bluuebunny/crossref_metadata_2025_split huggingface dataset:
A lightweight unsupervised approach for adverse health detection and digital biomarker discovery in people living with dementia
Authors: Bijlani Nivedita , Nilforooshan Ramin , Barnaghi Payam , Kouchaki Samaneh 
Published: June 2023

AbstractBackgroundSensor‐based remote health monitoring of persons living with dementia (PLwD) can be used to gain insights into their health and monitor the progression of their condition, with minimal intrusion. This helps minimize preventable hospital admissions, while allowing researchers to improve their understanding of dementia. Existing approaches for detecting activity and behavioural anomalies in PLwD are challenged by noise in data, lack of annotated datasets, multivariate data, scalability, data drift and explainability.MethodWe propose and evaluate a solution based on the Matrix Profile, an exact, ultra‐fast distance‐based anomaly detection algorithm, specifically the Contextual Matrix Profile (CMP), to detect anomalies that may indicate unusual activity and onset of UTI. Daily household movement data collected via passive infrared (PIR) sensors are used to generate CMPs from location‐wise sensor counts, duration and change in hourly movement patterns. We create CMP‐based multivariate anomaly detection models to generate a single daily normalized anomaly score for each patient. We discover digital biomarkers of anomalies and evaluate our method vs. three state‐of‐the‐art algorithms.ResultCMP‐based models yield up to 85% recall with only a 5% alert rate, when evaluated on a subset of 9363 days from 15 participant households with 41 clinically validated incidences of urinary tract infections (UTI) and hospitalization, collected by the UK Dementia Research Institute between August 2019 and July 2021. Our multidimensional CMP model offers the best balance of recall vs. anomalies raised, with excellent generalisation. We discover that bathroom early AM activity (midnight to 6 am) is the prime cross‐patient digital biomarker of anomalies. This validates findings in literature that unusual bathroom activity is a clinically significant feature in UTI for dementia. We also demonstrate a cross‐patient view of anomaly patterns.ConclusionWe address the need for anomaly detection and scoring using multivariate time series sensor data in remote health monitoring. The CMP allows configurability, ability to denoise and detect patterns, and explainability to clinical practitioners. With higher sensitivity, fewer alerts and better overall performance than state‐of‐the‐art methods, and the ability to discover digital biomarkers of anomalies, the CMP is a clinically meaningful unsupervised anomaly detection technique for dementia and beyond.
Integrated Mass Spectrometry‐based Pipeline for Characterization of Tau in Human Alzheimer’s Brain: Development and Comparison of Sample Preparation Methods
Authors: Azevedo Rita , Villain Nicolas , Boluda Susana , Fenaille François , Lamari Foudil , Becher Francois 
Published: June 2023

AbstractBackgroundTau protein aggregation into neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer’s disease (AD) and related tauopathies [1]. Though the mechanism of tau destabilization is not fully understood, tau protein exhibits several allele‐specific isoforms and post‐translational modifications (PTMs) specific to tau aggregates [2]. To explore in‐depth tau species in brain tissues of AD patients, we developed novel pipelines based on different tau fractions retrieved by buffer solubility, Filter Aided Sample Preparation (FASP) or immunoprecipitation, before high‐resolution mass spectrometry (HRMS) analysis.MethodAs a proof of concept, we used frozen brain samples from two AD patients (0.6‐1.2 g per replicate, middle frontal gyrus). The samples were divided and homogenized, ultracentrifuged at 180.000xg for 30min and solubilized in different buffers successively (2 replicates): (1) SarkMethodlow‐salt buffer, 10% Triton X‐100, sarkosyl buffer, and urea buffer; (2) RIPAMethodhigh‐salt buffer (twice), RIPA buffer and urea buffer; and, (3) GnHMethodguanidine hydrochloride and urea buffer. Then, we performed an antibody‐free approach by FASP or immunoprecipitation with a panel of commercial tau antibodies and analyzed on reversed‐phase capillary liquid chromatography, coupled with a qExactive HRMS.ResultHRMS demonstrated that the RIPA method performed better than the other methods for Tau analysis: coverage of 63% (full‐length, 2N4R) and 342 tau peptide‐spectrum matches (PSMs) (Sark: 49% and 183 PSMs; GnH: 41% and 169 PSMs). PTM‐modified tau species (phosphorylated, methylated, and acetylated) were primarily seen using the RIPA method (59 PSMs; Sark: 19 PSMs, GnH: 21 PSMs). Immunoprecipitation improved tau coverage and PTM detection compared to FASP.ConclusionThese findings highlight the best performance of the RIPA method followed by immunoprecipitation for the study of AD brain tau allele‐specific isoforms and PTMs using HRMS. Better characterization of Tau molecular profile in the brain of AD patients opens the gate for a better understanding of AD pathogenesis and represents an opportunity in the biomarker field.[1] Mroczko, B. et al. Int J Mol Sci 2019, 20, E4661, https://doi.org/10.3390/ijms20194661.[2] Boyarko, B.; Hook, V. Front. Neurosci. 2021, 15, 702788, https://doi.org/10.3389/fnins.2021.702788.
