bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Arginine Metabolism in Early‐onset Alzheimer’s Disease and Frontotemporal Dementia
Authors: Mein Hannah , Jing Yu , Lladó Albert , Zhang Hu , Liu Ping 
Published: December 2023

AbstractBackgroundThe semi‐essential amino acid L‐arginine is metabolically versatile with a number of bioactive metabolites that are involved in synaptic plasticity, learning and memory, cerebral blood flow and microtubule stabilization processes. Altered brain arginine metabolism is evident in patients with late‐onset Alzheimer’s disease and has been implicated in the disease pathogenesis. However, the brain arginine metabolic profile is yet to be investigated in early‐onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).MethodUsing high performance liquid chromatography and liquid chromatography/mass spectrometry, we measured the concentrations of L‐arginine and its downstream metabolites L‐citrulline, L‐ornithine, agmatine, glutamate, glutamine, GABA, putrescine, spermidine and spermine in the hippocampus and frontal and temporal cortices from EOAD (n = 27‐28/region), FTD (n = 27‐31/region) and control (n = 9‐17/region) cases.ResultThere were significantly reduced levels of L‐ornithine in all three brain regions in both groups of dementia cases compared to the controls. Furthermore, the putrescine levels were significantly reduced in all brain regions examined in the FTD cases, and in the temporal cortex and hippocampus of the EOAD cases. In the hippocampus, there were increased L‐arginine levels, but decreased agmatine levels, in both the EOAD and FTD cases relative to the controls.ConclusionThis study demonstrates for the first time that brain arginine metabolism is altered similarly in both EOAD and FTD cases, and therefore suggests that altered L‐arginine metabolism may be a common mechanism involved in the neurodegenerative processes in these two early‐onset dementias. Further research is required to investigate the mechanisms for these metabolite changes and to explore the therapeutic potential of targeting L‐arginine metabolism in EOAD and FTD.
The effect of light exposure on cognitive outcomes at long term follow up in an at‐risk dementia population
Authors: Schrire Zoe M , Gordon Christopher J , Palmer Jake R , Mowszowski Loren , Michaelian Johannes C , Naismith Sharon L , Hoyos Camilla M 
Published: December 2023

AbstractBackgroundCircadian disturbances are a common occurrence in older adult population but are more prevalent in people with dementia. For some individuals, these occurrences begin many years prior to the onset of clinical symptoms and have been suggested as a potential risk factor. As light is the primary synchroniser of the circadian system, the current study aimed to examine if 14‐day light exposure could predict cognitive outcomes of older adults with varying risks of dementia at 2‐year follow‐up.MethodThe study was a retrospective analysis of 195 participants (age = 67, 60.7% female) who attended the Healthy Brain Ageing Clinic in Sydney. At baseline, participants were neurocognitively assessed and wore an actigraph for 14 days and then completed another neurocognitive test battery at their follow‐up. Binary logistic regression was used to determine if participants converted to either Mild Cognitive Impairment (MCI) or dementia was predicted from light exposure (average and maximum) and average time spent in >1000 lux (OR = 1.00), adjusting for age, sex and years of education. Linear regression was used to investigate the relationship between light variables and differences in verbal memory, processing speed and executive function composite scores from baseline to 2 years.ResultLight exposure at 2 years prior did not appear to predict cognitive performance. There was a trend towards moderate to bright light increasing risk of cognitive decline.ConclusionFurther research is needed to understand light exposure and the relationship to circadian rhythms and cognition. As previous light therapy research has been inconclusive, future research will inform treatment approaches.
Biomarker interplay between CSF p‐tau and 18F‐PI‐2620 PET in Alzheimer’s disease and 4R‐tauopathy
Authors: Dilcher Roxane , Wall Stephan , Franzmeier Nicolai , Katzdobler Sabrina , Barthel Henryk , Wagemann Olivia , Palleis Carla , Weidinger Endy , Fietzek Urban , Kurz Carolin Isabella , Ferschmann Chrsitian , Scheifele Maximilian , Eckenweber Florian , Zaganjori Mirlind , Gnörich Johannes , Danek Adrian , Bürger Katharina , Janowitz Daniel , Rauchmann Boris‐Stephan , Stöcklein Sophia , Perneczky Robert , Schoeberl Florian , Zwergal Andreas , Höglinger Günter , Bartenstein Peter , Villemagne Victor L , Seibyl John , Sabri Osama , Levin Johannes , Brendel Matthias 
Published: December 2023

