bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acarbose ameliorates western diet‐induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer’s disease
Authors: Sonsalla Michelle M , Babygirija Reji , Johnson Madeline , Cai Samuel , Yeh Yang , Calubag Mariah , Trautman Michaela , Lamming Dudley 
Published: December 2023

AbstractBackgroundMany age‐related diseases are major risk factors of Alzheimer’s disease (AD), such as type II diabetes mellitus and cardiovascular disease. As such, there is a growing body of interest in determining if already in use geroprotective interventions for these disorders may also be beneficial in AD. One such intervention is acarbose, an anti‐diabetic drug that improves glucose homeostasis, reduces risk of myocardial infarction, and extends lifespan in various mouse models.MethodWe administered either a western diet or a western diet containing acarbose to diet‐induced obese male and female 3xTg mice starting at 6 months of age. Over the following 6 months, we examined a number of facets of metabolic health and analyzed cognitive function using Barnes maze. After sacrificing mice at 12 months of age, we analyzed aspects of AD pathology in the brain using Western blotting and immunohistochemistry.ResultBoth male and female 3xTg mice treated with acarbose exhibited decreased body weight and adiposity despite increased food consumption. Acarbose‐treated mice also had an overall improvement in glycemic control and increased energy expenditure. Female mice showed dramatic improvements in cognition and AD pathology, and males exhibited minor improvements as well. Preliminary data also suggest that there is increased gliosis in mice fed a western diet, which may be ameliorated by acarbose.ConclusionIn the context of a western diet, acarbose has dramatic benefits on metabolic health, cognitive health, and AD pathology. This suggests that there is potential for already in use geroprotective pharmaceuticals such as acarbose to ameliorate AD pathology.
Exploring the multimeric tau interactome and its convergence with human tauopathy
Authors: Shapley Sarah M , Bagchi Pritha , Bowen Christine A , Dammer Eric B. , Rangaraju Srikant , Seyfried Nicholas T 
Published: December 2023

AbstractBackgroundNeurofibrillary tangles (NFTs) comprised of the phosphorylated Tau protein are a core pathological feature of Alzheimer’s disease (AD) and several other neurodegenerative diseases collectively termed tauopathies include progressive supranuclear palsy, corticobasal degeneration, and subtypes of frontotemporal dementia. Physiological Tau is involved in many processes essential for cell function via protein‐protein interactions. However, under pathological conditions, the gain or loss of Tau protein interactions is an important consequence of disease pathophysiology and may result in the ‘rewiring’ of Tau protein‐protein interaction (PPI) networks. Therefore, modeling and identifying Tau interacting partners could reveal signaling mechanisms and therapeutic targets in tauopathies.MethodTo gain an unbiased understanding of the aggregated Tau interactors, we generated a split Turbo Tau (sTurbo Tau) proximity labeling system. We chose to express the isolated Tau repeat domain (RD) containing a pro‐aggregation P301L familial tauopathy substitution. Immunocytochemistry (ICC) and Western blot (WB) were performed in sTurbo Tau expressing cells following biotin labeling. Biotinylated proteins were affinity purified and analyzed in triplicate via mass spectrometry (MS) to identify these Tau interacting partners. Differential expression and Gene Ontology (GO) analyses were performed. We overlapped the sTurbo Tau interactors in cell culture and Tau interacting partners in AD brain lysates to further validate our model.ResultICC displayed speckle‐like Tau‐positive aggregates in the cytoplasm and nucleus that colocalized with biotin. WB with streptavidin dye also revealed high and low molecular weight biotinylated proteins in sTurbo Tau cells. MS identified nearly 1,900 proteins enriched in sTurbo Tau lysates compared to controls. GO analysis of these putative Tau interacting proteins confirmed various pathways, including cellular structural components, RNA binding, and translation. This overlap revealed 176 shared partners with roles in translation, synaptic processing, RNA‐binding, and proteasome function. Candidate spliceosome proteins, U1‐70K, U1A, and SNRPD2, have previously been shown to aggregate and colocalize with Tau in AD. Additionally, HSP90 family members were enriched in the overlapped datasets and are the target of mechanistic studies.ConclusionCollectively, we established a cell‐based Tau proximity labeling approach to identify Tau co‐aggregation partners relevant to human AD. This provides insight into novel pathways and therapeutic targets in disease.