Biomarkers for the detection of progressive early Alzheimer’s Disease
Authors: Cai Yuan , Liu Wanting , Fan Xiang , Shi Lin , Au Lisa Wing Chi , Mok Vincent C.T. 
Published: June 2023

AbstractBackgroundWe investigated the ability of MRI, plasma, and cognitive biomarkers in detecting preclinical or prodromal Alzheimer’s Disease (AD) who will progress to the next syndrome stage of the cognitive continuum.Method589 subjects with longitudinal cognitive data were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which included 227 cognitive unimpaired (CU) and 362 mild cognitive impairment (MCI) subjects. Preclinical or prodromal AD was defined by a low amyloid beta (Aβ)42 (A+) and high phosphorylated ‐tau (p‐tau) (T+) on cerebrospinal fluid (CSF) assessment at baseline. The following baseline MRI biomarkers were derived by an automatic segmentation tool (AccuBrain®): AD‐resemblance atrophy index (AD‐RAI), quantitative medial temporal lobe atrophy (QMTA) and hippocampus volume (HV). Plasma biomarkers included p‐tau 181, neurofilament (NFL) and APOE ε4. Montreal Cognitive Assessment (MoCA) score was collected for all subjects at baseline. Conversion (C+) was defined as subjects progressed from CU to MCI and from MCI to dementia within 4 years.ResultsOf the 589 subjects (mean [SD] age, 72.2 [6.9] years; 314 men [53.3%]), 96 (16.3%) were A+T+C+ and 180 (30.6%) were A+T+C‐. In the ROC analysis, AD‐RAI achieved the best detection ability than other individual biomarker with a sensitivity of 83.4%, a specificity of 69.4% and an AUC of 87.8%. A combination of AD‐RAI, plasma p‐tau 181, APOE ε4 and MoCA score achieved the best detection ability with AUC of 89.8%, sensitivity of 85.1% and specificity of 80.2%. In the subgroup analysis, the combination of AD‐RAI, plasma p‐tau 181, APOE ε4 and MoCA score also showed good accuracy in identifying A+T+C+ subjects in the CU group (AUC = 87.6%) and in the MCI group (AUC = 89.3%).ConclusionA panel of MRI, plasma and cognitive biomarkers might help to detect progressive early AD subjects.