AbstractBackgroundReliable biomarkers for detecting different abnormal tau protein isoforms between neurodegenerative diseases are currently missing. Phosphorylated tau (p‐tau) in the cerebrospinal fluid (CSF) is acknowledged as a 3/4R tau biomarker in AD but not in other tauopathies. The positron emission tomography (PET) radiotracer 18F‐PI‐2620 has the potential to detect abnormal 3/4R‐tau in patients with Alzheimer’s disease (AD) and 4R‐tau in Progressive Supranuclear Palsy (PSP) or Corticobasal Syndrome (CBS). This study investigates the interplay between tau‐PET and CSF p‐tau in AD and 4R‐tauopathies.MethodIn this cross‐sectional analysis, 52 patients with AD, 54 patients with PSP/CBS, and 11 controls underwent lumbar puncture and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. Independent t‐tests assessed group differences in standardized uptake value ratios for the 20‐40min time window (SUVr20‐40) and p‐Tau. Quantitative and voxel‐wise multiple regression analyses tested the association between SUVr20‐40 and p‐tau and group interactions, using R and SPM and controlling for age and sex. ROC analyses were performed to evaluate biomarker performance in differentiating patient groups.ResultPatients with AD showed elevated CSF p‐tau levels (p<0.05; >61 pg/ml) and SUVr20‐40 in temporal, parietal, occipital, frontal, cingulate‐insula, striatum, and amygdala (p<0.05). In patients with AD the two biomarkers correlated positively (p<0.05). Patients with clinically suspected 4R‐tauopathies did not show elevated p‐tau levels but demonstrated high tau‐PET uptake in the lentiform nucleus (p<0.05), compared to controls and AD. ROC analyses showed that temporal SUVr20‐40 (87.3%) and p‐tau levels (80.8%) were able to differentiate AD from 4R‐tauopathies, while the lentiform nucleus tau‐PET showed moderate performance at discriminated patients with 4R‐tau from those with AD (56.7%) and healthy controls (66.3%). Interestingly, the AUC increased to 70%, when excluding patients with CBS.ConclusionThe specific combination of CSF p‐tau levels and 18F‐PI‐2620 PET SUVR in disease‐specific regions facilitates biomarker‐guided stratification of AD and clinically suspected 4R‐tauopathies.
Comparative identification of Veterans with mild cognitive impairment or Alzheimer’s disease extracted from clinical notes and administrative data
Authors: Berlowitz Dan , Aguilar Byron J. , Li Xuyang , Shishova Ekaterina , Jasuja Guneet , Morin Peter J , Miller Donald R , O'Connor Maureen K. , Nguyen Andrew H. , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming 
Published: December 2023

AbstractBackgroundRegistries that identify people with mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) will be critical in targeting interventions to delay disease progression. Optimal methods to identify people for inclusion in such registries remain uncertain. We now compare approaches that rely on International Classification of Diseases (ICD)‐10 codes to the use of natural language processing (NLP) of clinicians’ notes.MethodWe used data from the Department of Veterans Affairs (VA) considering all Veterans aged 50 or older from the fiscal year 2019. People for the “ICD” cohorts were identified based on at least one code for either AD or MCI. For the “NLP” cohorts, we used electronic clinician notes and previously validated algorithms that search for keywords ("Alz*” or “Mild Cognitive Impairment”), excluding false positive cases identified through text screening such as “family history.” The number and overlap of people identified by the ICD‐ and NLP‐based approaches were compared.ResultOverall, 144,942 Veterans documented with either ICD coding or clinical notes using NLP as probable AD patients were identified; 32,498 (22.4%) people were identified by ICD codes and 141,816 (97.8%) people by clinical notes. Only 20.3% of the Veterans were identified by both clinical notes and ICD; 77.5% were identified by clinical notes alone and only 2.2% by ICD alone. In contrast, for the 134,699 Veterans with MCI, 95,324 (70.8%) people were identified by ICD codes and 79,232 (58.8%) people by clinical notes. Veterans identified by both ICD and clinical notes consisted of 29.6% of the sample, compared to 41.2% by ICD and 29.2% by clinical notes.ConclusionIdentification of patients with MCI or AD in electronic clinical notes using NLP is an alternative approach for developing a disease registry to the traditional methodology based on ICD coding in administrative databases. The differences in case identification between NLP‐ and ICD‐based approach may have reflected a clinical practice pattern in making clinical judgments regarding MCI and AD and documenting MCI and AD assessments in clinical notes as opposed to administrative records among the US Veterans.
Lipidomic dysfunction accompanied phosphatidylethanolamine deregulation is a potential detection biomarker and drug target for early Alzheimer’s disease of obesity population
Authors: Qi Shaohua , Yang Li , Li Xuping , Yin Zheng , Zhao Hong , Willa Hsueh , Xia Weiming , Wong Stephen T.C. 
Published: December 2023