Sex prevalence in mild behavioral impairment: a systematic review and meta‐analysis
Authors: Mudalige Dinithi M , Goodarzi Zahra , Ebrahim Inaara , Guan Dylan X. , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundMild behavioral impairment (MBI) leverages the risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high‐risk group for incident cognitive decline and dementia. While sex differences in NPS prevalence have been reported in Alzheimer’s dementia, these differences have not been well explored in dementia‐free samples. Here, we investigated sex differences in MBI prevalence across normal cognition (NC) and mild cognitive impairment (MCI). We also included rater in the analyses (i.e., self, informant, clinician), given that dementia‐free older adults may self‐report symptoms or attend clinic without an informant.MethodsEMBASE, MEDLINE, PsycINFO, and grey literature were systematically searched for articles mentioning MBI. Retrieved abstracts and full‐text articles were screened by two independent reviewers and included if sex‐specific MBI prevalence was reported. A standardized data extraction sheet was used for demographics, cognitive diagnosis, rater, and MBI prevalence within each sex. A risk of bias assessment was conducted. A random‐effects meta‐analysis calculated the pooled prevalence of MBI in each sex, stratified by cognitive diagnosis (NC, MCI, and combined NC/MCI samples) and symptom rater.ResultA total of 5783 articles (EMBASE n = 2752, MEDLINE n = 1798, PsycINFO n = 1233) were retrieved from the search; 165 full‐texts were screened, and 64 were included for data extraction (Figure 1). In females, MBI prevalence increased as cognitive status declined from NC (25%) to mixed cognition (32%) to MCI (43%) [Table 1]. MBI prevalence was highest when reported by informants (35%), followed by clinicians (23%), and self‐reports (20%) [Table 2]. Similarly, in males, MBI prevalence increased with declining cognition (NC = 27%, NC/MCI = 37%, MCI = 48%). MBI prevalence was highest when reported by informants (40%), followed by self‐reports (23%) and clinicians (22%).ConclusionIn both males and females, approximately a quarter of NC and nearly half of MCI participants had symptoms of MBI; prevalence was slightly greater in males. Informants reported MBI symptoms more than clinicians or participants themselves. These findings suggest that MBI is prevalent in dementia‐free older adults of both sexes and that informants are essential given the increasing MBI prevalence with declining cognition.
Mediation Analysis Identifies Amyloid Imaging Genetic Patterns for Cognitive Outcomes in Alzheimer’s Disease
Authors: Lee Brian N , Bao Jingxuan , Tong Boning , Risacher Shannon L , Saykin Andrew J. , Moore Jason H , Kim Dokyoon , Davatzikos Christos , Long Qi , Ritchie Marylyn D. , Shen Li 
Published: December 2023

AbstractBackgroundPrevious genetic studies of Alzheimer’s Disease (AD) utilized features derived from florbetapir (AV45) PET imaging (Lee et al., BMC Genomics 85(2022)). Genetic analysis of florbetaben (FBB) PET FreeSurfer‐defined ROI‐specific SUVrs provided by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) can extend this work by nominating ROIs likely to play a specific role in mediating genetic effects on AD‐related cognitive decline. Nominated ROIs may be suitable targets for biomedical interventions that slow the progression of AD.MethodGenetic and neuroimaging data were obtained from the ADNI 3 cohort. Amyloid burden measurements (SUVrs) were extracted and intensity‐normalized using the provided whole‐cerebellum reference region SUVr (Landau et al., 2021 ADNI). Imputed genotyping data included 5,402,690 variants from 308 individuals. Genome‐wide association studies predicted FBB changes in each of 68 FreeSurfer cortical ROIs utilizing age, gender, years of education, and the first 10 principal components as covariates. Within each individual imaging feature, FDR‐corrected P value thresholds determined significance (ɑ = 0.05). Mediation analysis combined identified SNP‐imaging feature associations with clinical cognitive score data to determine if changes in amyloid burden mediate genetic effects on clinical outcomes.Result149 unique SNPs and 28 unique imaging features were implicated in 881 FBB SNP‐feature associations (P values as low as 8.97e‐9). Although most associations are linked to known AD genes, a number of SNPs on chromosomes 18, 15, 14, 12, 6, 4, and 2 were also identified (Fig 1). Significant GWAS associations were carried forward to identify 83 mediation relationships (Bonferroni P < 1.56e‐6). An especially large number of significant causal mediation relationships implicated the entorhinal cortex and parahippocampal gyri, both of which play a significant role in learning and memory (Fig 2).ConclusionGenetic association traced some of the variation in FBB measures of amyloid burden to genetic drivers throughout the genome. Mediation analysis confirms that the FBB measures in the entorhinal cortex and parahippocampal gyri mediate the effects of some genetic findings on learning and global cognition. Future analyses of FBB measures as imaging endophenotypes may inspire pathway analyses and integrate additional clinical or biological information.
