bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic performance RT‐QuIC based detection of alpha‐synuclein seeds in a clinical cohort with cognitive impairment
Authors: Esteller Diana , Guillén Núria , Sarto Jordi , Ramos‐Campoy Oscar , Falgàs Martínez Neus , Molina Laura , Borrego‐Écija Sergi , Ruiz‐García Raquel , Naranjo Laura , Antonell Anna , Lladó Albert , Sanchez‐Valle Raquel , Balasa Mircea 
Published: December 2023

AbstractBackgroundLewy Body Dementia (LBD) is the second most common neurodegenerative dementia. To date, no validated biochemical marker is available to support clinical diagnosis. The development of the Real‐Time Quaking‐Induced Conversion (RT‐QuIC) assay for detecting alpha‐synuclein (aSyn) seeds in biological samples can be a sensitive biomarker specific for the diagnosis easily applicable in a clinical setting. We aimed to describe the diagnostic performance of RT‐QuIC aSyn assay in cerebrospinal fluid (CSF) to diagnose LBD in a clinical cohort with cognitive impairment.MethodA cohort of subjects with cognitive impairment (neurodegenerative and non‐neurodegenerative) with available CSF sample at the moment of first evaluation was selected by convenience sample in our database. Subjects had clinical follow‐ups ranging from 6 months to 12 years and current clinical diagnosis according to established consensus criteria. The diagnostic performance of RT‐QuIC aSyn for the diagnosis of LBD were evaluated.ResultThe test was evaluated in 155 subjects (age 65 years (SD 11), MMSE 24 (SD 4.5), 56% male) with the following clinical diagnoses: LBD (n = 40), Alzheimer’s disease (AD) (n = 73)(all with compatible CSF profile), frontotemporal dementia (FTD) (n = 7), non‐neurodegenerative mild cognitive impairment (MCI) (n = 21), other neurodegenerative diagnoses (n = 12) and healthy controls (n = 2). aSyn was detected in 33/40 (83%) LBD patients, 7/73 (10%) AD, 0/7 FTD patients, 0/21 MCI patients, 0/12 patients with other neurodegenerative diseases and 0/2 healthy controls.Only 3/7 (42%) LBD subjects with a negative RT‐QuIC asyn fulfilled criteria for LBD (established or prodromal) at the moment of first evaluation as compared with 23/33 (69%) of LBD with positive RTQuIC suggesting a more initial disease in the negative group at the moment of CSF sampling.The sensitivity and specificity of the assay were 83% and 94% respectively for the diagnosis of LBD, with a PPV of 83% and a NPV of 94%.ConclusionDetection of αSyn seeds by RT‐QuIC has a good performance in identifying patients with LBD in a clinical cohort of cognitively impaired subjects. The test also identifies aSyn co‐pathology in a subgroup of subjects diagnosed with AD.
Cognitive functions in patients with Human Immunodeficiency virus. Infection in Nigeria: assessment using computer assisted neuropsychological test batteryhi7
Authors: Sunmonu Taofiki Ajao , Ogunrin Olubunmi Akindele , Komolafe Morenikeji Adeyoyin , Imarrhiagbe Frank I 
Published: December 2023

AbstractBackgroundThere is paucity of information on the cognitive functions in patients with HiV infection in NigeriaMethodFifty patients with HIV infection were studied along age,sex and level of education matched 50 HIV negative controls subjects.The patients underwent general physical and neurologically examinations. Laboratory investigations such as blood glucose test, CD4 cell counts, Full blood counts,CXrays, HIV clinical staging were done for all patients Fepsy neuropsychological Test battery was used for cognitive asssessment in all the study participants.ResultThe patients with HIV infections performed worse on measures of psychomotor speed (auditory reaction times, visual reaction times, attention concentration(Binary choice reaction times and computerized visual searching tasks) than the controls The prevalence of sevvere cognitive infection in HIV patients was 20%.Presence of anaemia and advanced HIV disease stage were predictive of cognitive impairment in the patients with HIV infection.ConclusionHIV Associated Cognitive Disorder is common in patients with HIV in this study
Understanding the molecular mechanisms of TDP‐43 neurotoxicity in ALS and FTD to inspire targeted therapies
Authors: Polymenidou Magdalini , Wiersma Vera I 
Published: December 2023

