bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinguishing Early Mild Cognitive Impairment from Late Mild Cognitive Impairment through Free‐Water Diffusion Tensor Imaging: A Comparative Analysis
Authors: Bergamino Maurizio , McElvogue Molly M. , Stokes Ashley M. 
Published: January 2025

AbstractBackgroundMild Cognitive Impairment (MCI) represents an intermediate stage between normal age‐related cognitive decline and more severe degenerative conditions such as Alzheimer's disease. Understanding the differences between Early‐MCI (EMCI) and Late‐MCI (LMCI) is crucial to facilitate early diagnosis and future clinical interventions. This study employed free‐water diffusion tensor imaging (FW‐DTI) to explore the differences in white matter alterations between EMCI and LMCI. Additionally, voxel‐based correlations between FW‐DTI metrics and Mini‐Mental State Examination (MMSE)/Geriatric Depression Scale (GDS) were studied.MethodsIn this study, a total of 56 healthy controls (HCs) with a mean age <age> of 74.2 (±6.5) years, 43 individuals with EMCI with <age> of 72.1 (±8.1) years, and 28 subjects with LMCI with <age> of 73.8 (±6.0) years were included. Magnetic resonance imaging (MRI) data, acquired at 3T, were downloaded from the ADNI database. Pre‐processing steps included denoising, brain extraction, correction for eddy current, and alignment of diffusion data. FW‐DTI metrics were computed using a custom Matlab script. Statistical analysis was conducted using ANCOVA, employing a linear model with gender and age as covariates (significance for FDR<0.05). Linear models were also used for correlations.ResultsStatistical differences between EMCI and LCMI were found for MMSE (Z=4.275;p<0.001). No differences were found for GD (Table 1). Figure 1 depicts group‐wise differences in the free‐water fraction (f) and FW‐Fractional Anisotropy (FW‐FA) across all study cohorts. Differences in the f index (f‐EMCI<f‐LMCI) were found in the forceps major, corpus callosum, and right fornix between EMCI and LMCI. Differences in FW‐FA metric (FW‐FA‐EMCI>FW‐FA‐LMCI) were observed in the forceps major, corpus callosum, right sagittal stratum, and right fornix, shedding light on specific white matter tracts implicated in the progression from early to late MCI stages. Voxel‐based correlations between FW‐DTI metrics and MMSE/GD are illustrated in Figure 2.ConclusionsIn conclusion, our study reveals critical insights into the white matter changes associated with EMCI and LMCI, with significant implications for future research and clinical practice. The observed correlations between diffusion metrics and cognitive scores, mainly in LMCI group, underscore the potential of the FW‐DTI in enhancing our understanding of MCI progression and informing early diagnostic strategies.
Plasma biomarkers in dementia with Lewy bodies: evidence from memory clinic settings
Authors: Vrillon Agathe , Bousiges Olivier , Götze Karl , Demuynck Catherine , Muller Candice , Ravier Alix , Schorr Benoit , Philippi Nathalie , Cognat Emmanuel , Hourregue Claire , Dumurgier Julien , Lilamand Matthieu , Cretin Benjamin , Blanc Frédéric , Paquet Claire 
Published: January 2025

AbstractBackgroundIncreasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain.MethodWe conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n=104), Alzheimer’s disease (AD, n=76) and neurological controls (NC, n=27). Measured biomarkers included plasma Aβ ratio, p‐tau181, NfL and GFAP using SIMOA and plasma YKL‐40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n=90) were stratified according to their CSF Aβ profile.ResultsDLB patients displayed altered plasma Aβ ratio, p‐tau181 and GFAP levels compared with NC and altered plasma Aβ ratio, p‐tau181, GFAP, NfL and sTREM2 levels compared with AD patients (Figure 1, a‐f). Plasma p‐tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC]=0.80) and NC (AUC=0.78) and combining biomarkers did not improve diagnosis performance. Plasma p‐tau181 was the best standalone biomarker to differentiate amyloid‐positive from amyloid‐negative cases (AUC=0.75) and was associated with cognitive status. Combining plasma Aβ ratio, p‐tau181 and NfL increased performance to identify amyloid copathology (AUC=0.79). Principal component analysis identified different segregation patterns of plasma biomarkers in AD and DLB groups (Figure 1, g‐h).ConclusionAmyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p‐tau181 has potential contribute to identify Aβ copathology in DLB.