AbstractBackgroundWhite adipose tissue in obesity produces bioactive factors associated with an unprecedented risk of cognitive impairment. Extracellular vehicles (EVs) mediate crosstalk between adipose tissue and central nervous system (CNS) of obese patients results in lipid dysfunction interweaved with numerous signaling pathways to affect CNS. Our study aims to uncover the biomarkers to reflect unbalanced lipid homeostasis during the early phase of Alzheimer’s disease (AD) and investigate novel targets for developing early‐stage AD therapeutics.MethodClinically collected human white adipose tissues from 7 lean and 12 obese donors were forward to gas chromatography‐mass spectrometry tandem analysis for lipidomic data acquisition. Principal component analysis, quantitative comparison, and systemic assay were applied to dissect and profile the lipidomic data and identified phosphatidylethanolamine (PE) as the absolute distinguishing index of obese individuals. More than 1,000 bioactive compounds were then screened and analyzed to identify hits that can recover the PE flux balance while simultaneously suppressed the expression of pathology proteins for early stage of AD. We selected a high‐ranking drug hit for validation with in vitro and in vivo systems, including the 3D Alzheimer’s disease in a dish (3DDS) assay and 3xTg and 5xFAD mice. Pathology and behavior assessments were performed to confirm the anti‐AD effect of the repositioned drug.ResultOur analysis indicates that the disturbance of PE homeostasis can serve as a potential biomarker to discriminate lipidomic dysfunction from healthy controls while PE also can be used to predict the conversion from mild cognitive impairment to AD. We screened our drug compound library and verified a known drug, ebselen, as a potential anti‐AD drug with in silico analysis and high content screening using 3DDS assay and transgenic mouse models. Pathology and behavior assessments with the AD mouse models generated robust evidence supporting the druggability of lipid homeostasis against early‐stage AD.ConclusionEVs mediated crosstalk between adipose tissue and CNS of obese patients in promoting cognitive impairment and mechanically disturbing lipid quiescent states in the CNS. Maintaining lipid homeostasis, particularly the PE level in the CNS via pharmacology strategy, would open up a new avenue for combating AD.
Response of the elderly to cognitive intervention through brainHQ training software; LatAm‐FINGERS Mexico
Authors: Martínez‐Galindo Joyce Graciela , Salinas‐Contreras Rosa Maria , Vigil‐Martinez Ana , Sosa‐Ortiz Ana Luisa 
Published: December 2023

AbstractBackgroundComputerized training has been used to improve cognitive functioning and has been shown to be effective in a wide range of populations. However, its use in elders can be complicated due to many factors including schooling, motivation, perception of difficulty and unfamiliarity with the technology. For the multidomain dementia prevention program LatAm‐FINGERS, the brainHQ software is being used to perform the cognitive training. The aim of this work is to show the perception of participants about this program.MethodTwenty‐five urban‐Mexican elders cognitively healthy but with risk factors for dementia, are receiving the cognitive training through brainHQ. They indicated in a 5‐point Likert scale (1 = low, 5 = high) how enthusiastic and fearful they felt to begin the training and how difficult it has been. They also reported if they used a smartphone, a computer or a tablet before and how comfortable they felt using it.ResultsParticipants were between 60‐77 years old, with an average age of 70.9 ± 4.7 years old and an average schooling of 9.33 ± 3.5 years, 56% were females. Most of the sample (92%) uses smart technology, mainly smartphones, but only 8% feels very comfortable using it, 55% reports regular comfort and 37% feels not comfortable at all. When asked about brainHQ training, over half of the sample (56%) reported high enthusiasm, 68% reported little fear and more than half reported some degree of difficulty (see figure 1). No significant differences between men and women were found. Using Spearman`s test, a significant negative correlation between schooling and perceived difficulty was found (rho = ‐.68, p = .03), but not between schooling and enthusiasm or fear.ConclusionIn general, the participants have a good attitude towards the use of brainHQ, although they reported not feeling very comfortable with the use of intelligent technologies, they were enthusiastic about starting the training, and most of them were not afraid. However, the perceived difficulty could hinder training, especially in those with less schooling, therefore, it is important to develop strategies that encourage them to continue with the program to obtain the benefits of computerized training.
The generalizability of proposed reference values for plasma neurofilament light chain in cognitively healthy adults in Thailand
Authors: Rianaree Juthamas , Anukoolwittaya Prakit , Hiransuthikul Akarin , Hemachudha Pasin , Hemachudha Thiravat , Thanapornsangsuth Poosanu 
Published: December 2023