AbstractALS and FTD are fatal and incurable neurodegenerative diseases, characterized by accumulation of pathologic forms of RNA‐binding proteins, predominantly TDP‐43. The functional consequences and potential neurotoxic effects of the highly heterogeneous TDP‐43 aggregates observed in postmortem brains are debated. Combining structural protein analysis with cellular systems we uncovered a novel and unexpected mechanism that counteracts pathologic aggregation of TDP‐43. More recently, we described two distinct mechanisms of aggregation resulting in either nuclear of cytoplasmic TDP‐43 aggregates, resembling the neuropathological heterogeneity described in FTD patients and potentially unravels the origins of heterogeneous pathological species occurring in TDP‐43 proteinopathies. We also showed that FTD heterogeneity is associated with alternate pathological TDP‐43 conformations, reminiscent of prion strains. We used advanced microscopy techniques to explore the differences in the physical and seeding properties between these pathological TDP‐43 aggregates. We found that the subcellular environment and organization of TDP‐43 aggregates differs in patient brains in a subtype‐specific manner. When isolated and introduced in cells, these distinct TDP‐43 assemblies triggered neoaggregate formation with seeding potencies and morphologies that mimicked human brain pathology. To study neurodegeneration phenotypes in human neurons, we developed a new methodology for generating human neuronal networks with remarkable maturity, longevity and reproducibility. Combining high density multielectron arrays and single cell RNA sequencing, we demonstrated the potential of these cultures for modeling neurodegeneration. In this new model, we identified novel RNA targets of TDP‐43, which we found abnormally accumulated in neurons with TDP‐43 pathology in human brains of ALS and FTD patients. The implications of these studies for understanding the mechanisms of neurodegeneration and inspiring therapeutic approaches will be discussed.
Overview on epidemiology and neuropathologic staging of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic changes (LATE‐NC)
Authors: Nelson Peter T 
Published: December 2023

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is increasingly appreciated to have a very large impact on public health. The goal of this presentation is to provide an overview about what is known about the epidemiology of LATE, and also to describe some recent changes to the criteria for the diagnostic classification of LATE neuropathologic change (LATE‐NC). The prevalence of LATE‐NC and Alzheimer’s disease neuropathologic changes (ADNC) are each challenging to assess definitively, due to the requirement of state‐of‐the‐art autopsy verification across human populations.MethodA set of neuropathologic and clinical data were compiled from 13 high quality community‐ and population‐based longitudinal studies. The total number of participants included was 6,196, and the average age of death was 88.1 years. This study provided a credible estimate of the current prevalence of LATE‐NC in advanced age, with or without comorbid ADNC. Diagnostic classification also must take into account neuropathologic heterogeneity.ResultLATE‐NC was seen in almost 40% of participants and in ∼25% of those lacking ADNC. A total of 3,267 of these participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP). Another focus of the talk is recent research findings that have enabled increasingly precise guidance on how to differentiate LATE‐NC from other subtypes of TDP‐43 pathology (e.g., FTLD‐TDP and amyotrophic lateral sclerosis [ALS]), and how to render diagnoses in unusual situations in which TDP‐43 pathology does not match the staging scheme proposed in 2019. Specific recommendations are made about when to avoid the diagnostic term of LATE‐NC, based on current knowledge. Neuroanatomical regions of interest in LATE‐NC are specified factoring in neuropathologic data from different research centers.ConclusionLATE‐NC is a very common dementia, differentiable from ADNC or FTLD, and recent studies have refined our ability to make the diagnosis of LATE‐NC with increasing specificity. Areas needing additional study will be highlighted.
Discovery and optimization of the first‐in‐class TDP‐43 PET tracer
Authors: Seredenina Tamara , Vokali Efthymia , Dreyfus Nicolas , Chevallier Elodie , Afroz Tariq , Jaquier Thomas , Serra Andreia Monica , Clavel Mathieu , Rathnam Monisha , Melly Tania , Kroth Heiko , Pfeifer Andrea , Kosco‐Vilbois Marie 
Published: December 2023

