bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective evaluation of plasma phopshorylated tau in real‐life memory clinic in Thailand
Authors: Luechaipanit Watayuth , Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Supharatpariyakorn Thirawat , Sarutikriangkri Yuthachai , Tangnimitchoke Suchart , Likitjaroen Yuttachai , Sukprakun Chanan , Tepmongkol Supatporn , Hemachudha Thiravat 
Published: December 2023

AbstractBackgroundDespite the substantial accuracy of plasma phosphorylated tau (p‐tau) in diagnosing Alzheimer’s disease (AD) in research cohorts, data on real‐life memory clinic patients are limited. Additionally, previous biomarker studies have often been geographically restricted, raising concerns about generalizability to underrepresented populations. We prospectively assessed the diagnostic accuracy of plasma p‐tau181 in a memory clinic in Thailand.MethodPatients at their early symptomatic stages (i.e. no more than mild dementia) who presented with memory impairment were consecutively enrolled between October 2021 and August 2022. They prospectively underwent routine clinical assessment and plasma p‐tau181 quantification (Simoa). Within 10 weeks, amyloid and tau‐positron emission tomography (PET) were performed using [18F]‐Florbetaben and [18F] PI‐2620, respectively. The diagnostic performance of plasma p‐tau181 (using a predefined cut‐off derived from an independent cohort), neurocognitive specialists and regional tau‐PET (Braak stage III‐IV) were compared head‐to‐head using amyloid‐PET as the reference standard.ResultAmong 51 participants enrolled, 36 (70.6%) were female. The median age was 72 years (interquartile range: 64.5‐76.0). Amyloid‐PET was positive in 43 (70.6%) of the participants. Plasma p‐tau181 had an area under the curve (AUC) of 0.84 (95% confidence interval (CI) 0.73‐0.94), sensitivity of 0.80 (95%CI 0.64‐0.90), specificity of 0.75 (95%CI 0.51‐0.90), and accuracy of 0.78 (95%CI 0.65‐0.88) for detecting amyloid‐PET positivity in early symptomatic patients. In comparison, clinical diagnosis by neurocognitive specialists had an AUC of 0.70 (95%CI 0.56‐0.85), sensitivity of 0.65 (95%CI 0.49‐0.79), specificity of 0.75 (95%CI 0.51‐0.90), and accuracy of 0.69 (95%CI 0.55‐0.80), whereas tau‐PET had an AUC of 0.88 (95%CI 0.79‐0.97). The AUC of p‐tau181 was not significantly different from clinical diagnosis (p = 0.15) or tau‐PET (p = 0.48), however, tau‐PET significantly outperformed clinical diagnosis (p = 0.03).ConclusionThe diagnostic performance of plasma p‐tau181 is substantial in the diverse population of a specialized memory clinic. Its discriminative accuracy was comparable to a second‐generation tau‐PET and showed tendency towards superiority to clinical assessment. The findings of our study may serve as a guide for the cost‐effective implementation of plasma p‐tau into real‐life clinical practice.
