bluuebunny/crossref_metadata_2025_split huggingface dataset:
Memory Performance in Mild Sporadic and Familial Behavioral Variant Frontotemporal Dementia: Findings from the ALLFTD Consortium
Authors: Boeve Brad F. , Fields Julie A. , Syrjanen Jeremy A. , Johnson Noah , Kremers Walter K. , Staffaroni Adam M. , Huey Edward D. , Rascovsky Katya , Weintraub Sandra , Ramos Eliana Marisa , Knopman David S. , Miyagawa Toji , Forsberg Leah K. , Heuer Hilary W. , Boxer Adam L , Rosen Howard J. ,   ALLFTD Consortium
Published: December 2023

AbstractBackgroundMemory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.MethodAssessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.ResultData from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).ConclusionThese data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.
Investigating Dendritic Spine Morphology as a Mediator of Cognitive Outcomes in Aged Diversity Outbred Mice
Authors: Ouellette Andrew R , Herskowitz Jeremy H , Greathouse Kelsey M , Weber Audrey J , Hadad Niran , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundThe intersection of genetic diversity, memory, and synaptic function is a critical component in better understanding age‐related cognitive decline. Diversity Outbred mice offer the opportunity to investigate cognitive aging across a genetically diverse population in a controlled lab environment. DO mice exhibit an appreciable amount of variance in Contextual Fear Memory and Acquisition (CFM, CFA), which can be linked to individual differences in genetic background (Ouellette A. et al, 2022, Cell Reports). Here, we investigate the role of dendritic spines as a mediator of individual age‐related changes in memory.Methods524 DO mice (289 female, 235 male) were aged to either 8 or 18‐months. All mice received contextual fear conditioning (CFC) at 8mo, while another suet received an additional recall test at 17mo and renewal at 18mo. After CFC a subset of brains from each cohort were collected for spine morphology analyses (females, n = 42). One CA1 pyramidal neuron from each brain was imaged and quantified for the density of thin, stubby, mushroom and/or filipodia classified spines in addition to spine volume.ResultsWhile was not a decline in CFM or CFA between 8 and 18mo, we observed expectedly wide range in individual memory outcomes. Thin spine density significantly decreased between 8mo and 18mo, and stubby spine density increased. Spine volume across all spine types increased with age. Apical thin spine density explained 61% of the variance in CFM outcomes, while thin spine volume explained 79% and 43% of variance CFA in apical and basal dendrites respectively. Thin spine density, however, did not associate with CFA outcomes.ConclusionsWe have linked dendritic spine density and morphology as a potential mediator of individual outcomes across a genetically diverse population. Our results suggest that there may be an age‐related conversion of thin to stubby spine types, and that mice with fewer thin spines are more likely to have better CFM outcomes, coinciding with reports of thin spines as dynamic “learning spines” rather than “memory storage” spines (Hayashi, Y. 2005, Neuron). We also show that the size of these “learning” thin spines may be more important memory acquisition than their total density.
Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters
Authors: Heylen Annelies , Vermeiren Yannick , Van Dam Debby , De Deyn Peter Paul 
Published: December 2023

AbstractBackgroundDespite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.MethodMonoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.ResultSignificant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values > 0.9.ConclusionThese findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.
Females Derive Greater Neuroprotective Benefits from Social Connectedness than Males
Authors: Manchella Mohit K. , Logan Paige E. , Perry Brea L , Peng Siyun , Risacher Shannon L , Saykin Andrew J. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundSocial connectedness is associated with better cognitive performance among older adults. Previously, we found that bridging (access to an expansive network of diverse and loosely connected individuals) and bonding (close and supportive relationships to familiar others) associated with preserved gray matter density (GMD). We sought to examine whether sex modulates these relationships in the Social Networks and Alzheimer’s Disease study (SNAD).MethodWe analyzed baseline data of 176 SNAD participants (58 male, 118 female; 117 cognitively‐unimpaired, 59 cognitively‐impaired; average age 68.57+/‐12.26 years). Bridging and bonding metrics were collected via in‐person interviews. We ran analyses in the pooled sample split by sex. Demographics and biomarkers between sexes were compared. Correlations between MRI regions of interest and bridging and bonding in males and females were performed. Voxel‐wise covaried for age, education, and intracranial volume in SPM12 yielded statistical maps for males and females which were corrected for family‐wise errors at p<0.01.ResultTable 1 shows demographic and biomarker comparisons between males and females. In females greater social bridging was significantly associated with (left p = 0.004, right p<0.001), as well as left frontal lobe thickness (p = 0.002), putamen (p = 0.011), and thalamus volumes (p = 0.002). No significant associations were observed for social bridging in males. Greater social bonding was significantly associated with preserved right frontal pole (p = 0.018) and caudal anterior cingulate thickness (p = 0.017) in females and greater right orbitofrontal thickness (p<0.001) in males (Figure 1).Our 3D voxel‐wise regression maps showed that in females greater social bridging was associated with preserved GMD of the frontal, temporal and parietooccipital lobes, while males showed no significant associations (Figure 2). In females greater social bonding was associated with preserved GMD in the lateral temporal and parietal lobes, while in males the associations were localized to the medial frontal and right orbitofrontal lobe (Figure 2).ConclusionWomen compared to men showed stronger effects of social enrichment on GMD and subcortical structures. Social bridging and bonding were associated to different brain regions in males and females. These results suggest that females may have a greater social‐based protection against neurodegeneration compared to their male counterparts.
Glia response on Amyloid plaque microenvironment protects against pathological tau conversion in Alzheimer’s disease resilience
Authors: Garfe Nur Jury , You Yanwen , Redding Javier , Martinez Pablo , Karahan Hande , Kim Jungsu , Troncoso Juan C , Reeves Cristian A Lasagna 
Published: December 2023

AbstractBackgroundAymptomatic Alzheimer’s disease (AsymAD) subjects have an intrinsic capacity to tolerate the presence of Aβ‐plaques and neurofibrillary tangles (NFTs) without developing cognitive impairment. In contrast to typical demented Alzheimer’s disease (AD) brains, AsymAD brains show distinct neuroinflammatory response and less accumulation of soluble pathological tau species at synaptic levels. The link between these observations and AD neuropathology is not fully understood, but increasing evidence suggests that the local plaque microenvironment plays a key role in the Aβ plaque‐associated tau pathogenesis. In this work we aim to identify the main molecular contributors of resiliency against amyloid and tau aggregation in AsymAD brains.MethodWe conducted a detailed histological and biochemical analysis using postmortem brain cortex samples from age‐matched controls (N = 21), demented AD (N = 22), and AsymAD subjects (N = 30). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the Aβ‐plaque microenvironment in AsymAD versus typical demented AD cases.ResultThere was no difference observed in the overall amyloid plaque burden between AsymAD and demented AD brains. However, immunofluorescence analyses indicates that AsymAD cases have the capability to form a glial barrier surrounding filamentous plaques, thereby avoiding the pathological conversion of tau. This observation is supported by biochemical analysis, which reveals that AsymAD cases have lower levels of high molecular weight tau and less seeding activity in soluble fractions. Using spatial whole transcriptomics to further characterize the plaque niche, we found an enrichment of migration signaling and autophagy in the AsymAD plaque niche, but not in AD. We are currently investigating the significance of these two molecular pathways in the Aβ plaque‐associated tau pathogenesis.ConclusionOur study provides new insights into the mechanism of Alzheimer’s disease resilience focus in the local Aβ plaque‐associated tau pathogenesis and potentials therapeutic approach to cognitive deterioration
Distinct pools of cholesterol regulate APP maturation and Aβ42/40 ratio
Authors: Kruijff Iris Daphne , van der Kant Rik 
Published: December 2023

