bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Time‐Delayed Effective Connectivity for Normal Cognition and MCI under Motion Detection Tasks: an EEG Study
Authors: Sun Boxin , Deng Jinxian , Renli Alina Brighty , Kavcic Voyko , Ren Jian , Giordani Bruno , Zhang Rong , Li Tongtong
Published: January 2025

Background

Existing work suggested that AD pathology can affect the direction and intensity of information signaling in functional brain regions. The present study evaluates the time‐delayed effective connectivity of normal controls (NC) and patients with mild cognitive impairment (MCI) under motion‐detection tasks and explores identification of possible anomalies and deviated patterns in effective connectivity associated with AD pathology.

Method

Our research focuses on task‐based EEG (64‐channel), where participants were asked to perform a motion direction discrimination task. The current dataset includes 56 consensus‐diagnosed, community‐dwelling African Americans with subjective cognitive complaints (ages 60‐90 years, 28 normal controls (NC) and 28 MCI patients) recruited through the Wayne State Institute of Gerontology and Michigan Alzheimer’s Disease Research Center.

The successive motion‐task performance periods examined include: (I) stimulus onset to Go/No‐Go indication, (II) Go (or No‐Go) indication to motion‐stop, and (III) the Button‐Press period. For each period, we evaluated the time‐delayed effective connectivity across all the possible EEG region pairs using causalized convergent cross‐mapping (cCCM) of the current source density. For each region pair, the delay (within 50ms) that results in the largest cCCM value (which reflects the intensity of the information flow) is taken as the dominant delay. Within the NC/MCI group, the directed signaling path (with cCCM value > 0.7) that appears in more than 80% of the participants is defined as a common active path of the group.

Result

Our analysis shows that: (i) Delayed effective connectivity is noticeably stronger than its zero‐delay counterpart, indicating the existence of non‐zero transmission delays in inter‐region information transfer; (ii) NC and MCI may share common active paths, but each group has their own, unique common paths; (iii) Both NC and MCI groups have fewer common active paths in the Go and Button‐Press periods than during the stimulus onset and No‐Go periods, which may imply that brain effective connectivity is more focused during task execution.

Conclusion

Time‐delayed effective connectivity analysis may enable identification of possible signaling pathways in the brain and of dissimilarities in pathway usage between NC and MCI associated with AD pathology.

Funding: NSF‐2032709/Li; NIH‐1R21AG046637‐01A1/Kavcic; NIH‐1R01AG054484‐01A1/Kavcic; NIH‐P30AG072931/Paulson; NIH‐P30AG024824/Yung.
Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in mild cognitive impairment (MCI)
Authors: Madrid Andy , Breen Coleman E , Papale Ligia A , Clark Lindsay R. , Asthana Sanjay , Johnson Sterling C. , Keles Sündüz , Hogan Kirk J. , Alisch Reid S
Published: January 2025

Background

Whole genome methylation sequencing (WGMS) in blood identifies extensive differential DNA methylation between persons who are cognitively unimpaired (CU) and those with late‐onset dementia due to Alzheimer’s disease (AD). Here we investigate differentially methylated positions (DMPs) in persons with mild cognitive impairment (MCI) compared to persons with and without AD.

Method

WGMS data quantified DNA methylation levels at 25,406,945 CpG loci in 382 blood samples from 99 persons with MCI, 109 persons with AD and 174 cognitively unimpaired persons in the Wisconsin Alzheimer’s Disease Research Center (WADRC) and the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Beta‐binomial models were developed to test for significant DNA methylation levels between groups, accounting for batch effects, estimated white blood cell proportions, sex, body mass index (BMI), and age. P‐values were corrected and a local false discovery rate (lFDR) was computed.

Result

WGMS identified 10,262 MCI‐associated DMPs (Figure 1). We identified 1,984 genes comprising one or more DMPs (e.g., ACE, ANK3, and HLA‐DQA1) encode proteins that participate in biological pathways relevant to neuronal function including synapse organization, dendrite formation and potassium ion transmembrane transport. Interrogation of DMPs among all two‐group comparisons (i.e., MCI:CU, AD:CU, and AD:MCI) identified 65 overlapping DMPs (Figure 2). Twelve of the overlapping DMPs are associated with 4 genes. Neighboring TDG and C12orf73 share 10 DMPs on chromosome 12q23.3, FHIT and RXFP1 comprise 1 DMP each. The remaining shared 53 DMPs are intergenic. We further investigated DMPs with progressive changes in DNA methylation levels from CU to MCI to AD. We identified 570 DMPs with increasing or decreasing DNA methylation levels were identified, including DMPs in enhancer‐promoter interactions in genes previously associated with AD, including KANSL1 (Figure 3).

Conclusion

WGMS identifies differentially methylated CpGs in known and newly detected genes and enhancers in blood from persons with and without MCI and AD and reveals progressive dysregulation of DNA methylation levels between CU, MCI, and AD.
Effects of Intermittent Theta Burst Preconditioning on 40Hz Gamma Wave Synchronization
Authors: Ahn Donghyun , Roh Sungwon , Lee Haram , Kim Haein , Lee Youngseok , Jeon Jin Yong
Published: January 2025

In the treatment of Alzheimer’s disease (AD), traditional 40Hz gamma wave stimulation, while effective in improving cognitive function, has been limited by the lengthy duration of treatment. To address this, our study sought to enhance the time efficiency of 40Hz stimulation by utilizing intermittent theta‐burst stimulation (iTBS) as a pretreatment. Experiments were conducted on AD mouse models, divided into four groups: no stimulation, 40Hz stimulation only, iTBS stimulation only, and combined iTBS and 40Hz stimulation. The groups were assessed for cognitive function and behavioral changes, as well as neuro‐pathological indicators.

