bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained connectivity correlates of motor function in Alzheimer’s disease
Authors: King Jace B , Duff Kevin , Hoffman John M. 
Published: December 2023

AbstractBackgroundIn addition to cognitive deficits, issues with motor control are present across the dementia spectrum. Traditional functional connectivity measures synchrony of intrinsic activity between brain regions and is altered in patients with Alzheimer’s disease in regions supporting motor function; however, less is known regarding the temporal stability of that synchrony. Sustained connectivity uses the width of cross correlation curves of BOLD time series to reflect the relative duration of synchronous activity between brain regions. This study investigates sustained connectivity across the dementia spectrum in motor regions.Method109 participants were included in this analysis and included 32 individuals with mild cognitive impairment (MCI) (18 F, 73.84 ± 5.14), 30 with Alzheimer’s disease (AD) (19 F, 77.37 ± 6.45), and 47 control individuals (29 F, mean age 72.13 ± 4.68). All study participants completed MP2RAGE structural imaging and two 15‐minute resting fMRI scans. Preprocessing steps included segmentation, motion realignment, registration to MNI space, and regression of motion parameters. Sustained connectivity values were averaged across both scans and only participants with more than 50% volumes remaining after censoring were included in analysis. A 17 resting‐state network parcellation was used to evaluate sustained connectivity across the brain with each network treated as a single ROI. A linear regression analysis was used to compare sustained connectivity across groups controlling for mean head motion, age, and sex. T statistics and p‐values are reported for across group sustained connectivity values.ResultAcross all three groups, sustained connectivity with the dorsal and ventral somatomotor networks was significantly increased across a number of resting‐state networks including the central visual, anterior ventral attention, and lateral temporal default mode network (DMN; all dorsal) and the somatomotor association, anterior ventral attention, medial frontoparietal, lateral temporal and lateral DMN (all ventral; Figure 1; pFDR < .05).ConclusionThese data suggest sustained connectivity may be a potential metric for assessing progressive cognitive decline in dementia. Our results indicate that sustained connectivity may be used to track changes in the temporal duration of functional connectivity in motor networks in individuals with intact cognition, mild cognitive impairment, and Alzheimer’s disease.
PD‐L1 blockade therapeutic effect in Tau P301S (line PS19) mouse model of tauopathy
Authors: Baruch Kuti , Kertser Alexander , Medina Sedi , Arad Michal , Yoles Eti , Schwartz Michal 
Published: December 2023

AbstractBackgroundThere is a growing understanding that Alzheimer’s disease (AD) and tauopathies are not merely brain‐centric conditions, but encompass also dysfunction of the peripheral immune system that impacts disease onset and progression. We have previously shown, in several mouse models of AD, that blockade of the PD‐1/PD‐L1 immune checkpoint pathway facilitates homing of specialized immune cells to the brain, where these cells mitigate different pathomechanisms, ultimately leading to function improvement. Here, we tested PD‐L1 blockade in the Tau P301S (line PS19) mouse model of tauopathy.MethodsTau P301S mice were treated with anti‐PD‐L1 antibody, or isotype control, and tested for the functional effect of the treatment on parameters of cognitive performance and brain pathology, at different time points after treatment. Pharmacokinetic and pharmacodynamic events following treatment were evaluated to monitor the peripheral and central immune response. Treatment effects were also evaluated in TREM2 knockout Tau P301S mice.ResultsDose‐dependent effect of anti‐PD‐L1 treatment was detected at 14‐ and 28‐days post‐treatment, with respect to cognitive performance of PS19 mice, as measured by T maze task. At the different timepoints following treatment we found reduction in cerebrospinal fluid total tau protein levels, and reduction in cortical phosphorylated tau (Ser404) protein levels. The functional effect on improvement of cognitive performance following anti‐PD‐L1 administration was also observed in TREM2 knockout Tau P301S mice, suggesting that the therapeutic effect of anti‐PD‐L1, is independent of TREM2 expression.ConclusionsPD‐L1 blockade evokes an immune response that leads to functional improvement on cognitive performance and reduced brain pathology in Tau P301S mice. These findings, taken together with our previous reports of anti‐PD‐L1 therapeutic effect in other AD or tauopathy mouse models, substantiate the generalization of this treatment approach ‐ targeting the peripheral immune system in order to drive brain tissue repair in neurodegenerative conditions.
A rapid realist review of co‐producing and co‐facilitating Recovery College Dementia Courses
Authors: Handley Melanie , Wheeler Charlotte , Duddy Claire , Wong Geoff , Moniz‐Cook Esme , Hackmann Corinna , Fox Chris , West Juniper 
Published: December 2023

AbstractBackgroundRecovery Colleges have been established internationally as a service model for people with mental health conditions based on the principles of recovery, co‐production and adult learning. In the UK, NHS mental health services and third sector organisations are widening their use to include post‐diagnostic support for people with dementia. However, guidance for how to adapt the Recovery College model for people with dementia is lacking.MethodA Rapid Realist Review built an initial programme theory for how and why Recovery College Dementia Courses worked for people who co‐produced and attended them. Using a realist logic of analysis, we synthesised evidence from academic and grey literature. The initial programme theory was refined in four online workshops with people with dementia and staff with experience of recovery colleges.ResultStaff committed to recovery‐focused approaches recognised co‐producing Recovery College Dementia Courses as an opportunity to work within their core values. Course development is often additional to staff’s caseload, therefore time for this needed to be agreed with managers who recognised the potential for courses to foster person‐centred service cultures. Staff attendance to courses altered perceptions of service‐user/service‐provider relationships. Through co‐facilitated courses, people with dementia shared their experiences of living with the condition, giving staff the opportunity to understand people’s challenges and strengths beyond a set of clinical presentations.Registration and attendance depended on staff knowing about courses and understanding who might benefit. Additionally, receiving a diagnosis of dementia was recognised as overwhelming and follow‐up contact with services varied. This meant there was no consistent approach for who received information about courses or when. Discussion with someone knowledgeable about the course was considered important to overcome internalised negative perceptions about dementia and feelings of hopelessness. These responses to diagnosis were major barriers to attendance and were experiences that Recovery College Dementia Courses sought to tackle.ConclusionImproving access to post‐diagnosis support for people with dementia and those who support them is important for helping people live well with their diagnosis. This initial programme theory provides the foundation for a primary study of Recovery College Dementia Courses to inform guidelines of international relevance.
The role of Alzheimer’s risk factor ApoE4 on intracellular Aβ aggregation
Authors: Konings Sabine C , Martinsson Isak , Nyberg Emma MC , Gouras Gunnar K , Klementieva Oxana 
Published: December 2023

AbstractBackgroundApolipoprotein E4 (ApoE4) is the main genetic risk factor for Alzheimer’s disease (AD). Previous research supports that ApoE4 increases amyloid‐β (Aβ) aggregation and plaque deposition. However, it remains poorly understood how ApoE4 affects the aggregation of Aβ prior to plaque seeding on a cellular level. The aim of this project is to use high‐resolution techniques to study intraneuronal Aβ accumulation at a synaptic and subcellular level and investigate how different ApoE isoforms influence this.MethodThe aggregation of Aβ in cultured primary neurons expressing human APP/Aβ will be studied using a correlative approach combining infrared spectroscopy and super‐resolution microscopy. Infrared spectroscopy allows us to study protein aggregation by looking at alterations in β‐sheet structures. Super‐resolution microscopy gives insights into the subcellular localization of Aβ and in changes in synaptic phenotypes. Human ApoE3 and ApoE4, derived from ApoE3 knock‐in (ApoE3‐KI) and ApoE4‐KI primary astrocyte cultures, are used as a physiological source to treat APP/Aβ primary neurons with human ApoE isoforms.ResultWe established an approach to obtain human ApoE3 and ApoE4 from primary mouse astrocytes and previously showed that Aβ and ApoE intersect inside neurons. In addition, we established a high‐resolution infrared spectroscopy approach for studying individual amyloid structures directly in neurons. In primary neurons generated from an human APP(NL‐F/NL‐F) knock‐in model we characterized the aggregation of intracellular Aβ and synaptic phenotypes with age. Additionally, an approach to supply primary neurons with human ApoE for longer time periods has been tested and allows to study chronic effects of human ApoE on Aβ aggregation inside neurons.ConclusionOur novel approach to study intraneuronal Aβ aggregation in cultured neurons potentially will contribute to new insights into where and how Aβ aggregates and will help to better understand how ApoE isoforms affect Aβ aggregation.
IBC‐Ab002 Fc modifications for fast clearance are associated with advantageous safety profile
Authors: Kertser Alexander , Baruch Kuti , Yoles Eti , Schwartz Michal 
Published: December 2023

AbstractBackgroundImmune checkpoint inhibitors (ICI) have been suggested as a unique therapy for treating neurodegenerative diseases. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody developed by ImmunoBrain Checkpoint (IBC) for the treatment of Alzheimer’s disease (AD).In cancer patients, ICI treatments are often associated with immune‐related adverse events (irAEs), which are side effects that manifest as either temporary or permanent autoimmune conditions caused by drug administration. One example of such an event is T cell‐mediated pancreatic tissue damage leading to autoimmune diabetes. The management of irAE often involves treatment discontinuation until symptoms relief, which has unwanted impact on the effectiveness of therapies that depend on continuous drug exposure.Unlike common ICI used in oncology, PD‐L1 blockade mechanism of action in mouse models of neurodegenerative diseases was shown to be dependent on transient immune system stimulation. Accordingly, IBC‐Ab002 antibody was designed with modifications on its Fc backbone that shorten its circulation half‐life, to meet the pharmacokinetic and pharmacodynamic characteristics needed for treating AD.MethodSurrogate antibodies that block mouse PD‐L1 and share the same hIgG1 Fc‐modifications as IBC‐Ab002 were generated and tested for their propensity to accelerate the onset of autoimmune diabetes in NOD transgenic mice, which spontaneously develop type 1 diabetes. Mice were monitored for their blood‐glucose levels, weight, and survival – for both the acute and long‐term duration following antibody administration.ResultWe found that administration of a therapeutically effective dose of IBC‐Ab002’s surrogate antibody led to fewer cases of premature diabetes onset in NOD mice, when compared with an antibody variant that contains no Fc‐modifications. Furthermore, no excessive weight loss, change in the time‐course of spontaneous diabetes onset or early mortality, were found following IBC‐Ab002’s surrogate treatment, compared with isotype‐control treated mice, in a 200‐days follow‐up assessment.ConclusionWe demonstrate that the clearance rate of the antibody inversely‐relates to the probability of developing an adverse immune response, and that no delayed long‐term irAEs are expected once full clearance of the antibody was achieved. Overall, these findings suggest that shortening the half‐life of anti‐PD‐L1 antibodies in treatments that do not necessitate continuous exposure can considerably increase the safety profile.
Causal association between circulating angiopoietin‐1 levels and the risk of Alzheimer’s disease
Authors: Guo Xingzhi , Li Rui 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), characterized by cognitive decline and memory loss, is the most common neurodegenerative disorder. Angiopoietin‐1 is a protein that plays a role in the formation and maintenance of blood vessels and has been suggested to be involved in the development of AD. However, the causal relationship between angiopoietin‐1 and AD is not well understood.MethodTo investigate the causal relationship between angiopoietin‐1 levels and AD risk, we performed a Mendelian randomization (MR) analysis using instrumental variables (IV) identified from genome‐wide association studies (GWAS) summary statistics on blood angiopoietin‐1 levels (N = 3,301) and AD (N = 63,926). Seven different methods, including inverse variance weighted (IVW), MR‐Egger, weighted median, simple median, maximum likelihood, simple mode, and weighted mode, were applied to calculate the causal estimate. Pleiotropic test and heterogeneity analysis were also assessed to evaluate the stability of the estimates.ResultUsing the IVW method, genetically determined human blood angiopoietin‐1 levels were causally associated with a decreased risk of AD (odds ratio [OR] = 0.86, 95%CI = 0.78‐0.94, P = 0.001), which was further validated using other approaches (Figure 1A). The leave‐one‐out analysis plot showed that there was no significant outlier driving the overall causal estimate between angiopoietin‐1 levels and AD (Figure 1B). The results of MR‐PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global, MR‐Egger intercept test, and Cochran’s Q test showed that there were no obvious directional horizontal pleiotropy and heterogeneity, indicating good stability of the present MR study.ConclusionOur study provides evidence for a causal relationship between angiopoietin‐1 levels and a reduced risk of AD. However, further validation and replication of these findings are needed to confirm our results.
Neuro‐immune and behavioral consequences of low dose radiation, social isolation and sex differences in the longevity MCAT mouse model
Authors: Rubinstein Linda , Paul Amber , Mhatre Siddhita D. , Iyer Janani , Puukila Stephanie , Ruiz Steffy Tabares , Alwood Joshua , Tahimic Camdice , Ronca April 
Published: December 2023

AbstractBackgroundThe multi‐organ physiological responses to spaceflight stressors resemble aging on Earth. We simulate space environment together with environmental stress, as a model of accelerated aging. Redox dys‐homeostasis was shown to contribute to aging‐related pathologies such as Alzheimer’s and Parkinson’s. The MCAT transgenic mice (overexpressing human catalase in the mitochondria), have increased life span, delayed age‐related pathology and enhanced hippocampal spatial learning and memory.MethodOur study uses 1‐year old C57BL/6NJ male and female mice that underwent exposure to 0.5 gray of gamma radiation together with social isolation. In order to determine ROS contribution to neuro‐behavioral stress response, we used the longevity MCAT mouse model in which human catalase is overexpressed in the mitochondria. We aimed to determine whether in older mice quenching ROS, will mitigate the neuro‐behavioral consequences of low dose ionizing radiation and social isolation and whether sex differences will be detected. We have performed multiple behavioral tests which focused on performance, memory, physical stance, and stress, together with plasma and hippocampal neuro‐immune panels.ResultWe have detected both sex and radiation/isolation effects; the older females look physically better, are faster and perform better almost in all behavioral tasks compared to their male counterparts. On the other hand, they are more sensitive to low dose radiation and isolation in many cases. Interestingly, many of the neuro‐immune changes caused by radiation and social isolation were mitigated in the MCAT mice. In a plasma multiplex cytokine panel, corticosterone (7‐ and 90‐days post radiation), and hippocampal cytokine and microglial activation at the end of the experiment, we have detected significant changes due to radiation, isolation, sex and genotype in both short and long post radiation period. Our focus is now on applying advanced statistical modeling to correlate the behavioral tests with our recent molecular findings to look for specific biomarkers that could predict behavioral deficits caused by various environmental stresses.ConclusionQuenching ROS in older mice partially mitigates neuro‐immune consequences of environmental stresses. Significant sex differences were detected, pointing out the importance of examining both sexes, for better personal medicine. The study points out that anti‐oxydant meassures could help older isolated population.
Associations between self and study partner report on the CFI with regional tau in a multi‐cohort study
Authors: Amariglio Rebecca E. , Jadick Michalina , Robinson Talia L , Klinger Hannah M , Buckley Rachel F. , Marshall Gad A , Vannini Patrizia , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. 
Published: December 2023

AbstractBackgroundSelf‐report of cognitive decline is an early behavioral manifestation of Alzheimer’s disease at the preclinical stage, often thought to precede study partner‐report. Prior work has shown associations between subjective cognitive decline and amyloid, but less is known about tau deposition, particularly once tau has spread to neocortex. Using a multi‐cohort study of cognitively unimpaired individuals, we examined associations between self‐ and study partner‐report, amyloid and regional tau. Specifically, we hypothesized that greater self‐ and study partner‐report of cognitive decline would be observed with tau in the medial temporal lobe (MTL), whereas study partner‐report would be more strongly associated with neocortical (NEO) tau compared to self‐report.Method698 cognitively unimpaired individuals (55% elevated‐amyloid, mean age = 72.5, 58% female) came from the A4, LEARN, HABS, and SCD/IADL Studies. All participants underwent Flortaucipir‐PET quantified by SUVr. A MTL tau composite and a NEO tau composite were derived. An internally derived amyloid cut‐off was used for each study. Participants and their study partners completed the Cognitive Function Index (CFI), a 15‐item questionnaire asking about cognitive functioning over the last year. A series of linear regression models using tau (MTL vs. NEO) to predict CFI (self vs. study partner) were conducted, adjusting for age, sex, education, amyloid status and cohort.ResultWe first examined amyloid status and CFI and found elevated‐amyloid was associated with higher self‐report (t = 2.8, p = 0.017), but not study partner‐report (t = 1.5, p = 0.12). Building on this model, greater MTL tau was associated with greater self‐report (t = 3.30, p<0.001) and study partner‐report (t = 3.4, p<0.001), but not amyloid status. Greater NEO tau was associated with greater self‐report (t = 3.2, p = 0.002) and study partner‐report (t = 4.1, p<0.00001), but not amyloid status.ConclusionIn this multi‐cohort study of cognitively unimpaired individuals, elevated‐amyloid was associated with greater self‐report CFI, but not study partner‐report. When accounting for amyloid status, both MTL and NEO tau were significantly associated with both self and study‐partner report, but effects were numerically stronger for study partner for NEO tau. These findings suggest that CFI report both from the participants and their study partners is valuable at the preclinical stage, but may evolve with increasing tau spread.
Remote, unsupervised measurement of dyadic subjective cognitive change in the Brain Health Registry
Authors: Aaronson Anna , Ashford Miriam T. , Jin Chengshi , Tank Rachana , Camacho Monica R , Fockler Juliet , Flenniken Derek , Truran‐Sacrey Diana , Mackin Scott R , Weiner Michael S. W. , Nosheny Rachel L 
Published: December 2023

AbstractBackgroundEarly, efficient identification of Alzheimer’s disease (AD) risk is a critical need. Dyadic subjective report from a participant and an informant/study partner (SP) who knows the participant well, may be a reliable and accurate method for assessing AD risk.MethodThe Caregiver and Study Partner Portal within the Brain Health Registry (BHR; an online registry and cohort) is a scalable tool for remotely obtaining dyadic data. All BHR participants are asked to identify a potential SP, who is invited to separately enroll and consent. SPs complete a demographic survey and questionnaires pertaining to cognition, behavioral symptoms, activities of daily living, and the health of the participant. Participants and SPs both complete an online adaptation of the Everyday Cognition Scale (ECog) to assess subjective cognitive change. We analyzed demographic characteristics of the dyads enrolled in BHR and measured correlation between SP and self‐report ECog scores. We used ADNI ECog data to estimate cut points likely to indicate cognitive impairment (1.43 for SP‐report scores and 1.65 for self‐report scores) and determined the number of BHR participants who are possibly impaired based on these cut points.ResultOut of 93,134 BHR participants, 10,494 (11.3%) have an enrolled study partner (Figure 1). The mean SP‐report ECog score is 1.35±0.50 and mean self‐report ECog score is 1.46±0.47. SP and self‐report ECog scores are correlated (r = 0.47, p < 0.001) (Figure 1). Out of 8,374 participants with available SP‐report ECog scores, 2,194 (26.2%) are possibly impaired. Out of 10,018 participants with available self‐report ECog scores, 2,384 (23.8%) of participants are possibly impaired (Figure 2).ConclusionThese findings demonstrate the feasibility of collecting online, dyad‐report demographic and subjective cognitive change data from a large cohort of participant‐SP dyads. The study failed to recruit an ethnoculturally and educationally diverse cohort of dyads. The positive correlation between self‐ and SP‐report ECog scores suggests dyad concordance in subjective report of change. Future efforts will focus on improving study partner enrollment and BHR task completion, increasing dyad diversity, and investigating the ability of remote dyadic measures to track cognitive decline and clinical progression along the AD continuum.