Familial FTD in China:progress and prospects
Authors: Chen Qin 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is a set of clinical syndromes characterized by progressive abnormalities in behavior, executive function, language, with a strong genetic background. However, the familiar FTD studies were rare in China. Here we aim to review the previous cross‐sectional reports of Chinese FTD patients with gene mutations, as well as the update status of the longitudinal familiar FTD study by the Chinese Familial Frontotemporal Lobar Degeneration Consortium (CFFC).MethodTo review current status of Chinese FTD patients with gene mutations, we performed a comprehensive electronic searches of Medline, PubMed, and Embase databases were performed by using the combination of a number of medical subject headings, Emtree subject headings, and free‐text terms (“frontotemporal lobar degeneration” or “frontotemporal dementia” for clinical categories; “Chinese” or “China” for ethnics). To start a multi‐center longitudinal cohort of familiar FTD, we established the CFFC in October 2022 by involving 7 top teaching hospitals across China. Patients with MAPT, GRN and C9orf72 mutations were enrolled and followed up according the designed framework.ResultBased on the previous reports, genetic mutations accounted for 5.13%‐27.9% as reported in a few cross‐sectional cohort of Chinese FTD patients. Mostly reported pathogenic variants were MAPT, followed by GRN, TBK1, CHCHD10, C9orf72 repeat expansions, VCP, and SQSTM1. Up till now, there were 26 pedigrees with MAPT mutations, 11 pedigrees with GRN mutations and 9 pedigrees with C9orf72 repeat expansions mutations have been enrolled in the longitudinal multi‐center cohort study by CFFC.ConclusionThe high prevalence of MAPT mutations in Chinese patients with FTD, may implies a genetic heterogeneity between Chinese and other ethnics. Longitudinal studies with larger sample size to modeling the trajectory of biomarkers in genetic mutation carriers for earlier diagnosis and intervention are needed in the future.
Global platform trial design for tau (MAPT) mutation carriers
Authors: Staffaroni Adam M. , Quintana Melanie , Wendelberger Barbara , Tartaglia Carmela , Heuer Hilary W. , Russell Lucy L. , Gendron Tania F , Petrucelli Leonard , Heller Carolin , Wolf Amy , Cobigo Yann , Sanderson‐Cimino Mark E. , Forsberg Leah K. , Kornak John , Cash David M , Boeve Brad F. , Rosen Howard J. , Rohrer Jonathan D. , Boxer Adam L. ,   Frontotemporal Dementia Prevention Initiative (FPI) Investigators
Published: December 2023

AbstractBackgroundPathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers.MethodALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD.ResultFive treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect.ConclusionPlatform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure.
Longitudinal associations between mild behavioral impairment, sleep disturbance, and progression to dementia
Authors: Mudalige Dinithi M , Guan Dylan X. , Ghahremani Maryam , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundClinical guidelines recommend incorporating non‐cognitive markers into dementia screening to improve detection. Two of these markers are mild behavioral impairment (MBI) and sleep. MBI is a neurobehavioral syndrome capturing later‐life emergent and persistent neuropsychiatric symptoms, which represent a change from longstanding behavior or personality, as a high‐risk group for incident cognitive decline and dementia. Sleep disturbances include difficulties initiating and maintaining sleep, are common in older adults and are associated with greater risk for dementia. We investigated the longitudinal associations between MBI and sleep disturbance and their association with incident dementia.MethodsData were obtained from the National Alzheimer’s Coordinating Center. MBI was derived from Neuropsychiatric Inventory Questionnaire (NPI‐Q) based on a published algorithm. The presence of sleep disturbance was obtained from the NPI‐Q nighttime behaviors item. Cox proportional hazard regressions, adjusted for age, sex, education, and cognitive diagnosis, were used to determine the associations between 1) baseline MBI and incident sleep disturbance (n = 8348); 2) baseline sleep disturbance and incident MBI (n = 9679) and 3) baseline sleep disturbance, with and without concurrent MBI, and incident dementia (n = 12296).ResultsDemographics are summarized in Table 1. As per Table 2, the rate of developing sleep disturbance was 3.3‐fold higher in older adults with MBI at baseline compared to those without MBI (95%CI: 2.96‐3.67; p<0.001). Likewise, the rate of developing MBI was 2.1‐fold higher in older adults with baseline sleep disturbance compared to those without sleep disturbance (95%CI: 1.84‐2.36, p<0.001). The incidence rate of dementia was 2.23‐fold greater in older adults with both MBI and sleep disturbance, relative to sleep disturbance alone (95%CI: 1.65‐3.00; p<0.001).ConclusionsIn this group of dementia‐free older adults, we found a bidirectional relationship between MBI and sleep disturbance. Sleep disturbance was more strongly associated with incident dementia when co‐morbid with MBI. This relationship might suggest a common etiology for MBI and SD, as both were linked with incident dementia. Thus, including both sleep disturbance and MBI into modeling may improve dementia prognostication. Future studies should incorporate biomarkers and additional clinical markers for Alzheimer’s disease and other neurodegenerative disease into the modeling to better understand these relationships.