The results revealed that the group receiving combined iTBS and 40Hz stimulation showed significant improvements in cognitive function and behavior from the fifth day of treatment, compared to the groups receiving only a single type of stimulation. This indicates that the combined stimulation is not only effective but also significantly reduces the treatment time, demonstrating rapid effects. Therefore, the combination of iTBS and 40Hz stimulation presents a new approach in AD treatment, enhancing both time efficiency and therapeutic effectiveness. These findings offer important implications for future clinical research and applications.
Preclinical efficacy and rationale of targeting lysine280‐acetylated tau for Alzheimer’s disease therapy with ADEL‐Y01, humanized monoclonal antibody
Authors: Kim Min‐Seok , Song Ha‐Lim , Kim Na‐Young , Mun Yeon‐Seon , Kim Dong‐Hou , Yoon Seung‐Yong
Published: January 2025

Background

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer’s disease (AD) can be explained by prion‐like cell‐to‐cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding‐ and propagation‐competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies including AD. However, the mechanism that links tau acetylated on lysine 280 (tau‐acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau‐acK280 is critical for tau propagation processes including secretion, aggregation, and seeding.

Method

We developed an antibody, Y01, that specifically targets tau‐acK280, tested its efficacy in vitro and in vivo tauopathy models, and solved the crystal structure of Y01 in complex with an acK280 peptide.

Result

Upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau transgenic mice through antibody‐mediated neutralization and phagocytosis, respectively. Crystal structure confirmed that Y01 directly recognizes acK280 and the surrounding residues.

Conclusion

Based on our observations that tau‐acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy. ADEL‐Y01 is currently undergoing a phase‐1 clinical trial in the United States through a collaborative effort between ADEL and Oscotec.
Polyphenols derived from Sorghum bicolor grains exhibit the ability to alleviate amyloid beta in Alzheimer’s Disease
Authors: Abdulraheem Rasheed A. , Bharadwaj Prashant , Li Zhaoyu , Coorey Ranil , Johnson Stuart , Martins Ralph N , Fernando Warnakulasuriya Mary Ann Dipika Binosha
Published: January 2025

Background

Accumulation of amyloid beta 42 (Aβ42) senile plaques is the most critical event leading to Alzheimer’s disease (AD). Currently approved drugs for AD have not been able to effectively modify the disease. This has caused increasing research interests in health beneficial nutritious plant foods as viable alternative therapy to prevent or manage AD. Sorghum bicolor presents strong antioxidants, anticancer, anti‐inflammatory and antidiabetic properties. However, there is no published data on how this widely available and cost‐effective food could benefit people living with AD.

Method

Polyphenols were extracted from three Sorghum varieties with black, reddish‐brown, and red pericarp. The individual polyphenols compounds were identified using an Agilent 1290 infinity 2 UHPLC system coupled to an Agilent 6475 LC‐QQQ LC‐MS/MS. The polyphenol extracts were screened using in‐silico, MC65 cell and Caenorhabditis elegans AD models. The activities of the extracts against Aβ42 aggregation were analyzed using molecular docking, fluorescence, toxicity, and healthspan assays.

Result

Through the application of molecular docking, polyphenols extracted from Sorghum bicolor grains were identified for their potential to inhibit Aβ42 aggregation. Positive interactions were observed between the polyphenols and Aβ42. Cell studies indicated increased viability of MC65 cells, possibly attributed to the inhibition of Aβ42 aggregation. In the Alzheimer’s disease model of Caenorhabditis elegans, enhanced body bending, and pharyngeal pumping were observed compared to controls, suggesting a reduction in pathology. The order of activities was found to be red pericarp < reddish‐brown pericarp < black pericarp sorghum.

Conclusion

The polyphenol extracts from black pericarp Sorghum bicolor grain could be a candidate ingredient in the development of complementary dietary supplement for AD therapy. Future investigation include lifespan, and fluorescence imaging to unravel the mechanisms underlying the observed health benefits prior to study in AD animal models.
Prefrontal cortex functioning in simple and choice stepping in older adults with mild to moderate dementia – A functional near‐infrared spectroscopy (fNIRS) cross‐sectional study
Authors: Chan Wayne LS , Yeung Michael KC , Tam Yee Kiu , Tang Pui Man , Wong Ka Chun , Wong Ka Long , Wong Lok Yiu
Published: January 2025

Background

Older adults with dementia have a high fall risk. Choice stepping (i.e., being able to execute rapid, accurate and efficient steps to reach a designated target) is an important indicator of the risk of falls in older adults. Choice stepping performance is determined by both physical (e.g., dynamic balance) and cognitive function (e.g., executive function). The prefrontal cortex may play an important role in mediating choice stepping performance. However, the prefrontal cortex activity of older adults with dementia in choice stepping is unclear.

This study aims to evaluate and compare the activity of the prefrontal cortex in simple and choice stepping in healthy older adults and older adults with mild to moderate dementia.