AbstractBackgroundDespite being an established biomarker for quantifying neuroaxonal injury in research, the clinical utility of neurofilament light chain (NFL) for assessing individual patients is limited, primarily due to the confounding effect of aging on its levels. Although many studies reported age‐specific cutoff values in neurologically healthy population of European descent in high‐income countries, evidence suggests that the value of neurodegenerative biomarkers may differ in ethnically and socioeconomically underrepresented populations. In this study, we aimed to evaluate the acceptability of the reported NFL cutoff values for local clinical use by examining specimens from healthy Thai cohorts.MethodThis study enrolled participants without neurological disorder and normal cognitive examination from two distinct cohorts in Bangkok, Thailand, ranging in age from 40 to 90 years old. Plasma levels of NFL were quantified using the single molecule array. By utilizing reference data from previous studies (Simrén et al., 2022; Bornhorst et al., 2022), the proportion of participants exceeding the proposed cutoff values were estimated and compared to the expected values. Furthermore, the cohort was stratified by age group and methods similar to prior studies were employed to determine age‐specific cutoff values.ResultOne hundred and three participants were included, comprising of 69 females (67%), with a median age of 65.4 years (interquartile range (IQR): 56.7, 70.3) and a cognitive z‐score of 0.11 (IQR: ‐0.44, 0.63). Using the reference threshold from prior studies, plasma NFL were elevated in 4 participants (3.9%, 95% confidence interval: 1.0‐9.6%) which is consistent with the expected prevalence of 5% (as 95th percentile cutoffs were used). Subsequently, we determined age‐specific plasma NFL cut‐off values for each decade through quantile regression, values ranging from 7.2 pg/mL for 40‐50 years to 58.2 pg/mL for >80 years.ConclusionOur initial findings suggest that the previously established cutoffs for plasma NFL may be applicable in Thailand. Nonetheless, further studies with a larger and more diverse sample size may be necessary in order to fully validate the generalizability of these cutoffs and potentially establish more specific thresholds for local use.
Cognitive and sleep evaluation of Myotonic dystrophy type I: A protocol for a case‐control study
Authors: MISHRA RINKLE , Gupta Anu , Garg Divyani , Padma Vasantha , BHATIA ROHIT , Macken William L , Dalal Ashwin , Ahmad Tanveer , Reyaz Alisha , Pitceathly Robert D. S. , Thangaraj K , Hanna Michael G , Vishnu Venugopalan Y ,   ICGNMD Consortium
Published: December 2023

AbstractBackgroundMyotonic dystrophy type 1 (DM1) is one of the most common inherited muscular dystrophies in adults. It is caused by CTG repeat expansions in the 3' untranslated region (UTR) of the DMPK gene on Chromosome 19. Apart from muscle, the disease can involve the eye, heart, brain and endocrine system. Cognitive and sleep disturbances are common but poorly recognized non‐motor manifestations of DM1.MethodWe plan to recruit 30 genetically proven DM1 patients from the prospective MRC‐funded International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) cohort. Neuromuscular phenotyping will be done by the same neuromuscular expert. The muscle strength will be assessed by the Medical Research Council scale and Muscular Impairment Rating Scale (MIRS). We will exclude patients with severe depression. An age and sex‐matched control group of 30 healthy participants will be included to evaluate patients’ cognitive profiles. A comprehensive neuropsychological evaluation (NPS) to assess multiple cognitive domains will be conducted on all patients. A prescheduled sleep history, Epworth Sleepiness Scale (ESS), Pittsburg sleep quality index (PSQI) and full‐night diagnostic polysomnography will be done in all patients.ResultThe outcomes include the NPS domains comparing cognitive impairment compared to controls and the severity and type of sleep apnea (apnea‐hypopnea index [AHI])ConclusionThe study will investigate the DM1 cognitive profile and its relationship with sleep disturbance using motor scales, neuropsychological assessment and polysomnography.
Anatomical characterization of pT217‐tau in aged rhesus macaque association cortices: Relevance for trans‐synaptic propagation in sporadic Alzheimer’s Disease
Authors: Datta Dibyadeep , Mentone SueAnn , Morozov Yury , van Dyck Christopher H , Arnsten Amy F. T. 
Published: December 2023

AbstractBackgroundTau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network affecting the dorsolateral prefrontal cortex (dlPFC) with advanced neurodegeneration. Recent discoveries indicate that phosphorylated tau (pT217‐tau) can be captured in CSF and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixed monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in ERC and dlPFC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.MethodWe used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐33 years) to localize pT217‐tau in ERC layer II, which show the earliest signatures of tau pathology in AD and dlPFC layer III critical for working memory.ResultpT217‐tau immunolabeling was predominantly observed in postsynaptic compartments and accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy.ConclusionpT217‐tau accumulates in ERC and dlPFC subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to “seed” tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD.