bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring a weighted composite score for harmonization of 18F‐MK6240 and 18F‐ Flortaucipir: linearity and correlations with cognitive measures in a head‐to‐head tau PET dataset – The HEAD Study
Authors: Finn Quentin , Povala Guilherme , Bauer‐Negrini Guilherme , Franco Andrea , Vo Tam , Lussier Firoza Z , Amaral Livia , Gordon Brian A. , Klunk William E , Lowe Val J. , Oh Hwamee , Rosa‐Neto Pedro , soleimani‐meigooni David N. , Baker Suzanne L. , Masdeu Joseph C. , Pascoal Tharick , Pascual Belen 
Published: January 2025

AbstractBackgroundHarmonization of the two most commonly used Tau PET tracers, 18F‐Flortaucipir and 18F‐MK6240 has proven to be complex. Unlike the centiloid scale for amyloid tracers, Tau PET SUVRs of the two tracers are not linearly comparable and vary markedly in dynamic range and sensitivity.MethodTau PET SUVRs for Braak stage (1‐6) in 18F‐MK6240 and 18F‐Flortaucipir were obtained from the Longitudinal multicenter head‐to‐head harmonization of tau‐PET tracers (HEAD) project. For training, we used 13 amyloid confirmed AD, 24 amyloid confirmed MCI and 66 amyloid negative controls. To assess linearity and correlations with neuropsychological tests, we included the training data as well as 74 subjects of unknown or inconsistent amyloid status. Two methods of generating outcome measures were used. (1) As a stand‐in for Tau load, similar to the centiloid scale, a score of 100, 50 or 0 was given to participants of the training set by multiplying CDR score by 100. Hierarchical and ridge regression were performed for each tracer using PET‐Braak SUVRs as predictive variables. Regression coefficients were used to calculate an outcome measure for all participants. (2) Principal component analysis (PCA) was applied for each tracer to the vectors of PET‐Braak regional SUVR of the training subset. Projections along the principal axis were calculated for both modalitiesResultHierarchical, ridge regression and PCA all yielded composite measures with good linear dependence between the two tracers (r2 for hierarchical, ridge and PCA were 0.84, 0.80, 0.80, respectively). Regions remaining in the hierarchical regression analyses varied between tracers: predictive regions for 18F‐MK6240 were PET‐Braak 1, 4 and 5, while 18F‐Flortaucipir used only PET‐Braak 1 and 5. Composite measures correlated well with MMSE and total MOCA score with all composite measures r < ‐0.61.ConclusionWhile both tracers may have different sensitivities to regional Tau distributions and disease stages, weighting multiple regions differently for each tracer gives a composite score linearly comparable across tracers that correlates with neuropsychological measures. This study is limited by the low total tau load and impairment level of all participants and would benefit from the inclusion of patients with more disease progression.
Acceptance of wearable technology for the early detection of dementia‐causing diseases: perspectives from the CODEC II cohort
Authors: Wilson Sarah , Beswick Emily , Morrell Rachel , Bhogal Sharandeep , Tolley Clare , Whitfield Tim , Wing Kieran , Ardle Ríona Mc , Walker Zuzana , Slight Sarah 
Published: January 2025

AbstractBackgroundWith global dementia prevalence estimated to reach 139 million by 2050,(1) early detection of dementia‐causing diseases is crucial for promoting preventative interventions. Wearable technologies have the potential to detect early signs; however, they need to be acceptable amongst users. We explored user’s perspectives on the acceptability of wearable devices.MethodA sub‐group of participants from a research cohort, Predictors of COgnitive DECline using digital devices (CODEC‐II), were recruited. Participants used four wearables (smartwatch, EEG headband, active and passive smartphone app) for two weeks every three‐months over a year. Semi‐structured interviews were conducted with participants after the first two weeks. A framework thematic analysis approach was used, assisted by N‐Vivo (QSR, version 14.23.2). The Intelligent Systems Technology Acceptance Model(2) aided in refining key themes.ResultTwenty‐one participants were interviewed, including those with subjective cognitive decline (n=10), mild cognitive impairment (MCI) (n=7), dementia with Lewy bodies (n=1), and caregivers (n=3). Key themes included ease of use, data security, usefulness, intention of use. Many participants expressed low digital self‐efficacy, relying on the research team for support with technology setup and troubleshooting. Those with MCI needed more assistance with synching data, and experience difficulty with some cognitive testing games in the active smartphone app. Some participants expressed concerns surrounding the potential for someone to hack data generated from their device. Others questioned the accuracy of the study smartwatch, as they compared its outputs to their personal ones. Participants with professional or caregiving responsibilities described how their busy lifestyle hindered their ability to use the active smartphone app every day; this was not expressed by retired individuals.ConclusionAcceptance of using different wearable technologies for the early detection of dementia‐causing diseases varied amongst participants. Researchers should consider the difficulty level of cognitive testing games for those with cognitive impairment. Future work must explore ways to support individuals with low digital self‐efficacy, ensuring digital health equity is supported.References:Prince et al., 2015, The global impact of dementia, World Alzheimer reportVorm and Combs, 2022, Integrating transparency, trust, and acceptance: The intelligent systems technology acceptance model (ISTAM). International Journal of Human–Computer Interaction.
Application of a Plasma Amyloid Beta Test in Clinical Practice
Authors: Pavlik Valory , Yu Melissa , Lin Chi‐Ying Roy , Yonce Shayla 
Published: January 2025

AbstractBackgroundThe gold standard Alzheimer’s disease (AD) diagnosis with amyloid PET or CSF sampling is costly and not widely available. There is growing interest in utilizing plasma biomarker tests to provide etiologic clarity in the earliest symptomatic phases. We report the uptake, and biomarker results in relation to clinical diagnosis, of a brain amyloid probability score (APS) with the Precivity AD™ test (C2N Diagnostics) offered to clinician‐selected eligible patients during their clinical workup in a memory clinic.MethodEligibility criteria included: MMSE>=22, a CDR global score <=1.0, and a diagnosis of subjective memory complaint (SMC), mild cognitive impairment (MCI) or early AD. Consensus clinical diagnoses were assigned according to NIA‐AA criteria prior to obtaining PrecivityAD™ results. The APS, derived from a regression equation including plasma Aß42/ 40, age, and APOE genotype, has a reported accuracy of 86%. To identify selection factors for referral, we used logistic regression to assess the independent association of age, sex, race/ethnicity, years of education, MMSE score, number of APOE e4 alleles, and diagnosis between participants and a sample of non‐participating patients meeting the same eligibility criteria.ResultSixty patients were consented over 9 months. Average age was 70.8±8.06, 60.0% were male, and 11.3% persons of color. Fifty‐five percent of those with MCI received a high APS, compared to 15.4% of those with SMC. Forty‐one percent of MCI patients had a low APS compared to 61.5% with SMC (Table 1). Only a diagnosis of probable AD was associated with enrollment (less likely).ConclusionPrecivityAD™ probability scores were generally consistent with the clinical diagnosis. An intermediate or high APS required clinician counselling regarding the implications of and indications for further testing given the clinical diagnosis. The high representation of SMC patients may reflect provider and/or patient desire for additional information on prognosis. The low usage in patients with probable AD may reflect a greater degree of provider certainty in clinical diagnosis. Longitudinal follow‐up of cognitive changes, and analysis of PET imaging results in those referred for additional testing will clarify the clinical utility of this plasma biomarker.
Intranasal lithium in Ryanodex formulation vehicle inhibits inflammation and pyroptosis in aged 5XFAD mice brains
Authors: Bhuiyan Piplu , Zhang Wenjia , Chae Rebecca , Kim Kyelee , St. Louis Lauren , Wang Ying , Liang Ge , Liu Jia , Wei Huafeng 
Published: January 2025

AbstractBackgroundThis study investigates the therapeutic versus side effects of intranasal lithium chloride (LiCl) in Ryanodex formulation vehicle (RFV) to inhibit inflammation and pyroptosis and to ameliorate on cognitive dysfunction and depressive behavior in 5XFAD mice.Method5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or oral LiCl (3 mM/kg) dissolved in RFV starting at 2 or 9 months old and the continuous treatment lasted for 12 weeks. Behavior was examined for depression, cognition, olfaction, and motor function at the ages of 5 or 12 months. Body weights were monitored monthly. At 6 or 13 months old, blood and brain were harvested. Blood biomarkers for thyroid (TSH: thyroid stimulating hormone) and kidney (creatinine) function were measured by ELISA. Immunoblotting determined the proteins expression levels of type 1 InsP3 receptors (InsP3R‐1), oxidative stress (4‐HNE, MDA), pyroptosis activation pathway regulatory proteins, proinflammatory versus neuroprotective cytokines, and synaptic proteins in aged mice brains.ResultCompared to WT mice, significant memory loss and depression behavior existed in both adult and aged 5XFAD mice, and both were abolished by intranasal LiCl in RFV Intranasal LiCl in RFV significantly inhibited the pathological proteins increase of InsP3R‐1, MDA‐modified proteins by pyroptosis pathway activation proteins (NLRP3, cleaved caspase‐1, N‐terminal GSDMD) in aged 5XFAD mice brains, in comparison with aged WT mice brains. Furthermore, intranasal LiCl in RFV significantly reduced protein levels of cytotoxic cytokines (IL‐1β, IL‐18, IL‐6, TNF‐α), alleviated the activation of astrogliosis and microgliosis, and increased cytoprotective cytokine IL‐10 and inhibited PSD‐95 synapse protein loss in aged 5XFAD mice brain. Intranasal LiCl did not affect blood TSH but significantly inhibited abnormal age‐dependent increase of blood creatinine in 5XFAD mice. Intranasal LiCl in RFV did not affect body weight, smell, or motor function significantly in either WT or 5XFAD mice.ConclusionIntranasal LiCl in RFV ameliorates memory loss and depressive behavior in 5XFAD mice without side effects or organ toxicity, with chronic use. Intranasal LiCl in RFV effectively inhibited, oxidative stress, inflammation and pyroptosis in aged 5XFAD brains.
MRI Correlates of Executive Function in Cognitively Normal Older Subjects
Authors: Shakibajahromi Banafsheh , Dolui Sudipto , Brown Christopher , Taghvaei Mohammad , Khandelwal Pulkit , Wu Qichao , Sadaghiani Shokufeh , Yushkevich Paul A. , Wolk David A , Detre John A. 
Published: January 2025

AbstractBackgroundCerebral small vessel disease (CSVD) is the most prevalent cause of vascular cognitive impairment. Executive function impairment and white matter (WM) lesions occur early in CSVD, the latter typically in periventricular WM (PVWM) ‐ the least perfused brain region. Accounting for vascular risk factors (VRF) and amyloid status in cognitively normal older subjects, we assessed the relationship between Trail‐making test (TMT) performance and MRI measures preceding WM lesions: arterial spin labeling (ASL)‐derived cerebral blood flow (CBF) and diffusion tensor imaging (DTI) indices in normal‐appearing WM (NAWM) and normal‐appearing PVWM (NAPVWM).Method133 cognitively normal adults (>50y) from Penn Alzheimer’s Disease Research Center were included. TMT:B minus TMT:A (TMT:B‐A) was used as a metric of executive function. We categorized participants into amyloid‐positive (A+) and amyloid‐negative (A‐) groups based on PET. VRFs included hypertension, diabetes, obesity, hypercholesteremia and smoking. WM hyperintensity (WMH) masks were derived from FLAIR MRI using a deep‐learning model to calculate WMH volume and to mask WMH voxels. We extracted mean CBF and DTI indices (fractional anisotropy (FA) and mean diffusivity (MD)) in NAWM and NAPVWM using a perfusion‐based PVWM mask. NAPVWM relative CBF (rCBF) was defined relative to global CBF. Using linear regression, we assessed the associations of TMT:B‐A with VRF presence and imaging metrics in each group adjusting for age, sex and education. The relative importance of these variables was measured through random forest regression.ResultThe mean (SD) age was 70 (6) with 64% females. 23 subjects were A+ and 79 were A‐. Neither VRF presence nor imaging metrics were significantly associated with TMT:B‐A in A+ group. In A‐ group, after adjustment for covariates, VRF (Beta= 0.319, P=0.009), NAPVWM rCBF (Beta= ‐0.240, P=0.035)), NAWM MD (Beta=0.266, P=0.022) and NAPWM MD (Beta=0.255, P=0.029) were significantly associated with TMT:B‐A. WMH volume was not associated with TMT:B‐A (P= 0.668). In A‐ group, NAPWM MD and NAPWM rCBF were the most important determinants of TMT:B‐A relative to the other variables in the random forest model (Figure 1).ConclusionCBF and MD in NAPVWM are associated with executive function in normal aging and might be an early biomarker of CSVD.
Acceptance of using digital technologies to aid the timely detection of dementia: perspectives from Boston University Alzheimer’s Disease Research Centre
Authors: Beswick Emily , Wilson Sarah , Popp Zachary T , Rahman Salman , Khan Raiyan R , Tolley Clare , Low Spencer , Slight Sarah 
Published: January 2025

AbstractBackgroundUsing digital technologies to detect the early signs of dementia‐causing diseases could improve the timely detection of these diseases. To support this approach, we explored users’ perspectives on the acceptability of using a variety of digital technologies.MethodA sub‐group of participants from Boston University’s Alzheimer’s Disease Research Centre were recruited. Participants used up to nine study technologies (active smartphone apps (n=3), passive apps (n=2), wrist worn activity monitor (n=2), EEG headband (n=1), Oximeter ring (n=1)) for two weeks, every three‐months, over a year. Semi‐structured interviews were conducted after the first two weeks. A framework thematic analysis approach was applied to the interview transcripts, assisted by N‐Vivo (QSR, version 14.23.2). The Technology Acceptance Model(1) aided in refining key themes.ResultTwenty‐four individuals were interviewed: 13 with mild cognitive impairment (MCI) and 11 without cognitive impairments. Three key themes emerged; perceived usefulness, intention to use and enjoyment of use. Participants were excited about the possibility of using digital technologies to remotely monitor their brain health, but some raised concerns that this could reduce personal interaction with their healthcare professional. Participants with pre‐existing health conditions, questioned the accuracy of the technology. For example, a participant wondered what effect an oxygen mask used for sleep apnoea would have on the data collected from the oximeter ring, reducing their perceived usefulness of the devices. Many participants using seven or more devices reflected on the burden of using multiple devices, finding it was challenging to familiarise themselves with them and then remember to use them all. Participants with MCI enjoyed the cognitive stimulation they felt after using the gamified cognitive tasks in the active smartphone apps, whereas participants without cognitive impairment wanted more variety to improve engagement.ConclusionResults highlight the acceptability of a variety of digital technologies for the timely detection of dementia‐causing diseases and discussed the burden of using multiple devices. Future research should explore how pre‐existing health conditions could affect the accuracy of digital technologies to improve real world applicability.ReferencesDavis FD. Perceived usefulness, perceived ease of use, and user acceptance of information technology. MIS quarterly. 1989 Sep 1:319‐40.
Genome‐wide mediation analysis reveals amyloid and tau imaging genetics patterns in Alzheimer’s Disease
Authors: Mu Shizhuo , Rathore Saima , Bao Jingxuan , Yang Shu , Hooli Basavaraj , Shen Li ,   for the ADNI
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurological disorder with an unclear cause, and its amyloid and tau hypotheses need deeper investigation to understand their link to genetic variants and AD outcomes. To bridge this gap, we conduct a mediation analysis using the genotyping, amyloid and tau imaging, and cognitive data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) to delineate specific mediation pathways from genetic variants such as single nucleotide polymorphisms (SNPs), to regional amyloid/tau protein aggregation in the brain, and to cognitive outcomes.MethodADNI provides genotyped data and harmonized phenotypes. We further imputed, harmonized, annotated the genotyping data. Post‐quality control and subject matching resulted in 1,051 individuals for amyloid and 525 for tau imaging measurements. We first conducted genome‐wide association study (GWAS) on 5,302,064 variants to prioritize SNPs significantly associated with cognitive scores. Subsequently, we employed a mediation model to explore how regional amyloid and tau imaging measures mediate the genetic effects on cognitive scores. Specifically, we used prioritized SNPs from GWAS as exposure, two cognitive scores (ADAS‐Cog13 and MMSE) as outcomes, and amyloid and tau imaging measures from 68 cortical regions as mediators. Additionally, we contrasted results from GWAS‐identified SNPs with five candidate AD SNPs.ResultWe assessed amyloid and tau aggregation in 68 cortical brain regions as mediators for SNP effects on cognitive scores; see Figure 1 for top findings. After Bonferroni correction, we found 9,551, 34,402, 5,636, and 193,002 mediation relationships for SNP‐amyloid‐ADAS13, SNP‐amyloid‐MMSE, SNP‐tau‐ADAS13, and SNP‐tau‐MMSE respectively. Tau aggregation demonstrated a broader impact on AD across cortical regions compared to amyloid. Although 4 of the candidate AD SNPs showed no signal, one of them, rs429358, demonstrated strong amyloid and tau mediated genetic effects on cognitive outcomes. Our results also showed that amyloid and tau hypotheses have different regional mediation patterns (Figure 2). For example, bankstss region only influences the tau pathway, while caudal anterior cingulate only affects the amyloid pathway.ConclusionOur genome‐wide mediation analysis has identified top cortical regions and SNPs associated with amyloid‐ and tau‐mediated cognitive declines in AD. These results yield new insights into AD etiology linking genetic determinants, cellular hallmarks, and phenotypic outcomes.