Methods

This study was a cross‐sectional study. Twenty‐nine healthy older adults and 28 older adults with a diagnosis of mild to moderate dementia who could walk for 10 meters independently were recruited. Hemodynamic changes occurring in the participants' prefrontal cortices during simple and choice stepping were recorded by multichannel fNIRS. Choice stepping reaction time test was used to evaluate the choice stepping performance of the participants.

Results

The choice stepping reaction time of the dementia group was significantly higher than that of the healthy control group (p < .001). The activations of several areas of the prefrontal cortex (left dorsolateral, left ventrolateral, left and right orbitofrontal cortices) during choice stepping tasks were significantly increased in the dementia group compared to the control group (all p < .047). A significantly higher activation in the right frontopolar cortex was also found in the choice stepping task compared to that in the simple stepping task in the dementia group (p = .040).

Conclusion

Older adults with mild to moderate dementia showed a higher prefrontal cortical activation during choice stepping compared to healthy older adults. Choice stepping may demand more on the executive function of older adults with mild to moderate dementia compared to healthy older adults. Further studies using a larger sample size are required to explore the prefrontal cortical activity during different stepping tasks in older adults with dementia.
Multidimensional Modeling of Biological Aging: Integrating Gait, Eye Movement, Rest‐State Functional Connectivity, and Plasma Biomarkers in non Dementia Elderly Individuals
Authors: Lin Jingyi , Ouyang Ziyu , Xu Tianyan , Shen Lu , Jiao Bin
Published: January 2025

Background

Aging exhibits significant variation among individuals, with biological age as a more reliable predictor of current health status compared to chronological age. Predicting biological age is crucial for facilitating timely interventions aimed at improving the adaptation to the aging process. Given the intricate and multifactorial nature of aging, a scientific approach involves constructing a prediction model for biological age that incorporates multiple dimensions systematically.

Method

This study enrolled 908 non‐dementia elderly participants, and their eye movement, gait, rest‐state functional connectivity (rs‐FC), and plasma GFAP and NfL level were measured. These parameters were used to assess an individual's biological age using logistic regression.

Result

We identified 26 gait features, 2 eye‐tracking features, 19 rs‐FC features, and plasma GFAP level that exhibited significant correlations with age (p<0.05). Initially, prediction models were constructed separately using different categories of indices. Notably, gait features demonstrated robust prediction performance for age (R2=0.783; MAE=1.852). Subsequently, combining all indicators for the prediction model resulted in an exceptional level of performance (R2=0.939; MAE=1.080).

Conclusion

A quantitative model of biological age was successfully constructed from a multi‐dimensional and systematic perspective, proving effectiveness in predicting an individual's biological age. This comprehensive approach, incorporating diverse indices, enhances the accuracy and reliability of age prediction models.
Non‐invasive quantification of [18F]‐PI‐2620 binding to tau deposits in the brain using an image‐derived input function
Authors: Bhattarai Anjan , Holy Emily Nicole , Wang Yiran , Spencer Benjamin A. , Wang Guobao , DeCarli Charles S. , Fan Audrey P.
Published: January 2025

Background

This study quantified tau binding in the brain with 18F‐PI2620 PET using a non‐invasive Image‐Derived Input function(IDIF), derived using a new total‐body EXPLORER PET/CT scanner (Spencer et al.,2021). Additionally, we explored how PET scan duration influences the quantification of kinetic parameters across brain regions of interest(ROIs) that are vulnerable in Alzheimer’s Disease.

Method

The study cohort included 15 individuals (10 cognitively unimpaired, 3 mild cognitive impairment, and 2 AD; ages=68‐92 years; all tau negative) from the UC Davis ADRC. Dynamic total‐body 18F‐PI‐2620 PET images were acquired over 90 minutes using the uEXPLORER (resolution=2.344 mm isotropic voxels, framing protocol:30×2s,12×10s,7×60s,16×300s). Brain cropped PET images were motion corrected (Jenkinson et al.,2002), and linearly registered to individual T1‐weighted(T1W) MRIs (Jenkinson & Smith, 2001). Grey matter ROIs, including the medial temporal(MT), posterior cingulate(PC), and lateral parietal(LP) cortices, were obtained parcellating T1W images (Desikan et al.,2006).

Dynamic time activity curves for each brain ROI were fitted to a reversible two‐tissue compartmental model(2TCM), accounting for delay, using a subject‐specific IDIF(plasma and metabolite‐corrected) derived from the descending aorta of the same images (Figure 1). ROI‐specific micro and macro kinetic parameters were estimated. Logan graphical analysis (Logan,2000) was also used to estimate total distribution volume(VT).

Result

2TCM with IDIF demonstrated high‐quality fits of 18F‐PI2620 binding across grey matter ROIs (Figure 1). Perfusion (K1) was observed to be reduced in MT compared to PC and LP (Figure 2A).

All kinetic parameters remained relatively stable after the 60‐minute scan window across all ROIs. Notably, K1 showed stability after 30 minutes of scan duration across all ROIs (Figure 2 and 3).

A strong correlation was observed between VT estimated using 2TCM and Logan plot analysis, across all ROIs LP(r=1.00, p<0.001), MT(r=0.96, p<0.001), PC(r =1.00, p<0.001).

Additionally, significant negative correlation was observed between binding potential and perfusion across all ROIs (r=‐0.40, p=0.007).