Synaptic proteins in pre‐symptomatic Alzheimer's disease: genes implicate synaptic biomarkers to the early detection of cognitive decline
Authors: Ao Jiarui , Labonté Anne , Picard Cynthia , Brinkmalm Ann , Blennow Kaj , Breitner John C.S. , Zetterberg Henrik , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: January 2025

AbstractBackgroundThe heterogeneous etiology of “sporadic” Alzheimer’s disease (sAD) includes genetic influences. To better understand synaptic dysfunction in AD pathogenesis, we used protein quantitative train loci (pQTL) assessments and a polygenic risk score (PRS) to examine the relationship between synaptic integrity and longitudinal cognitive performance in the presymptomatic phase of the disease.MethodThe PREVENT‐AD cohort includes symptom‐free elderly participants at risk of AD because of their family history. A second resource, the Quebec Founder Population (QFP) brain bank, derives from the descendants of the 17th and 18th century French settlers in Eastern Canada. We used Olink Proximity Extension Assays to measure the soluble synaptic proteins ADAM 22 (post‐synaptic) and ADAM23 (pre‐synaptic) in 120 CSFs, while immunoprecipitated SYT1 (pre‐synaptic) and SNAP25 (pos‐synaptic) were analyzed in 141 CSF samples using a quadrupole–orbitrap mass spectrometer. The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) indicated cognitive trajectory. Genotyping was performed using the Illumina Infinium Omni 2.5M‐8 array. Cortical RNAs (n=86) from the QFP cohort were processed using GeneChip WT Pico Kit. Statistical analyses included sex, education and APOE e4 status as covariates.ResultAmong PREVENT‐AD participants who remained cognitively unimpaired over the past 11 years, we observed significant correlations between a PRS constructed from pQTL ADAM 22 CSF concentrations and delayed memory (R2 = 0.06, p = 0.0132), visuospatial constructional memory (R2 = 0.274, p = 0.00408) and total index scale (R2 = 0.202, p = 0.0454), but only trend‐levels association with immediate memory (R2 = 0.1, p = 0.0747). We also found similar correlations between PRS constructed from of CSF ADAM 23, CSF SYT1, CSF SNAP25 concentrations and the different RBANS subscales. Significantly lower cortical mRNA levels for ADAM22 (p = 0.062), ADAM23 (p = 0.0030), SYT1 (p = 0.033) and SNAP25 (p = 0.0036) were found in the autopsied AD brains compared to autopsied control brains.ConclusionCSF synaptic protein levels show promising correlations with emerging cognitive deficits and provide insights toward a possible compensatory mechanism in the early presymptomatic phase of the disease.
Comparison of olfactory and cognitive measures to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort
Authors: Devanand Davangere , Lee Seonjoo , Knopman David S. , Vassilaki Maria , Luchsinger Jose A. , Motter Jeffrey N 
Published: January 2025

AbstractBackgroundInexpensive, non‐invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro‐imaging biomarkers to predict cognitive decline and dementia in the population‐based Mayo Clinic Study of Aging (MCSA).MethodAt the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow‐up had the following procedures: modified Blessed Information‐Memory‐Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C‐Pittsburgh compound B (11C‐PiB). A subsample (n=556) also had 18F‐fluorodeoxyglucose (18F‐FDG) PET scans. The utility of these baseline measures to predict cognitive decline (cognitively unimpaired to mild cognitive impairment [MCI] or dementia, or MCI to dementia) was examined during follow‐up (mean 8.1 SD 3.4 years). Transition to dementia was a secondary outcome.ResultAmong 647 participants without dementia (mean age 74.0 SD 8.1 years; 54.4% male) at baseline, 102 participants manifested cognitive decline and 34 participants transitioned to dementia. In Cox regression survival analyses for cognitive decline, PiB PET showed the strongest predictive utility (hazard ratio HR 5.05, 95% CI = 3.32‐7.69, p<.001). Impaired BSIT (HR 3.46, 95% CI = 2.34‐5.11, p<.001), impaired BIMCT (HR 3.63, 95% CI 2.46‐5.36, p<.001), MRI and FDG measures were also significant predictors. After adjusting for age, sex and education, these predictors remained significant with attenuated effects (PiB HR 3.89, 95% CI 2.54‐5.95, p<.001; BSIT HR 2.77, 95% CI 1.85‐4.14, p<.001; BIMCT HR 3.3, 95% CI 2.21‐4.95, p<.001). After adding these demographic variables in the model, the combination of BSIT and BIMCT showed strong predictive utility (C‐index=0.85), similar to PiB PET (C‐index=0.84). Combining all predictors showed a C‐index of 0.89. These measures showed similar but stronger results for dementia transition.ConclusionTests of global cognition and odor identification provide a brief, non‐invasive, inexpensive method comparable to PET amyloid imaging for identifying community‐dwelling persons likely to decline cognitively or transition to dementia. Other potential uses for this combination include identification of persons likely to benefit from disease‐modifying medications and determination of eligibility for prevention trials.