AbstractBackgroundIntracellular aggregation of TDP‐43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) and 30‐50% of patients with clinical diagnosis of Alzheimer’s disease. Sensitive fluid or imaging biomarkers of TDP‐43 pathology are currently not available. Direct detection of TDP‐43 aggregates by positron emission tomography (PET) holds promise for a more accurate diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials.MethodsUsing ACI’s Morphomer® small molecule library focused on brain penetrant and beta sheet binding compounds, initial hits were identified, and iterative medicinal chemistry applied to discover compounds with optimized properties. Radiobinding and autoradiography experiments on FTLD‐TDP brain samples were used to evaluate affinity and target engagement. These techniques were also used to assess selectivity over other aggregation‐prone proteins using brain material from Alzheimer’s (AD) and Parkinson’s disease (PD) cases. Brain pharmacokinetic (PK) profile was obtained in mice, followed by assessment of brain uptake, distribution and washout for selected 18F radiolabeled compounds in non‐human primates (NHP).ResultsSeveral chemical series showing nanomolar binding affinity to aggregated TDP‐43 from patient brain samples were identified. The specificity of binding was further confirmed by high resolution autoradiography enabling visualization of target engagement on TDP‐43 inclusions in FTLD‐TDP brain sections. In addition, the most advanced compounds differentiated FTLD‐TDP from control by classical autoradiography on patient brain sections. Selectivity over amyloid beta, alpha‐synuclein and Tau was observed. The compounds with the most favorable brain penetrantion properties demonstrated fast and substantial brain uptake and fast and complete washout in NHPs.ConclusionsFirst‐in‐class TDP‐43 PET ligands have been discovered with the potential to identify FTLD‐TDP pathology by PET. These tools may finally allow the ability to detect and follow the progression of TDP‐43 pathology in the brains of living patients with certain TDP‐43 proteinopathies.
Measuring the volume of Thalamic nuclei in cognitively unimpaired, middle‐aged individuals from the PREVENT‐Dementia cohort
Authors: Shah Sita , Dounavi Maria‐Eleni , Malhotra Paresh A , Lawlor Brian A , Naci Lorina , Koychev Ivan , Ritchie Craig W , O'Brien John T 
Published: December 2023