Resolvin E1 ameliorates diabetes‐related cognitive impairment via ChemR23
Authors: Zhang Jiawei , Zhao Yuwu , Wang Xiuzhe 
Published: June 2023

AbstractBackgroundDiabetes mellitus (DM) is an independent risk factor for cognitive dysfunction. The resolvin E1 (RvE1)/ChemR23 axis is involved in the progression and complications of DM. However, the impact of the RvE1/ChemR23 axis on diabetes‐related cognitive impairment remains unclear.MethodAging‐related behavioral changes in db/db diabetic mice and age‐matched nondiabetic controls were assessed, and changes of ChemR23 in the hippocampus were studied.ResultThe results showed that db/db mice exhibited age dependent learning and memory impairments in the Morris water maze test, along with reduced expression of ChemR23 in the hippocampus compared with age‐matched wild‐type mice. Moreover, neuronal damage, oxidative stress, and neuroinflammation were also observed in db/db mice. A moderate dose of RvE1 for 4 weeks elicited a significant reduction in memory loss, along with reduced neuronal damage, alleviation of oxidative stress, and attenuated neuroinflammation in diabetic mice but not in ChemR23‐knockout diabetic mice.ConclusionCollectively, our study suggested that RvE1 could ameliorate DM‐related cognitive dysfunction by reducing oxidative stress and neuroinflammation in a ChemR23‐dependent manner.
Establishing and validating unbiased cut‐offs for tau PET with Gaussian mixture model in Alzheimer’s disease
Authors: Quattrini Giulia , Ferrari Clarissa , Alchera Nicola , Ribaldi Federica , Garibotto Valentina , Frisoni Giovanni B , Pievani Michela , Marizzoni Moira 
Published: June 2023

AbstractBackgroundTau PET positivity (T+) is recommended in Alzheimer’s disease (AD) trials involving preclinical and prodromal AD. As unbiased cut‐offs are still lacking, we established and validated data‐driven T+ PET cut‐offs for AD.MethodData were from ADNI (estimation cohort) and Geneva memory center (validation cohort). 18F‐Flortaucipir standardized uptake value ratios (SUVr) were computed for a global temporal meta‐ROI and for cortical regions corresponding to Braak‐based stages I‐VI in amyloid negative (Aβ−) cognitively normal (CN), Aβ+ CN, Aβ+ MCI and AD. For Tau PET data‐driven cut‐off estimation, Gaussian mixture model (GMM) was applied on the global and regional SUVr distributions in Aβ− CN and AD (n = 269). The GMM cut‐offs’ performance was compared with published 18F‐Flortaucipir cut‐offs (Mattsson et al., 2017) by assessing the percentage of T+ subjects within each diagnostic group.ResultCut‐offs were 1.36 for temporal meta‐ROI and ranged 1.20‐1.39 for stages. In the validation cohort, all Aβ− CN were tau negative (T−), while T+ percentage increased along the Aβ+ continuum (CN<MCI<AD) for temporal meta‐ROI (33<64<75) and stages I‐II (50<73<75), III (17<55<58), IV (17<57<75), V (0<18<50) and VI (0<5<33). Previously published cut‐offs reported a higher frequency of T+ in the AD spectrum and identified T+ subjects in the Aβ‐ CN group.ConclusionGMMs unbiased 18F‐Flortaucipir SUVr cut‐offs showed lower T+ percentage in Aβ− CN than published cut‐offs, possibly indicating lower false positive rates and suggesting that they might be useful for the in‐vivo assessment of participants eligibility in future preclinical and prodromal AD trials.