The relationship between amyloid burden, hippocampus, and cholinergic integrity
Authors: Lee Li‐Hua 
Published: January 2025

AbstractBackgroundHippocampal atrophy and degeneration of cholinergic pathways are prominent neuroimaging findings in early Alzheimer’s disease (AD). However, whether these image findings are related to amyloid accumulation is still debated.MethodFrom 2021 to 2023, we recruited 116 participants from memory clinic in Cardinal Tien Hospital, Taipei, Taiwan. All our participants received complete neuropsychological tests, 3.0 T brain MRI and amyloid positron emission tomography (PET). Hippocampal volumes were measured through high‐resolution T1 weighted images. DTI metrics such as MD (mean diffusivity) or FA (fractional anisotropy) values were derived from DSI studio. In this study, we use cingulum bundle, external capsule and uncinate fasciculus to simulate cholinergic pathway.ResultOur study included 41 healthy individuals, 61 with mild cognitive impairment (MCI), and 14 with mild dementia. Significant differences were observed across these groups in hippocampal volumes, MD values of cholinergic tract, and amyloid SUVR values. Our linear regression analysis, which adjusted for variables including sex, age, and education level, demonstrated that these three neuroimaging markers are significant predictors of cognitions. Notably, the analysis revealed that hippocampal volume, amyloid SUVR and the MD values of the cholinergic pathways independently predict the severity of cognition. When evaluating the association between amyloid SUVR, hippocampal volume and cholinergic integrity by multilinear regression models which were controlled with age, sex, and presence of APOE4 carrier status, we found that hippocampal volume is significantly associated with the amyloid burden (β = −0.215; p = 0.022), while cholinergic MD values are not related to amyloid SUVR.ConclusionAmyloid accumulation is associated with hippocampal atrophy, but not cholinergic integrity in our study. The impairment of cholinergic integrity may be due to etiologies other than amyloid. Neuroimaging markers focusing on cholinergic integrity should be closely observed independently from others. Multitargeting treatments, in addition to anti‐amyloid, may be required for better efficacy in the prevention and treatment of cognitive decline in AD.
Therapeutic effects of class I HDAC inhibitor CI‐994 in Alzheimer’s disease
Authors: Lu Wenyan , Kawatani Keiji , Jeevaratnam Suren , Bu Guojun , Kanekiyo Takahisa , Li Yonghe 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of age‐related dementia, and the presence of amyloid‐β (Aβ) plaques and tau‐containing neurofibrillary tangles is associated with the neurodegeneration and cognitive impairment in this incurable disease. Growing evidence shows that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in AD, and HDACs have been highlighted as a novel class of anti‐Alzheimer targets. Moreover, restoring Wnt/β‐catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy for AD. CI‐994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI‐994 can cross the blood‐brain barrier and is a cognitive enhancer.MethodWe evaluated the therapeutic potential of CI‐994 in human patient‐specific iPSC‐derived neurons and cerebral organoids with APOE ε4/ε4 genotype or carrying MAPT p.P301L mutation.ResultWe found that CI‐994 is not only a potent class I HDAC inhibitor but also a novel modulator of Wnt/β‐catenin signaling, and that activation of Wnt/β‐catenin signaling by CI‐994 is associated with elevated Wnt co‐receptor LRP6 protein level. Moreover, CI‐994 increased synaptic protein levels, enhanced spontaneous synaptic firing and network formation, and decreased tau phosphorylation in iPSC‐derived neurons. Finally, CI‐994 significantly increased histone acetylation, activated Wnt/β‐catenin signaling, and decreased Aβ production and tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids.ConclusionOur findings indicate that CI‐994 is a novel potential therapeutic candidate for AD.
Multichannel template‐based spatial normalization precision in older adult brain QSM
Authors: Abid Rasheed , Niaz Mohammad Rakeen , Ridwan Abdur Raquib , Wu Yingjuan , Evia Arnold M , Bennett David A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundQuantitative Susceptibility Mapping (QSM) offers significant potential for studying metal and iron homeostasis in the brain and serves as a diagnostic tool for various pathologies, such as Alzheimer’s disease. However, the precision of QSM spatial normalization for older adults depends on the quality and representativeness of the chosen template and the type of information used during image registration. This study compares three available QSM templates in terms of their representativeness and precision of inter‐subject matching for older adult QSM data.MethodThe study used 3D T1‐weighted MPRAGE and multi‐echo 3D GRE data from 100 non‐demented older adults (aged 67.8‐97.2 years). QSM templates from the recently developed MIITRA templates were compared with two other publicly available templates (HybraPD and MuSus‐100). Five registration pipelines using ANTS image registration toolbox were employed. Single‐channel registration of the susceptibility maps to QSM templates, multichannel registration of T1‐weighted images and susceptibility maps to T1‐weighted and QSM templates (at 25%, 50% and 75% weights correspondingly) and finally, single‐channel registration of T1‐weighted images to T1‐weighted templates. Average log‐Jacobian maps of deformations were generated for each participant. Finally, inter‐subject pairwise (100x99/2 = 4950 pairs) normalized cross‐correlation of magnetic susceptibility maps of participants in template space was calculated for each registration approach.ResultSpatial normalization of older adult brains required less deformation when registering to MIITRA templates compared to other templates, indicating that MIITRA templates are more representative of the older adult brain (Figure 1). Furthermore, pairwise normalized cross‐correlation was higher when using single‐channel registration of susceptibility maps to QSM templates than other methods (Figure 2). Overall, the highest spatial matching of magnetic susceptibility maps of the older adult brains was achieved when using single‐channel registration of magnetic susceptibility maps to MIITRA‐QSM template.ConclusionThe study highlights the importance of template and registration pipeline selection in spatial alignment of magnetic susceptibility maps of the older adult brain. The MIITRA atlas proved more representative of the older adult brain, as evidenced by lower deformation requirements. Single‐channel registration of magnetic susceptibility maps of older adult brains to the MIITRA‐QSM template allowed higher inter‐subject spatial matching compared to other available templates.
