bluuebunny/crossref_metadata_2025_split huggingface dataset:
Event‐based modeling of T‐N mismatch reveals distinct spatio‐temporal trajectories of subtypes with likely co‐pathology in Alzheimer’s disease
Authors: Lyu Xueying , Yushkevich Paul A. , Hrybouski Stanislau , Li Yue , Duong Michael Tran , Xie Long , Wisse Laura E.M. , de Flores Robin , Irwin David J , Dickerson Bradford C. , Nasrallah Ilya M. , Das Sandhitsu R. , Wolk David A 
Published: January 2025

AbstractBackgroundThe heterogeneity of Alzheimer’s disease (AD) and lack of well‐validated markers of co‐pathologies present a substantial challenge for therapeutics. We previously found phenotypes defined by Tau (T) ‐ Neurodegeneration (N) discordance linked to non‐Alzheimer’s pathologies (e.g. TDP‐43, vascular disease). In this work, we aim to leverage T‐N mismatch for identifying distinct spatial‐temporal progression patterns of non‐AD pathologies.MethodWe performed T‐N regression on 1040 scan pairs (n = 722 individuals) from ADNI, using cortical thickness (N) and 18F‐Flortaucipir uptake (T) in 20 bilateral cortical regions of interest. As in previous work, residuals were identified as canonical (T∼N), vulnerable (N>T) and resilient (N<T). Here, we apply SuStaIn, a phenotype discovery and stage inference algorithm, to standardized T‐N residuals in canonical and vulnerable cases (n=608), expecting the latter would reflect co‐pathologies.ResultBesides the "canonical" subtype (S0), SuStaIn identified three subtypes with distinct T‐N mismatch (N>T) progression profiles (Figure 1). Two exhibited different but progressively diffuse spatial patterns of T‐N mismatch — the anterior subtype (S1) starting from frontal, and the posterior subtype (S2) initiating from occipital/temporal regions. The third subtype (S3) exhibited temporal‐limbic mismatch patterns, with spreading to anterior limbic regions. The three mismatch subtypes had worse cognition, greater age and larger rate of amyloid positivity than canonical subtype (Table 1). SuStaIn‐identified stage was associated with age and worse cognition but not tau severity (Figure 2A‐C), indicating the stages do not represent AD progression. The anterior subtype had the largest white matter hyperintensity (WMH) volume, increasing with higher stages (Figure 2D), suggesting an association with vascular disease. The temporal‐limbic subtype demonstrated poorest memory performance (Figure 2E) and may be associated with TDP‐43 pathology, as suggested in our prior work. 90.1% with longitudinal scans did not change subtype or transitioned from canonical to mismatch subtypes (Figure 2F), supporting the stability of classifications.ConclusionWe identified distinct T‐N mismatch progression trajectories in AD, potentially reflecting progression of co‐pathologies. It is important to better define these groups in the context of anti‐amyloid therapies to better understand their effectiveness in populations with likely co‐pathology and whether these mismatch trajectories driven by non‐AD factors would continue independent of treatment.
The impact of late‐onset epilepsy as a co‐occurring condition of Alzheimer's disease on tau levels in older adults with Down syndrome
Authors: Queder Nazek , McMillan Liv , Sathishkumar Mithra , Taylor Lisa M. , Keator David B. , Doran Eric , Hom Christy L. , Krinsky‐McHale Sharon J. , Petersen Melissa , O'Bryant Sid E. , Brickman Adam M. , Head Elizabeth , Mapstone Mark , Silverman Wayne , Lott Ira T. , Yassa Michael A. 
Published: January 2025

AbstractBackgroundThere is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co‐occurring disease is closely associated with Alzheimer’s disease (AD) related cognitive deterioration. Therefore, understanding the impact of late‐onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late‐onset seizures, childhood‐onset seizures, and no seizures.MethodWe analyzed data from 54 participants (52 +/‐ 6.5 years, 66% females) with DS enrolled in the Alzheimer’s disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood‐onset of seizures. A 2‐to‐1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra‐sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences.ResultThe results showed significant differences in ptau181 levels between individuals with late‐onset seizure disorder, individuals with childhood‐onset of seizures, and controls (F(2,51)= 9.649; p<.001). Post‐hoc analysis revealed that individuals with late‐onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood‐onset (p<.001) and controls (p = 0.002), with no differences between childhood‐onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta‐ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta‐ROI compared to controls.ConclusionOur findings suggest that the levels of ptau181 could be impacted by late‐onset seizure disorder. These results shed the light on the importance of assessing the impact of co‐occurring disorder on AD related biomarkers. Future research will explore the impact of late‐onset seizure disorder on AD‐related brain biomarkers longitudinally.
