bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoassay and Immunohistochemistry of TDP‐43 and the association with annual rate of hippocampal atrophy in Alzheimer's disease
Authors: Youssef Hossam , Gatto Rodolfo G. , Pham Nha Trang Thu , Petersen Ronald C. , Dickson Dennis W. , Petrucelli Leonard , Whitwell Jennifer L. , Prudencio Mercedes , Josephs Keith A. 
Published: January 2025

AbstractBackgroundTransactive response DNA‐binding protein of 43 kDa (TDP‐43) is implicated in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Immunohistochemically stained TDP‐43 is linked to faster rates of hippocampal atrophy (HA) in AD. However, it is unclear whether phosphorylated TDP‐43 (pTDP‐43) measured using an immunoassay is also associated with HA. We explored associations between pTDP‐43 levels, TDP‐43 immunohistochemistry, and annual rate of HA in AD. We hypothesized that higher pTDP‐43 levels would be associated with positive TDP‐43 immunohistochemistry, and faster rates of HA.MethodThirty‐seven cognitively impaired participants from the Mayo Clinic Alzheimer’s Disease Research Center underwent serial brain MRIs and brain autopsy. Hippocampal TDP‐43 was detected histochemically, and pTDP‐43 was quantified using biochemical assay. Hippocampal volumes were measured using the longitudinal pipeline in FreeSurfer‐7 and annualized HA rates were calculated. Linear regression analyzed the relationship between HA and pTDP‐43 biochemical assay levels. pTDP‐43 was categorized as positive (≥400) or negative (<400), and logistic regression tested the association of these levels with HA rates. The correlation between TDP‐43 immunohistochemistry status and biochemical assay levels was evaluated using descriptive statistics. All analyses were adjusted for potential confounders.ResultsThe mean age at death was 83.5 (±9.9) years with 49% females. Median scan interval was 3‐years. A negative relationship was observed between age at death and annual HA rate (β=‐3.1; 95% CI [‐5.3,‐0.9]; p=0.007), and a positive relationship was observed between pTDP‐43 level and annual HA rate (β=0.02; 95% CI [0.003,0.03]; p=0.015). A one‐unit increase in HA rate was associated with a 3% increase in the odds of being pTDP‐43 positive (≥400) (odds ratio=1.03; CI [1.007,1.05]; p=0.014). Cases that tested positive for Immunohistochemistry TDP‐43 had significantly higher mean pTDP‐43 immunoassay levels (1508 ± 2072 vs. 202 ± 131; p=0.008). More cases with positive IHC TDP‐43 surpassed the pTDP‐43 immunoassay cut‐off level of 400 vs the negative participants (p=0.003).ConclusionHigher pTDP‐43 levels in the hippocampus are linked to faster HA in AD and correlated with immunohistochemistry TDP‐43 positivity. These findings underscore the role of TDP‐43 in AD neurodegeneration. The biological and clinical implications of these observations necessitate further exploration in subsequent studies.
Intracellular adhesion molecule 1 in prodromal Alzheimer’s disease
Authors: Behfar Qumars , Behfar Stefan Kambiz , Onur Oezguer A. 
