bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics associated with progression to probable Dementia with Lewy Bodies in a cohort with late onset psychosis
Authors: Gibson Lucy L , Mueller Christoph , Stewart Robert , Aarsland Dag 
Published: December 2023

AbstractBackgroundA psychiatric‐onset prodrome is increasingly recognised in Dementia with Lewy Bodies (DLB) and while late‐onset psychosis is associated with increased risk of developing dementia, it is not clear what proportion of patients with psychotic disorders go onto develop DLB. Among patients with late onset psychosis, we aimed to identify the proportion who developed DLB and to characterise the clinical features and characteristics of those who convert to DLB.MethodAnonymised data collected between 2006‐2021 was retrieved from clinical records from a large London mental health service for patients who were ≥50 years when first diagnosed with a psychotic disorder. Patients with dementia diagnoses >3 months later were identified and a natural language processing (NLP) algorithm was used to identify patients with probable DLB, with two of the core features (visual hallucinations, parkinsonism, fluctuations or sleep disturbance) identified in the free text at the time of dementia diagnosis. Predictors of progression to DLB were investigated including demographic factors, Health of the National Outcome scale for older people (HoNOS65+) and key clinical features at the time of psychosis diagnosis identified with NLP.ResultIn 3784 patients with late onset psychosis, 321 (8.5%) received a diagnosis of dementia from mental health services during the follow‐up period (mean time to dementia diagnosis 3.66±3.13 years). A high percentage (30.5%, n = 98) of those who developed dementia met criteria for probable DLB. Presence of hallucinations, falls, parkinsonism, fluctuations or drowsiness at the time of late onset psychosis diagnosis was associated with an increased relative risk of later developing probable DLB. Adjusted multivariate Cox proportional hazard models suggested that older age and higher scores on HoNOS cognitive and hallucinatory items at baseline were significant predictors of faster progression to DLB.ConclusionDLB is overrepresented in patients with late‐onset psychosis who later develop dementia; a psychiatric prodrome in dementia should give a high index of suspicion for DLB. In patients with late‐onset psychosis, risk factors for future progression to DLB include cognitive impairment, older age, hallucinations, falls, fluctuations, parkinsonism and drowsiness. Where these hallmarks are present at the time of psychosis, close follow up could facilitate the earlier identification of DLB.
Jedi‐1/MEGF12‐mediated phagocytosis controls the pro‐neurogenic properties of microglia in the ventricular‐subventricular zone
Authors: Morrison Vivianne E , Houpert Matthew G , Trapani Jonathan B , Brockman Asa A , Kingsley Philip J , Katdare Ketaki A. , Layden Hillary M , Hiebert Scott W , Nguena‐Jones Gabriela , Trevisan Alexandra J , Maguire‐Zeiss Kathleen A , Marnett Lawrence J , Bix Gregory J , Ihrie Rebecca A , Carter Bruce D 
Published: December 2023

AbstractBackgroundThe act of engulfing cellular debris profoundly shapes phagocyte phenotypes and, thus, determines tissue‐specific phagocyte function. A population of microglia with unique characteristics resides in the ventricular‐subventricular zone (V‐SVZ) neurogenic niche in neonatal mice. It is unclear whether these microglia perform phagocytosis and to what extent their phagocytic activity would support neurogenesis. We asked whether V‐SVZ‐resident microglia phagocytose apoptotic neurons and investigated whether the novel receptor Jedi‐1 mediates this process.MethodWhole brain tissue or micro‐dissected V‐SVZ was collected from wild‐type and Jedi‐1 knockout (JKO) pups at postnatal day 7 (P7) and processed for immunofluorescent labeling, cytokine analysis, LC‐MS analysis of lipid mediators, microglia‐enriched culture and engulfment assays, or bulk RNA sequencing. Proliferating cells were labeled during a one‐hour pulse of EdU, delivered to the pups subcutaneously at P7. Microglia‐specific deletion of Jedi‐1 was induced with Tamoxifen, administered to the lactating dam twice daily from P1‐P3. In vivo rescue was performed via intracerebral injection of interleukin‐1 receptor antagonist at P4, followed by tissue collection at P7 for downstream analysis.ResultWe show that V‐SVZ microglia express Jedi‐1 and that Jedi‐1 is necessary for microglial phagocytosis both in vitro and in vivo. Furthermore, we show that loss of Jedi‐1 transforms microglial identity, leading to a neuroinflammatory phenotype consistent with that observed in neurodegenerative diseases and the aging brain. We demonstrate that loss of Jedi‐1 reduces the proliferation and neuronal differentiation of neural precursor cells in the V‐SVZ and that this effect is due to the loss of Jedi‐1 specifically in microglia. Finally, we provide evidence that the neurogenesis deficit is due to elevated interleukin‐1β levels and that in vivo inhibition of IL‐1 signaling rescues neurogenesis in the Jedi‐1 knockout V‐SVZ.ConclusionThe discovery that Jedi‐1 activation engenders pro‐neurogenic microglia reveals previously unknown aspects of postnatal neurogenesis and microglial function. It also provides a platform for future research on pathways that dictate microglial phenotypic changes at all life stages, both in health and in disease. Finally, these findings may provide opportunities to explore neuroprotective/neuroregenerative microglial‐targeted therapies.
PET biomarkers in behavioral variant Frontotemporal dementia: analysis of an Argentine cohort.
Authors: Guimet Nahuel Magrath , Falasco German , Bagnati Pablo Miguel , Vazquez Silvia , Bérgamo Yanina , Herrera Julio Jose , Fernandez Laura , Urrutia Leandro , Mendez Patricio Chrem , Allegri Ricardo Francisco 
Published: December 2023

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by early and progressive changes in behavior, emotional processing and executive control. This entity represents a diagnostic challenge in which positron emission tomography (PET) may play a key role in the diagnosis and follow‐up in vivo with a minimally invasive method. The aim of this work is to evaluate PET biomarkers in a cohort of patients with a clinical diagnosis of bvFTD.Method21 normal controls (NC: 64 ± 9 years) and 20 patients with a diagnosis of probable bvFTD (65 ± 7 years) were evaluated by: neurological, neuropsychological, neuropsychiatric evaluation and PET imaging biomarkers: [18F]‐FDG, [18F]‐AV1451 (TAU), [11C]‐PIB. For neuroimaging processing and analysis, they were spatially normalized to an FDG template. Group comparisons (voxel‐based) of each biomarker were performed by t‐test (SPM12) using cerebellar gray matter as reference tissue, and for inter‐biomarker uncoupling comparison a covariate of uptake in total cortex was used.ResultIn the statistical comparison between NC vs. bvFTD groups (p<0.05), hypometabolism is observed at the frontotemporal level and hypermetabolism in the precentral region (FDG). Amyloid marker (PIB) uptake shows no significant difference between groups in much of the cortex, except in the precentral region. TAU uptake shows a significant difference, greater in bvFTD, at frontal, parietal and precuneus levels. In the uncoupling between FDG and TAU biomarkers, it is observed that hypometabolism is related to an increase in TAU uptake in medial and inferior temporal regions. Differences between PIB and TAU are mainly observed in frontotemporal regions. There was an association between clinical symptoms (mainly apathy) and the anatomical distribution of [18F]‐FDG, [18F]‐AV1451 radiotracers (TAU).ConclusionPET biomarkers are a valuable tool in the diagnosis of bvFTD. The [11C]‐PIB may be of paramount importance in the differential diagnosis of FTvc FTD with Alzheimer’s disease. FDG is a very sensitive biomarker of neuronal metabolism and its variations, sometimes losing specificity. Advances in tracers such as [18F]‐AV1451 (TAU) can provide important information on the underlying neuropathological process. The combined use of these tools brings us closer to understanding the biological phenomena behind the cardinal symptoms of bvFTD.
Speech markers of depression dimensions across the spectrum of cognitive functions
Authors: Soleimani Laili , Cho Sunghye , Kia Arash , Beeri Michal S , Liberman Mark Y , Grossman Murray , Nevler Naomi 
Published: December 2023

AbstractBackgroundDepression is a common among patients with cognitive impairment and encompass different dimensions, which may vary in their association with cognitive outcomes and biological substrates. Previous studies have shown a shift toward the use of more negative words in written documents and social media posts of depressed patients with intact cognitive function. To objectively characterize depression dimensions across the spectrum of cognitive functions, we explored their association with the emotion‐based measures of speech in participants of memory clinic.MethodsThis study capitalized on semi‐structured digitized speech data collected at the hospital of University of Pennsylvania. Subjects (n = 302, 40% female, mean age = 67.13±9.59 years, education = 15.82±2.84 years, Mini‐Mental Status Exam (MMSE) = 24.36±5.04) were native English speakers with cognition ranging from normal cognition to mild dementia. Participants were instructed to describe the Cookie Theft scene using complete sentences and their descriptions were digitally recorded. Emotion‐based measures of the content words, including valence (i.e., the pleasantness), arousal (the intensity of emotions), and dominance (the word power), were rated based on published norms. Each emotional measure was averaged per speaker. Depression dimensions were defined based on itemized Geriatric Depression Scale – 15 item (GDS‐15) including Dysphoria, Withdrawal‐Apathy–Vigor (WAV), anxiety, hopelessness and Subjective Memory Complaint. Non‐parametric partial correlations examined associations between speech emotion‐based measures and depression scores adjusting for age, sex, education and MMSE.ResultsOverall depression score (total GDS) did not correlate with the speech measures. However, when examining specific depression dimensions, higher WAV and hopelessness correlated with reduced valence (WAV: r = ‐0.21, P = 0.00, hopelessness: r = ‐ 0.14, P = 0.01) and dominance (WAV: r = ‐ 0.18, P = 0.001, hopelessness: r = ‐ 0.16, P = 0.004). We did not find a significant association between emotional word scores and other depression dimensions.ConclusionPatients with high apathy and hopelessness select words that carry more negative and less powerful emotional valence. Our findings highlight the potential applicability of speech biomarkers in characterization of depression dimensions across spectrum of cognitive and are consistent with previous findings that reported more negative bias and more submissive speech in depressed patients.
Modelling Latent Environmental Modifiers of Polygenic Risk for Late‐Life Depression Using Structural Equation Modelling
Authors: Elsheikh Samar , Marshe Victoria , Kennedy James L. , Pare Guillaume , Fischer Corinne E. , Felsky Daniel , Mueller Daniel 
Published: December 2023

AbstractBackgroundOur understanding of the interplay between genetic and environmental factors (Gene x Environment Interaction, or GxE) determining mental health disorders has improved through the proliferation of genome‐wide interaction association studies (GWIAS) and targeted GxE analyses. Moreover, multivariate modelling approaches, such as structural equation modelling (SEM) and polygenic risk scores (PRS), offer opportunities for the integration of clinical and genome‐wide genotype data in building improved biopsychosocial models of mental illness aetiology and their response to treatment.MethodWe propose to construct a SEM framework to uncover the inter‐correlation and directed structure of mental health phenotypes by leveraging the joint predictive capacity of PRS for comorbid traits that share underlying biological and environmental risk pathways. The proposed model will be capable of linking latent constructs to their observed measurements; these will include disease severity, comorbidities and clinical histories, and behaviours and lifestyle factors such as physical and social activity.ResultOur gene‐by‐environment SEM (GESEM) will be initially developed and tested using four well‐characterized clinical cohorts for older adults diagnosed with late‐life depression and treated with antidepressants (CAN‐BIND, IRL‐GREY, STOP‐PD II and IMPACT; n = 1,238). The primary outcome will be antidepressant remission. Multiple PRS will be calculated to capture underlying genetic risk across vulnerable pathways which contribute to comorbidities. This selection will be made based on new, largely unpublished work from our group on the impact of PRS and targeted GxE studies on psychiatric outcomes across the lifespan. Each PRS will be calculated using both clumping and thresholding (PRSice‐2) and continuous shrinkage (PRS‐CS‐auto) methods across selected cohorts using well‐powered publicly available GWAS summary statistics. The multilevel GESEM model will include interactions between symptoms and comorbidities (i.e., observed measurements), which are caused by unobserved factors (i.e., latent constructs), and are subject to modification by background PRS. We will compare our GESEM model against existing SEM‐based approaches to GxE, including local SEM (LOSEM).ConclusionAn open‐source R package of the analytical code will be created and shared with the research community. This work has the potential to improve upon existing PRS‐based predictive models in a clinical setting.
Braak‐stage II atrophy links lower locus coeruleus – medial temporal lobe connectivity to cognitive decline in preclinical AD
Authors: Schneider Christoph , Prokopiou Prokopis C. , Papp Kathryn V. , Hsieh Stephanie , Schultz Aaron P. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundIn preclinical human Alzheimer’s disease (AD), novelty‐related functional connectivity of the locus coeruleus (LC) with the medial temporal lobe (MTL) (ConnLC‐MTL) predicted beta‐amyloid (Aβ)‐related longitudinal cognitive decline. In animals, LC lesions in AD models led to dwindling LC projections to the hippocampus, hippocampal atrophy, and cognitive impairment. Following these observations, we investigated the contribution of cross‐sectional and longitudinal atrophy in early Braak stages as a potential mechanism underlying this relationship.MethodWe included 128 participants of the Harvard Aging Brain Study (HABS) with baseline Pittsburgh Compound‐B Positron Emission Tomography – Distribution Volume Ratio (PiB PET, DVR; 36 Aβ+), as well as baseline functional and longitudinal structural MRI (ntot = 372; ∼ every 3 years; follow‐up 5±3.4 years) and yearly cognitive assessments (PACC5 = Preclinical Alzheimer’s Cognitive Composite; ntot = 874; follow‐up 6.5±3.3 years) (Table 1). ConnLC‐MTL values were derived voxel‐wise and averaged across significant clusters. FreeSurfer‐estimated cortical thickness and hippocampus/amygdala volume (adjusted for intracranial volume) were z‐scored and averaged in two variables (THV2/THV3), encompassing regions associated with Braak stage II and III respectively (Table 1). Baseline associations were evaluated with linear models, longitudinal relationships between ConnLC‐MTL and THV2/THV3 with mixed‐effects models (random intercept and slope). Mediation of ConnLC‐MTL and PACC5 slopes (year 5‐13) by THV2/THV3 slopes (year 0‐5) was calculated (n = 79; bootstrapped n = 1000; Table 1). All models contained age, sex and education as covariates.ResultAt baseline, ConnLC‐MTL positively associated with THV2 (p = 0.005) and with PACC5 (p = 0.045), but not with THV3 (p = 0.26; Figure 1A‐C). Longitudinally, ConnLC‐MTL did not predict changes in THV2 nor THV3. However, we observed faster cortical atrophy with lower ConnLC‐MTL at higher levels of neocortical PiB (THV2: p = 0.02; THV3: p<0.001; Figure 1D‐E). Finally, THV2, but not THV3, mediated the relationship between ConnLC‐MTL and PACC5 decline (p = 0.024) and this effect was stronger in PiB+ individuals compared to PiB‐ (p = 0.026; Figure 2).ConclusionWorse LC‐MTL connectivity was associated with downstream atrophy in the target Braak‐stage II areas, which impacted cognitive performance in preclinical AD. Given that in similar previous animal findings activation of the norepinephrine LC system reversed memory deficits, maintaining optimal ConnLC‐MTL may be a promising intervention target to delay disease progression.
Domain‐specific cognitive decline associates with differential regional tau burden in the Alzheimer’s disease spectrum
Authors: St‐Onge Frederic , Binette Alexa Pichet , Chapleau Marianne , Breitner John C.S. , Villeneuve Sylvia 
Published: December 2023

