bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Two Plasma pTau217 Simoa Assays Against Amyloid‐PET
Authors: Figdore Daniel , Bornhorst Joshua A , Graff‐Radford Jonathan , Vemuri Prashanthi , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Algeciras‐Schimnich Alicia 
Published: January 2025

AbstractBackgroundTau phosphorylated at threonine 217 (pTau217) is one of the most promising blood‐based biomarkers of Alzheimer’s disease (AD). This study compares the performance of two plasma pTau217 immunoassays on the Simoa platform for detection of abnormal amyloid‐PET.MethodPlasma samples from 112 individuals without cognitive impairment and 114 with mild cognitive impairment (MCI) or AD related dementia were evaluated. Testing was performed on the Quanterix Simoa® HD‐X Analyzer using the ALZpath Simoa® pTau217 and the Simoa® ACC pTau217 (Janssen antibodies) commercial assays. Amyloid‐PET imaging was performed using 11C‐Pittsburgh Compound B and a standard uptake value ratio (SUVR) cutoff of ≥1.52 (≥25 Centiloid) was used for abnormal (n= 147) vs. normal (n= 79) classification. Passing‐Bablok regression analysis and Spearman’s correlation coefficient (rho) were used to estimate bias and correlation between the assays, respectively. Correlation of each assay with Amyloid‐PET SUVR was evaluated. Amyloid‐PET status as the outcome and plasma pTau217 as predictor was used to estimate the area under the receiver operating characteristic (ROC) curve (AUC).ResultThe pTau217 concentrations between the two assays showed an excellent correlation (Spearman’s rho= 0.94 [95% CI= 0.93 to 0.96, p<0.0001]). However, the Passing‐Bablok regression analysis equation for ALZpath (x‐axis) and ACC (y‐axis) was y= 0.1324x ‐ 0.0019, showing that measured pTau217 concentrations with the ALZpath assay were higher (∼87%) than with the ACC assay (concentrations ranged 0.057 to 3.5 pg/mL and 0.003 to 0.5 pg/mL, respectively). Correlations between amyloid‐PET SUVR and the two pTau217 immunoassays were almost identical with Spearman’s rho= 0.70 (95% CI= 0.62 to 0.76, p<0.0001) for ALZpath and 0.69 (95% CI= 0.61 to 0.75, p<0.0001) for ACC. The AUC for detection of an abnormal amyloid‐PET among the MCI/AD group was 0.88 (95% CI= 0.81 to 0.95) for ALZpath, and 0.89 (95% CI= 0.83 to 0.96) for ACC.ConclusionAnalytically, the two Simoa® pTau217 assays correlate well with each other, but results are not interchangeable due to a significant proportional bias. Clinically, the performance of the assays was largely equivalent for the detection of abnormal amyloid‐PET by AUC analysis based on their almost identical correlations with amyloid‐PET SUVR.
Serotonin 5‐HT2C receptor agonism in presymptomatic APP/PS1 mice rescues seizure‐induced premature mortality Perhaps we just plainly state what is happening
Authors: Sanz Aaron Del Pozo , Davidson Stephanie , Barker‐Haliski Melissa 
Published: January 2025

AbstractBackgroundSeizures in Alzheimer’s Disease (AD) are increasingly recognized to occur and can increase cognitive decline and reduce survival compared to unaffected age‐matched peers (Lyou et al. 2018). Administration of antiseizure medicines (ASMs) to AD patients with epileptiform activity may improve cognition (Vossel et al. 2021), yet whether ASMs also beneficially confer long‐term survival benefits in AD is unknown. We have reported that young (presymptomatic) APP/PS1 mice exhibit enhanced chronic focal seizure susceptibility and premature seizure‐induced mortality, which is associated with dysregulated hippocampal serotonin system tone (5‐HT), altered neuroinflammation, and elevated soluble β‐amyloid (Aβ) levels (Del Pozo et al, 2024). We thus hypothesized that lorcaserin, a selective 5‐HT2C receptor agonist, and cannabidiol, a broad‐spectrum anti‐inflammatory and 5‐HT modulating ASM would reduce seizure susceptibility and seizure‐induced excess mortality by attenuating inflammation and normalizing 5‐HT system dysregulation in kindled presymptomatic APP/PS1 mice.MethodsMale and female 2‐month‐old APP/PS1 and their wild‐type (WT) littermates underwent corneal or sham kindling, a model of chronic focal seizures (Beckman et al. 2020), for 15 days until achieving criterion (N = 8/group/sex). APP/PS1 mice received either lorcaserin [10 mg/kg, (b.i.d.)], cannabidiol [100 mg/kg (q.d.)], or vehicle (VEH) i.p. during kindling. Seizure acquisition and survival were quantified. Kindling‐induced changes in soluble Aβ levels in isolated hippocampus were then measured by western blot. Neuroinflammation was quantified by immunohistochemistry.ResultsWhereas lorcaserin administration in neither male nor female APP/PS1 mice did not affect seizure severity or kindling versus APP/PS1‐VEH, cannabidiol administration blunted female kindling rate. Both male and female APP/PS1 mice treated with lorcaserin exhibited significant improvements in survival. Despite effects on seizure burden in males, an opposite effect of treatment occurred on mortality: only cannabidiol effectively prevented excess seizure‐induced mortality of APP/PS1 mice. The extent of neuroinflammation and other pathological AD hallmarks (soluble Aβ) will be further discussed.Conclusion5‐HT2C agonism rescues seizure‐induce premature mortality independently of direct effects on seizure susceptibility in APP/PS1 mice. CBD shows a sex‐dependent effect, only reducing male seizure‐induced mortality. These results support the use of pharmacological reduction of neuronal hyperexcitability as a strategy to modify disease burden and improve long‐term outcomes in AD.