Metabolic PET brain networks predict clinical conversion prior to amyloid positivity in cognitively unimpaired individuals
Authors: Limberger Christian , Martins Gabriel Colissi , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Peixoto Guilherme G. Schu , de Bastiani Marco Antônio , Machado Luiza Santos , Povala Guilherme , Pascoal Tharick A. , Rosa‐Neto Pedro , de Souza Débora Guerini , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundThe default‐mode network (DMN) consists of brain regions with higher resting activity levels. Amyloid‐ß (Aß) deposition in Alzheimer’s disease (AD) occurs predominantly throughout the DMN, suggesting that activity within the network may facilitate disease processes. Indeed, increased neural activity is positively associated with Aß production. In this context, variations in DMN activity and associated metabolic networks may be linked to the risk of developing AD. However, how patterns of metabolic disruption relate to the progression of AD pathology remains unknown. Here, we investigated whether the metabolic brain networks (MBNs) architecture predicts clinical conversion in cognitively unimpaired (CU) individuals.MethodWe selected CU individuals negative to amyloid and tau (A‐T‐) from the ADNI cohort with [18F]FDG‐PET imaging data at baseline. These patients were divided in stable (non‐converters, n = 18) and clinical progressors (converters, n = 22). Individuals were age‐ and APOEe4‐matched (Table 1). The mean [18F]FDG standard uptake value ratio (SUVR, pons as reference) of brain regions of interest (ROIs) was extracted based on the DKT atlas. MBNs were assembled with a multiple sampling bootstrap scheme and corrected for group imbalance with the Adaptive Synthetic Sampling Approach for Imbalance (ADASYN) and for multiple comparisons using FDR (p < 0.05).Result[18F]FDG regional SUVRs presented no differences between groups (Figure 1). However, converters had a prominent brain PET metabolic hyperconnectivity compared to non‐converters, with a 1.5 fold‐change in connection density (p < 0.001, Figure 2A). Notably, this hyperactivation was not limited to the ROIs comprising the DMN; MBNs constructed with all brain regions reveal that the brains of converters typically display metabolic hyperactivity before the onset of CI (Figure 2B).ConclusionOur findings suggest the existence of early metabolic alterations at the network level in amyloid negative converters. This corroborates the notion that early soluble forms of amyloid, considered synaptoxins, may trigger brain metabolic hyperconnectivity. MBNs hold promise as biomarkers for detecting individuals at risk of clinical progression, even before amyloid positivity status.
Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Authors: Ottoy Julie , Su Min , Yin Eric , Rahmouni Nesrine , Stevenson Jenna , Soucy Jean‐Paul , Benedet Andrea L. , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Gauthier Serge , Black Sandra E , Rosa‐Neto Pedro , Goubran Maged 
Published: January 2025

AbstractBackgroundIn‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.MethodNinety‐one participants from the Translational Biomarkers in Aging and Dementia cohort (45% Aß‐positive, 39% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐NAV4694), tau‐PET (18F‐MK6240), and plasma Aß42/40, ptau181, ptau217, and ptau231. We investigated the associations of TSPO‐PET SUVR in white matter lobes (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for demographics and global cortical TSPO‐PET. Longitudinally, we investigated the interaction between time (up to 2y) and baseline white matter TSPO‐PET SUVR on cognitive decline, adjusted for demographics and cortical amyloid.ResultWhite matter TSPO‐PET was increased globally with older age and frontally with male sex (p<0.05). In impaired individuals, TSPO‐PET was elevated in temporo‐occipital white matter regions compared to controls (p=0.01‐0.02). The occipital increases were associated with reactive astrogliosis (p=0.011) and higher‐Braak tau‐PET (p=0.003‐0.034 for Braak3‐4) and plasma ptau181 (p=0.014) (Figure 1A‐B), but not with Aß, ptau231 or ptau217. In addition, higher occipital TSPO‐PET was associated with lower fibre integrity (fractional anisotropy, p=0.025) but not free water. Finally, in relation to cognition, higher occipital and parietal TSPO‐PET was significantly associated with impaired memory and language, respectively, independent of Aß (Figure 1C). Longitudinally, within the same patient, higher white matter TSPO‐PET at baseline was significantly associated with favorable clinical outcome over time (Figure 1D).ConclusionIncreased microglia reactivity (TSPO‐PET) in posterior white matter may indicate later‐stage AD associated with astrogliosis, tau, and dysfunction of the memory and language domains. Another novel finding is that individuals with higher white matter TSPO‐PET at baseline displayed better clinical prognosis over time. As such, assessing white matter inflammation could be promising to evaluate target engagement in clinical trials of anti‐inflammatory drugs and to subtype patients for better patient‐centric treatment outcome.
Evaluation of feasibility, added value and satisfaction of remote digital self‐assessment for mild cognitive impairment in primary and specialized routine care with the app neotivCare
Authors: Düzel Emrah , Schoettler Michael , Sommer Harriet , Griebe Martin 
Published: January 2025

AbstractBackgroundTimely diagnosis of mild cognitive impairment (MCI) in Alzheimer’s disease (AD) is crucial for early interventions, but its implementation is often challenging due to the complexity and time burden of required cognitive assessments. Remote unsupervised self‐testing of cognition can potentially addres this health care challenge. We conducted the to date largest evaluation of feasibility and experienced added value of unsupervised digital remote assessment in primary and specialized health care in Germany.MethodThis is a prospective, multicentric health care research evaluation survey called “re.cogni.ze”. Its goal is to evaluate physician satisfaction with a remote digital assessment solution (neotivCare) in primary and specialized routine care in Germany. Physicians in different regions of Germany have been recommending the app to approximately 1000 patients for a 12‐week self‐assessment of cognition. Last patient out is on 31st January 2024. The primary endpoint is the evaluation of physicians' and patients' overall satisfaction with neotivCare in comparison to neuropsychological questionnaires / standard procedures using a Likert scale. Secondary endpoints include user‐friendliness, qualitative assessment of acceptance, and potential improvements on medical routine services.ResultThis is first large scale assessment of feasibility, satisfaction and experienced added value of remote digital self‐assessment of MCI in routine care. The data will be analysed according to prespecified endpoints after data closure on the 31st January 2024.ConclusionThe study results will provide insights into the feasibility, efficiency, and acceptance of new digital tools for MCI diagnosis in routine care. The re.cogni.ze survey will thus provide proof‐of‐concept information for the implementation of remote digital cognitive assessment apps for MCI into medical routine care.