Conclusion

This study highlights the utility of a non‐invasive descending aorta IDIF derived using a total‐body EXPLORER PET/CT scanner to quantify 18F‐PI‐2620 grey matter kinetics. Preliminary findings suggest that a 60‐minute scan window may be sufficient for reliable quantification of kinetic parameters, while a 30‐minute scan time may suffice for perfusion alone. These findings warrant validation in a cohort involving tau positive individuals.
Neural Correlates of Dual‐Functional Local Dynamic Stability in Older Adults
Authors: Zhou Sa , Lin Feng Vankee
Published: January 2025

Background

To maintain local dynamic stability (LDS), both cognitively and physically, without being interfered with by internal or external disturbance is important for functional independence but declines as ages. However, some older adults are capable of high dual‐functional LDS. Understanding the brain differences between these older adults and their counterparts may help discover protective mechanisms for functional independence in old age. The purpose of the study was to compare the brain topology between older adults with heterogenous dual‐functional LDS.

Method

Cognitively and physically healthy older individuals (n = 52) were recruited and categorized into four groups (low cognitive/low physical, low cognitive/high physical, high cognitive/low physical, and high cognitive/high physical LDS groups) based on the intra‐individual variability of performance in selected cognitive and physical tasks relying on speed processing and attention. Brain topology was measured via diffusion tensor imaging and quantified with clustering coefficients reflecting segregation and characteristic path lengths reflecting integration, respectively, based on graph theory methods.

Result

After correcting for multi‐comparison, the high dual‐functional LDS group exhibited significantly higher integration between the inferior frontal and postcentral areas but lower integration between the frontal and temporary areas within the left hemisphere, compared to the other three low cognitive/physical stability groups.

Conclusion

Integration in selective brain networks may contribute to maintaining the dual‐functional LDS in older adults.
Genetics, atrophy, liquid biomarkers and cognitive tests in Alzheimer’s disease: an integrated and multimodal analysis pipeline to understand the neurodegenerative mechanisms
Authors: Squillario Margherita , Reggiani Francesco , Pardini Matteo , Piana Michele
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly (50–75%) and the causes of the sporadic form are not yet clear. The genetic predisposition is relevant (60–80%), but alone is not sufficient to trigger those initial processes that lead to neurodegeneration and to the slowly atrophy of the brain. Several public datasets containing multimodal data centered on AD have emerged since the beginning of 2004 when ADNI come out. An appropriate integration of various data types (e.g., biomedical images, GWAS/WES, cognitive tests, liquor protein expression) is pivotal to understand this phenomenon.

Methods

Objective 1: we will develop a merged multimodal AD‐centered dataset from a careful selection of public database. Objective 2: we will develop a user‐friendly analysis tool starting from the multikernel/deep learning pipeline devised to properly address the analysis of multimodal data. Objective 3: in the merged multimodal AD‐centered dataset we will evaluate the predictive performance of gene‐SNPs panels, retrieved from the literature, using the developed tool. We will identify clusters of genes‐SNPs (of the panel) and of specific neurodegenerative markers correlating with the atrophy (measure by FDG‐PET) of the most affected brain regions through a weighted correlation network analysis (WCNA). Objective 4: we will validate those clusters in silico, in an independent partition of the merged multimodal dataset and/or in independent AD public dataset.

Results

The analysis of the merged multimodal AD dataset with the proper multimodal‐oriented tool, will identify genes‐SNPs signatures that correlate with atrophy starting from (i) promising genes‐SNPs panels identified in the literature and (ii) neurodegenerative biomarkers (identified in cognitive tests, abundance protein dataset, imaging data) that correlate more strongly with atrophy.

Conclusions

The final aim of the integrated multimodal dataset explored with the multimodal‐oriented analysis tool is to verify the existence of endophenotypes characterizing groups of AD patients defined based on the different brain‐region atrophic component.
The cerebrospinal fluid Neutrophil gelatinase‐associated lipocalin (NGAL) concentration in Alzheimer’s Disease (AD)
Authors: Doroszkiewicz Julia , Kulczynska‐Przybik Agnieszka , Borawska Renata , Mroczko Jan , Slowik Agnieszka , Mroczko Barbara
Published: January 2025

Background

Alzheimer’s disease (AD), a prevalent neurological illness, is the most common form of dementia worldwide. Given that AD symptoms manifest gradually, it is imperative to discover new biomarkers that support early diagnosis of this diseases. Some research indicates that Neutrophil gelatinase‐associated lipocalin (NGAL) may influence a number of neurobiological processes, including inflammation occurring in the central nervous system. Moreover, this protein was discovered in brains of AD patients. Literature data suggests that NGAL could be a potential biomarker of severity of Alzheimer’s disease. Therefore, the purpose of our research was to assess the usefulness of the measuring of the concentration of soluble NGAL in cerebrospinal fluid in the diagnosis of AD patients as well as compare it with classical AD biomarkers.

Method

The concentrations of NGAL were measured in cerebrospinal fluid (CSF) of 20 AD patients and 20 non‐demented controls using ELISA method. Classical biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181 were assessed by immunoenzyme assays.

Result

NGAL concentrations were significantly higher in AD patients in comparison to non‐demented controls. Additionally, increased CSF levels of NGAL correlated positively with Tau and pTau181 proteins as well as negatively with Aβ‐42/Aβ‐40 ratio in the whole study group.