Application of blood biomarkers for the future anti‐Aβ antibody therapy in Japan
Authors: Kasuga Kensaku , Tsukie Tamao , Igarashi Kazuya , Ishiguro Takanobu , Miyashita Akinori , Onodera Osamu , Ikeuchi Takeshi 
Published: January 2025

AbstractBackgroundWith the approval of Lecanemab in Japan following the U.S., biomarker‐based diagnosis of AD will be required in daily practice. However, PET or CSF are limited by cost, low availability, and invasiveness. In addition, frequent MRI is required to monitor amyloid‐related imaging abnormalities (ARIA), an adverse event unique to anti‐Aβ antibodies. Blood biomarkers are expected to be inexpensive, less invasive, and acceptable for frequent testing in daily practice.MethodOf the cases analyzed for AD‐related CSF biomarkers for diagnostic purposes from Department of Neurology, Niigata University and related facilities, 217 plasma available cases were included. Of the 217 cases, 113 were clinically diagnosed as Alzheimer's clinical syndrome (ACS) and 104 as non‐ACS, including 6 cerebral amyloid angiopathy related inflammation (CAAri) cases. CSF Aβ42/40 ratio, phosphorylated tau (pTau181), neurofilament light chain (NfL), and plasma pTau181 and NfL were measured. According to the research framework, AD was determined when both CSF Aβ42/40 ratio (as A marker) and CSF pTau181 (as T marker) were positive. The ROC curve was used to verify the accuracy of plasma pTau181 in differentiating AD from non‐AD, and the accuracy of plasma NfL in differentiating AD from CAAri, which has been suggested to share a common pathology with ARIA.ResultPlasma pTau181 differentiated AD group (CSF A+T+) from non‐AD group with high accuracy (AUC = 0.867). Plasma pTau181 also differentiated A+ group from A‐ group with high accuracy (AUC = 0.913, sensitivity 89.7%, specificity 82.9%). When the low‐risk threshold was made more stringent (Sensitivity 90%, 95%, 100%), negative predict value increased (78.1%, 88.9%, 100%). When the high‐risk threshold was made more stringent (Specificity 90%, 95%, 100%), positive predictive value increased (78.1%, 88.9%, 100%). However, as a trade‐off, the number of the intermediate risk group increased (16%, 35%, 81%). Plasma NfL discriminated CAAri group from AD group (ACS and CSF A+T+) with high accuracy (AUC = 0.947).ConclusionIn Japanese clinical practice, plasma pTau181 is considered to be useful for detecting AD pathology, and is expected to be utilized for screening of anti‐Aβ antibody therapy. Plasma NfL may also be useful in screening for adverse events of anti‐Aβ antibodies.
Increased levels of Matrix Metaloproteinase‐10 and Adenosine Deaminase in blood are associated with reduced cognition
Authors: Michopoulou Sofia , Amin Jay , Kipps Christopher , Sussams Rebecca , Lunnon Katie , Holmes Clive , Teeling Jessica 
Published: January 2025

AbstractBackgroundNeuroinflammation and activation of the immune system can influence Alzheimer’s disease (AD) progression. This is mediated by inflammatory molecules, which exacerbate the production of β‐amyloid, the propagation of tau pathology, and neuronal loss. By measuring CSF markers of inflammation in a heterogeneous clinical cohort we found that levels of Adenosine Deaminase (ADA) and Matrix‐Metaloproteinase‐10 (MMP‐10) increase in patients with AD.Despite promising results of immune markers in CSF, a substantial limitation for wide clinical application is the requirement for a lumbar puncture, which is an invasive procedure only available in specialist settings. Using alternative fluid markers, such as blood sample measurements, would enable wider use of immune markers in AD diagnosis.Here we evaluate if measurement of ADA and MMP‐10 markers in blood samples is associated with cognitive decline.MethodBlood samples from 98 participants, including 41 healthy controls and 57 patients with amnestic mild cognitive impairment (aMCI) in the ICOS study were analysed. Participants were monitored at six‐monthly intervals over two years. Blood samples obtained during the third monitoring visit at 12 months post recruitment were analysed in this study. The levels of MMP‐10 and ADA in these samples were measured using the OLINK platform. Correlation analysis and Receiver Operator Characteristic (ROC) curves were used to evaluate if these markers of inflammation are associated with cognitive function.ResultADA, an enzyme that regulates immune homeostasis, showed a weak but statistically significant increase in blood concentration with decreasing MoCA cognitive test scores (Rho=‐0.2, p=0.023). MMP‐10, an enzyme involved in blood brain barrier function, also showed a weak but statistically significant increase with decreasing MoCA scores (Rho=‐0.25, p=0.006).ROC analysis indicates that both ADA and MMP‐10 are weak predictors of amnestic MCI. They can differentiate between healthy controls (MoCA 26‐30) and patients with aMCI (MoCA 18‐25) with Areas Under the Curve of only 0.57 and 0.64, respectively.ConclusionIn this study, blood levels of ADA and MMP‐10 were significantly associated with cognitive impairment. Their predictive ability of aMCI is weak and further work is required to establish the prognostic capabilities of immune markers in blood samples in larger patient cohorts.