Published: January 2025

AbstractBackgroundAge represents the predominant risk factor for Alzheimer's disease (AD) dementia. Nevertheless, not every elderly individual undergoes age‐related processes that inevitably lead to dementia. The aging process is characterized by cellular senescence, manifesting as morphological changes and the secretion of immune signaling mediators linked to systemic low‐grade inflammation. Consequently, our investigation aimed to assess the correlation between cerebrospinal fluid (CSF) levels of specific senescence‐associated secretory phenotype (SASP) proteins and accelerated biological aging. Furthermore, we sought to determine whether this acceleration has an impact on the progression along the Alzheimer's disease continuum.MethodBiological age was computed utilizing established epigenetic clocks, employing genome‐wide DNA methylation (DNAm) data derived from blood samples collected in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In addition, BrainAge, a neuroimaging‐based aging clock, was calculated. Age acceleration was ascertained through residuals obtained by regressing predicted biological age against chronological age. Linear and Cox regressions were employed to evaluate the correlation between SASP and the acceleration of biological age, as well as the associated risk of progression from prodromal mild cognitive impairment (MCI) to AD.ResultIn our SASP panel, intercellular adhesion molecule 1 (ICAM‐1), Interleukin 8 (IL‐8), matrix metalloproteinase 3 (MMP‐3), plasminogen activator inhibitor 1 (PAI‐1), tissue inhibitor of metalloproteinases 1(TIMP‐1), vascular endothelial growth factor (VEGF) and stem cell factor (SCF) associated significantly with chronological age. Next, we observed that DNAm acceleration was associated with higher risk of progression to AD, and ICAM‐1 was the only SASP factor which was found associated with DNAm age acceleration, and explained part of the effect of age‐acceleration on progression from MCI to AD.ConclusionOur findings provide supporting evidence on the contribution of biological age‐acceleration to the progression of AD. Herein, ICAM‐1 might serve as a standalone biomarker determining how biological age‐acceleration affects the progression along the AD continuum.
Seed amplification assay‐determined alpha‐synuclein associates with Alzheimer’s pathology, clinical symptoms, and cognitive change
Authors: Jonaitis Erin M. , MacLeod Karen R , Jennifer Lamoureux , Jeffers Beckie , Studer Rachel L , Middleton John , Wilson Rachael E , Chin Nathaniel A. , Hermann Bruce P , McEvoy Sean , Zetterberg Henrik , Johnson Sterling C. , Lebovitz Russ , Langhough Rebecca E. 
Published: January 2025

AbstractBackgroundThe high prevalence of mixed‐pathology dementias suggests that multi‐drug treatments may improve clinical outcomes; thus, in‐vivo biomarkers for co‐pathologies are needed. We investigated a novel assay for detecting seeds of misfolded alpha synuclein (αSyn) and explored its relationship to outcomes including Alzheimer’s disease (AD) biomarkers, clinical features, and cognitive trajectories, in two community‐based cohorts enriched for AD risk.MethodCerebrospinal fluid (CSF) obtained from participants in the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (N=418 participants; 515 LPs; Table 1) was assayed using a clinically validated, qualitative Syn seed amplification assay (SAA; Amprion). Co‐occurrence of αSyn pathology (αSyn‐SAA+), and AD pathology (CSF amyloid, Aβ42/40 and pTau181/Aβ42, and tau, pTau181, positivity), and clinical symptoms (neurological finding; Parkinsonian signs; etc) were examined with chi‐square tests. Cognitive trajectories were modeled retrospectively using separate mixed effects models of Trail‐Making Test B, Backward Digit Span, Digit Symbol Substitution, and a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). Models included subject‐level random intercepts and age slopes and standard covariates (sex, education, and practice with the battery). For each outcome, we examined whether αSyn‐SAA+ modified age trajectories (centered; linear and quadratic terms; models 1A‐4A). In models 1B‐4B, we further examined effects of αSyn‐SAA+ after adjusting for age× and age× interactions. Nonsignificant quadratic interaction terms were removed (p>0.1).ResultαSyn‐SAA+ co‐occurred with binary pTau181/Aβ42 (p=0.048) and pTau181 (p=0.0045), but not Aβ42/40 (p=0.14). Among pTau181/Aβ42+ participants, 20/119 (17%) were also αSyn SAA+, compared to 27/287 (9%) pTau181/Aβ42‐ participants. For pTau181+ and pTau181‐, the proportions were 18/89 (20%) and 30/322 (9%), respectively. αSyn‐SAA+ participants had greater cognitive impairment (p=0.00050) and additional neurological findings (p=0.026), but did not differ (p>=.17) on Parkinsonian signs, REM behavior disorder, or depression. αSyn‐SAA+ participants declined faster in Digit Symbol performance after accounting for Alzheimer’s pathology (model 3B: = ‐0.20, p=0.045; Table 2; Figure 1).ConclusionResults suggest significant co‐pathology in an AD‐risk enriched cohort. Relationships with cognitive impairment provide evidence for the clinical utility of αSyn SAA in this population. Steeper age‐related decreases in Digit Symbol performance among αSyn SAA+ individuals suggest possible association with preclinical cognitive change.
Memory Consolidation, Brain Atrophy, and Metabolism in Amyloid Positive and Negative Amnestic Mild Cognitive Impairment
Authors: Teixeira Camila Vieira de Ligo , Keith Cierra M , Haut Mark W , Mehta Rashi , Phelps Holly , Ward Melanie , Miller Mark , Navia R. Osvaldo , Coleman Michelle M , Marano Gary D , Wang Xiaofei , Pockl Stephanie , Rajabalee Nafiisah , McCuddy William T , D’Haese Pierre‐Francois , Rezai Ali R , Wilhelmson Kirk 
Published: January 2025

AbstractBackgroundThe existing literature has established that Alzheimer's disease (AD) is typically characterized by changes in memory‐associated temporal and parietal lobe atrophy and hypometabolism. However, some individuals clinically diagnosed with AD do not have biomarkers consistent with AD pathology. In this cross‐sectional study, we aimed to investigate differences in memory consolidation, temporal and parietal lobe atrophy, as well as temporal and parietal lobe metabolism within a clinically diagnosed cohort of individuals with amnestic Mild Cognitive Impairment (aMCI) who were either positive or negative for amyloid.MethodWe retrospectively analyzed clinical data from 149 participants: 78 aMCI amyloid positive (A+), 48 aMCI amyloid negative (A‐), and 41 healthy subjects (HP). To analyze memory performance, we used the CVLT 1. % retained (CVLT%), 2. discrimination (CVLT‐D), 3. false positive (CVLT‐FP), and 4. intrusions errors (CVLT‐I). Entorhinal, supramarginal and angular cortical thickness were computed using CAT 12 and DKT atlas, and hippocampus volume using SLANT. A subset of the aMCI participants had an FDG‐PET, and we extracted the metabolism in the brain regions of interest for analysis. ANOVAs explored differences between groups on memory, brain atrophy, and metabolism (adjusted p<.002). Pearson’s correlations examined relationships between CVLT, MRI values, FDG‐PET measures, and biomarker data (adjusted p<0.0009).ResultA+ exhibited worse performance on CVLT%, CVLT‐D, and CVLT‐FP compared to A‐ and HP, and A‐ was worse on those tests compared to HP. There were no significant differences in the hippocampal volume or entorhinal thickness between biomarker status; A+ showed more atrophy in supramarginal and angular thickness than A‐ and HP. A+ showed hypometabolism in the entorhinal cortex compared to A‐. While hippocampus volume was related to CVLT%, CVLT‐D and CVLT‐FP, CVLT% was positively related to all the metabolism in all areas analyzed except hippocampus.ConclusionIn our memory clinic cohort characterized by biomarker status, our findings indicated that factors beyond AD might contribute to memory consolidation, temporal lobe atrophy, and temporal lobe. In addition, by inference, adding parietal atrophy to mesial temporal atrophy worsens memory consolidation.
Anti‐Amyloid Treatments for Alzheimer’s Disease: Patients’ and Families’ Perception and Experience with Drug Consultation
Authors: Lapins Allison , Lucca Kate , Morhardt Darby , Welch Sarah 
Published: January 2025

AbstractBackgroundDrug consultations for the new anti‐amyloid therapies for Alzheimer’s Disease are currently taking place at the Northwestern Neurobehavior and Memory Clinic with potentially eligible patients and their families. Study aims are to: 1) measure patient and family perception, barriers and concerns of the drug treatment following a formal consultation or informal discussion with a neurologist, and 2) gather data on the patient and family experience with the drug consultation as a method for making an informed decision.MethodsParticipants who are potentially eligible for anti‐amyloid therapies and have a drug consultation with their behavioral neurologist will be asked to participate in our study survey. Patients who are potentially eligible for anti‐amyloid therapies must be in the early stages of the disease and have biomarker evidence of Alzheimer’s Disease pathology. Interested participants complete the survey over the phone with a study team member. The survey asks questions aimed to measure interest in starting this treatment (before and after consultation), concerns and barriers surrounding the treatment, as well as overall experience with the drug consultation.ResultThis study is underway with data collection and will have preliminary results to share in the coming months.ConclusionWe expect that drug consultations with patients and families on the new Alzheimer Disease therapies will help to identify concerns, understanding of the risks and benefits and overall impact of taking these newly available treatments.
Developing a novel brain‐based biomarker of mild cognitive impairment using time‐domain functional near‐infrared spectroscopy
Authors: Dubois Julien , Field Ryan M , Jawhar Sami , Koch Erin M , Aghajan Zahra M. , Miller Naomi , Perdue Katherine L , Taylor Moriah 
Published: January 2025

AbstractBackgroundMild cognitive impairment (MCI) is largely under‐diagnosed by primary care physicians. There is an urgent need to develop new objective screening tools to assist with early detection of MCI. Time‐domain functional near‐infrared spectroscopy (TD‐fNIRS) can be used to measure brain function in clinical settings and may fill this need.MethodMCI patients (n=21) and control older adults (HC; n=24) participated in brain recordings using TD‐fNIRS during rest and cognitive tasks implicated in MCI: 1) Verbal fluency task (VFT) consisting of interleaved blocks reciting words (control: weekdays; semantic: words from a given category; phonological: words starting with a given letter); 2) N‐back task targeting working memory by testing memory for patterns with specific memory loads (0‐, 1‐ and 2‐backs) in a block‐design manner.Raw data, i.e. the distributions of the times of flight (DToFs) of photons at two wavelengths (690 and 905nm), underwent standard preprocessing to obtain moments of DToFs and corresponding changes in the concentrations of oxygenated/deoxygenated hemoglobin. Features related to brain function, systemic physiology, and head optical properties were extracted. For tasks, behavioral metrics were also computed.ResultFirst, we looked for features that significantly differentiated between MCI and HC groups during a resting state session (watching a 7‐minute audiovisual segment; Figure 1A). Multiple features, including head optical properties and prefrontal fractional Amplitude of Low Frequency Fluctuations (fALFF) were statistically different between MCI and HC (Figure 1B). Next, we explored the tasks both in terms of behavior and neural features. In VFT, behavior was significantly different between groups (Figure 2A), which is expected from prior literature. Additionally, whole‐brain hemodynamic activation maps, as computed using Generalized Linear Models (GLM) revealed areas with significant differences between the two groups (Figure 2B). Similarly, for the N‐back task, multiple behavioral metrics were separated between the groups (Figure 3A) and group‐level GLM showed brain regions with significantly different activations between groups, specifically medial prefrontal cortex (Figure 3B).ConclusionWe demonstrated significant group‐level differences between MCI vs healthy controls using TD‐fNIRS. As such, with ongoing data collection, we seek to validate these findings and employ classification techniques for MCI detection.
Impacts of a Comprehensive Dementia Care Management Program on Patient and Caregiver Health and Wellbeing
Authors: Tan Zaldy S , Qureshi Nabeel , Spivack Erica , Rhinehart Deana , Gatmaitan Dyane , Guinto Augustine , Kremen Sarah , Sicotte Nancy 
Published: January 2025

AbstractBackgroundThe United States faces a growing challenge with over 6.5 million people living with dementia (PLwD). PLwD and their caregivers struggle with cognitive, functional, behavioral, and psychosocial issues. As dementia care shifts to home settings, caregivers bear increasing responsibilities, leading to increase strain. This study assesses the initial impacts of a pragmatic dementia care model, the Cedars‐Sinai C.A.R.E.S. Program, on patient and caregiver health and wellbeing.MethodsThe Cedars‐Sinai C.A.R.E.S. Program is an integrated care management program that enrolled eligible patients aged 65 and older with a dementia diagnosis or dementia medication within the health system. Enrolled patients underwent comprehensive assessments of patient and caregiver health and wellbeing using the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q) (patient), Patient Health Questionnaire (PHQ) 2 and 9 (caregiver), and Modified Caregiver Strain Index (MCSI) (caregiver) at baseline and follow up one‐year after enrollment. We calculated overall and sub‐assessment scores for each measure and compared the scores using t‐tests to test for statistical significance.ResultsTo date, of the 431 were enrolled in the C.A.R.E.S. Program, 80 completed their baseline and follow‐up health and wellbeing assessment. Assessment scores were higher (worse health and lower wellbeing) at baseline than at follow up for all measures. For the NPI‐Q, the overall score decreased from 23.54 (SD = 15.68) to 20.74 (17.71) (p = 0.29), the distress sub‐assessment score decreased from 10.7 (7.94) to 9.42 (8.85) (p = 0.34), and the severity sub‐assessment score decreased from 8.3 (5.6) to 7.36 (6.48) (p = 0.33), though none were statistically significant. Similarly, caregiver depression decreased from 1.12 (1.41) to 0.8 (1.19) using the PHQ‐2 (p‐0.13) and decreased from 4.73 (5.32) to 4.22 (4.61) using the PHQ‐9 (0.52). Finally, caregiver strain decreased from 9.84 (6.25) to 8.47 (5.84) (p = 0.15).ConclusionsThe Cedars‐Sinai C.A.R.E.S. Program offers a promising approach to dementia care. While there were differences in assessment scores at baseline and follow‐up, differences were not statistically significant. As the program continues to enroll patients and they complete their assessments, we expect the increase in statistical power will help determine whether differences are real or due to chance.
Longitudinal associations of microstructural changes, amyloid, and cognition in preclinical Alzheimer's disease
Authors: Vannini Patrizia , Bertazzoli Giacomo , Rodriguez‐Vieitez Elena , Ramseyer Max , Diez Ibai , Sepulcre Jorge , Hanseeuw Bernard J , Lois Cristina , Gagliardi Geoffroy Pierre , Westin Carl‐Fredrik , Johnson Keith A , Sperling Reisa A , Marshall Gad A 
Published: January 2025

AbstractBackgroundA novel method using diffusion‐weighted imaging (DWI) allows for assessing microstructural injury in the gray matter by measuring cortical mean diffusivity (cMD). Previous studies have shown that altered cMD is related to amyloid (Aβ) cross‐sectionally and can predict longitudinal cognitive decline and clinical progression, suggesting utility in clinical trials. However, the longitudinal associations between these measures are unknown. This study aimed to investigate the longitudinal associations among cMD, Aβ, and cognition, in individuals who were cognitively normal (CN) at baseline.MethodsThe study sample comprised n=156 CN older adults (73.8±6.1 y/o;92 [59%] women) from the Harvard Aging Brain Study. All participants underwent structural MRI, DWI, and 11C‐Pittsburgh compound‐B‐PET at baseline and after 4 years. Cognitive assessment using the Preclinical Alzheimer Cognitive Composite‐5 (PACC‐5) was collected at baseline and yearly for an average of 9.7±3.2 years. Generalized linear models (GLMs) were used to assess the regional (focusing on brain areas vulnerable to early Aβ accumulation) change in Aβ on change in cMD, covarying for baseline cortical thickness, change in cortical thickness, age, and sex. GLMs were used to assess the impact of change in regional cMD by Aβ group, on the rate of change in cognition covarying for baseline cMD, baseline age, sex, and education.ResultsOverall, Aβ and cMD signal increased over the 4‐year period. 44 participants (28%) exhibited an initial high Aβ burden (Aβ+, thresholded using 1.186 SUVR). An increase in Aβ pathology (over 4 years) predicted a concomitant increase in cMD in the isthmus cingulate (ßstd=6.8e‐06;p=0.019). Post hoc stratified analyses by Aβ‐status revealed that this effect was only observed in the Aβ+individuals (ßstd=1.6e‐05;p=0.023, Figure 1A). Moreover, a significant interaction between Aβ and cMD signal predicted cognition, such that an antecedent increase in cMD was related to a steeper cognitive decline in Aβ+ individuals (ßstd=‐0.061;p=0.004, Figure 1B).ConclusionAmyloid accumulation is associated with a concomitant increase in cMD, suggesting that it may reflect microstructural alterations in response to Aβ aggregation. Moreover, an increase in cMD over time predicted cognitive decline in at‐risk individuals. Overall, metrics of cortical diffusion may provide important outcome measures in Aβ‐modifying clinical trials for detecting drug‐induced changes in cortical microstructure.