AbstractBackgroundChanges in amyloid precursor protein (APP) processing towards an increased Aβ42/40 ratio is a major hallmark of Alzheimer’s disease (AD). For sporadic AD, it is unknown what drives this increase, but cholesterol has been shown to regulate APP maturation via export from the endoplasmic reticulum (ER). Brain cholesterol metabolism is tightly regulated via the initiation or inhibition of cholesterol synthesis, storage, uptake, and export. The latter two processes are regulated by apolipoprotein E (APOE), a major cholesterol carrier. Here we test whether cholesterol can affect the Aβ42/40 ratio using cholesterol metabolism‐targeting drugs.MethodDifferent isogenic human iPSC lines were used: APOE2/2 (protective), APOE3/3 (normal), APOE4/4 (AD risk) and APOE knockout (KO). iPSCs were differentiated to neurons via NGN2 overexpression and treated with cholesterol targeting interventions (statins, ACAT inhibitors, LXR agonists). Secreted levels of sAPPα, sAPPβ, Aβ40, Aβ42 and the ratio of Aβ42/40 were determined.ResultInhibiting cholesterol synthesis (statins) and cholesterol esterification (ACAT inhibitors) in the ER reduced levels of sAPPα, sAPPβ, Aβ42 and Aβ40, but did not affect the Aβ42/40 ratio. Induction of cholesterol export and inhibition of its synthesis (LXR agonists) caused a strong increase in Aβ42/40 ratio. At low LXR agonist concentrations, we observe increased Aβ42 levels, while Aβ40 remained unchanged. At higher concentrations, both Aβ42 and ‐40 levels decreased, while maintaining the elevated Aβ42/40 ratio. sAPPα and sAPPβ levels changed in similarly to Aβ40. APOE genotype did not affect responses to LXR agonists.ConclusionOur results indicate that inhibition of cholesterol synthesis or esterification in the ER influence overall APP processing. The LXR‐induced increase in Aβ42/40 ratio seems to depend on changes in a separate cholesterol pool. A previous study proposed that Aβ40 is mainly produced by PSEN1 in the plasma membrane, whereas Aβ42 is mainly produced by PSEN2 in the endo‐lysosomal system. Re‐localization of cholesterol might therefore be responsible for this ratio change, possibly in a PSEN‐dependent manner. Interestingly, the effects on Aβ processing are independent of APOE, as the APOE KO showed similar changes on all peptide levels. Our findings can help to further elucidate the interplay between cholesterol metabolism and Aβ processing.
Comparison of plasma Ab42, Ab40, and p‐tau181 assessed on two different platforms with CSF AD biomarkers and amyloid (PiB) PET
Authors: Sutphen Courtney L. , Rudolph Marc D. , Lockhart Samuel N. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Register Thomas C. 
Published: December 2023

AbstractBackgroundAs blood‐based biomarkers of Alzheimer’s disease enter clinical diagnostic use, key considerations remain including the concordance with CSF or amyloid PET and the comparability of results between different assay platforms.MethodParticipants (n = 42) from the Clinical Core of the Wake Forest ADRC, were selected using CSF Aβ42/Aβ40 values which clearly indicated amyloid pathology status (‐ or +). A subset of 29 participants had amyloid (PiB) PET measures within one year of CSF. Participants were considered amyloid positive when CSF Aβ42/40 ≤0.058 and/or amyloid PET was adjudicated as “positive”. CSF and plasma Aβ42, Aβ40, and pTau181 were assessed using the Lumipulse platform at the Wake Forest ADRC; plasma Aβ42, Aβ40, and pTau181 were also assessed using the Quanterix SIMOA platform at the National Centralized Repository for Alzheimer’s disease. CSF and plasma from each participant were collected on the same day.ResultAmyloid positive and negative groups differed significantly in age and APOE‐ε4 status (Table 1). Although raw values between plasma platforms differed significantly, biomarkers were highly correlated (Table 2). The correlation between CSF and plasma was: Lumipulse for Aβ42/Aβ40 (ρS = 0.76, p<0.0001) and pTau181 (ρS = 0.64, p<0.0001) and SIMOA Aβ42/Aβ40 (ρS = 0.63, p<0.0001) and pTau181 (ρS = 0.50, p = 0.0009). When comparing groups positive or negative for either CSF or PET, the ROC AUC for plasma Aβ42/Aβ40 was 0.94 for Lumipulse and 0.92 for SIMOA. Ptau181 AUC was 0.80 for Lumipulse and 0.82 for SIMOA. Figure 1 shows a clear relationship between decreasing Aβ42/Aβ40 and increasing pTau181 in the CSF which is present but diminished in Lumipulse plasma and largely absent in SIMOA plasma data.ConclusionRaw values from both platforms differed significantly which may limit generalizability and translatability of plasma data across platforms, but results were correlated. CSF values correlated marginally with both Lumipulse and SIMOA plasma. Plasma indices performed better than previously reported in other AD cohorts, likely due to our stringent CSF‐based selection criteria, and AUC did not differ between Lumipulse and SIMOA for either Aβ42/Aβ40 or pTau181. Further work is underway to expand the dataset and define population‐based cutoffs which also consider comorbidities, such as chronic kidney disease.
Amyloid ratios in plasma and CSF are biomarkers of pre‐symptomatic Alzheimer’s disease
Authors: Fonteh Alfred N. , Wu Xiaomeng , Astraea Natalie , Elenberger Tamara , Buennagel David P , Sin Caleb , Spezzaferri Mitchell , Rising Shant , Nolty Anne , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong 
Published: December 2023