ALZpath pTau217: Multi‐cohort performance, cross‐assay comparison, and clinical launch for the identification of Alzheimer’s Disease pathology
Authors: Chaby Lauren E , Borello Jacob , Vaughan Timothy , Portbury Stuart D , Frykman Hans , Mammel Anna , Encarnacion Mary , Serrano Geidy E , Wilson Rachael E , Du Lianlian , Jonaitis Erin M. , Johnson Sterling C. , Jeromin Andreas 
Published: January 2025

AbstractBackgroundBlood‐based AD biomarker tests will be essential clinical tools to provide accessible and affordable screening and monitoring for AD disease‐modifying therapeutics (DMT) as well as advancing overall clinical care. Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer’s disease (AD) pathology using blood. We describe a multi‐cohort evaluation of the Simoa ALZpath pTau217 assay in plasma, including memory clinic patients, as well as performance in the context of other commercially available pTau217 assays. Finally, we discuss the clinical launch of ALZpath pTau217 including pTau217 reference intervals and clinical cutoffs in the context of other pTau217 assays.MethodThe ALZpath pTau217 assay is an ultra‐sensitive blood‐based test developed on the semi‐automated single‐molecule array Simoa platform; it is the first commercially available pTau217 test and has been used in over 40 cohort studies with over 50,000 sample tests. To enable clinicians to leverage ALZpath pTau217 to inform care decisions, ALZpath Dx has been validated in partnership with Neurocode CLIA‐certified laboratory.ResultWe discuss multi‐cohort ALZpath pTau217 findings for the prediction of amyloid and tau burden, measured using PET imaging and post‐mortem histology. In a pTau217 cross‐assay evaluation, ALZpath pTau217 had the strongest relationship with amyloid load as measured by (PiB) PET in a population of healthy and MCI individuals in comparison with other blood‐based AD biomarker assessments including the integration of multiple biomarkers. We discuss pTau217 reference intervals derived from multiple normative populations and compare pTau217 levels detected across multiple pTau217 assays, demonstrating that reference intervals are currently highly assay specific, highlighting the importance of efforts underway to develop a pTau217 reference standard. Finally, we report the clinical launch of ALZpath Dx, including pTau217 clinical cutoffs derived from cross‐cohort analyses, and the implications for the dementia clinical care system.ConclusionMulti‐cohort findings support ALZpath pTau217 as a high performing diagnostic biomarker for Alzheimer’s disease with high accuracy in determining amyloid burden across all stages of AD continuum. ALZpath pTau217 performance capabilities can support timely AD identification and intervention and facilitate scalable DMT implementation.
Reducing Screen Failure Rates Due to Biomarker Cut‐offs in Early AD Trials with a Prognostic Model
Authors: Tam Angela , Laurent César , Dansereau Christian 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) trials have high screen failure rates. Recent trials have enriched for individuals based on tau pathology in addition to amyloid pathology, which can exacerbate screen failures. We explored enrichment for decliners with a model that forecasts clinical progression, AD‐Px, while minimizing screen failures and avoiding strict tau cut‐offs.MethodIn amyloid‐positive early AD participants from ADNI (adni.loni.usc.edu), we quantified screen failure rates due to tau enrichment with CSF phosphorylated tau 181 (ptau‐181) measured by the Roche Elecsys assay at a 26.9 pg/mL cut‐off. That cut‐off best separated AD and cognitive unimpaired participants. We performed power analyses to estimate sample sizes for detecting 30% treatment effects at 80% power for two‐arm trials enrolling participants at this cut‐off. We compared the screen failure rates and sample size estimates of the ptau‐181 cut‐off against enrichment with decliners predicted by AD‐Px. AD‐Px is a machine learning model that uses APOE4 status, demographics, clinical assessments, and CSF biomarkers to predict individual risks of decline over 2 years. We replicated these analyses in an independent cohort of amyloid‐positive early AD participants from NACC (naccdata.org).ResultIn ADNI, 36.2% of participants failed to meet the ptau‐181 cut‐off, and 453 individuals were required to power a trial. AD‐Px screened out only 16.7% of participants, while maintaining equivalent statistical power with a sample size estimate of 453. Compared to the ptau‐181 cut‐off, AD‐Px had a 53% smaller screen failure rate (p < 0.001) (Fig. 1). In NACC, the ptau‐181 cut‐off screen failed 42.1% of participants and a power analysis estimated a sample size of 518 individuals. Selecting AD‐Px decliners in NACC, however, screen failed only 11.6% patients and required a sample size of 508 individuals. In NACC, AD‐Px had a 72% smaller screen failure rate compared to ptau‐181 (p < 0.001) (Fig. 2).ConclusionAD‐Px effectively reduces screen failure rates caused by restrictive biomarker cut‐offs, enabling more flexible inclusion criteria while maintaining statistical power. By substantially reducing screen failure rates, AD‐Px can accelerate patient enrollment, lower screening costs, and shorten trial durations without compromising sample quality.
