bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locus coeruleus integrity exhibits distinct anatomic vulnerabilities to regional tau and amyloid accumulation: parallel and intersecting mechanisms?
Authors: Jacobs Heidi I.L. , Becker Alex , Riphagen Joost M. , Thibault Emma G. , Farrell Michelle E. , Properzi Michael J , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. 
Published: December 2023

AbstractBackgroundThe locus coeruleus (LC) is one of the first regions to accumulate tau in Alzheimer’s disease (AD). As the disease progresses, tau in the LC has been related to increasing allocortical tau. Recent autopsy work reported that LC neurodegeneration correlated with parietal amyloid, suggesting that the LC may impact both Ab and tau, but with regionally varying contributions. We investigated whether cross‐sectional and longitudinal relationships between in vivo LC integrity and regional tau or Ab are uniquely determined by one pathology or exhibit shared vulnerabilities.Method213 individuals from the Harvard Aging Brain Study (mean age:71.6 years, 58% female; 11% cognitively impaired; Figure 1) who underwent 3T LC‐MRI, Ab‐ and tau‐PET imaging were included. Of these, 62 individuals received a second MRI and PET session. For the LC, we extracted the 5 highest normalized intensity voxels. PET‐data was referenced to cerebellar gray and partial volume corrected. Linear regressions associated LC integrity to tau or Ab and variance contributions were quantified. Mixed effects models examined LC changes to changes in tau or Ab. Mediation analyses examined whether local Ab mediated relationships between LC integrity and local tau. Analyses were adjusted for age, sex and multiple comparisons using FDR‐correction.ResultLC integrity was negatively associated with medial‐lateral temporal tau, and widespread Ab. Multivariable analyses demonstrated that LC integrity associated uniquely with tau in medial temporal lobe (MTL) regions and with Ab in frontoparietal regions. LC integrity was associated with both tau and Ab in inferior temporal (IT) and posterior cingulate cortices, and mediation analyses showed that LC integrity – tau associations in these regions were Ab‐mediated (Figure 2). Longitudinal analyses revealed stronger local associations between LC integrity and tau changes, compared to Ab. LC integrity changes were uniquely associated with tau changes in MTL, but longitudinal LC integrity‐IT tau correlations were mediated by local Ab (Figure 3).ConclusionThe LC may have anatomically distinct cortical tau and Ab‐pathways in AD, with MTL correlations being almost uniquely tau‐related, frontoparietal associations uniquely Ab‐related and lateral temporal regions showing Ab‐mediated tau accumulation. Potential underlying mechanisms can include synaptic plasticity alterations, glial activation or neuronal hyperactivation.
Never too late: Episodic memory after basic literacy acquisition in illiterate adults
Authors: Resende Elisa de Paula França , Santos Tomaz Kelle Luisa , Friedlaender Clarisse Vasconcelos , Rocha João Victor de Faria , Lourandes Aida , Ruppert Emma Patrice , Assenção Joanna de Castro Magalhães , Grinberg Lea T. , Rosen Howard J. , Rincon Luciana Paula , Ribeiro Norton Gray Ferreira , Constantina Dulce , Zacarias Ana Paula , Caramelli Paulo , Maciel Francisca Izabel Pereira 
Published: December 2023

AbstractBackgroundFormal education acquired early in life protects against dementia, but whether acquiring education later in life can decrease dementia risk is less clear. Episodic memory impairment is one of the first symptoms of Alzheimer’s Disease. Therefore, we aimed to identify whether a late life literacy training delivered to illiterate adults could improve episodic memory as a mechanism of cognitive reserve enhancement, eventually contributing to prevent dementia in this population.MethodsWe ran a clinical trial with 108 illiterate adults cognitively healthy allocated into two groups at baseline: the intervention group (n = 57) that attended classes focused on learning how to read and write and the control group (n = 51), that attended regular classes (not focused on literacy training), for 6 months. We used the Free and Cued Selective Reminding (FCSRT) test to evaluate the episodic memory. Participants also underwent a thorough neuropsychological investigation and rsfMRI. The primary outcome measure was defined as the change in the free recall sum‐of attempts scores of the FCSRT. We used linear mixed effect models to calculate the change over time and between the intervention and control groups controlling for age and sex. ClinicalTrials.gov Identifier: NCT04473235ResultsSeventy seven participants completed the study. The control group had 38 participants aged 58.5 ±8.5 years, being 78.9 women and 92.1 Blacks. The intervention group had 39 participants aged 59.6 ±9.7 years, 79.5 women and 87.1 Blacks, with no significant differences in demographics between groups. Participants improved their episodic memory over time (FCSRT free recall sum of attempts: F = 21.5, p<0.001, FCSRT delayed recall: F = 27.1, p<0.001 and FCSRT efficacy: F = 26.2, p<0.001, but with no difference between the control and the intervention groups. The rsfMRI measurements are under analysis.ConclusionAttending a late life literacy program in adulthood improved episodic memory, regardless of whether the intervention was focused on learning how to read and write or just attending regular classes. The results shed light into a possible low cost tool to increase cognitive reserve through improving episodic memory, eventually preventing dementia in vulnerable populations.
Psycho‐social impact of the diagnostic work‐up at a specialized, fast‐track memory clinic
Authors: Abaci Alara , Hendriksen Heleen M.A. , Aspö Malin , Sundell Maria , Wiggenraad Fleur , Rydén Marie , Kivipelto Miia , van der Flier Wiesje M. , Mangialasche Francesca , Visser Leonie N.C. 
Published: December 2023

