bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated detection of cognitive symptom severity and mild cognitive impairment in Parkinson’s disease
Authors: Ferrante Franco Javier , Grisales Daniel Escobar , Lopez María Fernanda , da Cunha Pamela Lopes , Sterpin Lucas , Cuevas Pedro Chaná , Muñoz Edinson , Estienne Claudio , Hesse Eugenia , Amoruso Lucía , Arroyave Juan Rafael Orozco , Garcia Adolfo M.
Published: January 2025

Background

Beyond dementia syndromes, cognitive symptoms are highly prevalent in Parkinson’s disease (PD), often manifesting as mild cognitive impairment (MCI). Yet, their detection and characterization remain suboptimal because standard approaches rely on subjective impressions derived from lengthy, univariate tests. Here we introduce a novel approach to detect cognitive symptom severity and identify MCI in PD using fully automated word property analyses on brief verbal fluency tasks.

Methods

A total of 384 Spanish speakers with PD completed taxonomic, thematic, and phonemic fluency tasks, requiring them to name animals, supermarket items, and words starting with /p/, respectively. We automatically quantified six objective properties from each word: semantic variability (SV), granularity, length, frequency, phonological neighborhood, and concreteness. In Study 1, these properties were fed to a support vector regression with hyperparameter tuning to predict Mattis Dementia Rating Scale (MDRS) scores as indices of cognitive severity. Predicted MDRS scores were correlated with actual MDRS scores, adjusting for clinical factors (disease duration, motor symptom severity, medication dose). In Study 2, we used the same properties to compare (via a generalized linear model, adjusting for clinical variables) and classify (via ridge regression) between a carefully matched sample of 70 patients with and 75 patients without MCI. Feature importance analyses were conducted in both studies to identify which properties best captured patients’ cognitive profiles.

Results

In Study 1, MDRS scores predicted by word properties were strongly correlated with actual MDRS scores (R = 0.53, p = .02). In Study 2, patients with MCI exhibited lower SV in taxonomic and thematic fluency, lower granularity and length in taxonomic fluency, higher phonological neighborhood in taxonomic fluency, and higher concreteness in phonemic fluency (p‐values < .05). Machine learning analysis of all properties showed robust subject‐level discrimination between patients with and without MCI (AUC = 0.79). Across both studies, machine learning results were mainly most consistently driven by SV and granularity, pointing to reduced semantic consistency and precision as key cognitive markers of PD.

Conclusions

Automated word property analysis from brief fluency tasks can predict cognitive symptom severity and distinguish cognitive phenotypes of PD, opening new avenues for scalable neuropsychological screenings.
Wake slow waves and aperiodic activity during resting‐state EEG correlate with amyloid burden and hypometabolism
Authors: Champetier Pierre , Albero Claudia , Pereira Filipa Raposo , Herzog Rubén , Chaumon Maximilien , Houot Marion , George Nathalie , Arnulf Isabelle , Oudiette Delphine , Andrillon Thomas ,   INSIGHT‐preAD group
Published: January 2025

Background

Spectral power of slow rhythms in resting‐state EEG increases along Alzheimer's disease (AD) continuum. Besides, recent studies have revealed 1) the importance of analyzing the aperiodic component of an EEG power spectrum and 2) the intrusions of sleep‐like slow waves identifiable in wake EEG of animals and young adults. Importantly, the occurrence of these wake slow waves is known i) to increase after sleep deprivation, ii) to be associated with markers of sleepiness, and iii) to predict behavioral errors at different tasks. Our objective was to investigate the links between AD biomarkers and 1) the aperiodic component of the EEG signal and 2) wake slow waves.

Method

314 elderly individuals with memory complaints from the INSIGHT‐preAD cohort (76.5 ± 3.5 years, range: 70‐85 years) were recruited. Participants underwent a 5‐year follow‐up, including 1) high‐density EEG recordings (256 electrodes) at rest (2 sessions of 2 min) each year, 2) neuropsychological assessments each year, and 3) Florbetapir and 18F‐FDG PET scans at baseline to quantify amyloid burden and hypometabolism. For each EEG recording, characteristics of aperiodic activity (intercept and slope) and wake slow waves (density, amplitude, slope, and frequency) were determined. For each neuroimaging modality, mean standardized uptake value ratios (SUVRs) were computed in AD relevant brain regions. Associations between AD biomarkers (amyloid and FDG SUVRs) and EEG metrics (characteristics of aperiodic activity and slow waves) were tested using linear regressions controlled for age, sex, and education level, after FDR correction. Longitudinal effects, including neuropsychological metrics, will be tested using linear mixed effect models.

Result

At baseline, high amyloid burden was positively associated with 1) the intercept and slope of aperiodic activity and 2) the density and frequency of slow waves. Besides, hypometabolism was associated with lower slow wave density.

Conclusion

These preliminary results suggest that aperiodic activity and wake slow waves could serve as early EEG indicators of certain AD biomarkers. This seems particularly promising as these metrics are quantifiable on a simple resting EEG and at a very early stage, even before the onset of cognitive alterations. Longitudinal and neuropsychological data will be analyzed in the next few months.
Spatial Characterization of White Matter Hyperintensity Pathophysiology Across Disorders
Authors: Parent Olivier , Devenyi Gabriel A. , Bussy Aurelie , Pigeau Grace , Costantino Manuela , Fouquet Jérémie , Rodriguez Daniela Quesada , Dadar Mahsa , Chakravarty Mallar M.
Published: January 2025

Background

White matter hyperintensities (WMHs) are age‐related radiological abnormalities indicative of small vessel disease. It is unclear if WMHs in different regions represent similar pathophysiology and etiology. Here, we developed a framework to estimate WMH pathophysiology in vivo, which allowed us to precisely characterize spatial patterns of WMH tissue alterations associated with four disorders.

Method

We used data from 32,014 UK Biobank (UKB) participants. WMHs and normal‐appearing white matter (NAWM) were automatically segmented. Diffusion‐ and susceptibility‐weighted images were used to derive fluid‐, fiber‐, myelin‐ and iron‐sensitive microstructural markers. We calculated voxel‐wise normative models of NAWM microstructure using Bayesian linear regression with age (4th order B‐spline) and sex predictors in a custom UKB template space derived using multi‐spectral registration of T1w and fractional anisotropy (FA) images (Figure 1A‐B). Within‐subject WMH pathophysiology was estimated as the difference between WMH microstructure and predicted NAWM microstructure (Figure 1C).

Result

First, from between‐subject averages of WMH microstructural abnormality (Figure 2A), we used spectral clustering to derive spatial patterns of WMHs that share similar pathophysiological properties (Figure 2B). The first cluster (periventricular) has low abnormality. The second (posterior) and third (anterior) cluster both show fluid accumulation, fiber alterations, and myelin and iron loss, while the anterior cluster shows higher abnormality. Second, we assessed the differences between four disorders and age‐ and sex‐matched controls in terms of all WMH features with Cohen’s D. Ischemic heart diseases (n=2320) and hypertensive diseases (n=9852) demonstrated small but significant effects across measures, which were slightly higher in anterior regions. Stroke (n=320) demonstrated larger effects, which were more prominent in anterior regions. On the other hand, dementia (n=46) demonstrated smaller effects compared to stroke, reaching significance mostly in posterior regions despite the smaller sample size. Interestingly, the fractional anisotropy and orientation dispersion markers showed drastically inverted patterns of effects between stroke and dementia.

Conclusion

Our results separating anterior and posterior WMHs are consistent with accumulating evidence showing that posterior WMHs may be linked to Alzheimer’s pathology, whereas anterior WMHs may be associated with vascular pathologies. MRI pathophysiological markers may further help in distinguishing these etiologies.
The Dementia Care Partner Hub: A novel resource to support people living with dementia, care partners, and care teams
Authors: Gelmon Sherril B , Dawson Walter D , Reed Jenn Hollandsworth
Published: January 2025

Care partners of people living with dementia (PLWD) need information and access to many services and programs to support their person and maintain their own wellbeing. We conducted focus groups (n = 5) and interviews (n = 24) with care partners of PLWD and interviews with leaders of organizations serving PLWD in the Portland, Oregon region in 2022‐2023. A comprehensive review of organizational websites and relevant literature identified several US‐based role model programs and existing resources. Data analysis revealed community assets and unmet needs, and articulated resource priorities to inform current and future programs/services.

Dementia care partners need multiple supports for their caregiving: information about dementia; navigation and coordination; psychological support; recognition of care partner burden; leisure activities; day services; transportation; legal and financial services; home health; and fiscal support. While care partners were generally satisfied with their clinical care and research participation, feedback revealed deficits in accessing information and social supports which may not be within the scope of clinical sites.

We propose the creation of a Dementia Care Partner Hub (the “Hub”) to augment existing services and supports for care partners of PLWD. The Hub would be the central node of a regional network of existing services. Details of structure, scope, partnerships, funding, implementation and evaluation will be described in the presentation. While the original design was for implementation in Oregon, the concept could be implemented in other jurisdictions.

The Hub should serve all care partners in its service region, with a design that is responsive to the specific assets and needs of historically and currently underrepresented communities; this will ensure that the Hub supports care partners while attempting to ameliorate past inequities. It should augment and complement current clinical, research, and social programs by connecting care partners to programs and services. Community‐specific information for communities defined both by geography and by identity will ensure that the Hub equitably serves care partners with differing needs. Key elements to achieving this equity goal include language access, culturally appropriate information, and the ability for care partners to access the Hub from anywhere within the service region.
Structure‐activity relationship study of neuroprotective complex I inhibitor CP2
Authors: Petrova Olga , Trushin Sergey A , Nguyen Thi Kim Oanh , Ostroot Mark , Schellenberg Matthew , Johnson Graham , Trushina Eugenia , Sazanov Leonid
Published: January 2025

Background

We identified small molecule tricyclic pyrone compound CP2 as a mild mitochondrial complex I (MCI) inhibitor that induces neuroprotection in multiple mouse models of AD. One of the major concerns while targeting mitochondria is the production of reactive oxygen species (ROS). CP2 consists of two diastereoisomers, D1 and D2, with distinct activity and toxicity profiles. This study was designed to understand how structure of D1 and D2 affects their binding to MCI and the consequential impact on ROS production.

Method

The X‐ray crystallography and cryo‐electron microscopy (cryo‐EM) at global resolution of 3.25‐3.27Å were employed to identify the molecular structure of D1 and D2 and the D1 binding to the isolated ovine MCI. The assessment of the MCI inhibition and the extent of ROS generation were done in isolated MCI and human neuroblastoma MC65 cells using flow cytometry, a Seahorse extracellular flux analyzer, and the kinetic studies.

Result

In the closed conformation of MCI, D1 selectively binds to the deep Quinone‐site (Qd) but not to the shallow Q‐site (Qs), sharing the same binding pocket as rotenone. In the open MCI state, D1 exclusively binds to the Qs in contrast to rotenone, which binds Qd and Qs in both closed and open states. At the same concentrations, D1 inhibits respiration to a greater extent compared to D2 (5:1 ratio) and produces higher level of ROS.

Conclusion

Cryo‐EM unambiguously identified binding of D1 to both the Qd and Qs sites, contingent upon the conformational state of MCI. In contrast to rotenone, D1 binds Qd only in the closed conformation during catalytic cycle, leading to mild inhibition. Superimposing X‐ray crystallography data of D1 and D2 onto cryo‐EM data suggests that the orientation of the methyl group in D2 induces a flatter conformation, resulting in lower binding affinity to MCI, which correlates with lower inhibition and toxicity compared to D1. At physiologically relevant concentrations, CP2 (D1:D2 = 1:1) demonstrates low MCI inhibition yielding negligible ROS levels. This observation provides new insight into the absence of toxicity associated with CP2 treatment in vivo, further highlighting feasibility for the development of safe and efficacious MCI inhibitors.
Altered functional connectivity patterns between medial parietal and occipital in mild cognitive impairment during motion detection tasks
Authors: Gu Ming , Deng Jinxian , Sun Boxin , Kavcic Voyko , Li Tongtong , Giordani Bruno ,   Michigan Alzheimer's Disease Research Center
Published: January 2025

Background

Patients with cognitive impairment are likely to suffer from weakening of functional connectivity between certain brain regions, which may often be accompanied by increased connectivity between some other regions, the latter of which may reflect the compensatory mechanisms of the brain. In this EEG‐based study, we investigate the differences in functional connectivity between persons with normal cognition (NC) and MCI patients in motion detection tasks.

Method

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

We evaluated the functional connectivity at different time periods of the motion‐detection task across all the possible EEG region pairs using Pearson Correlation of the current source density (CSD). For each task trial, the successive time periods being examined included: (i) Pre‐Task resting‐state, (ii) Stimulus Onset to Go/NoGo indication, (iii) Go (or NoGo) indication to Motion‐Stop, (iv) Button‐Press period, (v) Post‐task resting‐state.

Results

Our analysis indicates that when the full band CSD signals were considered, MCI showed statistically significant (p‐value < 0.05) and increased functional connectivity between MP↔Occ in all the time periods during the motion task. In comparison, the Beta band, which is believed to be related to attentional deficits in the visual performance among older persons, showed similar trends with the full band, and consistent and statistically significant increased functional connectivity between MP and PCC were observed in the Button‐Press period across all frequency bands.

Conclusion

Our result suggests that MCI participants compensated for impaired connectivity in specific region pairs (see Figure 3) during the motion direction discrimination task by increasing the functional connectivity between MP and Occ to achieve comparable behavioral results to NC, and this may also be a particular indicator associated with MCI and AD pathology.

Funding: NSF‐2032709/Li; NIH‐1R21AG046637‐01A1/Kavcic and NIH‐1R01AG054484‐01A1/Kavcic; NIH‐P30AG072931/Paulson; NIH‐P30AG024824/Yung.
Proteogenomic Evaluation of Cerebrospinal Fluid in Alzheimer's Disease
Authors: Puerta Raquel , García‐González Pablo , de Rojas Itziar , Olivé Clàudia , García‐Gutiérrez Fernando , Sotolongo‐Grau Oscar , Smets Bart , Emon Asif , Sung Yun Ju , Frikke‐Schmidt Ruth , Marchant Natalie L , Lambert Jean‐Charles , Valero Sergi , Marquié Marta , Ramirez Alfredo , Cruchaga Carlos , Fernández Victoria , Cano Amanda , Boada Mercè , Socorro Alfredo Cabrera , Ruiz Agustin
Published: January 2025

Background

Alzheimer's disease (AD) is a complex disorder with a strong genetic component, yet many genetic risk factors remain unknown. Integrating genome‐wide association studies (GWAS) and high‐throughput proteomic platforms is a useful strategy to evaluate protein quantitative trait loci (pQTLs) and to detect candidate genes and pathways involved in AD. Due to the novelty of these techniques, the identification of reliable protein measures through a comprehensive quality control is mandatory.

Method

We researched the cerebrospinal fluid (CSF) proteome using the SOMAscan 7k (7289 proteins), and the Olink Explore (2943 proteins) platform in the Ace Alzheimer Center Barcelona CSF Cohort. To assess reproducibility and reliability of proteomic measures, we analysed 1) intra‐platform correlation of two independent SOMAscan assays using two aliquots of the same sample, and 2) inter‐platform correlation between SOMAscan and Olink techniques. We also explored associations of highly reliable proteins with the AD Polygenic risk score (PRS) and the conversion to AD dementia. Additionally, we have performed an extensive pQTLs mapping of the SOMAscan platform and analysed pQTLs of significant proteins linked to disease progression.

Result

Our results revealed 2469 proteins with high intra‐platform correlation (rho≥0.5), selected as candidates for further analysis. Moreover, over 600 proteins demonstrated strong inter‐platform correlation, reinforcing their robustness. Extending our analysis to the entire CSF cohort (n=1322), we identified 85 proteins (Padj.<0.05) associated with the AD‐PRS. Additionally, 93 significant proteins were linked with conversion to AD dementia. Strikingly, these conversion‐associated proteins exhibited 89 genome‐wide significant pQTLs in the genome, with more than 47% of the genetic signals localized within the APOE‐rs429358 locus.

Conclusion

Our findings emphasize the importance of reliability assessment of highly multiplexed proteomic panels. Using robust measures, we identified significant proteins related to AD genetic risk and disease progression. These insights deepen the AD pathogenesis understanding, expand future research and therapeutic interventions.
Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study
Authors: Hu He‐Ying , Hu Hao , Yu Jin‐Tai
Published: January 2025

Background

The heart‐brain connection has been proposed to correlate cardiac disorders with brain health. However, the associations between subclinical alterations in cardiac structure or function and Alzheimer's disease (AD) pathologies haven't been fully elucidated. This study aimed to delineate the interrelationships between the subclinical alterations in the left heart, cerebrospinal fluid (CSF) AD biomarkers, and cognition.

Method

Multiple linear regression analyses were conducted in 1,244 cognitively normal participants (mean age=65.5 years; 43% female) who had measurements of the left heart on echocardiograms (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers. Covariates included sociodemographic variables, lifestyle or other cardiovascular characteristics, and apolipoprotein E4 status. The mediating effects of AD pathology on heart‐cognition relationships were examined. Besides, differences in the cardiac parameters across the ATN categories were tested using ANOVA and logistic regression models.

Result

LA and LV enlargement (captured by increased diameters and volumes) and LV hypertrophy (captured by increased interventricular septal or posterior wall thickness and ventricular mass) were significantly associated with higher CSF levels of phosphorylated (p)‐tau and total (t)‐tau, as well as poorer cognitive function. Tau pathologies mediated the heart‐cognition relationships. Besides, left heart parameters were higher in stage 2 and suspected non‐Alzheimer's pathology groups than in healthy controls. Moreover, the accumulation of cardiac alterations further magnified their damage to the brain.

Conclusion

These findings suggested the close associations of subclinical cardiac changes with tau hyperphosphorylation, neurodegeneration and cognitive dysfunction. This study provided a comprehensive insight into the left heart condition and its impact on AD pathologies. The echocardiographic measurements of the left heart might help to identify the patients at risk of AD continuum, and we should early monitor the cardiac alterations in older adults to prevent dementia or AD.
Plasma biomarkers in a cohort of cases with dementia and in cognitively preserved nonagenarians
Authors: Gómez‐Tortosa Estrella , Agüero Pablo , Gonzales Alicia Ruiz , Wagner Sonia , Mahillo Ignacio , Ruiz Andrea , Sainz María José , Téllez Raquel , Cremades‐Jimeno Lucía , Sanchez‐Juan Pascual
Published: January 2025

Background

Recent reports support the use of plasma biomarkers of neurodegeneration and neuroinflammation, as determined through ultrasensitive single molecular arrays (SIMOA), to screen and diagnose patients with dementia. However, their translation to clinical settings requires further studies.

Methods

We evaluated plasma samples from 186 individuals including 72 patients with AD (supported by CSF biomarkers consistent with an A+T+N+ classification scheme), 44 with confirmed FTD, 48 cognitively intact nonagenarians, and 22 controls (ages 40‐83 years). We measured AD core biomarkers (Abeta40, Abeta42, total tau and p‐tau181), neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) using SIMOA with Quanterix assays. In cases with dementia we correlated AD plasma biomarkers with those in CSF, obtained by Lumipulse G600II immunoassay. We calculated the best plasma cutoff values for each biomarker to discriminate among AD, FTD and cognitively preserved individuals.

Results

As regards AD core biomarkers, AD cases showed lower Abeta42/Abeta40 ratio as compared to FTD cases and controls (p<0.001), and higher p‐tau (p=0.06 vs FTD, p=0.007 vs controls). These two biomarkers also showed a significant correlation with CSF values (Spearman p>0.001). GFAP was significantly elevated in dementia cases and nonagenarians as compared to controls with the following gradient: nonagenarians (median=344) > AD (314)> FTD (225); the same occurs for NFL with the following gradient: nonagenarians (median=41)> FTD (39.4) > AD (20). In the distinction between FTD and AD, plasma NFL showed better accuracy (AUC 0.80) than Abeta42/Abeta40 ratio (AUC 0.76), GFAP (AUC 0.68), and p‐tau (AUC 0.66). In cognitively preserved nonagenarians Abeta42 was significantly higher than in AD cases (p=0.001) and controls (p=0.01), tau and p‐tau was higher than controls but with no significant differences, while both NFL and GFAP were in the highest values of the four groups.

Conclusions

In this single‐center clinical cohort we confirm the different patterns of plasma AD core biomarkers in AD and FTD cases, as well as an opposite pattern of elevation regarding NFL and GFAP. Cognitively preserved nonagenarians have positive degeneration and inflammation biomarkers supporting resilience rather than resistance to AD.
Profiling Peripheral Blood Lymphocytes in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Low Yi Ling Clare , Sun Jiaqi , Huang Xin , Almeida Catarina F , Gu Ben J , Kagawa Yoshiteru , Masters Colin L. , Jin Liang , Pan Yijun
Published: January 2025

Background

In Alzheimer’s disease (AD), a major gap remains in the understanding of how the interplay between peripheral and central immune systems drives neuroinflammation and disease progression. More recently, the concept of brain lymph drainage has sparked interest as it may shed light on how the dynamics of T cell interactions contribute to AD. Our preliminary study aims to characterize alterations in the peripheral blood lymphocyte population among individuals with AD‐dementia and mild cognitive impairment (MCI), as compared with cognitively unimpaired (CU) individuals.

Method

The peripheral blood lymphocyte population of 142 participants (AD‐dementia=34, MCI=47, CU=63) recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study was profiled. Peripheral blood samples were collected for flow cytometry analysis. Cell surface markers facilitated the identification of various B and T cell populations including CD19+ pan B cells, CD4+ helper T cells, CD8+ cytotoxic T cells, CD4+CD25+CD127‐ regulatory T cells, CD4+CD8+ double positive T cells, and TCRγδ+ T cells, further categorized into subsets of CD4‐CD8‐, CD4‐CD8+ and CD4+CD8‐ TCRγδ+ T cells.

Result

The study revealed a lower percentage of CD4+CD25+CD127‐ regulatory T cells in the AD‐dementia group compared to the CU group (P=0.034, AD=6.89±1.83, CU=8.27±2.21). Significant intergroup differences were identified in the CD4+CD8+ double positive T cell population (P=0.0363), with the MCI group displaying the highest levels (0.60±0.34), followed by the AD‐dementia (0.47±0.24) and CU group (0.42±0.23). Additionally, TCRγδ+ T cells were found to be elevated in the AD‐dementia group when compared with the CU group (P=0.0023, AD=15.4±14.4, CU=7.70±9.51). Intergroup variations were also observed in the subsets of CD4+CD8‐TCRgd+ T cells (P=0.0002) and CD4‐CD8+TCRgd+ T cells (P=0.0004). However, no significant differential changes were found between the groups for CD19+ pan B (P=0.24), CD4+ helper T (P=0.29), and CD8+ cytotoxic T (P=0.56) cell populations.

Conclusion

This preliminary analysis highlights disease status‐associated changes in the peripheral blood lymphocyte profile, offering potential insights into the role of peripheral immunity in AD pathology. Further research targeting alterations in the peripheral blood lymphocyte profile is warranted to uncover novel biomarkers, enabling early detection or prediction of disease severity/progression of AD.
Trimethylamine‐N‐Oxide regulates cognitive function in Alzheimer’s Disease patients and mice model through brain‐gut‐microbiota axis
Authors: Zhang Wenbo , Lü Yang
Published: January 2025

Background

The regulatory role of Trimethylamine‐N‐oxide (TMAO) for cognition from the perspective of microbiota‐gut‐brain (MGB) axis in AD remains unclear.

Method

In clinical cohort study for effects of 24‐week computerized cognitive training (CCT), registered on clinicaltrials.gov (NCT06094452), plasma TMAO levels were quantified using ELISA in MCI (n=39) and mild AD patients (n=35). Correlation analyses were conducted to assess the relationship between changes in TMAO levels and cognitive function (ADAS‐cog score) and gut microbiota indices. In animal model experiments, C57/BL6 aged mice and APP/PS1 transgenic mice were administrated by water feeding with 1.2% TMAO for 16 weeks and 1.0% of its inhibitor 3,3‐Dimethyl‐1‐butanol (DMB) for 8 weeks. TMAO levels in plasma and cerebrospinal fluid (CSF) were measured by ELISA. Cerebral blood flow (CBF) activation was detected by a laser speckle imaging system. Cognitive behavior was evaluated using Morris Water Maze test. The expressions of BBB function proteins (ZO‐1, Occludin, and PDGFRβ,) and neuroinflammatory markers (HMGB1 and IL‐1β) were detected by western blotting. The deposition of β‐amyloid (Aβ) plaques and neuronal survival in hippocampus were visualized by histochemical and Nissl staining.

Result

TMAO was significantly increased in plasma of AD patients. After CCT intervention, TMAO was significantly decreased in the CCT group, and this decrease was positively correlated with ADAS‐cog (r=0.549), and negatively correlated with Shannon evenness (r= ‐0.372). TMAO changes were also negatively correlated with the relative abundance change of Roseburia (r=‐0.443), Lachnospiraceae_UCG‐004 (r=‐0.392), and Lactobacillus (r=0.480), while positively correlated with Ruminococcus_torgues (r=0.443), Fusobacterium (r=0.484) and Herbasporillum (r=0.365). In animal models, TMAO was increased in the plasma and CSF of APP/PS1 mice. After supplemented with 1.2% TMAO, the cognitive performances of C57 and APP/PS1 mice were significantly impaired. The activation amplitude of CBF was decreased, and the expression of BBB function proteins (ZO‐1, Occludin, and PDGFRβ) were significantly decreased. The expressions of neuroinflammation marker HMGB1 and IL‐1β were significantly increased; the accumulation of Aβplaques was increased with decreased neuronal survival. Circulating level of TMAO was decreased after DMB intervention, which showed cognitive protection effects.

Conclusion

TMAO may be a novel biomarker that regulates cognition of AD through MGB axis.
Critical Path for Alzheimer’s Disease (CPAD) Consortium: Data‐Driven Solutions for Clinical Trial Design and Informed Decision Making
Authors: Sivakumaran Sudhir , Priest Eileen , Lau Corissa , Irizarry Michael C. , Karten Yashmin
Published: January 2025

Background

To help improve the Alzheimer’s disease (AD) therapeutics research and development process, the Critical Path for Alzheimer’s Disease (CPAD) Consortium at the Critical Path Institute (C‐Path) provides a neutral framework for the drug development industry, regulatory agencies, academia, and patient advocacy organizations to collaborate. CPAD’s extensive track record of developing regulatory‐grade quantitative drug development tools motivates sponsors to share patient‐level data and neuroimages from clinical trials. CPAD leverages these data and uses C‐Path’s core competencies in data management and standardization, quantitative modeling, and regulatory science to develop tools that help de‐risk decision making in AD drug development.

Method

Clinical data are curated, standardized, and aggregated into analysis subsets, which are used to develop disease progression models that form the basis for clinical trial simulation (CTS) tools. Such tools help optimize patient and endpoint selection, and the design of efficacy studies. CPAD’s database includes raw neuroimages from contemporary datasets, which are used to lead two pre‐competitive efforts, in collaboration with leading academic and industry experts, to 1) test and validate a tau‐PET quantification method that harmonizes derived measures across tracers and cohorts, and 2) explore and evaluate the readiness of tau‐PET as a surrogate marker in AD drug development to support accelerated drug approval.

Result

As of November 2023, CPAD’s clinical trial repository contains 73 studies with over 100,000 individual de‐identified patient records, with a rich source of key AD biomarkers (biofluids and imaging). Different linear and non‐linear mixed effects models have been fit based on relevant biomarker combinations, characterizing the time course of clinically relevant outcome measures. To harmonize tau‐PET quantification, two different methods (a Centiloid‐like approach and a Joint Propagation model) were tested and validated across multiple tracers, cohorts and studies. A data and research plan has been drafted to explore and evaluate the readiness of tau‐PET as a surrogate marker in AD.

Conclusion

The precompetitive collaboration by CPAD is fundamental to the generation of actionable quantitative drug development tools for accelerating and advancing AD drug development and building consensus among stakeholders that provide confidence to sponsors for the adoption of the tools.
Automated linguistic and acoustic measures of verbal fluency as neurocognitive markers of mild cognitive impairment
Authors: Pérez Gonzalo Nicolás , Ponferrada Joaquín , Ferrante Franco Javier , Caro Iván , Bisé Joaquín Valdez , Migeot Joaquín , Welford Alejandro Sosa , Olavarria Loreto , Pelle Patricia , Chonchol Andrea Slachevsky , Ferrer Luciana , Garcia Adolfo M.
Published: January 2025

Background

Verbal fluency tasks are routinely employed in screening for mild cognitive impairment (MCI). Yet, traditional outcome measures focus on the number of valid responses, failing to reveal which specific semantic memory dimensions may be altered and limiting analyses to univariate methods. Building on recent findings on Alzheimer’s disease, we employed automated methods to establish which linguistic and speech timing features better discriminate MCI patients from healthy controls (HCs), including machine learning analyses, comparisons with standard neuropsychological tests, and brain‐behavior correlations.

Method

We recruited 106 native Spanish speakers (52 with MCI, 54 HCs), who completed phonemic and semantic fluency tasks as well as standard tests of attention (Trail Making Test‐A) and episodic memory (Free and Cued Selective Reminding Test). Responses in the fluency tasks were audio‐recorded and transcribed for automatic extraction of word properties (granularity, frequency, phonological neighborhood, word length, imageability, familiarity) and speech timing features (number of syllables, pauses, pause duration, phonation time, articulation rate, average syllable duration). These variables were compared between groups through a generalized linear model (GLM, with standard cognitive test scores as covariates) and fed into a binary classifier for subject‐level discrimination. Structural and functional brain measures were obtained from 63 participants and subjected to voxel‐based morphometry and seed‐to‐voxel resting‐state connectivity analyses. Correlations between behavioral and brain features were examined via multiple regressions.

Result

GLM analysis revealed significant group differences in specific word properties (granularity, frequency, word length, imageability), but not in speech timing features. Subject‐level classification was better when based on word properties (AUC = 0.72) than on speech timing features (AUC = 0.63), with maximal discrimination upon combining both dimensions (AUC = 0.78). MCI patients exhibited atrophy left temporal atrophy and altered connectivity between the right parahippocampus and fronto‐posterior cortical regions. Word frequency was negatively correlated with insular volume and granularity was positively correlated with the volume of fusiform and parahippocampal regions.

Conclusion

Automated analyses of word properties and timing features in verbal fluency tasks offer novel insights into cognitive decline, surpassing traditional tests in identifying MCI. Their widespread implementation could inaugurate a promising avenue to establish scalable markers of the condition.
KLOTHO KL‐VS genotype modifies the relationship between cardiorespiratory fitness and CSF biomarkers of neurodegeneration, synaptic dysfunction, and inflammation
Authors: Jarchow Mackenzie , Driscoll Ira , Breidenbach Brianne M. , Cook Noah R. , Gallagher Catherine L. , Johnson Sterling C. , Asthana Sanjay , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Cook Dane B. , Dubal Dena B. , Okonkwo Ozioma C
Published: January 2025

Background

Less adequate cardiorespiratory fitness (CRF) is associated with several aspects of Alzheimer’s disease (AD) pathology, including neuroinflammation, neurodegeneration and synaptic dysfunction, all of which are known contributors to the clinical outcome – progressive cognitive decline [1]. AD‐associated biomolecular changes also seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL‐VSHET) [2]. While KL‐VSHET and CRF both appear to mitigate aspects of AD pathology, they have been exclusively studied in isolation. Here we investigate whether the relationships between CRF (VO2 max) and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, synaptic dysfunction, and inflammation differ for KL‐VSHET compared to non‐carriers (KL‐VSNC).

Method

The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=132; MeanAGE=62.7) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center. Covariate‐adjusted (age, sex, parental AD history, APOE, and age difference between CSF sampling and exercise test) linear models examined the relationship between VO2 max and CSF biomarkers of neurodegeneration [α‐synuclein (α‐syn), neurofilament light polypeptide (NfL), total tau (tTau)], synaptic dysfunction [neurogranin (Ng)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), chitinase‐3‐like protein 1 (YKL‐40), interleukin 6 (IL‐6), S100 calcium‐binding protein B (S100B)] as a function of KLOTHO KL‐VS.

Result

The interaction between VO2 max and KL‐VSHET was significant for tTau (P=0.05), Ng (P=0.02), sTREM2 (P=0.02), and YKL‐40 (P=0.03) (Table 1; Figure 1), such that KL‐VSHET who were more fit had significantly lower levels of tTau, Ng, sTREM2, and YKL‐40 but not α‐syn, NfL, GFAP, IL‐6, or S100B (all Ps>0.63).

Conclusion

We report a synergistic relationship between KL‐VSHET and CRF with regard to neurodegeneration (tTau), synaptic dysfunction (Ng) and inflammation (sTREM2 and YKL‐40), suggesting a protective role for both KL‐VSHET and better cardiovascular fitness against unfavorable AD‐related changes. Their potentially shared biological mechanisms will require future investigations.

References

[1] Huuha, A.M., et al., Can exercise training teach us how to treat Alzheimer's disease? Ageing Res Rev, 2022. 75: p. 101559.

[2] Driscoll, I., et al., AD‐associated CSF biomolecular changes are attenuated in KL‐VS heterozygotes. Alzheimers Dement (Amst), 2022. 14(1): p. e12383.
Higher cardiorespiratory fitness is associated with higher cerebral myelination in normative aging
Authors: Faulkner Mary E , Gong Zhaoyuan , Bilgel Murat , Laporte John P , Guo Alex , Bae Jonghyun , Elango Palchamy , Bergeron Christopher M , Bouhrara Mustapha
Published: January 2025

Background

Age‐related white matter (WM) deterioration has been associated with several neurodegenerative diseases, including Alzheimer’s disease. Studies suggest that cardiorespiratory fitness (CRF) is important in preserving WM structure and function. However, clinical investigations of the relationship between myelin integrity and CRF are lacking. In this study, we evaluated the association between CRF, assessed by the maximum rate of oxygen consumption (VO2max), and cerebral myelin content, defined by myelin water fraction (MWF), throughout the adult lifespan. Understanding the mechanisms of WM degeneration is crucial for developing targeted interventions to maintain cognitive health into late life.

Method

After excluding subjects with cognitive impairments or unexploitable MRI data, a total of 110 cognitively unimpaired participants, ranging in age from 22 to 94 years, were drawn from the BLSA and GESTALT studies. Each participant underwent our BMC‐mcDESPOT MRI protocol for whole brain MWF mapping. VO2max was assessed using graded maximal treadmill test as per our established protocol. Fourteen WM ROIs were defined from the MNI structural atlas. For each ROI, a linear regression model adjusted for relevant covariates (Table 1) was used to determine whether 1) VO2max is significantly correlated with MWF, and 2) the strength of the correlation between VO2max and MWF depends on age (age×VO2max interaction). Continuous variables were z‐scored.

Result

Higher VO2max was significantly associated with higher MWF (Figure 1). This association was strongest in brain regions susceptible to early degeneration (Table 1), including the frontal lobes (β=0.28, p=0.011) and white matter tracts, such as the internal capsule (β=0.27, p=0.025) and corona radiata (β=0.27, p=0.016). Further, the interaction between age and VO2max exhibited i) a steeper positive slope in the older age group, suggesting that the effect of VO2max on MWF is stronger at older ages, and ii) a negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with more rapid demyelination with advancing age (Figure 2 & Table 1).

Conclusion

These original findings provide the first evidence that high CRF is important for the preservation of myelin integrity and slowing of age‐related neurodegeneration, laying the groundwork for further investigations including longitudinal and interventional studies.
A disease modification drug screening platform targeting neuronal hyperexcitability and seizures in Alzheimer’s disease‐associated mouse models
Authors: Knox Kevin M , Lehmann Leanne M , Sanz Aaron Del Pozo , Robinson‐Cooper Larissa , Davidson Stephanie , Barker‐Haliski Melissa
Published: January 2025

Background

Early‐onset Alzheimer’s disease (EOAD) associated with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants increases risk of seizures. Targeting epileptiform activity with antiseizure medicine (ASM) administration to AD patients may beneficially attenuate cognitive decline (Vossel et al, JAMA Neurology 2021). However, whether mechanistically distinct ASMs differentially suppress seizures in discrete EOAD models is understudied (Lehmann et al, Neurochem Res 2021). To fill this gap, we validated a moderate‐throughput drug screening program consisting of well‐established ASM discovery tests applied in three discrete EOAD‐associated models: PSEN2 knockout (KO), PSEN2‐N141I (Volga German variant), and APPswe/PS1dE9 mice. Critically, PSEN2‐N141I model does not demonstrate accumulated amyloid beta (Ab) whereas APP/PS1 mice show increased Ab expression by ∼6 months‐old. We hypothesized EOAD‐associated models would differentially influence focal seizure threshold, susceptibility to evoked focal seizures, and ASM sensitivity with advanced age.

Method

PSEN2 KO, PSEN2‐N141I, APP/PS1, and wild‐type (WT) mice were tested beginning at 2‐months‐old and up to 14‐months‐old in acute and chronic seizure screens: minimal clonic and 6 Hz focal seizure threshold, 6 Hz electroconvulsive test, corneal kindling, and kainic acid‐induced status epilepticus (KA‐SE), consistent with our published methods for ASM discovery (Barker‐Haliski et al, Neurochem Res 2017; Knox et al, Epilepsia 2021). Mice were assessed in two seizure threshold tests every 2 months until 12‐months‐old. Mechanistically distinct ASMs (diazepam, valproic acid, lamotrigine, and levetiracetam) profiled genotype‐specific pharmacosensitivity in the seizure assays (6 Hz, corneal kindling, and KA‐SE).

Result

Functional connectivity differences appeared as notable blunting of age‐related increases in 6 Hz seizure threshold of APP/PS1 mice by as early as 4‐months‐old (APP/PS1 median convulsant current: 24.6 mA [22.2‐26.9] versus WT: 31.7 [27.8‐36.9]). Chronic kindled seizure susceptibility varied by genotype, with ASM‐specific differences in seizure control between EOAD models. Specifically, kindled seizures of aged APP/PS1 mice were more sensitive to valproic acid and levetiracetam, whereas valproic acid and lamotrigine were more potent in aged PSEN2‐N141I mice.

Conclusion

EOAD‐associated risk genes do not equally influence age‐related seizure susceptibility or impact ASM efficacy; seizures in AD may require precision medicine interventions. Further ASM profiling focused on attenuating neuronal hyperexcitability may uncover novel disease‐modifying strategies for AD.
Pattern‐separation induced neural activations in midlife women at risk for AD
Authors: Zhuang Xiaowei , Yang Zhengshi , Cordes Dietmar , Caldwell Jessica ZK
Published: January 2025

Background

Sex‐specific functional‐brain changes during memory tasks have been reported along the Alzheimer’s disease (AD) continuum. However, mid‐life risk factor effects on memory‐related neural activation remain less clear in women with increased AD risk. Here we examined brain activations during a modified pattern‐separation task and their associations with verbal memory scores in midlife women at risk for AD due to family history.

Method

MRI data were acquired from 12 middle‐aged at‐risk women on a 3‐Tesla Siemens Skyra scanner (34 to 57 years old, mean‐age=50.83). Three task‐functional MRI (fMRI) runs were collected (TR=1.485s, 2mm isotropic, 524 time‐frames) during a modified pattern‐separation task with explicit encoding and recognition phases (detailed in Figure 1).

After preprocessing, a general linear model (GLM) was employed on time‐frames during the recognition phase across three sessions concatenated. Five conditions were modeled, including new‐objects correctly identified as new (Foils), same‐objects correctly identified as same (Hits), similar‐objects correctly identified as similar (LureCR) or falsely identified as same (LureFA), and all other trials. Whole‐brain voxel‐wise analyses were conducted to examine differential activations for lure discrimination (LureCR‐LureFA). The association between significant neural activations and participants' age, task performance, and verbal memory scores (RAVLT) were tested.

Results

Robust neural activations were observed during Hits, LureCR and LureFA conditions (Figure 2(A)).

Significant lure‐discriminative activity (LureCR‐LureFA) was observed in a cluster peaked at left inferior‐parietal, spanning across left‐angular, left‐middle‐temporal, and left‐supramarginal regions (red circle in Figure 2(B)). Neural activations in the left medial temporal region were positively correlated with age (correlation=0.61, p=0.04, Figure 2(C)), and positively correlated with task performance (partial‐correlation=0.83, adjusting for age, p=0.03, Figure 2(C)). A trend‐level negative association was observed between neural activations in the left inferior parietal region and RAVLT‐immediate scores (Figure 2(D)).

Conclusion

In 12 at‐risk women, we observed robust lure‐discriminative activations in the left temporal and inferior parietal regions for during an object pattern‐separation task. Greater neural activation in these regions was evident in participants with higher task accuracies, but older and worse RAVLT performances, potentially indicating a compensatory neural mechanism to achieve high accuracies in a pattern‐separation task in midlife women 10 or 20 years prior to a potential AD onset.