Phosphorylated tau is more closely associated with the spatial extent of tauopathy than with tau load
Authors: Macedo Arthur C. , Rahmouni Nesrine , Therriault Joseph , Wang Yi‐Ting , Servaes Stijn , Tissot Cécile , Hall Brandon J , Arias Jaime Fernandez , Socualaya Kely Monica Quispialaya , Trudel Lydia , Lussier Firoza Z , Brum Wagner Scheeren , Zimmer Eduardo R. , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Ashton Nicholas J. , Benedet Andrea L. , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Pascoal Tharick A. , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundRecent evidence indicated that cognitive impairment is more closely associated with the spatial extent of tauopathy (SEOT) than with tau load. It remains unclear whether this is also true for other markers of Alzheimer’s disease (AD) severity, such as fluid levels of phosphorylated tau (pTau). Here, we compared the link between fluid pTau and the SEOT and tau load in the brain, as assessed by PET.MethodWe studied individuals across the aging and AD continuum or with non‐AD neurodegenerative diseases from the TRIAD and ADNI cohorts. TRIAD participants underwent [18F]MK6240 tau‐PET and CSF and plasma pTau 181, 217, and 231. ADNI participants were evaluated with [18F]AV1451 tau‐PET and CSF pTau181. We calculated standard uptake value ratios (SUVR) as a proxy of tau load, and the proportion of abnormal voxels as a measure of the SEOT. Abnormal voxels were those 2.5 SD higher than the mean of a group of young adults. Spearman’s correlations assessed the associations of pTau with SEOT and tau load in a temporal meta‐region of interest (ROI) and Braak‐like cumulative ROIs. Correlation coefficients were compared in R using the cocor package.ResultWe included 325 participants from TRIAD (mean [SD] age, 68 [9.8] years) and 417 from ADNI (mean [SD] age, 71.8 [9.0] years). All pTau biomarkers showed significant correlations with SEOT and tau load in all ROIs (Figure 1A‐B). All pTau epitopes were more closely associated with SEOT than with tau load in Braak I‐V and I‐VI (Figure 2). In TRIAD, this was also observed in Braak I‐III and I‐IV for CSF pTau 217 and 231, and in Braak I‐II for plasma pTau 231. In ADNI, this was also seen for CSF pTau181 in Braak I‐II and I‐III. Tau load did not correlate better with pTau in any ROI.ConclusionPTau biomarkers seem to inform better on SEOT than on tau load. There is a trend for better performance of SEOT as an imaging correlate of pTau when studying late Braak stages. Future studies should investigate the relationship between these measures and the clinicopathological progression of AD.
Plasma biomarkers are stable for an extended period at –20°C: Implications for resource‐constrained environments
Authors: Ayele Biniyam A. , Whitehead Patrice L. , Gu Tianjie , Arvizu Jamie , Golightly Charles G. , Adams Larry D. , Pericak‐Vance Margaret A , Vance Jeffery M. , Griswold Anthony J. 
