bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Cardiometabolic Multimorbidity with Dementia and Alzheimer’s Plasma Biomarkers in Older Adults: a population‐based study
Authors: Liu Cuicui , Tian Na , Fa Wenxin , Liu Keke , Wang Nan , Wang Yongxiang , Hou Tingting , Du Yifeng , Qiu Chengxuan 
Published: December 2023

AbstractBackgroundIndividual cardiometabolic disorders are associated with an increased dementia risk. However, the relationship of cardiometabolic multimorbidity (CMM) with dementia has not been studied in Chinese older adults and the underlying mechanisms are poorly understood.MethodThis population‐based study included 5665 rural‐dwelling adults (age ≥60 years, 57.3% women) in the baseline examination (March‐September 2018) of the Multimodal Interventions to Delay Dementia and Disability in Rural China study. Cardiometabolic diseases (CMDs), which included heart disease, stroke, type 2 diabetes, and obesity, were assessed through clinical and neurological examinations. CMM was defined as the concurrent presence of two or more CMDs. Amyloid‐β(Aβ), total tau, and neurofilament light chain (NfL) were measured using Simoa platform in a subsample (n = 1434). Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were clinically diagnosed following international criteria. Data were analyzed using the general linear and logistic regression and mediation models.ResultOf the 5665 participants, 1091 (19.26%) were detected with CMM, and 302 (5.33%) were diagnosed with dementia (193 with AD and 98 with VaD). The multivariable‐adjusted odds ratios of CMM (vs. no CMD) were 3.00 (95% confidence interval [CI] 2.19‐4.11) for all‐cause dementia, 1.66 (1.11‐2.47) for AD, and 12.5 (6.47‐24.18) for VaD. There was a significant interaction between CMM and sex on the likelihood of dementia and subtypes (P for interaction<0.05), such that the associations of CMM with dementia and subtypes were stronger in men than in women. In the biomarker subsample, CMM was significantly associated with higher plasma NfL (demographic‐adjusted β coefficient = 0.059; 95% CI 0.028‐0.091), Aβ40 (0.034; 0.018‐0.049), and Aβ42 (1.068; 0.636‐1.501); the observed association remained significant even in the multivariable‐adjusted model (P<0.001). The mediation analysis showed that plasma NfL could mediate 19.46% of the association between CMM and AD (P<0.05), whereas plasma Aβ and total tau showed no significant mediation (P>0.05).ConclusionCMM is associated with increased likelihoods of dementia, AD, and VaD in older adults, especially in men. Neurodegenerative pathway might play a part in the association of CMM with AD.
Direct Electrophysiological Imaging Measure as a Novel Method for Detection of Onset of Medial Temporal Atrophy in Healthy Population
Authors: Shainer Tamara , Bregman Noa , Trabulus Noa , Hadad Rafi , Maynard James , Brill Silviu , Tanne David 
Published: December 2023

AbstractBackgroundMedial temporal atrophy (MTA) has long been demonstrated as a prognostic measure for transition from normal cognition to MCI and from MCI to Dementia, often but not only due to Alzheimer’s disease (AD). However, brain scans availability and costs do not allow for it to be implemented as common practice, for early detection of MTA in cognitively normal patients.We tested “Delphi”, a non‐invasive measure that probes brain network responses via induction of focused magnetic stimulation over selected brain networks in order to detect MTA.MethodA multicenter study (3 US, 2 OUS), in which one site recruited the derivation cohort (n = 220) which was used for establishing “Delphi” thresholds, and four sites recruited the validation cohort (n = 263, mean age 61.5 (±7.1), 57% females).The study included healthy subjects aged 50‐75 with at least one risk factor for stroke or dementia and no history of neurodegenerative disease.All subjects underwent multiple evaluations including a neurological exam, cognitive tests, MRI scans and “Delphi”. Three experienced neuroradiologists blindly rated the scans for MTA (Schelten’s scale, ‘Normal’‐MTA = 0, ‘Abnormal’‐MTA> = 1) and other findings.Result263 subjects were included in the validation cohort, out of which 23 subjects were rated MTA≥1 (69% MTA = 1, 17% MTA = 2 and 13% MTA = 3) while the rest were MTA = 0 on MRI scanning.Out of the total sample 11% had abnormal result in MMSE (≤27) and 15% had abnormal result in MoCA (≤23) and only 13% had abnormal result in each of MMSE and MoCA in the MTA≥1 subgroup.“Delphi” discriminated subjects with MTA = 0 from MTA≥1 with AUC = 0.81, sensitivity = 82% [95%CI 62.86%:93.02%], specificity = 75% [95% CI 63.62:81.0%].ConclusionBrain network physiology evaluation using the “Delphi” technology may serve to detect early stages of MTA, preceding cognitive impairment with substantial accuracy in the outpatient office setting in a generally healthy population. This could allow the expansion of the physician’s in‐office tools, potentially improving patient management.
Development of TDP‐43 immunotherapy blocking transmission of seeding‐competent species from ALS/FTD
Authors: Afroz Tariq 
Published: December 2023