Genotype Phenotype characterisation, Imaging profile and novel genetic mutations from a large cohort of Frontotemporal Dementia from India
Authors: Ramakrishnan Subasree , Pon Arun Gokul , Bosco Susan , Arshad Faheem , Arunachal Gautham , Kulanthaivelu Karthik , Alladi Suvarna 
Published: December 2023

AbstractBackgroundDegenerative dementia like Frontotemporal dementia (FTD) are complex heterogeneous disorders with variable phenotypes, patterns of atrophy and pathogenicity. Advanced genetic studies from India are sparse and earlier techniques mostly reported negative results. Current study aims to evaluate the clinical, radiological and genetic profile of FTD/FTD overlap syndromes, to perform whole exome sequencing and to explore genotype phenotype correlations.MethodSubjects with dementia fulfilling standard criteria’s for FTD/FTD Overlap and AD were recruited from Dept. of Neurology, NIMHANS, India Demography, pedigree analysis, clinical, cognitive and neuropsychological evaluation and blood sampling for genetic analysis by next generation sequencing and MRI as per ADNI protocol were performed. RT‐PCR was done for analysing c9orf.Results133 FTD/FTD overlap were recruited. Mean age at onset was 56 ± 9.8 years in FTD There were 87 men and 75 women. Family history was documented in 43%. 42% had family history in first degree relatives, 11% had history in second degree and 4% in third degree relatives. Mean ACE scores were 43.8± 24.7. Frontotemporal atrophy was noted in 90% in MRI (n = 115). 41% had Grade 1 (mild) global cortical atrophy score .MRI also revealed characteristic features like diffusion restriction, white matter lesions (CSF1R) basal ganglia calcification with bone cysts(TYROBP) and Corpus callosal atrophy(TREM2)11 novel gene mutations including one each of CSF1R, TREM2, TYROBP, SQSTM1, GRN, MAPT, PSEN2 and four cases of C9orf were detected (Pathogenic in 11 and Variant of unknown significance in 26), out of the 100 samples sequenced and analysed (ACMG guidelines). VUS like GBA, PANK2, PLAG26, PRNP, LRRK2, DCNT etc. were also identified. Sanger validation confirmed the pathogenic mutations. Novel variants of CSF1R, TREM2 and TYROBP, primary microgliopathy as causative genes are being first time described from India. SQSTM1 presented as bvFTD without ALS overlap, GRN as non‐fluent aphasia, MAPT as bvFTD and PSEN2 as non‐fluent PPA and two patients with C9orf presented as bvFTD and two others as FTD‐ALS.ConclusionGenotype‐phenotype correlations along with neuroimaging and pedigree analysis has aided in early diagnosis, prognostication and novel and unique genetics causes shedding light on underlying FTD mechanism from our cohort.
Development of the MIITRA QSM template: a high‐resolution magnetic susceptibility template of the older adult brain in the MIITRA atlas space
Authors: Abid Rasheed , Ridwan Abdur Raquib , Wu Yingjuan , Niaz Mohammad Rakeen , Zhang Shengwei , Evia Arnold M , Bennett David A. A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundA QSM template of the older‐adult brain is not yet available. This study constructed a high resolution QSM template of the older‐adult brain for the MITRA atlas using data from a large, diverse, community cohort of non‐demented older‐adults.MethodMagnetic susceptibility maps were generated for the 400 older‐adult paricipants used in the construction of MIITRA using the Morphology Enabled Dipole Inversion(MEDI) on the 3D 5‐echo GRE data(0.7×0.7×1.3mm3) and upsampled to 0.7×0.7×0.65mm3 using nonlocal upsampling. The first GRE echo of each participant were N4 bias field corrected, then upsampled to 0.7×0.7×0.65mm3 using non‐local upsampling and converted to synthetic T1w images using mri_synthsr. The original 3D T1w MPRAGE(1×1×1mm3) data were upsampled to 0.5×0.5×0.5mm3. The synthetic T1w images were linearly registered to the upsampled T1w data and the resulting transformations were used to forward‐map magnetic susceptibility values from the native space of each participant to exact physical locations in MIITRA space. A sparse representation based data‐fusion approach was used on the transformed signals to generate the final 0.5×0.5×0.5mm3 resolution template, denoted as MIITRA_QSM(Fig.1). Since no other magnetic susceptibility template of the older‐adult brain is currently available, we compared MIITRA_QSM to a young adult template named MuSus‐100(1×1×1mm3,100 participants,mean age 24 years) in terms of image quality and magnetic susceptibility properties.ResultVisual showed that MIITRA_QSM template includes fine details, has the expected QSM contrast, highest values in subcortical, brainstem, and cerebellar structures known for their high magnetic susceptibility(especially in older adults), lower values in the white compared to gray matter, and higher values in white matter of the frontal lobe compared to parietal and occipital lobes. When compared to MuSus‐100, MIITRA_QSM showed better delineation of cortical structures and higher image sharpness(Fig.2), as well as higher magnetic susceptibility values in most subcortical brain structures(Fig.3A), Cortical structures from the two templates exhibited more similar magnetic susceptibility values(Fig.3B).ConclusionMagnetic susceptibility values in specific subcortical, brainstem and cerebellar structures are higher in the MIITRA_QSM template compared to a young adult template, probably due to increased metal deposition in these structures with aging. The new template is expected to greatly enhance the accuracy of voxel‐wise and atlas‐based QSM studies on older‐adults.