AbstractBackgroundThe thalamus consists of multiple nuclei involved in processes such as sleep and cognition. Individuals with AD, mild cognitive impairment (MCI) and asymptomatic individuals with risk factors for early‐onset AD display a reduction in thalamic volumes (Lee et al., 2013; Zidan et al., 2019). The pulvinar, anteroventral, centromedian and mediodorsal nuclei are amongst the thalamic nuclei affected in AD and MCI (Bernstein et al., 2021). Our aim was to investigate thalamic nuclei volumes and their association with cognitive performance in middle‐aged, cognitively unimpaired individuals with respect to dementia family history (FHD).Method701 participants were recruited into the PREVENT‐Dementia study. 645 T1‐weighted 3T MRI scans underwent thalamic segmentation using Freesurfer 7.1.0. The 24 sub‐nuclei were grouped into 6 regions (Table 1); 1) Anterior, 2) Lateral, 3) Ventral, 4) Intralaminar, 5) Medial and 6) Posterior (Iglesias et al., 2018). Cognitive performance was evaluated using the COGNITO battery.Differences in volumes with respect to parental FHD and the effect on cognitive performance was analysed using robust linear regression, with age, sex, years of education and total intracranial volume as covariates and FDR correction for multiple comparisons.ResultIndividuals with a FHD had significantly smaller volumes of the medial thalamus (pFDR = 0.037), particularly the mediodorsal medial (MDm, p = 0.016) and lateral (MDl, p = 0.016) nuclei (Figure 1).Individuals with a FHD performed significantly better on the delayed (p = 0.015) and descriptive recall (p = 0.03) tests. Larger volumes of the MDm (p = 0.003) and MDl (p = 0.036) were associated with a faster processing speed in those without FHD. Larger volumes of the MDl were also associated with greater recall in narrative and descriptive recall tests (p = 0.007 and p = 0.025, respectively) in those without FHD (Figure 2).ConclusionIndividuals without FHD have larger volumes of the MDm and MDl nuclei, which appear to exert a protective effect on cognitive performance, whilst having little effect in those with FHD. This could represent initial dysregulation in the disease process, which could be further evaluated with functional imaging or longitudinal follow up to assess for cognitive decline.
Prosody variations to improve cognitive processing in Alzheimer’s patients
Authors: Rodero Emma , Rodríguez‐de‐Dios Isabel , Larrea Olatz , Mas Lluis 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of the most widespread diseases in our society. Social interaction and communication with caregivers represent a challenge (Lowery, 2013). Few studies have taken a communication perspective on this problem. These studies show the importance of a satisfactory communicative exchange to improve the relationship between caregivers and Alzheimer patients (AP) (McGilton et al., 2017;Small et al., 2009). However, the variable prosody has yet to be deeply explored, yet it may be highly relevant to the quality of communication (Small et al., 2009). The main objective of this project was to analyze what prosody strategies improve communication between AP and their caregivers.MethodAn experiment was designed with a corpus of informative instructions related to AP’s routines. Different audio versions were produced with prosody variations: pitch (high or low), intensity (high or low), speed (fast and slow), intonation (monotonous, soft, or marked), emphasis/stress (soft or marked), and attitude (paternalistic style or loving style). The experiment was conducted with two groups of participants over 65 years old (77 on average): the experimental group, 30 subjects in a soft state AD, and the control group, 30 subjects without AD. The dependent variables (likeability, comprehension) were evaluated with yes/no (green/red buttons) questions after listening to the voice instruction with different prosody variations. Recognition was assessed with a specific test.ResultResults showed that the most effective strategies were the intonation variations (soft or marked), the use of emphasis (soft or strong), the loving style when talking, the middle pitch, and the paused or slow speed. The least effective ones were speaking with high intensity (volume), fast speech rate, paternalistic style, and monotonous intonationConclusionIn light of the findings, the prosody variations strategies can significantly improve the communication exchanges between AP and their family members and/or caregivers.
The Bidirectional Association of TBI and Dementia/MCI among older US Veterans
Authors: Yaffe Kristine , Gardner Raquel C. , Peltz Carrie , Bahorik Amber L , Xia Feng , Albrecht Jennifer S 
Published: December 2023

AbstractBackgroundPrior studies have reported a link between traumatic brain injury (TBI) and risk of adverse neuropsychiatric outcomes including dementia. However it is unclear how prevalent these conditions are prior to TBI and if they are predisposing factors in addition to sequalae.MethodsWe studied older (age >55 years) US veterans who were followed for care at Veterans Affairs Medical Centers across the nation from 2000 to 2019. We first identified all veterans with an incident TBI diagnoses defined as no prior TBI diagnosis, having been seen in an emergency department (ED), having a brain imaging scan (primarily CT) within one day of ED visit and with a subsequent new TBI diagnosis in the electronic medical record (EMR). We then determined 2‐year age‐adjusted prevalence rates (rate per 1000 person‐years and 95% confidence interval or CI) for dementia and mild cognitive impairment (MCI) prior to and post incident TBI. We also compared prior TBI prevalence to prevalence among 1:3 matched (on age and index date) veterans without TBI.ResultsThere were 13,709 primarily male veterans with incident TBI with mean age of 77.7 sd 9.1 years, 81% were non‐Hispanic White. Compared to the 41,127 veterans without TBI (mean age = 77.9, sd 9.1), veterans prior to having an incident TBI had almost a six‐fold greater pre‐TBI age‐adjusted prevalence of dementia (104.9; 95% CI 100.8‐109.0 vs 18.6; 95% CI 17.6‐19.7, p<0.001) and MCI (48.0; 95% CI 45.2‐50.7 vs 8.1; 95% CI 7.4‐8.8, p<0.001). After the incident TBI diagnosis, the age‐adjusted prevalence rates were even higher: dementia (193.5; 95% CI 187.7‐199.2) and MCI (59.3; 95% CI 56.0‐62.6).ConclusionsAmong older US veterans, there is a bidirectional association with dementia/ MCI and TBI with very high prevalence prior to TBI (compared to those without TBI) and even greater prevalence after TBI. These findings highlight the importance of prevention strategies for both pre‐ and post‐TBI cognitive impairment.
Impact of Dementia on Days at Home after Traumatic Brain Injury among Older Medicare Beneficiaries
Authors: Albrecht Jennifer S 
Published: December 2023