AbstractBackgroundAccumulation of pathological transactive response DNA binding protein 43 (TDP‐43) into intracellular inclusions underlies frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). TDP‐43 pathology is present as a co‐pathology in other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and chronic traumatic encephalopathy (CTE). Multiple mechanisms contribute to spreading of TDP‐43 pathology including transmission across synaptic terminals, exosomes and release of misfolded TDP‐43 from dying neurons. In fact, cerebrospinal fluid (CSF) obtained from ALS/FTLD‐TDP patients contains seeding‐competent TDP‐43 species. Therefore, antibody‐mediated clearance of pathological TDP‐43 represents an attractive therapeutic strategy. Our approach is to develop a TDP‐43‐specific immunotherapy that exploits Fcγ receptor‐mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP‐43 function.MethodHigh affinity monoclonal antibodies (mAbs) were generated against various regions of TDP‐43 using AC Immune’s SupraAntigen® platform and evaluated in mechanistic assays in vitro and in vivo models of TDP‐43 proteinopathies. A real‐time quaking‐induced conversion (RT‐QuIC) assay was established using patient’s CSF to evaluate the inhibitory properties of the lead therapeutic mAb on the seeding mechanism. Studies to evaluate the pharmacology and safety of the antibody were carried out in non‐human primates.ResultTargeting the C‐terminal domain of TDP‐43 but not the RNA recognition motifs reduced TDP‐43 pathology and prevented neuronal loss in vivo. This rescue was dependent on Fcγ receptor‐mediated immune complex uptake by microglia. The latter also promoted phagocytic capacity of ALS patient‐derived microglia. Importantly, the antibody efficiently neutralized seeding‐competent pathological TDP‐43 species in CSF from ALS patients. These beneficial effects were achieved while preserving physiological TDP‐43 function demonstrating safety of targeting TDP‐43 by immunotherapy. Modelling from non‐clinical pharmacokinetic studies of the antibody predicted a half‐life supporting target saturation in humans when administered monthly.ConclusionOur studies confirm the presence of extracellular seeding‐competent TDP‐43 species in the CSF of patients with ALS/FTLD‐TDP patients, providing an explanation for the spread of pathology including the non‐contiguous pattern of clinical manifestations observed in ALS. In addition, the binding and inhibitory properties of our lead therapeutic mAb in multiple patho‐mechanistic assays support clinical development in TDP‐43‐driven neurodegenerative diseases.
Linguistic features correlate with biomarkers in very early AD
Authors: Liu Yi‐Chien , Chou Chia‐Ju , Lee Chia‐Ying , Chang Chih‐Ting 
Published: December 2023

AbstractBackgroundLinguistic features in speech have been proven to be sensitive in detecting early Alzheimer disease (AD). However, whether linguistic features correlate with clinical cognitive tests or biomarkers is still debated.MethodIn this study, we recruited 35 AD subjects and 25 normal controls from the memory clinic from 2020 to 2022. Subjects with positive amyloid PET (based on visual rating and quantitative SUVr) and evidence of cognitive impairment (MMSE≦26 or CDR≧0.5) were recruited. On the other hand, negative amyloid PET and no evidence of cognitive impairment were required for normal controls. All participants also received 3.0 T brain MRI and completed comprehensive neuropsychological tests. Among these tests, we collected speech samples from picture description test. The picture descript test includes three Taiwanese‐culture‐based pictures. The collected connected speech was analyzed based on 16 standard linguistic features.ResultsIn our cohort, the MMSE scores of the AD group are lower (20.17 ± 4.99 V.S. 29.04 ± 1.21, p<0.001). 66% of AD group were still in MCI stage and 60% progressed (CDR‐SB change≧1) during follow‐up (1.71 years). Linguistic features including total word frequency, mean length of utterance (MLU), passive ratio and long pause ratio were statistically different between AD and controls. SUVr (standardized uptake value ratio) of amyloid in AD group didn’t correlate with MMSE or CDR‐SB. SUVr correlated with total words, content words, total number of sentences and scores of Wechsler Logical Memory test in AD group. Hippocampal volume correlates with MMSE and CDR‐SB in AD group. Hippocampal volume also correlates with unique words, long pause ratio, scores of digit span test and Boston naming test in AD group.ConclusionAmyloid load didn’t correlate with clinical severity in very early stage of AD. But it correlates with the amount of speech production and episodic memory test. On the other hand, hippocampal volume correlates with clinical severity, the number of unique words in speech, dysfluency, executive function and naming ability.
Omics analysis of Alzheimer’s disease stratified by the microglial polygenic effect
Authors: Kikuchi Masataka , Miyashita Akinori , Hirota Yu , Hara Norikazu , Hasegawa Mai , Sakakibara Yasufumi , Sekiya Michiko , Saito Yuko , Murayama Shigeo , Iijima Koichi M. , Ikeuchi Takeshi 
Published: December 2023