AbstractBackgroundThe CSF amyloid to tau ratio can isolate cognitively healthy participants into normal Aβ42/tau (CH‐NAT) or a pathological Aβ42/tau (CH‐PAT) with a low or high risk of cognitive decline, respectively. We aim to determine if plasma Aβ42/tau ratios can differentiate CH‐NAT from CH‐PAT participants.MethodStudy participants (> 65 years of age) were recruited, and demographic, neurological, and neuropsychological data were obtained in an ongoing HMRI Brain Aging study. Overnight fasting plasma and CSF were collected within a month of examination, and the levels of Aβ38, Aβ40, Aβ42 (MSD 6E10 kit), and total tau were quantified using the MSD electrochemiluminescence platform. Differences in fluid biomarker levels and the plasma ratios (n = 55) and CSF ratios (Aβ42/Aβ40, n = 41, Aβ42/tau, n = 55) were determined using nonparametric student t‐test and correlations using a Spearman test.ResultAβ40 and Aβ42 levels were higher (15‐18‐fold, and 10‐14‐fold, respectively), while tau levels are 8‐13‐fold higher in CSF than in plasma. Plasma and CSF Aβ40 were not distinct in CH‐NAT compared with CH‐PAT. In contrast, Aβ42 levels were 30.9% lower in CH‐PAT (16.3 ± 18.3 pg/ml) compared with CH‐NAT plasma (23.6 ± 26.4 pg/mL) (p < 0.05). CSF Aβ42 levels in CH‐PAT (171.6 ± 124.6 pg/mL) were lower by 47.6% compared with CH‐NAT (327.6 ± 182.6 pg/ml) (p < 0.0001). The Aβ42/Aβ40 ratio was significantly lower in both plasma and CSF (Table 1A). Similarly, the Aβ42/tau ratio was significantly lower in plasma and CSF (Table 1B). Individually, plasma levels of Aβ42 and tau did not correlate with CSF levels. However, the ratio of Aβ42 to total tau in plasma significantly correlated with the CSF ratios (Spearman r = 0.36, p = 0.0071). Finally, CSF Aβ42/Aβ40 ratio correlated with Aβ42/tau ratio for all samples, CH (n = 100) and MCI (n = 35) (Fig. 1).ConclusionWhile not as robust as CSF ratios, plasma Aβ42/Aβ40 and Aβ42/tau ratios can isolate cognitively healthy participants with lower risk from participants with a higher risk of cognitive decline. Thus, plasma represents a less invasive medium for the biomarker classification of aging participants.
Rates of change in structural and functional brain connectivity are associated with longitudinal changes in episodic memory in non‐demented older adults
Authors: Alm Kylie H. , Zhu Yuxin , Soldan Anja , Pettigrew Corinne , Faria Andreia , Hou Xirui , Lu Hanzhang , Mori Susumu , Albert Marilyn S. , Bakker Arnold 
Published: December 2023

AbstractBackgroundIndividual differences in brain connectivity have been associated with cognitive variability in older adults, making them ideal markers of early changes that may predict subsequent cognitive decline. Using MRI measures, we previously demonstrated that cross‐sectionally, both structural and functional connectivity each uniquely contributed to variability in episodic memory performance (Alm et al., 2022). The present investigation expanded on these findings to examine whether longitudinal changes in brain connectivity were related to changes in episodic memory.MethodAnalyses included 152 non‐demented BIOCARD study participants (at first scan, 135 cognitively normal and 17 with Mild Cognitive Impairment). Structural connectivity was measured using radial diffusivity (RD) and mean diffusivity (MD) of two limbic pathways (fornix and hippocampal cingulum) derived from diffusion‐weighted MRI. Based on our previous findings, the salience network was chosen as the functional connectivity network of interest, as measured by resting‐state fMRI. Delayed episodic memory was evaluated with a composite score. Separate linear mixed effects (LME) models with multivariate outcomes tested whether longitudinal changes in episodic memory were related to longitudinal changes in each measure of brain connectivity (mean follow‐up = 3.11 (0.96) years), covarying age, sex, education, and diagnosis. LME models were fit simultaneously, allowing for the random effects in each model to be correlated. Significant correlations between the random slopes indicated a relationship between longitudinal changes in outcome variables.ResultLongitudinal memory decline was associated with increases in fornix RD and MD (p’s < .01) and increases in salience network functional connectivity (p < .01), but not hippocampal cingulum measures (p’s > .05). When only cognitively normal participants were included, the fornix findings remained significant (p’s < .01); however, the salience network model failed to converge.ConclusionExtending prior cross‐sectional results, these findings show that rate of memory decline over time is associated with rate of change in both structural (fornix) and functional (salience network) connectivity markers, providing further evidence that both connectivity modalities uniquely contribute to episodic memory function. These may, therefore, be important brain markers in predicting person‐specific disease trajectories, considering structural connectivity at the earliest stages of aging and functional connectivity with disease progression.