Conclusion

Findings of our research suggest a potential role of NGAL in pathology of AD. However, follow‐up studies on larger study group are needed.
Resting‐state activity across cortical hierarchies provides readiness for memorizing in aging humans
Authors: Han Feng , Chen Xi , Varghese Leah , Cassady Kaitlin , Chadwick Trevor , Mason Suzanne , Jagust William J.
Published: January 2025

Background

The neural basis of memory aging remains elusive. The default mode network (DMN) supports memory encoding and retrieval, and its connectivity decreases in aging. Young adults with larger differences in resting‐state functional connectivity (rsFC) between higher‐order DMN and lower‐order sensory/motor network (SMN) have better cognition and memory. We combined resting‐state and task‐based fMRI during an associative memory task to explore how this cross‐hierarchical contrast of rsFC is linked to memory aging.

Method

We included resting‐state prior to (an object‐scene‐pair encoding) task fMRI from 16 young adults (YA; 24.6 ± 3.6 years; 7 females) and 42 cognitively normal older adults (OA; 76.8 ± 6.9 years; 24 females) in the Berkeley Aging Cohort Study. We subtracted the averaged rsFC within lower‐order regions from higher‐order ones, and correlated the cross‐hierarchy contrast of rsFC with age and memory task performance. Brain function contrast between the higher and lower order regions may also manifest as the temporal difference/delay of cortical activation, seen in propagating waves between hierarchical cortices. The propagating number (i.e., frequency) in each direction (“High‐to‐low” or “Low‐to‐high”) was therefore also correlated with memory performance and activation in anterior‐temporal (AT), posterior‐medial (PM), and hippocampal (HPC) memory regions during task‐fMRI.

Result

Among OAs, cross‐hierarchy contrast of rsFC decreased with aging (Spearman’s ρ = ‐ 0.32, p = 0.040) and in females (p = 2.3 ×10‐3). OAs with lower rsFC contrast had worse memory during retrieval (ρ = 0.36, p = 0.019; Figure 1). Memory scores were not correlated with mean rsFC within higher‐order regions or lower‐order ones. Propagating number along the “Low‐to‐high” direction decreased in OAs. More propagation was associated with better memory and lower task‐evoked activation in AT, PM, and HPC regions (all ρ strength > 0.35, p < 0.030; Figure 2&3).

Conclusion

Patterns of resting‐state functional connectivity related to hierarchical cortical organization are associated with aging and memory decline. In particular, slow propagating waves of cortical activation transiting across these hierarchies may serve a preparatory function, readying the brain for memory formation, a process that is affected by aging.
A comparison of tau aggregation and seeding competency of anti‐tau antibodies under clinical trials and their target epitopes itself
Authors: Kim Min‐Seok , Song Ha‐Lim , Yoon Seung‐Yong
Published: January 2025

Background

Abnormal aggregation and accumulation of tau is a hallmark of tauopathy including Alzheimer’s disease. Effective targeting of tau for therapeutic purposes requires a clear understanding of its epitope landscape with identification of a key pathogenic tau species. Despite numerous proposed and tested tau epitopes, ranging from the N‐terminus to the microtubule‐binding region and C‐terminus, the most effective target remains elusive.

Method

We compared the impact of tau aggregation and seeding using various peptides representing epitopes of anti‐tau antibodies in clinical trials or fragments of the MTBR found in the cerebrospinal fluid of tauopathies. We also evaluated the effects of several tau antibodies on the inhibition of tau aggregation and seeding using recombinant tau protein or AD brain extracts.

Result

Peptide containing acetylated lysine‐280 was most potent on tau seeding measured by tau‐FRET and on inducing tau aggregation evaluated by thioflavin T compared to other peptides. Further, inhibition of tau aggregation and seeding was most prominent in anti‐acetylated lysine‐280 antibody‐treated cells.

Conclusion

Our results demonstrate that acetylated lysine‐280 is the most potent inducer of tau aggregation and seeding. These findings offer valuable insights into the design of tau‐targeted therapeutics and highlight acetylated lysine‐280 as a promising target for the treatment of tauopathies.
Towards Automatic Early Detection: Assessing LANGaware's Language and Speech Biomarkers in Neurocognitive and Affective Disorders
Authors: Rentoumi Vassiliki , Vassiliou Evangelos , Sali Dimitra , Demiraj Admir , Paliouras George
Published: January 2025

Background

Recent advancements in automatic language and speech analysis, coupled with machine learning (ML) methods, showcase the effectiveness of digital biomarkers in non‐invasively detecting subtle changes in cognitive status. While successfully distinguishing between Alzheimer's Disease (AD) and Normal Control (NC) individuals, classifying Mild Cognitive Impairment (MCI) proves to be a more challenging task. MCI can progress to AD or result from various factors, including affective disorders, necessitating multiple expert examinations for accurate detection. Building upon previous research, we create an experimental setup to assess LANGaware’s biomarkers pool on three objectives: a) binary separation into Dementia and NC cohorts, b) broad three‐class separation into Dementia, NC, and MCI groups, c) binary differentiation into Depression coupled with Anxiety disorder and NC cohorts.

Method

Patient audio recordings and ASR‐generated transcripts were fed into LANGaware’s multimodal ML pipeline, extracting hundreds of linguistic and audio features, distilled into interpretable categories with a neural network assigning weights. These categorical values served as inputs to a final neural network layer generating probabilities for target labels (Dementia, NC). Similar methodologies were applied to our second (Dementia vs MCI vs NC) and third discrimination task (Depression/Anxiety vs NC), where the neural network allocated varying weights to input features for each of the aforementioned cases.