AbstractBackgroundRecent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of Alzheimer’s disease (AD). However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.MethodWhole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).ResultWe divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. The expression of APOE and TYROBP, signature genes of reactive microglia, was significantly upregulated in the AD patients with low PRS compared to the AD patients with high PRS and healthy subjects. In contrast, CX3CR1 and P2RY12, signature genes of homeostatic microglia, were downregulated.ConclusionThe stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.
Human interlaminar astrocytes with different APOE variants differentially contribute to Alzheimer’s disease pathology
Authors: Arranz Amaia M 
Published: December 2023

AbstractBackgroundIncreasing evidence for a direct contribution of astrocytes as well as different APOE variants to Alzheimer’s disease (AD) main pathological hallmarks comes from cellular and molecular studies in rodent models. Yet these models cannot fully mimic how human astrocytes affect AD pathology as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.MethodTo address these challenges, we established an approach to study human astrocytes carrying APOE3 and APOE4 isoforms within the AD brain environment by transplanting human induced pluripotent stem cell (hiPSC)‐derived astrocyte progenitors into neonatal brains of suitable AD model mice.ResultAPOE3 and APOE4 transplanted cells similarly differentiate into astrocytes within the mouse host brain and very often integrate in upper layers of one cortical hemisphere, where they acquire morphological phenotypes resembling human interlaminar astrocytes (h‐ILAs). Interestingly, in AD model mice APOE3 and APOE4 h‐ILAs differentially express and secrete the apoE protein (Figure 1), and differentially affect amyloid‐beta load (Figure 2), microglial responses (Figure 3) and neuritic dystrophy.ConclusionWe describe here a promising model that allows for the first time studying h‐ILAs in the AD brain environment. Importantly, our model reveals a differential contribution of h‐ILAs with different APOE variants to main pathological hallmarks of AD, which can potentially have important implications when developing novel astrocyte‐specific targeting therapeutics.
Inhibition of D3 receptors restores synaptic plasticity and memory impairment in aged and Alzheimerʼs disease mouse models
Authors: Tropea Maria Rosaria , Melone Marcello , Vacanti Valeria , Gulisano Walter , Leggio Gian Marco , Conti Fiorenzo , Puzzo Daniela 
Published: December 2023