Lifestyle Modification Exerts Protection Against Obesity‐Induced Neurodegeneration Via CD147‐Related Mechanism
Authors: Chanchalotorn Siwakorn , Pantiya Patcharapong , Thonusin Chanisa , Chunchai Titikorn , Ongnok Benjamin , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundCD147, also known as extracellular matrix metalloproteinase inducer, is a key mediator of inflammatory and immune responses in various kinds of neurodegenerative disease (1). However, the role of CD147 in obesity‐induced neurodegeneration has not been previously investigated. Therefore, this study aims to investigate the alteration of CD147 expression in the hippocampus of obese rats, both with and without lifestyle modification.MethodSeven‐week‐old male Wistar rats were divided into 4 groups (n = 5 per group), including 1) rats fed with a normal diet for 28 weeks [ND], 2) rats fed with a high‐fat diet (HFD) for 28 weeks [HFD], 3) rats fed with a HFD for 12 weeks followed by 40% caloric restriction for an additional 16 weeks [HFD‐CR], or 4) rats fed with a HFD for 12 weeks followed by exercise plus HFD for an additional 16 weeks [HFD‐EX]. At the end of week 28, cognitive function was determined by a novel object location test. The rats were then euthanized on the following day for molecular studies in the hippocampus.ResultWe found that hippocampal CD147 level exerted a strongly negative correlation with the level of cognitive function (Figure A). In addition, CD147 expression and its downstream consequences – p‐NFκB, MMP‐9, and TNF‐α – were upregulated in HFD‐fed rats (Figure B‐E). The HFD‐fed rats also exhibited an increase in activated microglia (CD68), along with decreased blood‐brain barrier protein (claudin‐5), dendritic spine density, and cognitive performance (Figure F‐I). Strikingly, both caloric restriction and exercise effectively reduced the expression of CD147 and its downstream consequences, as well as restored CD68, claudin‐5, dendritic spine density, and cognitive function in HFD‐fed rats (Figure B‐I).ConclusionOur findings suggested that CD147 is one of the detrimental mediators in obesity‐induced neurodegeneration (Figure J). Interestingly, an attenuation of obesity by lifestyle modification exerts protection against cognitive impairment via CD147‐related mechanisms (Figure J). Therefore, an inhibition of CD147 is considered as a therapeutic target to prevent cognitive impairment in obese individuals.