Renal function affects circulating levels of neurofilament light chain: MarkVCID‐CHARGE
Authors: Aparicio Hugo J , Himali Jayandra Jung , Satizabal Claudia L. , Li Zhiguang , Mbangdadji Djass , Pase Matthew P. , Gonzales Mitzi M. , Ghosh Saptaparni , Gudnason Vilmundur , Beiser Alexa S. , Longstreth W.T. , Psaty Bruce M. , Fornage Myriam , Tracy Russell P. , Launer Lenore J. , Bis Joshua C , Seshadri Sudha 
Published: June 2023

AbstractBackgroundPlasma NfL is a promising fluid biomarker for risk stratification and quantifying the extent of neuronal injury in conditions such as vascular cognitive impairment and dementia (VCID) and Alzheimer’s dementia. However, systemic factors such as kidney function can affect circulating levels and this requires further investigation to ensure appropriate use as a biomarker.MethodWe examined the cross‐sectional association between plasma NfL levels and renal function among adult participants from four community‐based studies in the MarkVCID‐Cohorts for Heart and Aging Research in Genomic Epidemiology consortium who were free from stroke, multiple sclerosis, dementia, and renal failure. Estimated glomerular filtration rate (eGFR, mL/min/1.73m2) was calculated using the CKD‐EPI equation and categorized using Kidney Disease: Improving Global Outcomes (KDIGO) classification. Plasma NfL was measured using single molecule array technology. Multivariable linear regression models were used to investigate the linear relationship between eGFR and NfL, overall and stratified by KDIGO category. Study level estimates were combined in meta‐analysis. Models were adjusted for age, sex, sub‐cohort, hypertension, diabetes, body mass index, smoking, and race. Factors affecting eGFR can also cause MRI brain injury, hence we examined whether any apparent increase in NfL levels in persons with a lower eGFR merely reflected greater brain injury by performing a sensitivity analysis in a subsample with brain MRI, additionally adjusting in a single model for brain volume, white matter hyperintensities, and free water.ResultIn meta‐analysis (n = 5,954), lower eGFR was associated with higher plasma NfL (β = ‐0.0073, standard error[SE] = 0.0021, P = 0.0006). This relationship persisted within categories of reduced renal function, eGFR 60‐74 (mild), 45‐59 (moderate), and 15‐44 (severe) (P‐values<0.0001), but was not evident with normal eGFR ≥90 (P = 0.3) or mildly decreased eGFR 75‐89 (P = 0.2). Further adjustment for white matter hyperintensities, brain volume, and free water among a subgroup with brain MRI (n = 2192) did not change the associations of eGFR and NfL (β = ‐0.0065,SE = 0.0025, P = 0.0091).ConclusionReduced renal function is associated with higher circulating NfL, even at an eGFR range (60‐74) considered normal in clinical practice. Adjusting for renal function may improve the accuracy of plasma NfL as a biomarker for risk stratification or for assessment of neuronal injury in conditions such as VCID.
Aerobic exercise prevents white matter microstructural degeneration in MCI adults
Authors: Kim Jeongchul , Barcus Richard A. , Lipford Megan E. , Lockhart Samuel N. , Jung Youngkyoo , Craft Suzanne , Baker Laura D , Whitlow Christopher T. 
Published: June 2023

AbstractBackgroundWhile the use of non‐pharmacological interventions—such as physical activity, nutritional supplementation and cognitive stimulation—to prevent or delay cognitive decline and the onset of Alzheimer’s disease (AD) has received increasing attention, evidence supporting the benefits of these interventions have been mixed, and underlying mechanisms are not well‐understood.MethodIn participants enrolled in the PACE‐2 trial, which examined the impacts of 6‐month physical activity intervention on brain and cognitive outcomes, we evaluated the effects of aerobic exercise (n = 15, 63±10 yrs) on longitudinal changes in brain morphometry and white matter microstructure compared to stretching exercise controls (n = 17, 67±7 yrs.) using MRI among pre‐diabetic mild cognitive impairment adults. High‐resolution structural T1‐weighted and diffusion‐weighted images (DTI) were acquired before and after exercise intervention. Group differences in MRI markers (cortical volume and thickness, white matter DTI and free water metrics) after intervention and their longitudinal changes were compared for 68 cortical (Desikan‐Killany Atlas) and 48 white matter (JHU WM Atlas) regions using FreeSurfer SPM, FSL and Nextflow.ResultNo statistically significant group difference in cortical thickness, volumes and conventional DTI metrics was observed. On the other hand, free water (FW)‐corrected fractional anisotropy (FA) remained unchanged in aerobic exercise group (p = 0.32) while FA decreased in stretching controls in the right cerebral peduncle(p<0.001), resulting in group differences in FW‐corrected FA after 6‐month exercise intervention (p = 0.02 after Bonferroni correction). These changes in stretching exercise group were negatively correlated with FW fraction changes (marker related with neuroinflammation) (r = ‐0.71, p = 0.001).ConclusionAerobic exercise could have neuroprotective effects by preventing white matter degeneration, and FW fraction and FW‐corrected imaging markers could be useful for more sensitive detection of early AD sign.