AbstractBackgroundDopamine D3 receptors (D3‐Rs) are involved in several functions such as reward and social behavior and they have been proposed as a therapeutical target for addiction, schizophrenia, and Parkinson’s disease. However, the role of D3‐Rs in cognition has been poorly investigated, with few studies demonstrating that the activation of D3‐Rs impairs attention and working memory. Results obtained in our laboratory suggested that D3 inhibition exerts a pro‐cognitive effect on long term potentiation (LTP) and recognition memory on healthy wild‐type (WT) mice. Based on these findings, here, we aimed to investigate whether the positive effect shown by D3 inhibition at the synapse could be exploited to counteract the synaptic plasticity and memory impairment found in aged and AD mice.MethodWe used D3 knock out (D3‐KO), WT at 18‐22 months of age as a physiological model of aging, the 3XTg transgenic mouse model of AD and a7 KO mice, recently found to present an AD‐like phenotype. The pharmacological inhibition of D3‐Rs was obtained with the selective antagonist NGB‐2904. To test whether the pharmacological inhibition of D3‐Rs or their genetic deletion could rescue LTP and memory impairment, we performed electrophysiological recordings at CA3‐CA1 synapses in hippocampal slices and behavioral experiments of novel object recognition, novel object location and Morris Water Maze.ResultWe found that D3‐Rs antagonism rescued the impairment of LTP, and different forms of memory in aged WT mice. Consistently, aged D3 KO mice showed no alteration of LTP and memory, suggesting that the genetic deletion of D3 receptors prevented the synaptic plasticity and memory decline that occurs with aging. The pharmacological inhibition of D3‐Rs was also able to rescue the memory impairment in both 3XTg and a7 KO mice.ConclusionIn conclusion, our findings suggest that the pro‐cognitive effect exerted by D3‐Rs inhibition or genetic deletion could represent a viable therapeutic strategy to treat the cognitive dysfunction occurring during aging and AD.
Upregulation of Wnt2b produces neuroprotective effects by alleviating mitochondrial dysfunction in Alzheimer’s disease
Authors: Xu Lingzhi , Li Bingqiu , Li Fangyu , Zhao Yu , Quan Meina , Jia Jianping 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly worldwide. Wnt signaling participates in multiple aspects of cellular function, and contributes to synapse formation, synaptic activity and neurogenesis in the brain, and dysfunction of Wnt signaling may aggravate the pathogenesis and progression of AD. Wnt2b has been studied in cancers or tumor‐related diseases, while the roles of Wnt2b in AD is still unknown. Wnt2b is also characterized as a mitochondria‐expressed protein which shuttles between mitochondria and the nucleus, and mitochondrial dysfunction contributes to the development and progression of the pathological process that underlies AD, especially at the early stage. This study investigated the relationship between plasma Wnt2b levels and AD, and explored the effect of Wnt2b on mitochondrial dysfunction in AD.MethodNormal cognitive (NC) and AD subjects, AD transgenic mice and in vitro model were used to investigated the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT‐qPCR, immunoblotting and immunofluorescence analysis were performed to assay canonical Wnt sign aling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis.ResultIn this study, we found plasma Wnt2b levels were lower in AD patients than NC subjects and positively correlated with cognitive performance (Figure 1). Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models (Figure 1). Next, Wnt2b overexpression and recombinant Wnt2b was used to endogenously (Figure 2) and exogenously (Figure 3) upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated.ConclusionOur study highlights that Wnt2b decline is associated with cognitive impairment in AD, and Our findings may advance the understanding of the importance of Wnt family in AD, and we propose that Wnt2b might be a potential diagnostic indicator and therapeutic target for AD.
Examination of the utility of the gold standard cutoff score for the Montreal Cognitive Assessment (MoCA) in Chinese American older adults: A pilot study
Authors: Ying Gelan , Spat‐Lemus Jessica , Xia Tianxu , Cai Dongming , Lai Randy , Neugroschl Judith A. , Aloysi Amy , Sano Mary , Zhu Carolyn W , Akrivos Jimmy , Hong Yue , Huang QiYing , Zeng Xiaoyi , Liu Linghsi , Cao Yiyu , Wang Wei‐Qian , Li Clara 
Published: December 2023

AbstractBackgroundThe gold standard cutoff (<26) for the Montreal Cognitive Assessment (MoCA) was developed using a predominantly White and English‐speaking sample. However, the diagnostic value of this cutoff score in a culturally and linguistically diverse population, such as older Chinese Americans, has been understudied and remains inconclusive. As such, this pilot study aimed to examine specific psychometric properties of the standard cutoff score on Chinese language versions of the MoCA for detecting mild cognitive impairment (MCI) and dementia in Chinese American older adults.MethodThe Chinese language versions of the MoCA was administered to 88 older Chinese Americans (19 MCI, 26 dementia, and 43 normal cognition ‐ NC) from Mount Sinai’s Alzheimer’s Disease Research Center (ADRC) in Mandarin/Cantonese by trained psychometricians. All participants self‐reported as Chinese Americans who were primarily Cantonese‐ or Mandarin‐speaking. Exclusion criteria included: not proficient in Cantonese/Mandarin and history of psychiatric disorder(s). Diagnoses were assigned at a consensus conference. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to detect MCI and dementia from NC and were then compared to previously published findings in a primarily White English‐speaking sample.ResultThe gold standard cutoff yielded poor sensitivity to detect MCI and dementia from participants with NC (both 0.47) in this study cohort, but comparable specificity (MCI vs. NC = 0.84; dementia vs. NC = 1.00) to previously published findings (MCI: sensitivity = 0.90, specificity = 0.87; dementia: sensitivity = 1.00, specificity = 0.87). NPV was poor (MCI: NPV = 0.41; dementia: NPV = 0.53), while PPV was similar in detecting both MCI and dementia (MCI: PPV = 0.87; dementia: PPV = 1.00) to previous findings (MCI: PPV = 0.89, NPV = 0.91; dementia: PPV = 0.89, NPV = 1.00).ConclusionThe MoCA cut off score had poor sensitivity and NPV, but excellent specificity and PPV in detecting MCI and AD in our cohort. These findings suggest that the traditional cutoff score may not be appropriate for screening of cognitive impairment in older Chinese Americans. As the most frequently administered cognitive screening tool, the MoCA cutoff score should be adjusted for older Chinese Americans with limited to no English proficiency. Future studies in a larger cohort of older Chinese Americans are needed to establish a true gold standard for this specific population.