Reference
1. Kaushik DK, Hahn JN, Yong VW. EMMPRIN, an upstream regulator of MMPs, in CNS biology. Matrix Biol. 2015;44‐46:138‐46.
Vagus Nerve Stimulation Provides Neuroprotection Against Doxorubicin‐induced Chemobrain Via Activations of Both Muscarinic and Nicotinic Acetylcholine Receptors
Authors: Siripakkaphant Christsanutth , Ongnok Benjamin , Prathumsap Nanthip , Khuanjing Thawatchai , Chunchai Titikorn , Arunsak Busarin , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundChemotherapy, particularly treatment with doxorubicin (Dox), is known to cause neurotoxicity in the brain known as chemobrain. Dox administration causes neuroinflammation, mitochondrial dysfunction, and subsequent cognitive decline (1). Additionally, cancer survivors who received Dox were found to have an increased risk of developing dementia (2). Interestingly, the activation of the parasympathetic nervous system by vagus nerve stimulation (VNS) exerted neuroprotective effects on Alzheimer’s disease (3). However, the neuroprotective effects of VNS against Dox‐induced chemobrain have never been investigated. Moreover, whether the therapeutic effects of VNS are achieved via stimulation of nicotinic acetylcholine receptors (AChRs) or muscarinic acetylcholine receptors (mAChRs) needs further investigation.MethodTwenty male Wistar rats were divided into sham‐operated and VNS device‐implanted groups. After 2 weeks of recovery, all sham‐operated rats were divided and received either 0.9% NSS (Control; n = 4) or 3 mg/kg Dox for 6 doses (Sham; n = 4) via intraperitoneal injection. In addition, all VNS device‐implanted rats were treated with 3 mg/kg Dox for 6 doses and then randomly divided into 3 groups to receive either 0.9% NSS (VNS; n = 4), a mAChR antagonist (atropine; 1 mg/kg/day, VNS+Atro; n = 4), or a nAChR antagonist (mecamylamine; 7.5 mg/kg/day, VNS+Mec; n = 4). At the end of treatment protocol, cognitive function was assessed using the novel object location (NOL) task. The brains were obtained for further molecular studies.ResultDox treatment impaired cognitive performance in rats, as demonstrated by a decrease in the preference index in the NOL task (Figure A). Microglia in the CA1 region of Dox‐treated rats exhibited decreased process complexity and increased microglial volume, indicating reactivation of microglia (Figure B and C). Notably, Dox administration caused mitochondrial dysfunction in the brain, as evidenced by increased levels of mitochondrial reactive oxygen species (ROS) and mitochondrial membrane depolarization (Figure D and E). Importantly, the intervention with VNS rescued long‐term cognitive function in Dox‐treated rats by ameliorating all chemobrain pathologies (Figure A‐E). In contrast, the therapeutic effects of VNS were completely abolished by blocking either mAChRs or nAChRs using their antagonists (Figure A‐E).ConclusionThe findings suggested that VNS protected against Dox‐induced chemobrain through activations of both nAChRs and mAChRs.
Plasma Neurofilament Light Chain predicts neuroimaging alterations and functional decline in frontotemporal dementia
Authors: Borrego‐Écija Sergi , Juncà‐Parella Jordi , Ruiz‐García Raquel , Sarto Jordi , Martínez Neus Falgàs , Esteller Diana , Guillén Núria , Fernandez‐Villullas Guadalupe , González Yolanda , Pérez‐Millan Agnès , Tort‐Merino Adrià , Bosch Beatriz , Fort‐Aznar Laura , Antonell Anna , Naranjo Laura , Lladó Albert , Balasa Mircea , Sanchez‐Valle Raquel 
Published: December 2023

AbstractBackgroundPlasma Neurofilament light chain (pNfL) is a promising biomarker to discriminate Frontotemporal dementia (FTD) from other diagnoses such as Alzheimer’s disease (AD) or psychiatric disorders. Currently, the diagnostic criteria for FTD syndromes are structured hierarchically into “Possible”, “Probable” and “Definite” levels depending on the degree of confidence set by biomarkers. We aim to study the diagnostic and prognostic values of pNfL in the different confidence levels of FTD diagnosis.MethodPatients fulfilling criteria for FTD were classified as “Possible”, “Probable” or “Definite” FTD based on the current diagnostic criteria. pNfL levels were determined with SiMoA, and then compared to Control and AD groups, as well as within the different levels of confidence in the FTD diagnosis.Result187 subjects were included: 37 controls, 79 AD and 71 FTD (11 Possible, 49 Probable and 11 Definite). The FTD group showed higher concentrations of pNfL than the Control (p < 0.001, AUC: 0.817) and the AD groups (p < 0.001, AUC: 0.677) (Figure 1A and 1B).Within the FTD group, pNfL levels differed across the different diagnostic confidence levels (Figure 1C). Subjects with Probable and Definite FTD showed higher levels of pNfL than subjects with Possible FTD (p < 0.001 and p < 0.01 respectively). By contrast, the Possible FTD group did not show differences in pNfL concentrations with the control group. In that sense, the diagnostic value of pNfL varied according to the different grades of diagnostic confidence (Figure 1D), with cases with probable or definite FTD exhibiting an excellent AUC to distinguish from controls (AUC 0.860 and 0.908 respectively), but with no discrimination between possible FTD and controls (AUC 0.583).pNfL presented an excellent performance in the differentiation of structural or functional impairment in the neuroimage (AUC 0.94, and AUC 0.86 respectively) (Figure 2). Finally, higher baseline pNfL levels were associated with worse clinical progression in FTD cases (Figure 3).ConclusionpNfL were higher in FTD patients compared to controls or AD patients. However, we found significant variation across the different confidence levels of FTD diagnosis. Finally, pNfL predicted neuroimage alterations and a worse clinical progression in FTD patients.
The Effects of Estrogen on the Risk of Developing Dementia using the UK Biobank Data
Authors: Park Hee Kyung , Marston Louise , Mukadam Naheed 
Published: December 2023

AbstractBackgroundThe incidence of dementia increases with postmenopausal women, which prompted the investigation of the role of estrogen in the development of dementia. We aimed to investigate the role of estrogen in the UK Biobank.MethodA total of 273,201 women were included in this study. Comprehensive interviews, medical history, body mass index (BMI), and the apolipoprotein E (APOE) genotype were obtained. Reproductive characteristics, including estrogen length and history of surgery, were used as exposure variables. The Cox Proportional Hazard model was used to estimate hazard ratios (HR) for the development of dementia, adjusting for age, education, the Townsend deprivation score, the APOE genotype, family history of dementia, BMI, smoking status, diabetes mellitus, hypertension, and hyperlipidemia.ResultThe mean estrogen length was 37.25 years (8.03 years). About 19% of women had a history of surgery. Compared to women with the lowest overall exposure to estrogen (Estrogen length ≤33), women with higher levels of cumulative estrogen had a decreased risk of dementia (34≤Estrogen length ≤37, HR = 0.79, 95% CI = 0.72‐0.89, p<0.001; 38≤Estrogen length ≤42, HR = 0.72, 95% CI = 0.65‐0.79, p<0.001; 43≤Estrogen length, HR = 0.77, 95% CI = 0.70‐0.85, p<0.001). Compared to women without a history of surgery, women with a history of surgery had an increased risk of dementia (HR = 1.08, 95%CI = 1.00‐1.17, p = 0.038).ConclusionThis study found that longer estrogen length had a decreased risk for dementia and a history of surgery had an increased risk for dementia. The results of this study suggested that estrogen might have a protective role in women’s development of dementia. The exact biological mechanism of the protective effects of estrogen in the brain needs to be elucidated in the future.
Association between oral health and cognitive frailty in community‐dwelling older adults
Authors: Chen Jen‐Hau 
Published: December 2023

AbstractBackgroundCognitive frailty indicates the presence of both physical frailty and mild cognitive impairment (MCI) and has been associated with an increased risk of adverse health outcomes (e.g., mortality). Poor oral health has been related to cognitive impairment and physical frailty, respectively. However, the association between oral health and cognitive frailty remains unclear. This study aimed to explore the association between oral health and cognitive frailty in community‐dwelling older adults.MethodThis 10‐year cohort study (2011‐2021) is a part of an ongoing prospective cohort study. At baseline (2011‐2013), 605 non‐demented community‐dwelling older adults (aged 65+) with four biennial follow‐ups. Cognitive frailty was defined as the coexistence of MCI and physical frailty. Extended definitions of cognitive frailty were also assessed and defined as the coexistence of impaired cognitive domains and physical frailty. Oral health variables included tooth defects, dentition, and periodontal status. The generalized linear mixed model was used to explore the longitudinal association between oral health and cognitive frailty, adjusting for age, sex, lifestyle, comorbidity, and so on.ResultThe mean age of the study participants was 72.7 at baseline, and 53.4% were female. We found that tooth defect was associated with worsening of impaired memory‐frailty [adjusted odds ratio (aOR) = 1.13; 95% confidence interval (CI) = 1.03‐1.24] and impaired verbal fluency‐frailty (aOR = 1.07; 95% CI = 1.00‐1.11) over time; Dentition was associated with worsening of impaired executive function‐frailty (aOR = 1.10; 95% CI = 1.02‐1.18) over time; Periodontal status was associated with worsening of impaired memory‐frailty (aOR = 1.07; 95% CI = 1.02‐1.13) and verbal fluency‐frailty (aOR = 1.05; 95% CI = 1.00‐1.11) over time. No significant associations were found for traditional cognitive frailty and impaired attention‐frailty.ConclusionCognitive frailty is associated with oral health after adjusting for covariates. Inspection of oral health is helpful to predict the risk of cognitive impairment at an early stage. Further research on this topic is warranted to validate our findings.
Associations between metabolic syndrome and markers of brain pathologies: the role of sex‐differences
Authors: Marseglia Anna , Cooper Alexandra , Rydén Lina , Kern Silke , Shams Sara , Olof Lindberg , Blennow Kaj , Zetterberg Henrik , Zettergren Anna , Skoog Ingmar , Westman Eric 
Published: December 2023

AbstractBackgroundIn old age, cardiovascular and metabolic disorders rarely occur in isolation, but rather cluster together, in the so‐called metabolic syndrome (MetS). Although individual MetS components (obesity, hypertension, diabetes, and dyslipidemia) have been linked to dementia, their combined effect on cognition remains poorly explored. We recently showed that MetS was associated with clinically relevant cognitive decrements in otherwise cognitively healthy septuagenarians. However, the mechanistic underpinnings are unknown. This study investigates the association between MetS and markers of neurodegenerative and cerebrovascular pathologies, considering sex‐differences.MethodWithin the Gothenburg H70‐Birth cohort 1944, we included 741 cognitively intact septuagenarians with available brain MRI (n = 286 with cerebrospinal fluid [CSF] samples). MetS was identified according to standard criteria as the presence of at least three conditions: central obesity, raised blood pressure, raised blood glucose, reduced HDL‐cholesterol, or elevated triglycerides. MRI markers of brain pathology included overall (mean cortical thickness) and Alzheimer’s disease (AD; average cortical thickness in signature areas) neurodegeneration as well as cerebrovascular pathology including small vessel disease (SVD) and DTI’s microstructural white‐matter changes. CSF biomarkers included t‐tau, neurofilament light, and neurogranin (overall neurodegeneration), Aβ42 and p‐tau (AD), and CSF/serum albumin ration (blood‐brain barrier integrity). Analyses included linear, quantile, and logistic regression models as well as interaction and stratification by sex.ResultOverall, 410 participants (53%) had MetS; 196 were women. In multi‐adjusted regressions (by sex, education, heart disease, and APOE‐ɛ4 allele), MetS was associated with increased likelihood of neurodegeneration (OR = 2.0, 95%CI 1.4–2.9) and AD (OR = 1.8, 95%CI 1.4–2.6), high SVD burden (presence of ≥3 SVD compared to none: OR = 2.1, 95%CI 1.1‐4.3), and greater microstructural white‐matter changes. In the CSF sample, MetS was associated with higher CSF/serum albumin ratio. In analyses stratified by sex, men with MetS (reference: no‐MetS) had increased odds of higher SVD burden, particularly of enlarged perivascular spaces (ePVS; OR = 2.9, 95%CI 1.7–5.0). Such differences were not observed between women with and without MetS. No associations were observed between MetS and amyloid and tau biomarkers.ConclusionMetS in late‐life increased the likelihood of neurodegenerative and cerebrovascular pathologies. SVD, especially ePVS, appears more prominent in men with MetS than women.