collected.MethodsData: We analyse longitudinal MRI data in ADNI from 1622 participants: 556 cognitively unimpaired (CU) and 1066 cognitive impaired (CI), keeping the latest three visits for CU, and earliest for CI, to better target the transition from CU to CI.Model: A genetic algorithm explores combinations of 68 regions (averaged) defined by the Desikan‐Killiany atlas in FreeSurfer, separately for volume (including ventricles) and cortical thickness (all log‐transformed). We define CVR as the ratio of two data‐driven composite regions.Evaluation: A linear mixed‐effects model estimates 1) group separation in atrophy (t‐statistic, CU vs CI fixed effect) and 2) longitudinal precision (std of model residuals). We calculate 3) sample size estimates (SSE) for a hypothetical 12 months‐long clinical trial involving CI individuals designed for 80% power, with 20% treatment effect. Metrics 1 and 3 drive the biomarker discovery algorithm.ResultsTable‐1 shows our CVR metrics wrt traditional biomarkers from the literature (whole‐brain and hippocampus volume, average cortical thickness of all regions and a subset). CVR improved group separation by 1.7x, longitudinal precision by 1.7x and reduced sample size by 5.1x.DiscussionThe data‐driven biomarker from volumetric measures is the ratio of two composites (Figure‐1): one is highly linked to neurodegeneration, while the other takes advantage of more stable or growing regions, like the ventricles. Having these opposite characteristics in a ratio boosts its performance.ConclusionOur algorithm discovered a ratio‐based imaging biomarker that could vastly improve clinical trials in Alzheimer’s disease using routinely collected MRI.
Microglial deletion of C1q rescues AD cognitive decline and synaptic loss
Authors: Petrisko Tiffany J , Gomez‐Arboledas Angela , Chu Shu‐Hui , Tenner Andrea J 
Published: December 2023

AbstractBackgroundThe complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies have demonstrated constitutive deletion of the classical initiator protein, C1q, reduces pathology and synaptic loss in AD mouse model. As it is now known that microglia are the primary producers of C1q in the brain, the main objective of this study was to determine if microglial specific deletion of C1q would rescue cognitive impairment and synaptic loss in AD.MethodC1qaFLlFL:CX3CR1Cre (designated C1qΔMG)mice, which experience tamoxifen‐independent deletion of microglial C1q by 2 months of age, were crossed to Arctic: C1qaFl/Fl: mice to generate WT and Artic mice with and without the CX3CR1Cre transgene. At 10 months of age, mice underwent behavioral testing of hippocampal dependent spatial memory, including object location memory (OLM) and spatial reference Y‐maze. Tissue was collected at the end of testing and immunostained for pre (VGlut1) and post (PSD95) synaptic makers and Z‐stacks using superresolution microscopy in the CA1 of the hippocampus were obtained. The density of pre‐ and post‐synaptic puncta and their colocalization was assessed using IMARIS.ResultWhile both male and female Arctic mice displayed a significant impairment in long‐term memory, as assessed by OLM, microglial deletion of C1q rescued cognitive deficits in male but not female Arctic mice. Male Arctic C1qΔMGmice also performed better on Y‐maze testing than Arctic controls. Similar sex‐dependent results were observed in synaptic density. Female Arctic C1qΔMG mice displayed reduced levels of PSD95 and Vglut1 puncta compared to female Arctic mice, as well as a trending reduction in colocalization. In contrast, male Arctic C1qΔMG mice displayed increased levels of PSD95, trending reductions in VGlut1 compared to male Arctic controls, and trending increases in synaptic colocalization, suggesting an increase in functional synapses in the male mouse.ConclusionDeletion of C1q in microglia prior to amyloid plaque deposition protects against cognitive decline and synaptic loss in a greater extent in males than females.
Extracellular Tau Oligomers Damage the Axon Initial Segment by an Endogenous Tau‐Dependent Mechanism
Authors: Best Merci N , Lim Yunu , Ferenc Nina , Kim Nayoung , Wang Dora Bigler , Sharifi Kamyar , Wasserman Anna , McTavish Sloane , Siller Karsten , Jones Marieke K , Jenkins Paul M , Mandell James W , Bloom George S 
Published: December 2023

AbstractBackgroundNeuronal polarity and synaptic connectivity are compromised in Alzheimer’s disease (AD) and other tauopathies. The axon initial segment (AIS) is a key structure for regulating polarity and functions of neurons. It occupies the first 20‐60 µm of the axon, comprises a diffusion barrier that segregates axon‐enriched from somatodendritic‐enriched molecules, and has a high concentration of voltage‐gated ion channels that generate action potentials. Extracellular amyloid‐β oligomers compromise AIS integrity. However, effects on the AIS of toxic tau species, including extracellular oligomers (xcTauOs) that spread tau pathology from neuron to neuron by a prion‐like process, whereas unknown. Therefore, we wanted to test the hypothesis that AIS structure is sensitive to xcTauOs.MethodPrimary cortical neurons derived from either wild type (WT), or tau knockout (KO) mice were exposed to xcTauOs or vehicle. Quantitative western blotting and immunofluorescence microscopy with an antibody against the AIS‐enriched protein TRIM46 was used to monitor effects on the AIS. The same methods were also used to compare TRIM46 and two other AIS proteins, ankyrin‐G and neurofascin‐186 in human hippocampal tissue obtained from AD and age‐matched non‐AD donors.ResultIn cultured WT, but not TKO neurons, xcTauOs cause a trend toward AIS shortening and reduce the concentration of the resident AIS protein, TRIM46, without affecting total TRIM46 levels. Lentiviral‐driven human tau expression in tau KO neurons rescues TRIM46 sensitivity to xcTauOs. In human AD hippocampus, AIS length and TRIM46 concentration within the AIS are reduced in neurons containing neurofibrillary tangles (NFTs), without affecting the overall protein levels of multiple resident AIS proteins.ConclusionThese collective findings demonstrate that in cultured neurons, xcTauOs cause partial AIS damage by a mechanism dependent on intracellular tau, thereby raising the possibility that AIS reduction in AD is caused by xcTauOs working in concert with endogenous neuronal tau.
Validation of the European Cross‐Cultural Neuropsychological Test Battery (CNTB) for the assessment of mild cognitive impairment due to Alzheimer’s disease and Parkinson’s disease in Spain
Authors: Delgado‐Álvarez Alfonso , Nielsen T Rune , Delgado‐Alonso Cristina , Valles‐Salgado María , López‐Carbonero Juan Ignacio , García‐Ramos Rocío , Gil‐Moreno María José , Díez‐Cirarda María , Matias‐Guiu Jorge , Matias‐Guiu Jordi 
Published: December 2023

AbstractBackgroundThe Cross‐Cultural Neuropsychological Test Battery (CNTB) is a novel comprehensive neuropsychological battery developed from a multicultural approach. We aimed to validate the CNTB in patients from the majority population with Alzheimer’s disease (AD), including mild cognitive impairment (MCI) and mild dementia stages, and Parkinson’s disease with MCI (PD‐MCI).MethodsThirty patients with AD‐MCI, 30 with AD‐dementia (AD‐D), and 30 with PD‐MCI were enrolled. Each clinical group had a specific healthy control group (HC) with no differences in sex, age, or years of education. We performed intergroup comparisons, ROC analysis, and calculated the corresponding cut‐off points based on Youden’s index.ResultsAD‐MCI showed lower scores than HC in those subtests associated with episodic memory and verbal fluency, while AD‐D also scored lower in executive function and visuospatial tests with large effect sizes. Participants with PD‐MCI showed lower performance in memory and executive function, particularly on error scores, with large effect sizes, compared with HC. While AD‐MCI showed lower memory scores, PD‐MCI had a lower performance in executive functions, comparing both groups. We found evidence of convergent validity with standardized neuropsychological tests measuring the same cognitive domains. Cut‐off scores were similar to previous studies conducted in other cultures.ConclusionsThe CNTB showed appropriate diagnostic properties and convergent validity in AD and PD, including the early stages of the disease. This supports the utility of the CNTB for the early detection of cognitive impairment in AD and PD.
The effect of study partner characteristics on the reporting of neuropsychiatric symptoms in older adults with and without dementia
Authors: Guan Dylan X. , Mudalige Dinithi M , Munro Catherine E , Nosheny Rachel L , Smith Eric E. , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundValid assessments of neuropsychiatric symptoms (NPS) are key in older adults with or without dementia, often relying on study partner (SP) report. NPS are linked to poorer health outcomes, denoting higher risk for incident cognitive decline and dementia, especially when these NPS emerge in later life and persist (i.e., mild behavioral impairment; MBI). We investigated the effect of study partner (SP) characteristics on SP‐reported NPS in older adults with and without dementia (normal cognition or mild cognitive impairment), and compared MBI‐associated rates of incident dementia across different SP characteristics.MethodCross‐sectional (n = 26825) and longitudinal (n = 2526) analyses were conducted on participant‐SP dyads in the National Alzheimer’s Coordinating Center Uniform Data Set. NPS were measured using the SP‐rated Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI status in dementia‐free participants was defined by the presence of NPS across two consecutive visits. SP characteristics of interest were age, sex, and relationship to participant (spouse, child, other). Multivariable logistic regressions, adjusted for participant age, sex, education, and dementia status were used to model participant NPS presence/absence as a function of SP characteristics. Cox proportional hazards regression was used to compare the hazard of incident dementia in MBI participants across different SPs.ResultParticipant and SP characteristics are summarized in Table 1. Across the entire cohort, SPs who were younger, female, or a spouse or child of the participant were more likely to report participant NPS [Table 2]. Furthermore, in dementia‐free participants, female‐spouse SPs reported participant MBI with greater odds than male spouses, but non‐spouse SPs reported participant MBI similarly to one another with lower odds regardless of sex [Figure 1]. This interaction was not observed for NPS in dementia, which were highly prevalent regardless of SP sex and relationship to participant. Finally, participants with MBI reported by SPs who were spouses or children progressed to dementia at a greater rate than other SPs.ConclusionSP characteristics including age, sex, and relationship to participant are linked to greater endorsement of NPS in older participants with and without dementia. In scenarios where accurate assessments of NPS are required, SPs characteristics could be considered in recruitment and analysis.