Investigating retrotransposon‐derived eccDNA as a source of innate immune activation in tauopathy
Authors: Lambert Morgan Elizabeth , Ramirez Paulino , Sun Wenyan , Frost Bess 
Published: January 2025

AbstractBackgroundRetrotransposon‐derived extrachromosomal circular DNA (eccDNA) was extracted and sequenced from brains with Alzheimer’s disease, progressive supranuclear palsy, or healthy controls. Retrotransposon‐derived DNA was visualized outside of the nucleus in these phenotypes with phospho‐STING. Drosophila were used as a model to study extranuclear retrotransposon DNA.MethodDNA was extracted from post‐mortem human patients with AD (n = 6), PSP (FTD) (n = 6), or no pathology (n = 6). The DNA was treated with exonucleases to degrade linear DNA and the circular DNA was isolated. Post‐mortem cryosections of AD, PSP, or healthy control brains were used for fluorescent in‐situ hybridization (FISH) of retrotransposon sequences. Co‐immunofluorescence of phospho‐STING was performed on FISH tissue. Drosophila brains were also used for FISH of retrotransposons. Digital qPCR was used to measure copy number of retrotransposons in human and fly tissue.ResultPreliminary data suggests an increase in phospho‐STING in AD and PSP brains compared to controls. Preliminary data also suggests an enrichment of retrotransposon DNA in circular DNA sequencing in tau pathology compared to controls.ConclusionRetrotransposon‐derived eccDNA may be an activator of the cGAS‐STING pathway in AD and PSP.
LATE‐NC IN THE VERY ELDERLY– THE POPULATION‐BASED VANTAA 85+ ‐STUD
Authors: Mikhailenko Elizaveta , Colangelo Kia , Tuimala Jarno , Kero Mia , Savola Sara Emilia , Raunio Anna , Kok Eloise H , Tanskanen Maarit , Mäkelä Mira , Puttonen Henri , Mäyränpää Mikko I. , Kumar Darshan , Kaivola Karri , Paetau Anders , Tienari Pentti , Polvikoski Tuomo , Myllykangas Liisa 
Published: January 2025

AbstractBackgroundPopulation‐based cohort studies play a crucial role in unraveling the underlying causes of dementia among older individuals. While previous research has indicated an increase in limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) with age, only limited investigations have delved into this phenomenon within a population‐based context. In this study, we examined the prevalence of LATE‐NC and its correlations with other brain pathologies and cognitive function in individuals aged > 85 years.MethodEvaluation of the Vantaa 85+ study cohort, comprising 601 individuals aged >85 years residing in Vantaa, Finland in 1991, formed the basis of our investigation. Neuropathological assessments were conducted on 304 subjects (51%), with LATE‐NC staging feasible for 295. Dementia status and Mini‐Mental State Examination scores were established during baseline and three follow‐up assessments spanning from 1994 to 1999. LATE‐NC staging relied on TDP‐43 immunohistochemistry, following recently updated guidelines. Digital evaluation of arteriolosclerosis involved calculating the average sclerotic index of five randomly selected small arterioles in the amygdala, hippocampal regions, and frontal white matter. Fisher’s exact test, along with linear and logistic regression models, were employed to analyse associations between LATE‐NC, arteriolosclerosis, previously identified neuropathological variables (such as Alzheimer’s disease neuropathological change, Lewy‐related pathology, hippocampal sclerosis, and cerebral amyloid angiopathy), and cognitive metrics.ResultAmong the 295 subjects, LATE‐NC was present in 189 (64%), with stage 2 being the most prevalent (29%) followed by stage 3 (13%), while stages 1a, 1b, and 1c were less frequent (10%, 5%, and 8%, respectively). Stages 1a (P< 0.01), 2 (P< 0.001), and 3 (P< 0.001) were significantly associated with dementia and lower Mini‐Mental State Examination scores. LATE‐NC exhibited strong associations with Alzheimer’s disease neuropathological change (P< 0.001), hippocampal sclerosis (P< 0.001), diffuse neocortical Lewy‐related pathology type (P< 0.001), and amygdala arteriolosclerosis (P< 0.006). Across all six multivariate models, LATE‐NC emerged as one of the most robust independent predictors of dementia. Notably, LATE‐NC commonly co‐occurred with other neuropathological changes, with only a negligible percentage (<0.5%) of cases attributing dementia solely to LATE‐NC.ConclusionThis population‐based inquiry underscores the significant role of LATE‐NC as an independent determinant of dementia within the general late‐life population.