Digital speech markers of cognitive impairment in ALS‐FTD spectrum disorders
Authors: Shellikeri Sanjana , Cho Sunghye , Ash Sharon , Gonzalez‐Recober Carmen , Cousins Katheryn A Q , McMillan Corey T , Elman Lauren , Quinn Colin , Amado Defne A , Baer Michael , Irwin David J , Massimo Lauren , Liberman Mark Y , Nevler Naomi 
Published: January 2025

AbstractBackgroundComorbid cognitive impairment in amyotrophic lateral sclerosis (i.e., ALS‐FTD), is associated with adverse clinical outcomes and survival. It often exhibits clinical features of behavioral variant frontotemporal dementia (bvFTD) and/or non‐fluent agrammatic primary progressive aphasia (naPPA). Traditional cognitive assessments, such as the Edinburgh Cognitive Assessment Scale (ECAS), require trained personnel for administration. An additional repeatable, objective approach involves automatic analysis of picture descriptions. Prior research identified acoustic and lexical‐semantic impairments in bvFTD, PPAs, and ALS‐FTD (acoustics). This study extends the analysis to the complete speech feature set (n=30) in ALS‐FTD spectrum disorders.MethodANCOVAs (FDR adjusted) compared picture descriptions in n=51 ALS, n=22 ALS‐FTD (n=10 bvFTD‐dominant, n=4 naPPA‐dominant), and n=12 ALS with ECAS‐defined mild cognitive/behavioural impairment (ALS‐MCI). Backward selection identified the best feature subset. Post‐hoc assessments examined associations with ECAS behavioral, language, and executive scores. Longitudinal analysis compared within‐individual change over time in n=11 ALS vs. n=9 ALS+cog (combining ALS‐MCI with ALS‐FTD) with available longitudinal data. All models adjusted for bulbar motor scores.ResultALS‐FTD significantly differed from ALS and ALS‐MCI on twelve features at first visit: slow speaking and articulatory rates, reduced word count, less percent speech time, shorter speech segments, and longer and more frequent pausing. ALS‐FTD also exhibited fewer adjectives and prepositions, more repetitions, lower lexical diversity, and words with a lower mean age of acquisition (AoA). The best model comprising three features (percent speech, prepositions, and lexical diversity) strongly distinguished ALS‐FTD from ALS (AUC=0.90). ALS‐MCI did not differ from ALS on any speech measure. Acoustic measures were all significantly associated with behavioral, language, and executive scores. Fewer prepositions related to worse behavioral and language scores, and more repetitions and lower lexical diversity related to worse language scores. Mean AoA and articulatory rate were not linked to any ECAS sub‐domains. Longitudinally, ALS+cog exhibited increased partial words and reduced word AoA, while ALS showed no significant change.ConclusionAutomated speech analysis strongly distinguishes ALS‐FTD from ALS, declines with cognitive severity, and captures distinctive longitudinal changes in ALS‐FTD. These results highlight the potential of automated speech analysis as an objective tool for assessing cognitive impairment in ALS.