Result

In all scenarios, data were split into a 70% training set and a 30% testing set, validated against medical expert diagnosis. For binary separation, with 2927 Dementia and 815 NC instances, the model demonstrated 89% accuracy and an 85% macro‐averaged F1 score. For three‐class separation (3752 Dementia, 1117 NC, 5993 MCI instances), the model achieved 70% accuracy and a 71% F1 score. Discriminating affective disorders (1016 Depression/Anxiety, 1630 NC instances) resulted in 71% accuracy and a 71% F1 score.

Conclusion

The assessment suggests that our modelling approach aptly discerns language and speech patterns, distinguishing individuals with MCI from those with Dementia or in optimal health (NC). These outcomes contribute significantly to automatic evaluation, offering early diagnosis and timely treatment access. Our third experiment showcases the methodology's applicability in detecting affective disorders, specifically Depression and Anxiety, which may co‐occur with or precede MCI.
Markers of inflammation in cerebrospinal fluid can predict post‐assessment trajectory progression and classification on the ADCOMS scale
Authors: Evenden Dave , Michopoulou Sofia , Prosser Angus , Teeling Jessica , Kipps Christopher
Published: January 2025

Background

Neuroinflammation is an integral part of Alzheimer’s Disease (AD) pathology, whereby inflammatory processes contribute to the production of amyloid‐β, the propagation of tau pathology, and neuronal loss. We recently investigated data‐driven methods for determining distinct progression trajectory groups on the ADCOMS scale. This study evaluates whether biomarkers of inflammation in cerebrospinal fluid (CSF) can predict progression rate and membership of those progression rate groups.

Method

ADNI’s Biomarkers Consortium dataset provided 83 quality‐controlled CSF analyte biomarker levels taken at baseline for 307 subjects. Individual ADCOMS composite score trajectories were calculated for the same ADNI subjects, using ADAS‐Cog, MMSE, and CDR‐SB assessment raw data over time.

Progression rate for each subject was determined using linear regression. As a further step, each trajectory was partitioned into one of four progression groups using longitudinal clustering methods. These groups were labelled a) Fast, b) Intermediate, c) Slow, and d) None, the last indicating no overall progression.

Spearman rank correlation significance with individual trajectory slope was used to down‐select the 83 biomarkers. The resulting candidate list of 21 biomarkers were assessed for Pearson correlation with progression group membership and adjusted for false discovery rate. This resulted in a priority list of 7 biomarkers used in GLM Logistic regression models to predict progression group membership, and to calculate ROC and AUC summary values to distinguish Fast and Intermediate from Slow and no progression, and other group configurations.

Result

Decreased levels of ApoE, CD40, Chromogranin A (CgA), and VEGF, and increased levels of FABP, FGF4, and PPP were significantly correlated with progression rate and group (adjusted p‐value < 0.05). The Area Under the Curve (AUC) values ranged from 0.718 to 0.774 for between 3 and 7 biomarkers, with considerable variability in repeated 5‐fold cross‐validation. These results indicate a significant but moderate ability of CSF immune biomarkers to differentiate between progression trajectories.

Conclusion

Within ADNI’s clinical trial cohort, CSF biomarker levels of inflammation and immune metabolism demonstrated useful predictive power for progression trajectory group membership, prompting further work to refine the modelling to better understand the vascular and metabolic interaction complexities.
Multimodal neuroimaging and plasma biomarker evidence of white matter macrostructure loss in Parkinson’s dementia
Authors: Zarkali Angeliki , Hannaway Naomi , McColgan Peter , Heslegrave Amanda J , Veleva Elena , Laban Rhiannon , Zetterberg Henrik , Lees Andrew , Fox Nick C , Weil Rimona S
Published: January 2025

Background

Parkinson’s (PD) is common and debilitating with over half of patients progressing to postural instability, dementia or death within 10 years. However, onset and rate of progression is highly variable, reflecting heterogeneity in underlying pathology, and biomarker studies to‐date have been limited to a single modality or assessed patients with established cognitive impairment.

Method

We assessed multimodal neuroimaging and plasma biomarkers in 98 PD patients (mean disease duration at baseline 4.33 years) and 28 age‐matched controls followed‐up over 3 years. Of PD patients, 31 (31.6%) had a poor outcome (PD poor outcomes), defined as mild cognitive impairment, dementia, frailty, or death during follow‐up. We compared biomarkers of gray matter (cortical thickness), white matter macrostructure (fibre cross‐section) and microstructure (fibre density) at whole‐brain and tract level, structural and functional connectivity, and plasma levels of neurofilament light chain (NFL) and phosphorylated tau 181 (p‐tau) between PD who progress to poor outcomes versus those with good outcomes.

Result

We found extensive white matter macrostructural changes in PD who progress to poor outcomes already at baseline: with 19% reduction in fibre cross‐section and a subnetwork of reduced structural connectivity (105 nodes, 215 edges, p=0.017), particularly involving interhemispheric connections. Gray matter and functional connectivity were preserved. NFL but not p‐tau was increased in PD poor outcomes and correlated with white matter loss.