Published: January 2025

AbstractBackgroundThe Recruitment and Retention for Alzheimer’s Disease Diversity Cohorts in the Alzheimer’s Disease Sequencing Project (REAAD‐ADSP) aims to explore ADRD in diverse ancestral groups within the US and nine countries from sub‐Saharan Africa. While most laboratories store plasma samples ‐80°C for biomarkers, no studies at –20°C have been reported past 2 weeks. Only two sites in Africa possess ‐80°C freezers. As biomarkers can be frozen and thawed, we hypothesized they would be stable at –20°C. The present study was designed to investigate the stability of AD plasma biomarkers at –20°C over time to facilitate studies of plasma biomarkers in resource‐constrained regions.MethodsPeripheral blood was collected from six anonymous volunteers. Plasma was isolated via centrifugation and 200mL aliquots of plasma were made. Two aliquots per participant were stored immediately at ‐80°C and others at ‐20°C for two, four, six and fifteen weeks then moved to ‐80°C. Plasma biomarkers, pTau181 and Aβ42, Aβ40, NFL, and GFAP, were measured for each time point. Each aliquot was run in duplicate in the assay plate and two aliquots per participant per time point were assayed.ResultsThere was a range values at baseline for each biomarker across the six participants: pTau181: 1.6‐3.0pg/mL, Aβ42: 3.7‐6.3pg/mL, Aβ40: 56.2‐106.6pg/mL, NFL: 3.5‐14.9pg/mL, GFAP: 42.9‐71.1pg/mL. At week fifteen, the average change in pTau181 was 0.14pg/mL, less than a 10% overall change. The Aβ42/40 ratio showed a decrease of 3.6% in week 15 compared to the baseline. Variability in NFL and GFAP were higher with increases in all subjects in week 15. Such run variance has been noted for these biomarkers by the manufacturer, thus our results suggest that after fifteen weeks at ‐20°C the assays are performing within specifications.ConclusionUp to 15 weeks of storage of plasma at ‐20°C does not significantly change AD related plasma biomarker concentrations beyond assay specifications, though there are slight increases in GFAP and NFL. This suggests that locations lacking ‐80°C storage can utilize ‐20°C equipment and still maintain biomarker fidelity, allowing for greater representation of biomarker studies from low‐ and middle‐ income countries, increasing the diversity of studies in AD.
Neuroticism and risk of all‐cause dementia, Alzheimer’s disease, and vascular dementia: exploring modification by genetic risk and mediation by vascular and mental health
Authors: Gao Yaqing , Amin Najaf , Van Duijn Cornelia M , Littlejohns Thomas J 
Published: January 2025

AbstractBackgroundNeuroticism is a personality trait that is typically stable across the life course. Higher neuroticism has been linked to a higher risk of developing dementia in studies primarily consisting of small sample sizes. There is a need to explore the association in larger populations, whilst uncertainty remains regarding the mechanisms driving the associations.MethodWe selected 174,164 participants aged 60 years or older who were dementia‐free at baseline from the UK Biobank cohort. Cox proportional‐hazards models were used to assess the association between standardized neuroticism score (z‐score) with risk of all‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Models were adjusted for age, sex, ethnicity, Townsend‐deprivation index, education, smoking status, alcohol intake, and body mass index. We investigated effect modification by genetic predisposition for dementia and mediation through mental and vascular health conditions. The association between neuroticism and dementia‐related neuroimaging outcomes was investigated in a sub‐sample who underwent an imaging assessment (n = 39,459).ResultOver a median follow‐up of 13.5 years, 5,974, 2,741, and 1,364 participants developed all‐cause dementia, AD, and VaD, respectively. Each unit increase in neuroticism z‐score corresponded to an 11% (hazard ratio [HR] 1.11, 95% Confidence Interval [CI] 1.08‐1.14), 6% (HR = 1.06, 95% CI 1.02‐1.10]), and 15% (HR = 1.15, 95% 1.09‐1.21) higher risk of all‐cause dementia, AD, and VaD, respectively. The associations remained similar regardless of genetic predisposition for dementia risk. Depression, anxiety and stress‐related disorders, ischaemic heart disease, and hypertension mediated 38.5%, 12.8%, 10.9% and 10.4% of the total association between neuroticism and all‐cause dementia, with similar mediation proportions observed for dementia subtypes. Neuroticism was significantly associated with a lower volume of total grey matter and a higher volume of white matter hyperintensities, a marker of cerebrovascular health.ConclusionNeuroticism is associated with an increased risk of dementia, particularly VaD and cerebrovascular pathology, regardless of genetic risk. Mental and vascular health may mediate this association. Neuroticism could represent a marker for dementia risk stratification and addressing the increased burden of mental and vascular health conditions in individuals with higher neuroticism could, if causal, ultimately help prevent or delay the onset of dementia.
Optimization of SHIP1 Inhibitors for the treatment of Alzheimer’s disease
Authors: Jesudason Cynthia D , Lin Peter Bor‐Chian , Soni Disha , Perkins Bridget M , Lee‐Gosselin Audrey , Ingraham Cynthia M , Hamilton Will , Mason Emily R , Jordi Omar El , Souza Sarah , Jacobson Marlene , Salvo Jerry Di , Clayton Brent , Chu Shaoyou , Dage Jeffrey L. , Oblak Adrian L , Richardson Timothy I. 
Published: January 2025

AbstractBackgroundSHIP1 is a phosphatidyl inositol phosphatase encoded by INPP5D, which has been identified as a risk gene for Alzheimer’s disease (AD). SHIP1 is expressed in microglia, the resident macrophage in brain. It is a complex, multidomain protein that acts as a negative regulator downstream from TREM2. SHIP1 possesses a phosphatase (Ptase) domain flanked by a pleckstrin‐homology (PH) domain that binds phosphatidylinositol (3,4,5)‐trisphosphate[PI(3,4,5)P3] and a C2 domain that binds phosphatidylinositol (3,4)‐bisphosphate [PI(3,4)P2]. The Ptase domain converts PI(3,4,5)P3 to PI(3,4)P2. SHIP1 also has an SH2 domain that binds to ITIMs and ITAMs where it competes with kinases. Inhibiting SHIP1 is hypothesized to have potential therapeutic benefits, as it may improve TREM2‐mediated microglial responses to neurotoxins and promote an overall neuroprotective microglial phenotype to maintain a more resilient brain and slow the rate of cognitive decline in AD patients.MethodThe IUSM Purdue TREAT‐AD Center recently evaluated SHIP1 inhibitors and proposed 3‐((2,4‐Dichlorobenzyl)oxy)‐5‐(1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl)pyridine for target validation studies. Structurally related analogs were synthesized and tested for SHIP1 enzyme inhibition, AKT signaling, and microglia activation in a high‐content imaging assay using HMC3 and BV2 microglia‐like cell lines. Primary microglia were treated with an optimized SHIP1 inhibitor, and subsequent changes in fibril Aβ uptake and cell viability were assessed. The NanoString nCounter Neuroinflammation assay was used to measure transcriptomic profiles. For comparison primary microglial derived from both wild‐type and Inpp5d‐haploinsufficient mice were assessed.ResultNovel SHIP1 inhibitors have been discovered and preliminary Structure Activity Relationship (SAR) studies have been completed. These compounds have shown positive results for biochemical activity, target engagement and cellular pharmacology. Both Inpp5d deficiency and pharmacological inhibition increase amyloid uptake and cell viability in primary microglia. Elevated ERK and AKT phosphorylation, after amyloid exposure, were decreased by Inpp5d deficiency. Functional pathways associated with phagocytosis, apoptosis, cytokine production, and complement system activity were altered.ConclusionThese data demonstrate that SHIP1 inhibition promotes amyloid uptake through the complement system. SHIP1 inhibition also enhances cell survival and homeostasis in primary microglia. Further studies of SHIP1 inhibition and INPP5D knockdown in animal models may provide a potential therapeutic strategy for Alzheimer’s disease.
Optimizing primary care for cognitive impairment screening using agile implementation
Authors: Summanwar Diana , Brosch Jared R. , Hammers Dustin B. , Fowler Nicole R , Willis Deanna R 
Published: January 2025

AbstractBackgroundScreening for cognitive impairment in primary care faces challenges, including time constraints, provider apprehension, and limited diagnostic confidence. An effective initiative for improving screening must include strategies to foster behavioral change, and active provider engagement. Agile implementation science integrates findings from behavioral economics, complexity science, and network science, to address these challenges by confirming the demand to solve the problem; local solution adaptation; and the iterative ‘sprints’, or tests of change, that are focused on execution. This study, which is part of the Davos Alzheimer’s Collaborative (DAC) Early Detection Health System Preparedness Flagship program, explored workflows to support Digital Cognitive Assessment (DCA) in primary care, enhancing early detection of mild cognitive impairment (MCI) and dementia.MethodsBetween June 1, 2022, and May 31, 2023, seven diverse primary care clinics participated in the DAC program. The initiative’s core was the integration of offering and performing Linus Health Core Cognitive Evaluation Digital Cognitive Assessment (DCA) for patients aged 65 and above. The selection of the digital screening tool, process workflows, and improvement cycles were co‐designed by the primary care providers, clinic staff, the Patient Advisory Council, and the implementation team using Agile Implementation. A Brain Health Navigator (BHN) role was designed to fill workflow gaps in primary care evaluation of abnormal screening and facilitate specialty care transition for patients needing referral.ResultsAmong the seven sites, five sites engaged in agile implementation and had similar performances, with an increase in DCA completion observed. A total of 1808 DCA screenings were performed on 1722 unique patients. The agile implementation process facilitated clinic‐specific adaptations, which resulted in an increase in the overall number of eligible patients completing the DCA screening.ConclusionsThe adoption of an agile implementation process increased DCA screening uptake in primary care settings. The integration of a BHN and streamlined workflows proved crucial in enhancing the screening, diagnosis, and referral journey. This integration aligns with the principles of person‐centered care and facilitates service coordination. It also supports workforce initiatives and advances the field of health services research, ensuring that each step in the patient’s journey is both effective and efficient.
Dynamic Neurocognitive Adaptation in aging: developing and validation of a new scale
Authors: Cieri Filippo , Francesco Giulia Di , Bender Andrew R. , Cross Chad L. , Caldwell Jessica ZK 
Published: January 2025

AbstractBackgroundUp to 40% of current AD cases may have been preventable through protective factors, such as physical and cognitive activities, preventing neurodegeneration. Reserve, resilience, and resistance are key concepts in cognitive neuroscience of aging, and they share common adaptive mechanisms. In this paper we propose a development and validation of a new scale, called dynamic Neurocognitive Adaptation (dNA).MethodThis study included 815 participants (50% women) with a minimum age of 65 years, divided in two subsamples: exploratory factor analysis (EFA), and confirmatory factor analysis (CFA). Data collection utilized survey measures administered via Qualtrics. Our initial scale was composed of 30 items, investigating 7 different dimensions, explored by a 5‐point Likert scale reflecting frequency of activities. We investigated lifetime through 7 time‐windows, from childhood (0‐10) to old age (65+).ResultOur final scale is composed by 20 items divided among 4 dimensions (physical, cognitive, social, and creative). Scale assessment indicated that there were no issues found related to multi‐collinearity (r< 0.95) or non‐collinearity (r< 0.3). For the final model, KMO = .80 and Bartlett’s test of sphericity indicated all values ≤0.01. Our Cronbach’s alpha was .83.ConclusionWe have validated a reliable, novel, easy to complete, and comprehensive scale to assess lifetime adaptive behaviors, which can be applied in research on AD risk reduction, MCI, and in clinical practice. We underlined the dynamic role of time and the investigation of the creative dimension in aging. Our dNA can be used to personalize health recommendations in aging.
Individuals with Alzheimer’s disease living alone in Sweden receive limited comprehensive care
Authors: Religa Dorota 
Published: January 2025

AbstractBackgroundA significant number of individuals with Alzheimer’s disease (AD) reside independently in their homes, yet there is limited understanding of whether they receive comparable diagnostic and treatment standards for AD compared to their cohabiting counterparts. The prevalence of dementia is rising, particularly among the elderly, with approximately 150,000 individuals affected by dementia in Sweden, two‐thirds of whom have AD. The national quality registry SveDem (Swedish registry for cognitive (dementia disorders) was established to promote consistent and high‐quality dementia care across the country.MethodsConducted as a cross‐sectional cohort study utilizing data from the Swedish registry for cognitive/dementia disorders (SveDem), we focused on patients in the community diagnosed with AD between 2007 and 2015 (n = 26,163). Information on medications and comorbidities was extracted from the Swedish Prescribed Drug Register and the Swedish Patient Register.ResultAmong the study participants, 46% (11,878) lived alone, primarily comprising older women. After adjusting for confounding factors, living alone was associated inversely with the likelihood of receiving computed tomography (OR 0.90; 95% CI 0.82‐0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83‐0.99), and lumbar puncture (OR 0.86; 95% CI 0.80‐0.92). Additionally, living alone was negatively correlated with the utilization of cholinesterase inhibitors (OR 0.81; 95% CI 0.76‐0.87), memantine (OR 0.77; 95% CI 0.72‐0.83), and cardiovascular medication (OR 0.92; 95% CI 0.86‐0.99). Conversely, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08‐1.22), antipsychotics (OR 1.41; 95% CI 1.25‐1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02‐1.17). When mew data on other dementia were included: among the study participants up to 2018 (n = 80,004), 43.8% (35053) lived alone, primarily comprising older women (58.6%). The mean age was 79.6 (SD 7.9). The following age groups were included under 70 8456 (10.6%), 70‐79 27381 (34.2%), 80‐89 37628 (47.0%) and 90+ 6539 (8.2%).ConclusionIndividuals with AD living alone receive less comprehensive care compared to their cohabiting counterparts. Finding will be presented on other types of dementia.