AbstractBackgroundPatients presenting with distinct clinical variants of Alzheimer’s disease (AD) present differential patterns of tau pathology measured with positron emission tomography (PET). Yet, a single set of brain regions like a temporal meta‐ROI is often chosen to study the association between cognition and tau. Instead, we aimed to map the associations between regional tau and multiple cognitive domains, and to test whether using whole brain information yields stronger associations with cognition compared to a singular composite region.MethodWe included 372 amyloid‐positive ADNI participants that had at least one tau‐PET scan (163 cognitively unimpaired [CU], 132 with mild cognitive impairment [MCI], 77 with AD dementia). Composite cognitive scores for memory, executive functioning, visuospatial and language were used for cross‐sectional (closest score to tau‐PET) and longitudinal analyses. Individual rate of cognitive decline was computed using linear mixed effect models, leveraging all visits available for each participant. We did region‐wise analyses, relating tau in the 64 regions of the Desikan‐Killiany atlas plus the amygdalae with cognitive performance and rate of cognitive decline. We also derived a “spatial extent index” where we computed the number of abnormal tau regions and compared the performance of this index to detect cognitive impairment to what would have been found with a classical temporal meta‐ROI SUVR value.ResultNo regional association between tau and cognition survived FDR correction in CU participants. Cross‐sectionally and longitudinally, participants with MCI and with AD dementia, associations between tau and memory were predominant in the temporal lobe, associations with language were restricted mostly to the left hemisphere and associations with executive functioning spanned the entire cortex. (Fig 1) Comparing the sum of tau positive regions (spatial extent index) to tau SUVR in the temporal meta‐ROI, both measures were similarly associated with cognition, except for executive functioning at baseline where the spatial extent index was more strongly associated with cognition than the meta‐ROI. (Fig 2)ConclusionWhile temporal meta‐ROI tau SUVR may be sufficient to track non‐executive cognitive performance in individual with cognitive impairments, a whole brain measure may provide additional information regarding executive impairment occurring in AD.
Investigating the Role of Estrogen Receptor Alpha in Alzheimer’s Disease Pathogenesis in Down Syndrome
Authors: Andrews Elizabeth J. , Phelan Michael J. , Ngo Phong , Pascual Jesse R , Gonzalez Freddy , Wright Sierra , Kofler Julia , Ikonomovic Milos D , Lai Florence , Ances Beau , Handen Benjamin L. , Christian Bradley T. , Mapstone Mark , Head Elizabeth ,   Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS)
Published: December 2023

AbstractBackgroundPeople with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.MethodWe examined 34 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men (n = 19) and women(n = 15).ResultNo significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (r = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (r = 0.93; p = 0.00012) whereas men showed a weaker trend (r = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (r = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (r = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.ConclusionThese results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.