First GPR39‐imaging radiotracer to track zinc homeostasis in a rodent model of Alzheimer’s disease
Authors: Gollepalli Krishna Kumar , Bhoopal Bhuvanachandra , Damuka Naresh , Krizan Ivan , Miller Mack , Kumar JV Shanmukha , Bashetti Nagaraju , Whitlow Christopher T , Lockhart Samuel N. , Jadiya Pooja , Sai Kiran K. Solingapuram 
Published: January 2025

AbstractBackgroundThe G protein‐coupled receptor GPR39 is heavily associated with the pathogenesis of neurologic disorders, including Alzheimer’s disease (AD) and related dementia (ADRD). Its dysregulation of zinc 2+ (Zn2+) processes triggers metallic dyshomeostasis, oxidative stress, neuroinflammation, microtubule destabilization, synaptic dysfunction, and tau phosphorylation—all hallmarks of neurodegeneration. Hence, pharmacologic modulation of GPR39 could offer an effective treatment against AD and ADRD. With the right radiotracer, PET could be used to quantify GPR39 in brains in vivo and track distribution, target engagement, and dose occupancy of novel GPR39‐based agonistic drugs to regulate Zn2+ (dys)homeostasis function. In this abstract we report the development and validation of the first PET radiotracer, [11C]TMN‐1324 to image GPR39 in rodent models of AD.MethodGPR39 agonist TM‐N1324, was selected as the lead compound for its brain penetration and high GPR39 affinity—acts with and without Zn2+ to both human and rodent GPR39s. To validate [11C]TM‐N1324 imaging potential, we performed 0‐60 min dynamic PET imaging and post‐PET biodistribution with [11C]TM‐N1324 in (a) normal C57BL/J mice (4 mo, n=4) and (b) male Aβ‐overexpressing APP/PS1 transgenic (TG) mice and age‐matched wild‐type (WT) mice (12 mo, n=4/group). Brain autoradiography investigated regional uptake in the same cohort. TM‐N1324 blocking studies (n=4) confirmed in vivo GPR39 specificity of the radioligandResultRadiochemistry was fully optimized for high radiochemical purity (>98%) and molar activity (>48635 MBq/µmol) decay corrected to end‐of‐synthesis. PET imaging of rodents showed brain penetration and ∼65±4% blocking with TM‐N1324 pretreatment. It demonstrated ∼22±3% lower brain uptake in APP/PS1 TG mice compared to WT littermates (Figure 1). Autoradiography showed significant uptake in cortical regions (high GPR39‐expressing regions). Biodistribution showed ∼33±1% lower brain uptake in TG mice than WTs.ConclusionOur pilot study here with the first GPR39‐imaging PET radiotracer, [11C]TM‐N1324 demonstrated brain penetration, differential uptake in mouse model of AD, and regional specificity. By validating our highly specific GPR39 PET radiotracer for studying Zn2+‐based dyshomeostasis, we will elucidate GPR39 PET imaging strategies to monitor target responses to potential novel therapeutics.
Critical Modifying Effect of APOE 4 Allele and Sex on the Prospective Associations between Lipid Species and 10‐year Cognitive Decline in Biracial Community‐dwelling Older Adults: the Chicago Health and Aging Project (CHAP)
Authors: Ng Ted K.S. , Beck Todd , Liu Xiaoran , Desai Pankaja , Holland Thomas Monroe , Dhana Klodian , Krueger Kristin R , Wilson Robert S. , Evans Denis A , Rajan Kumar B 
Published: January 2025

AbstractBackgroundThere have been contradictory findings on the associations between lipids and cognitive decline, which could have been attributed to heterogeneity in APOE allele and sex.MethodWe analyzed a subset of the Chicago Health and Aging Project, comprising 3,496 biracial community‐dwelling older adults (58% African American & 64% women; mean follow‐up=4.6 years) with lipid panel and longitudinal cognitive tests. We ran adjusted mixed‐effects models and examined APOE allelic and sex differences.ResultTotal cholesterol and triglycerides, independently, was associated with longitudinal cognitive decline only in ε4 carriers. The associations of total cholesterol and, independently, triglycerides with longitudinal cognitive decline was driven by men and women ε4 carriers, respectively. LDL was associated with cognitive decline only in men ε4 carriers.ConclusionThe associations of lipids and cognitive decline were only present in ε4 carriers and are further dependent on and diverged according to sex, highlighting their importance in risk prediction and treatment. Hence, apart from examining lipid panel, it is critical to simultaneously consider APOE 4 status and sex to better inform precision medicine, particularly risk prediction and treatment.