AbstractBackgroundIncreasing numbers of concerned individuals seek diagnosis, information, and treatment at memory clinics. Biomarker tests for Alzheimer’s disease (AD) are being increasingly integrated into memory clinic practice, yet data about the implications for patients are lacking. We aimed to investigate the psycho‐social impact of the routine diagnostic work‐up with integrated biomarker assessments.MethodsThis observational study was conducted at the Karolinska University Hospital memory clinic (Solna, Sweden), in the context of the EU‐Fingers and LETHE projects. The harmonized diagnostic work‐up at this fast‐track clinic is comprehensive, including a neuro‐psychological evaluation, MRI, and CSF. All patients receive detailed results. From October 2021‐May 2022, all newly‐referred patients with MMSE>18 were invited, and 78/106(74%) eligible patients (59±5yrs, 50%F) completed >1 questionnaire‐assessments; after the first consultation(T1), just prior to(T2) and immediately after(T3) the disclosure consultation, and three months afterwards(T4). Questionnaires assessed Positive and Negative affect (T1/T2/T3/T4), Quality of Life (T1/T4), Stigma (T4), and Lifestyle change (T4). Patients received the following diagnoses: 51 SCD with negative AD‐biomarkers(SCD‐), 10 MCI with negative AD‐biomarkers(MCI‐), 3 MCI with positive AD‐biomarkers(MCI+), 11 Dementia, and 3 Other. In (repeated‐measures) ANOVAs, we compared time points and/or those with SCD‐/MCI‐ with MCI+/Dementia.ResultsSee Table 1 for Means (SD). The trajectories of both positive (p<.01) and negative (p<.01) affect were influenced by diagnosis (Fig. 1); those who received an MCI+/Dementia diagnosis temporarily decreased in positive affect and increased in negative affect, while we observed the opposite in those with SCD‐/MCI‐. For quality of life (Fig. 2), we found no change over time (p = .38), nor an effect of diagnostic group (p = .31). No group difference was found in perceived stigma (p = .52). Those who received an MCI+/Dementia diagnosis reported more healthy‐lifestyle changes, than those with SCD‐/MCI‐ (p<.01).ConclusionPatients’ feelings fluctuated throughout the diagnostic work‐up, influenced by the received diagnosis. Three months after, diagnostic groups did not differ in psycho‐social impact, except for lifestyle change. More research is needed to investigate the needs, outcomes and experiences of the increasing number of individuals without AD‐pathology who experience symptoms and seek care, to understand whom and when they can benefit (most) and from which healthcare setting/service.
Real‐world use and cost of health and social care services of 18,116 patients living with Alzheimer’s disease
Authors: Edwards Sophie , Hahn‐Pedersen Julie Hviid , Robinson Danielle E , Chan Mei Sum , Bray Benjamin D , Clark Alice , Ivkovic Milana , Michalak Wojciech , Wichmann Christian Ahmad , Berry Sasha D , Evans Marc 
Published: December 2023

AbstractBackgroundThe increasing prevalence of Alzheimer’s disease (AD) will substantially impact health and social care systems worldwide. In this study, we aimed to estimate the real‐world use and cost of health and social care services in a large cohort of AD patients in the United Kingdom.MethodWe conducted a retrospective cohort study using Discover‐NOW, a real‐world database containing linked primary and secondary care electronic health records of people living in North‐West London, England. A total of 18,116 patients diagnosed with AD were followed from first observed AD diagnosis to end of patient follow up, within the time window from 1 January 2010 to 31 December 2021. The baseline prevalence of 33 comorbidities, survival duration, health and social care resource utilisation and total direct health and social care costs (in 2019 terms) were estimated.ResultOf 18,116 patients with AD, 8,970 (50%) used social care after diagnosis. Most patients using social care were female (65% vs 62% in the general AD population) and were a similar age at diagnosis (median 82 years) compared to those who did not. Of the patients with social care utilisation, 5,248 (59%) resided in care homes and 2,636 (29%) received domiciliary care at home. Annual direct social and health care costs for each patient receiving social care were £25,664 and £6,248 respectively, constituting an annual total cost of £31,912. Median survival from time of AD diagnosis was 4.9 years in the general AD population and 1.9 years after care home admission. Patients who entered care homes, entered at a median age of 85 years and had higher baseline prevalence of stroke (11% vs 7%), chronic kidney disease (40% vs 35%), and atrial fibrillation (17% vs 13%) than the general AD population.ConclusionIn AD patients who used social care, social care costs were >4 times other healthcare costs. Slowing or delaying the requirement for social care would have a major impact on reducing the societal and economic burden of AD on patients and society.
Mild brain injury aggravates gliosis, toxic tau, and anxiety in the P301S model of TAUopathy
Authors: Marco Ana Royo 
Published: December 2023

AbstractBackgroundTraumatic Brain Injury (TBI) is a known risk factor for developing a neurodegenerative disease later in life, including Alzheimer’s Disease (AD) and other forms of tauopathy such as chronic traumatic encephalopathy (CTE) and frontal‐temporal dementia (FTD). Although several studies highlight the relationship between the severity and frequency of a TBI and the development of these tauopathies, the mechanism behind this association remains unknown. Proper meningeal lymphatic function is required for clearance of waste products and protein aggregates such as amyloid beta and tau from the brain parenchyma. While post‐TBI inflammation is beneficial for clearing debris and promoting tissue repair, prolonged glial activation and decreased meningeal lymphatic drainage have been linked to worsened cognitive function.MethodA mild TBI (mTBI) was delivered to three‐month‐old young adult mice overexpressing P301S mutant human tau (PS19) through the skull on the right inferior temporal lobe of the brain. Sham and TBI injured mice were tested on behavioral tests at 5 months of age. At 7 months of age, brains were examined for tau pathology and neuroinflammation using confocal microscopy.ResultFour months after mTBI, the brains of TBI PS19 mice exhibit increased levels of microglia and astrocytes, and increased P‐S202/T‐205‐Tau in the cortex and thalamus of the ipsilateral hemisphere compared to the contralateral side and to Sham PS19 controls. These findings correlate with our behavior study showing increased hyperactivity, risk‐taking behavior, and impaired short term working memory. PS19 TBI mice also present larger ventricles than their uninjured controls suggesting a potential loss of white matter in the cortex and/or hippocampus.ConclusionP‐S202/T‐205‐Tau orginated from the cortex near the injury site can aggregate and promote the formation of more toxic tau that spreads to deeper regions of the cortex and in the thalamus primarily through the thalamocortical circuit. Also, microglia and astrocyte activation and production of inflammatory mediators has been associated with synapse pruning and engulfment of damaged neurons expressing ‘eat me signals’ leading to neurodegeneration.
The APOE4 Allele Exacerbates Pathology in a Mouse Model of Prion Disease
Authors: Lizińczyk Anita M , Pankiewicz Joanna E. , Franco Leor A. , Diaz Jenny R , Sullivan Patrick M , Sadowski Martin J. 
Published: December 2023

AbstractBackgroundThe APOE4 allele is the strongest genetic risk factor in sporadic Alzheimer’s disease (AD). In allele‐dose dependent manner APOE4 increases AD risk, lowers age of onset, and accelerates the rate of dementia progression. Like AD, prionoses are conformational neurodegenerative disorders, which neuropathological hallmarks include accumulation of disease specific misfolded protein(s) and presence of reactive astrocytes and microglia. Accumulation of PrPSc, a toxic conformer of the cellular prion protein‐PrPC, is the initial culprit in prion pathogenesis. PrPSc buildup is associated with the presence of A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD), which proinflammatory character contributes importantly to neurodegeneration in prionoses. Despite similarities between AD and prionoses, and established effects of APOE4 on misfolded protein accumulation and MGnD activation in AD, effects of the APOE genotype on prion pathology remain uninvestigated.MethodAPOE2, APOE3, and APOE4 targeted replacement mice were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate (NBH) and subjected to repetitive behavioral testing. They were sacrificed at 15 or 23 weeks post inoculation (WPI), when they remained presymptomatic or showed overt neurological symptoms. Neuropathological and biochemical analyses were performed at either timepoint, while NanoStringTM analysis of microglia and astrocyte transcriptomic markers was done at 23WPI.ResultAPOE4 mice feature significantly shorter incubation period and more severe burden of neurological symptoms following prion inoculation than APOE2 and APOE3 mice. Neuropathological analysis reveals significantly higher burden of spongiforms changes in the brain cortex and greater load of reactive astrocytes and microglia in APOE4 mice compared to other APOE genotypes. APOE4 mice also show the highest level of total PrP and PrPSc and insoluble/soluble PrP index. Transcriptomic analysis reveals prion inoculation effects marked elevation of PAN and A1 reactive astrocyte markers, MGnD markers, and in pro‐inflammatory chemokines and cytokine receptors transcripts across all APOE genotypes but the NBH‐relative increase is the highest in APOE4 mice.ConclusionThe APOE4 allele promotes prion neurodegeneration through two separate mechanisms. It is associated with greater PrPSc accumulation and toxicity suggesting its role in the PrPSc metabolism and clearance. It also promotes acquisition of A1 and MGnD neurotoxic phenotypes by astrocytes and microglia, respectively.
Discrimination of Healthy Controls and Patients with Mild Cognitive Impairment based on Time‐Varying Functional Connectivity Analysis of Resting‐State EEG
Authors: Deng Jinxian , Sun Boxin , Li Tongtong , Kavcic Voyko , Hampstead Benjamin M. , Morgan Dave , Liu Mingyan , Giordani Bruno 
Published: December 2023

AbstractBackgroundDeveloping economically viable assessment tools that are highly sensitive to cognitive decline and neural dysfunction is critical for the study of neurodegenerative mechanisms and interventions to promote cognitive resiliency. Due to its high time resolution, accessibility, and affordability, EEG‐based detection of cognitive impairment is attracting considerable attention from the research community.MethodOur research is based on resting‐state EEG (eye‐closed, 64‐channel), and the current dataset includes 137 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 84 Normal Cognition, NC; 53 Mild Cognitive Impairment, MCI) recruited through the Wayne State Institute of Gerontology Healthy Black Elders Center and the Michigan Alzheimer’s Disease Research Center with subjective cognitive complaints.We first conducted joint time‐frequency‐spatial analysis on the time‐varying functional connectivity of all the possible pairs between the selected EEG regions of interest and generated the feature vectors for each subject. The selected features were then fed into a machine learning algorithm for the discrimination of NC and MCI. By tuning the observing window size (in time‐domain) and the number of features used, we obtained a series of different configurations of the discrimination model between NC and MCI, each with its own accuracy. The overall result is a combined output of the model under different configurations.ResultThe accuracy of the discrimination model was calculated under different window sizes and numbers of features. Our result shows that there are 11 window‐size‐and‐feature configurations which can achieve an accuracy in the range of 80.29%∼86.86%. We selected 21 configurations as voters and get the final discrimination result through majority voting (+1 for NC and ‐1 for MCI). Moreover, we obtained a soft output (i.e., a likelihood score) for each subject by combining all the votes which were weighted using the accuracy of each voter. For the 137‐sample dataset we are working with, the 10‐fold cross‐validation accuracy of the model is 91.97%.ConclusionOur analysis indicates that EEG‐based time‐varying function connectivity analysis is a promising technique for early detection of MCI. Potentially, the soft output we obtained for each subject might be used for prediction of possible cognitive decline.
Exploring the role of brain DNA methylomic signatures on gene expression dynamics of frontotemporal lobar degeneration
Authors: Fodder Katerine , Murthy Megha , Rizzu Patrizia , Toomey Christina E. , Hasan Rahat , Humphrey Jack , Raj Towfique , Lunnon Katie , Mill Jonathan , Heutink Peter , Lashley Tammaryn , Bettencourt Conceição 
Published: December 2023

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, which includes frontotemporal dementia and progressive supranuclear palsy. About 90% of the FTLD cases show either TDP‐43 or tau pathology (FTLD‐TDP or FTLD‐tau, respectively). Though aberrant brain DNA methylation has consistently been associated with Alzheimer’s disease and other neurodegenerative diseases, studies on FTLD are scarce. The main goal of this study was to investigate DNA methylation variation in FTLD bulk brain tissue and brain‐derived nuclei.MethodsWe used bulk frontal cortex genome‐wide DNA methylation profiles (Illumina 450K or EPIC microarrays) from three FTLD cohorts (N = 228). To identify unique and shared differentially methylated loci across FTLD subgroups/subtypes, we performed cohort‐specific epigenome‐wide association studies (EWAS) followed by a meta‐analysis. Additionally, we used weighted gene correlation network analysis to identify co‐methylation signatures associated with FTLD, FTLD pathological subtypes, and other disease‐related traits. To identify disturbed cell‐types and biological processes within disease associated signatures, we then carried out cell‐type and functional enrichment analyses. We also generated and have ongoing analysis of DNA methylation profiles (EPIC microarrays) of neuronal (NeuN+) and glial nuclei (NeuN‐) from FTLD‐TDP cases and controls (N = 40). Wherever possible, we also integrated additional DNA methylation, and gene and protein expression datasets.ResultsIn bulk tissue, the EWAS meta‐analysis identified four shared differentially methylated loci in FTLD, including hypomethylation in OTUD4, a gene we found to be upregulated (mRNA and protein) in FTLD. Two of the four meta‐analysis hits (mapping to OTUD4 and CEBPZ), were found to be co‐methylated within signatures strongly associated with FTLD. Disease‐associated signatures implicate transcription regulation, the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling, and specific brain cell‐types, including pyramidal neurons and oligodendrocytes, in FTLD. Preliminary analysis of the neuronal and glial datasets also revealed FTLD‐associated DNA methylation signatures, which will further inform on cell‐type‐specific changes in FTLD.ConclusionsOur findings identified novel FTLD‐associated loci, including OTUD4, and point to DNA methylation as an important mechanism in the dysregulation of biological processes relevant to the FTLD pathogenesis, such as RNA/stress granule formation.
Electroconvulsive therapy parameters for behavioral and psychological symptoms of dementia
Authors: Kapustin Daniel , Nidumolu Aditya , Amanullah Shabbir , Hassan Sameh 
Published: December 2023

AbstractIntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are a heterogenous group of non‐cognitive symptoms impacting up to 90% of patients with dementia, and include emotional disturbance, psychosis, agitation, aberrant motor behavior, and circadian rhythm disturbance. Multiple reviews have found ECT to be efficacious in treating BPSD that have not responded to other interventions. However, no published guidelines exist to inform clinicians about how protocols for ECT should be implemented in the treatment of BPSD. This study aims to identify ECT parameters commonly utilized for BPSD in the literature.MethodsMEDLINE and APA PsychInfo were searched from database inception until September 2022. Two reviewers independently screened and full text reviewed the retrieved articles. Articles included in the full text review stage discussed how ECT is implemented for patients experiencing BPSD.ResultsAfter duplicate removal, 800 unique citations were identified for screening. Of these, 160 were included in full text review. 32 studies were ultimately included (Figure 1). Characteristics of included studies are highlighted in Figures 2 and 3.Most studies utilized thrice weekly ECT, however, twice weekly was suggested to carry a lower risk of ECT‐related cognitive side effects. The number of sessions needed for response ranged between 2‐15, with improvement typically observed within 3‐6 treatments. The choice between unilateral and bilateral placement rests on weighing the risk of confusion with improved clinical response. Multiple authors recommend starting with unilateral treatment to reduce cognitive side effects and switching to bilateral if response is inadequate after 3‐5 sessions. Typical pulse width was 0.30‐0.37ms for ultrabrief and 1‐2s for brief treatment. Minimum recommendations for adequate seizure duration varied from 25 to 30 seconds on EEG and 15 to 20 seconds by observed motor movements. Stimulus dosage ranged between 1.5‐2.5x seizure threshold for bilateral placement, and 4‐6x seizure threshold for unilateral placement. Maintenance ECT was commonly used to reduce the risk of relapse.DiscussionECT is both safe and efficacious for patients with BPSD, and the present review focuses on commonly implemented ECT parameters in the literature. Notably, studies are limited by inconsistent reporting of ECT parameters and short follow‐up durations.