Conclusion

PD patients who progress to poor outcomes, show white matter macrostructural loss already at baseline, evident both from imaging and fluid biomarkers. Our findings highlight white matter imaging and plasma NFL as potential biomarkers of poor outcomes in Parkinson’s, informing the design of future clinical trials.
FDG‐PET patterns of LATE & co: disentangling the pathological heterogeneity of Tau‐negative amnestic syndromes
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Labrador‐Espinosa Miguel , Sanchez‐Juan Pascual , Schöll Michael , Grothe Michel J.
Published: January 2025

Background

About 20‐30% of clinically diagnosed AD dementia patients do not meet pathologic criteria for AD and this proportion is even higher in amnestic MCI. Among tau‐negative amnestic patients, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) has been described as a principal diagnostic alternative, especially at advanced age. LATE is characterized by a specific temporo‐limbic hypometabolic signature on FDG‐PET that may aid in differential diagnosis. However, little is known about the prevalence of this and other hypometabolism patterns among tau‐negative amnestic patients.

Method

360 cognitively impaired subjects (261 aMCI, 99 ADD) from the ADNI study who underwent 18F‐Flortaucipir Tau‐PET and 18F‐FDG‐PET were divided into Tau+ and Tau‐ using a visual read method. After screening Tau‐ patients for regional hypometabolism, LATE‐like hypometabolism patterns were identified using an automated pattern‐matching approach based on pathology‐specific FDG‐PET signatures derived from autopsy‐confirmed cases. FDG‐PET patterns among Tau‐ patients not fitting the LATE‐specific pattern were further examined using a hierarchical clustering approach. Group differences in age, hippocampal volume, and cognitive variables were studied.

Result

185 patients (162 aMCI, 23 ADD) were visually rated as Tau‐. Among those presenting any regional hypometabolism (N=95), 37 patients (39%) had a LATE‐like hypometabolism pattern (Figure 1). Hierarchical clustering of the remaining individuals revealed 3 different clusters suggestive of other neurodegenerative conditions, including a left‐lateralized temporal pole pattern reminiscent of semantic dementia (C1, 18%), a posterior‐occipital pattern characteristic for DLB (C2, 24%), and a more diffuse frontal pattern (C3, 19%). Compared to the other Tau‐ groups, the LATE‐like group was significantly older (p=0.02) and had more pronounced memory impairment (p=0.02) and hippocampal atrophy (p=0.03) (Figure 2). When initially screening Tau‐ patients for older age (>75y) and hippocampal atrophy, the majority of patients showed a LATE‐like FDG‐PET pattern (59%), but other patterns remained to be present in this population at smaller proportions (19%, 9%, and 13%, for C1, C2, and C3, respectively).

Conclusion

FDG‐PET provides valuable diagnostic information after a negative Tau‐PET scan. Among older tau‐negative patients with hippocampal atrophy, temporo‐limbic hypometabolism suggestive of LATE is the most prevalent pattern, but distinct hypometabolic patterns suggestive of other neurodegenerative conditions are also present in non‐negligible proportions.
Improved Disease Subtyping and Staging using Dual Biomarker Amyloid PET
Authors: Scott Catherine J , Coath William , Dickson John C , McQuaid Sarah J , Cash David M , Schott Jonathan M ,   the Insight 46 team
Published: January 2025

Background

Data‐driven disease progression models of Alzheimer’s disease (AD) have identified subtypes in regional patterns of Aβ deposition using amyloid PET. In addition to Aβ accumulation, early frame measures of tracer delivery from amyloid PET are strongly correlated with blood flow. This work explores whether combining tracer delivery with amyloid binding measures can improve the subtype and stage characterisation over amyloid binding alone.

Methods

Data was included from participants in three studies: Insight46, a neuroimaging sub‐study of the Medical Research Council National Survey of Health and Development (n=405), AVID2, a study of patients with a differential diagnosis of Alzheimer’s Disease (n=15), and YOAD, a study of patients with clinically diagnosed young onset Alzheimer’s disease (n=15). All participants underwent a full dynamic 18F‐Florbetapir PET/MR scan. PET images were reconstructed from 0‐2 and 40‐50 minutes post injection to generate the tracer delivery and amyloid binding images, respectively. T1 parcellations were used to calculate regional standardised uptake value ratios (SUVRs) using a cerebellar grey matter reference region. Tracer delivery and amyloid binding SUVRs for 6 cortical regions were converted into z‐scores, assuming unimodal and bimodal distributions respectively, and modelled using subtype and stage inference (SuStaIn). Participants fitted as stage zero were excluded.

Results

Figure 1 shows the three subtypes found using regional amyloid binding SUVR. Subtype 2 accumulates amyloid first in the occipital lobe, while for subtypes 1 and 3, which accumulate Aβ first in the precuneus and insula respectively, this is the last area to show Aβ deposition. Two distinct subtypes were found with blood flow SUVR; frontal or precuneus first blood flow reduction, Figure 2. When both measures are combined, Figure 3, the data show that subtypes 1 and 2 exhibit amyloid accumulation before blood flow changes, whereas subtype 3 shows blood flow changes in all regions first. The two blood flow subtypes are spread across all three combined subtypes, suggesting that each amyloid subtype may have several blood flow subtypes.

Conclusions

Combining blood flow and amyloid SUVR within SuStaIn reveals new patterns of disease progression compared to amyloid alone. This may help us better understand heterogeneity in aging and disease.
Small extracellular vesicles derived from plasma and the progression of Alzheimer's disease: insights into synaptic dysfunction and neuroinflammation
Authors: Singh Rishabh , RAI Sanskriti , Bharti Prahalad Singh , Chatterjee Prasun , Kumar Saroj
Published: January 2025

Background

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaques and neurofibrillary tangles, with chronic inflammation and synaptic dysfunction playing a significant contributor to disease progression and cognitive decline. Small extracellular vesicles (sEVs) are implicated in AD progression by facilitating the spread of pathological proteins and inflammatory cytokines. This study investigates the role of plasma‐derived sEVs (PsEVs) in synaptic dysfunction and neuroinflammation and their association with amyloid‐β and tau pathologies in AD progression.

Method

A total of 45 [15 each in AD, mild cognitive impairment (MCI), and age‐matched healthy control (AMC)] subjects were recruited, and written informed consent was obtained (Ethics Ref No: IECPG‐670/25.08.2022). PsEVs were isolated using a chemical precipitation method, and their morphology was characterized by transmission electron microscopy. The size and concentration of PsEVs were determined using nanoparticle tracking analysis (NTA). Antibody‐based validation of PsEVs was done using CD63, CD81, TSG101, and L1CAM antibodies. Synaptic dysfunction and neuroinflammation were evaluated with Synaptophysin, Glial Fibrillary Acidic Protein (GFAP), IL‐1β, and TNF‐α antibodies. AD‐specific markers, Aβ‐42, and pTau were examined using Western blot and ELISA.

Result

Our findings reveal higher concentrations of PsEVs in AD and MCI compared to AMC (p<0.0001). Aβ42 and pTau expression are significantly elevated in MCI (AUC = 0.9711, sn=100%, sp=80%, p<0.0001; AUC = 0.9689, sn=100%, sp=93.3%, p<0.0001, respectively); AD (AUC = 1, sn=100%, sp=100%, p= p<0.0001; AUC = 1, sn=100%, sp=100%, p<0.0001, respectively). Synaptophysin exhibits decreased expression from AMC to MCI to AD (p=0.047), whereas, IL‐1β, TNF‐α, and GFAP showed increased expression in MCI and AD compared to AMC (p=0.002, 0.0006, 0.0184, respectively). The increased levels of PsEVs correlate with synaptic dysfunction and neuroinflammation.

Conclusion

Elevated PsEVs and upregulated Aβ42 and pTau expression show high diagnostic accuracy in AD. The decreasing synaptophysin expression and increased neuroinflammatory markers in AD and MCI patients suggest synaptic degeneration and neuroinflammation as potential indicators. These findings support the potential of sEV‐associated biomarkers for AD diagnosis and highlight synaptic dysfunction and neuroinflammation in disease progression.
Regional differences in baseline demographic and clinical characteristics from the evoke and evoke+ trials of semaglutide for early Alzheimer’s disease
Authors: van der Flier Wiesje M. , Scheltens Philip , Feldman Howard H. , Hansson Oskar , Sano Mary , Bardtrum Lars , Johannsen Peter , Jeppesen Rose , Hansen Charlotte T. , Leon Teresa , Cummings Jeffrey L.
Published: January 2025

Background

Differences in patient characteristics across geographical regions may result in heterogeneity in clinical trial populations. evoke (NCT04777396) and evoke+ (NCT04777409) are two phase 3, multinational, randomised trials investigating semaglutide versus placebo in individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD) (early AD). We present baseline characteristics across the geographical regions in evoke/evoke+.

Method

Baseline data were pooled into five regions (Asia, Europe, Latin America [LATAM], North America and Rest of World [RoW]). Demographic and clinical characteristics were calculated for individual trials (evoke; evoke+), along with pooled data (evoke/evoke+ combined) for each region. Inclusion criteria were the same for both trials; except that evoke+ allowed the inclusion of participants with significant small vessel pathology (>1 lacunar infarct and/or >2 age‐related white matter changes [white matter >20 mm]).

Result

Of the 3,806 individuals with early AD enrolled, there were 1,986, 707, 602, 303 and 208 in Europe, North America, Asia, LATAM and RoW, respectively. Screening failure rates were 54.6‐67.8% across regions and highest in North America. Mean age was 71.7‐73.3 years, and 46.3‐59.1% of participants were female (Table 1). Cognitive scores were similar across regions: mean (standard deviation) Mini‐Mental State Examination score was 23.6 (3.3) to 24.6 (2.9) and Clinical Dementia Rating‐Sum of Boxes score was 3.5 (1.6) to 4.2 (1.8) (Table 2). In evoke+, small vessel pathology was lowest in Europe (2.3%) and highest in Asia (3.8%). Apolipoprotein E4 carrier status was lowest in the LATAM region (51.4%) and highest in the RoW (70.5%), and the proportion of individuals with type 2 diabetes ranged from 11.3‐21.1%. Overall, 51.9‐64.3% of individuals received AD medication, with the highest and lowest use in Asia and North America, respectively.

Conclusion

evoke and evoke+ successfully recruited individuals with early AD from all over the world, ensuring that semaglutide will potentially benefit individuals of various races and ethnicities. Despite this diversity, cognitive scores were largely similar across all geographical regions. Understanding this baseline data will allow for generalisation of the evoke/evoke+ results to worldwide populations with early AD.