Cholesterol‐related APOB Thr98Ile correlates with brain cortical APOB mRNA levels
Authors: Picard Cynthia , Aumont‐Rodrigue Gabriel , Poirier Judes 
Published: June 2023

AbstractBackgroundApolipoprotein B (APOB) is well‐known for its role in cholesterol metabolism. We recently showed that APOB protein levels are elevated in the CSF of patients suffering from sporadic Alzheimer’s disease (AD) compared to control individuals (Picard et al, Alzheimers Dement. https://doi.org/10.1002/alz.12442). Since rare coding APOB variants were discovered in association with early‐onset familial Alzheimer’s disease (Wingo et al, JAMA Neurol. 2019), we hypothesized that common APOB variants could influence molecular mechanisms leading to sporadic AD.MethodPublicly available genomic and transcriptomic data were screened for possible interactions between APOB single nucleotide polymorphisms (SNPs) and brain APOB mRNA levels. Potential regulatory SNPs were contrasted with blood cholesterol levels obtained from the Global Lipids Genetics Consortium (GLGC), in order to highlight their systemic effects. Brain tissue cholesterol levels were measured in frontal cortices of autopsy‐confirmed controls and AD subjects from the Douglas‐Bell Canada Brain Bank (DBCBB) using high performance liquid chromatography (HPLC). DNA extracted from those samples was used to perform APOB locus genotyping with the help of the Illumina Global Screening Array (GSA) chip.ResultThe APOB Thr98Ile variant commonly associated with familial hypercholesterolemia was found to correlate with a significant reduction of brain cortical APOB mRNA levels in three different cohorts. In GLGC cohort, this SNP strongly associates with elevated LDL‐cholesterol levels measured from blood samples of 188 578 individuals (p = 9.48E‐183). Our preliminary analysis shows that APOB Thr98Ile also correlates with elevated cholesterol levels (r2 = 0.36; p < 0.005) measured in brain cortical samples. Using public databases with available genotypic and AD‐related neuropathological data, inconsistent associations were found between APOB Thr98Ile variant and sporadic AD pathophysiological changes in the brain. Ongoing studies in our laboratory are examining the impact of APOB Thr98Ile variant on APOB mRNA and protein levels in relation to classical AD pathological markers in a large group of AD and control subjects.ConclusionAlthough APOB Thr98Ile is significantly associated with gene regulation and cholesterol levels measured in blood and brain samples, its effect on AD neuropathology remains to be clearly defined and is the subject of current investigations.
Plasma p‐tau181 for the differential diagnosis of cognitive impairment in a prospective, daily clinical practice cohort
Authors: Sarto Jordi , Guillén Núria , Ramos‐Campoy Oscar , Contador José , Fernandez‐Villullas Guadalupe , Tort‐Merino Adrià , Juncà‐Parella Jordi , Martínez Neus Falgàs , Borrego‐Écija Sergi , Ruiz‐García Raquel , Naranjo Laura , Vergara Miguel , Antonell Anna , Lladó Albert , Sanchez‐Valle Raquel , Balasa Mircea 
Published: June 2023

AbstractBackgroundCurrently used biomarkers for the differential diagnosis of cognitive impairment are expensive and/or relatively invasive, limiting their availability to the general population. Blood protein biomarkers have showed promising results for screening, differential diagnosis, and prognosis. We aimed to study the diagnostic performance of plasma p‐tau181 in a daily clinical practice, prospective memory clinic cohort.MethodAll patients referred for a first clinical evaluation with suspected cognitive impairment between January 1st, 2020 and March 30th, 2021, were invited to participate in the study. Plasma p‐tau181 was measured using SIMOA technology (Quanterix). Clinical diagnoses were made following current diagnostic criteria and blinded to plasma p‐tau181 results.ResultA total of 232 participants were recruited (mean age 69y, mean MMSE 24), including 25 cognitively unimpaired (CU) controls (mean age 67y, MMSE 28). Clinical diagnoses were AD (82 subjects, 43 of them with prodromal AD [CDR = 0.5]), 83 non‐neurodegenerative cognitive impairment (non‐ND, 75 of them CDR = 0.5), 22 frontotemporal dementia (FTD) and 20 Lewy body disease (LBD).Plasma p‐tau181 levels were statistically higher in AD (mean 2.39 pg/mL) compared with CU (mean 1.09 pg/mL), non‐ND (mean 1.43 pg/mL), FTD (mean 1.69 pg/mL) and LBD (mean 1.64 pg/mL) with a relatively good diagnostic performance for the differential diagnosis between AD and CU, non‐ND, LBD and FTD (AUC of 0.89, 0.80, 0.73 and 0.71, respectively).128 subjects (55% of the cohort) had specific AD biomarkers (CSF or PET) available. In this subgroup, p‐tau181 differentiated AD from CU and non‐ND (AUC 0.91 and 0.92, respectively) and prodromal AD from CDR = 0.5 non‐ND participants (2.32 vs 1.02 pg/mL, p<0.001, AUC 0.90). Plasma p‐tau181 discriminated between a positive and negative amyloid beta status (defined by CSF/PET) with an AUC of 0.87 and AD subjects from those with a clinical diagnosis of LBD and FTD who had a negative amyloid beta status (AUC of 0.94 and 0.86, respectively). Plasma p‐tau181 correlated with CSF p‐tau181 (rs = 0.48, p<0.001).ConclusionIn our cohort of everyday clinical practice, plasma p‐tau181 is an accurate biomarker for predicting the AD pathophysiological process and discriminating AD from other neurodegenerative and non‐neurodegenerative causes of cognitive impairment.
Early identification of cognitive impairment among vulnerable older adults living at home
Authors: Brown Maria Teresa , Brangman Sharon A 
Published: June 2023

AbstractBackgroundAfrican Americans are twice as likely as Caucasians to develop Alzheimer’s Disease and Related Dementias (AD/ADRD) and less likely to seek a diagnosis before experiencing a crisis. This study evaluated the impact of adding Mini‐Cog© screenings to Area Agency on Aging (AAA) assessments on early detection of cognitive impairment among low‐income older adults.MethodMini‐Cog™ assessments were offered to new and existing clients of a AAA Neighborhood Advisor. Clients with scores indicating impairment were referred to an academic geriatric practice for comprehensive evaluation. Inclusion criteria were age 65 or older, English speaking, living at home in the Advisor’s service area, and not previously diagnosed as AD/ADRD. Data collected over 9 months included Mini‐Cog™ scores, age, race, ethnicity, and geriatric referrals. Quantitative analysis included bivariate descriptive statistics (significance alpha of .10) and simple linear regression (significance alpha of .05).ResultsOf 69 study participants, 84% were female, 54% African American, and 93% non‐Hispanic. Mean age was 74.7 years and mean Mini‐Cog™ score was 3.61 (range: 0‐5). Independent t‐tests show that African American participants had lower Mini‐Cog™ scores than Caucasians (3.35±.23 vs 3.91±.22, p = .092). Caucasian males were younger with higher cognition scores than Caucasian women and African American males were younger with lower scores than African American females. Participants qualifying for referral (18 or 26%) were significantly older than those who did not (74.4 vs 70.0, p<.05). Of 11 participants offered referrals, all Caucasians (3) declined and 5 of 8 African Americans (62%) accepted. Regression analysis determined that Mini‐Cog™ scores were associated with older age (β* = ‐0.255, SE = 0.02, p<.05) and being African American (β* = ‐0.261, SE = .344, p<.05) but not with sex, ethnicity, or living alone.ConclusionResults show that 25% of participants were identified with previously undetected cognitive impairment and that trained social service providers can effectively administer the Mini‐Cog™ instrument to assess cognitive impairment. Large scale studies are needed to further evaluate use of the Mini‐Cog™ instrument in early detection of cognitive impairment in minority and economically vulnerable older adults in non‐clinical settings.