Understanding synaptic loss in PSP brains with UCB‐J
Authors: Scarpa Miriam , Kumar Amit , Nordberg Agneta K 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) is a 4R‐tauopathy causing problems with balance, movement, vision, speech, and swallowing. There is a lack of biomarkers for PSP, which often leads to misdiagnosis, prescription of incorrect pharmacological treatments and likely underdiagnosis. Synaptic vesicle protein 2A (SV2A) PET‐tracer UCB‐J has shown great promise in imaging synaptic loss in many neurodegenerative diseases in vivo including PSP. UCB‐J‐PET imaging holds great potential for the early and accurate diagnosis of PSP, however, there is a substantial gap in knowledge around the extent of synaptic loss in PSP. Hence, it is of utmost importance to investigate synaptic changes in PSP brains with UCB‐J and to establish its correlation with other synaptic and neuropathological markers to gain a deeper understanding of underlying mechanisms for future biomarker validation.MethodWe performed specialized postmortem brain imaging (small and large frozen brain autoradiography) and radioligand binding assays (saturation, competition, and regional distribution), alongside immunohistochemistry and biochemical analyses in PSP and control (CN) brains.ResultSaturation studies in brain homogenates (BH) from the frontal cortex (FC) showed lower specific binding of 3H‐UCB‐J in PSP (Bmax: 348‐409 fmol/mg, Kd∼2.7nM) as compared to CN brains (Bmax:0.4‐0.5 pmol/mg, Kd∼3.5nM), indicating a loss in SV2A. Importantly, PSP brains showed much higher 3H‐UCB‐J specific binding in nuclear membrane P1‐fractions (Bmax 18.7‐22.1 pmol/mg, Kd ∼3.0nM) and synaptosomal‐membrane P2‐fractions (Bmax: 10.3‐12.3 pmol/mg, Kd∼2.4nM) as compared to BH (see above). Small section autoradiography showed lower 3H‐UCB‐J specific binding in PSP FC, but unexpectedly higher average specific binding in globus pallidus as compared to CN, suggesting regional differences and potential interaction with other brain tissue components/proteins.ConclusionOur findings clearly demonstrate that there are region‐specific changes in UCB‐J binding in PSP brains compared to CN and further reflect the need for its in‐depth validation in postmortem brains and correlation with other synaptic and neuropathological markers. Moreover, P2 fraction is most optimal for reflecting synaptic loss with UCB‐J. The ongoing regional distribution, biochemical and immunostaining studies will help elucidate changes in synaptic integrity in PSP.
Associations of CSF IL‐6 and IL‐8 concentrations with brain atrophy, memory decline and AD biomarkers change in cognitively healthy older adults
Authors: Capogna Elettra , Watne Leiv Otto , Sørensen Øystein , Guichelaar Carlijn Jamila , Halaas Nathalie , Idland Ane‐Victoria , Blennow Kaj , Zetterberg Henrik , Walhovd Kristine B ,   for the Alzheimer’s Disease Neuroimaging Initiative, Fjell Anders M , Vidal‐Piñeiro Didac 
Published: December 2023

AbstractBackgroundAging is characterized by increased neuroinflammation, which plays an early role in the etiology of Alzheimer’s disease (AD) (1) and cognitive decline (2). Cytokines play key roles in neuroinflammation in aging. We investigated whether levels of cerebrospinal fluid (CSF) interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) were associated with cognitive and brain decline and whether this relationship was mediated by baseline levels of CSF beta‐amyloid (Aβ‐42) and phosphorylated tau (p‐tau). Finally, we tested whether baseline IL‐6 and IL‐8 were related to changes in core AD biomarkers over time.Method219 older adults (62‐91 years), with baseline CSF IL‐6 and IL‐8, were followed over time (up to 9.50 years) by collecting longitudinal structural MRI, cognitive, and CSF data (n = 140). Linear mixed models (LME) were used to assess the effect of IL‐6 and IL‐8 on hippocampal atrophy, entorhinal thinning, lateral ventricle expansion, memory performance, and core AD CSF change. False discovery rate (pFDR) correction was applied to the models.ResultHigher CSF IL‐8 levels at baseline were associated with better memory performance over time, specifically in the context of lower levels of p‐tau (t = ‐2.00, pFDR = 0.05) and p‐tau/Aβ‐42 ratio (t = ‐2.15, pFDR = 0.03, Figure 1), while higher baseline IL‐6 were related to less CSF p‐tau changes over time (t = ‐2.61, pFDR = 0.02, Figure 2a). At trend levels, higher IL‐8 was associated with decrements of CSF Aβ‐42 levels over time (t = ‐2.25, uncorrected p = 0.02, Figure 2b), while higher IL‐6 was related to faster hippocampal volume decline with higher p‐tau/Aβ‐42 ratio (t = ‐2.21, uncorrected p = 0.03, Figure 2c).ConclusionIL‐6 and IL‐8 show a complex profile in cognitively healthy aging pointing towards a neuroprotective role, especially with lower levels of the pathological load.