AbstractBackgroundTraumatic brain injury (TBI) is a highly disabling event among older adults, contributing to disability in activities of daily living and elevated risk for nursing home admission. Older adults with Alzheimer’s disease and related dementias (ADRD) are more susceptible to TBI given increased fall incidence in this population, but how ADRD influences long‐term disability outcomes after TBI has been challenging to ascertain because of small sample sizes in prior work. Home time, a claims‐based measure of time spent at home and not hospitalized following a health‐related event, may aid in determining the association of ADRD and post‐TBI outcomes among older adults. Thus, the objective of this study was to examine the impact of TBI on home time among older adults with ADRD.MethodsWe conducted a retrospective cohort study using a random sample of Medicare administrative claims data for years 2010‐2018. Community‐dwelling Medicare beneficiaries aged ≥65 years hospitalized with a primary diagnosis of TBI were included and ADRD was defined at baseline (i.e. before TBI) using diagnostic codes. Home time was calculated by subtracting the number of days spent in a care environment or deceased from the total follow‐up available for each of the twelve follow‐up months post‐TBI. We modelled monthly days at home as a function of ADRD and covariates using generalized estimating equations.ResultsThere were 20,350 participants in the study, of whom 6,683 (33.8%) had a pre‐existing diagnosis of ADRD. In regression models that accounted for pre‐TBI days at home, demographic and clinical characteristics, and probability of survival, beneficiaries with ADRD spent fewer days at home following TBI compared to beneficiaries without ADRD (rate ratio 0.90; 95% confidence interval 0.89, 0.92). This disparity was equivalent to almost 50 fewer days spent at home over the year following TBI.ConclusionTBI resulted in a significant loss of home time over the year following injury, a loss markedly worse among older adults with ADRD.
Functional connectivity changes of the Locus Coeruleus in Alzheimer’s Disease
Authors: Hou Ruihua , Ali Mobeen , Brown Matthew 
Published: December 2023

AbstractBackgroundGrowing evidence indicates neurone loss in the Locus Coeruleus(LC) in patients with Alzheimer’s Disease(AD). The widespread projection and rich connectivity of the LC with multiple brain regions and its interaction with different neural networks suggests the importance of investigating the functional connectivity of the LC, an area of research which has been less studied.AimsThe primary aim of this study was to test for differences in functional connectivity of the LC between AD subjects and matched controls using neuromelanin‐sensitive MRI(NM‐MRI). The secondary aim of this study was to test for the effects of AD on the resting state networks.MethodsPre‐processing of the fMRI and structural MRI data from 23 AD subjects and 23 controls was completed using the FMRIB Software Library(FSL). The images were skull‐stripped, registered, and normalised to the MNI152_t1_2mm_brain template. LC masks were created from the NM‐MRI scans also using FSL. The subsequent data was processed using the CONN toolbox. Seed‐to‐voxel and ROI‐ROI analysis were used to produce connectivity maps and comparisons were conducted between AD and controls, left and right LC, mild and moderate AD, and resting state networks.ResultsAD subjects had connections from the LC to only 43 brain regions, compared to 80 brain regions in the controls. In comparison to controls, AD subjects had reduced LC connectivity in the subcallosal cortex(p‐FDR = 0.016417), increased LC connectivity in the right supramarginal and postcentral gyri(p‐FDR = 0.000002), and reduced connectivity in the default mode network(p‐FDR = 0.000286) and sensorimotor network(p‐FDR = 0.027524). The left LC in the AD subjects had significant connections to only 56 brain regions compared to 81 brain regions in the right LC. In particular, the left LC had decreased number of significant connections to the amygdala and vermis, compared to the right LC. The number of significant LC connections decreased with progression from controls to mild AD to moderate AD.ConclusionsThis study provides new evidence of reduced LC functional connectivity in AD patients and asymmetrical reduction in the LC skewed towards the left LC. LC connectivity reduction could indicate pathogenesis and progression of AD, aiding prediction of disease progression and development of novel intervention targets.