bluuebunny/crossref_metadata_2025 huggingface dataset:
Untargeted plasma proteomics nominates a novel set of plasma biomarkers for Alzheimer’s disease in African Americans
Authors: Kuchenbecker Lindsey A , Reddy Joseph S. , Heckman Michael G. , Lucas John A. , Ertekin‐Taner Nilüfer , Graff‐Radford Neill R , Carrasquillo Minerva M.
Published: January 2025

Background

Plasma biomarker development is of increasing interest due to improved accessibility compared to established diagnostic modalities for Alzheimer’s disease (AD). However, current plasma biomarker candidates have not been tested comprehensively in diverse populations, and these markers represent only a fraction of pathways perturbed in AD. Therefore, there is a need to identify novel plasma biomarkers that account for both disease heterogeneity and patient diversity. This study seeks to address these knowledge gaps through untargeted plasma biomarker discovery in African Americans (AA), an underrepresented group in AD research despite having a higher risk of developing AD compared to non‐Hispanic Whites.

Methods

Untargeted proteomics were performed using the SomaScan 7k assay on plasma samples from AA study participants clinically diagnosed as AD (n=142) or cognitively unimpaired (CU, n=144). Linear regression models adjusted for age, sex, and batch were implemented to identify differentially expressed proteins (DEPs). APOE was additionally adjusted for in a sensitivity analysis. DEPs with the lowest q‐values were selected as predictors in a receiver operating characteristic (ROC) analysis to assess their accuracy to discriminate AD versus CU individuals.

Results

A total of 153 DEPs were identified (q<0.05) when adjusting for age, sex, and batch, and 100 DEPs were identified when additionally adjusting for APOE. Of the 66 proteins overlapping between these models, SERPINA3, C7, IGFBP‐2, DKK3, SMOC1, and ACES had the lowest q‐values and were included in a ROC model adjusted for age, sex, and APOE. That model classified AD versus CU with an area under the curve (AUC) of 0.87 (95%CI: 0.83‐0.91), a 10.4% improvement over the base model including age, sex, and APOE (AUC=0.78; 95%CI: 0.72‐0.83). Despite the unbiased selection of proteins included in the ROC model, all selected proteins have been associated with AD and implicated in related functional pathways such as neuroinflammation, synaptic function, and insulin signaling.

Conclusion

This preliminary plasma biomarker panel demonstrates the potential diagnostic capabilities of biomarker discovery through untargeted proteomics. Future directions include validation of findings in external datasets, concomitant assessment of p‐tau217, and evaluation of machine learning models to define the optimal diagnostic and predictive set of plasma protein biomarkers for AD in AA.
The ADIS study: Early Diagnosis of Alzheimer's Disease by Immune Profiling of Cytotoxic Lymphocytes and Recording of Sleep Disturbances
Authors: Val‐Guardiola Andrea , Martínez Neus Falgàs , Krix Sophia , Lage‐Rupprecht Vanessa , Nevo Uri , Kirsch Stefan , Yoles Eti , Tort‐Merino Adrià , Balasa Mircea , Antonell Anna , Lladó Albert , Baruch Kuti , Moradi Soraya , Bintener Christophe , István Nagy , Fröhlich Holger , Sanchez‐Valle Raquel
Published: January 2025

Background

Sleep‐wake alterations are common symptoms in Alzheimer’s Disease (AD) associated with faster cognitive decline. Noradrenaline dysfunction and neuroinflammation have been proposed as potential driving mechanisms. The ADIS project aims to study the relationship between sleep‐wake patterns, immune signatures (peripheral blood cytotoxic lymphocytes), and noradrenergic markers across the AD spectrum.

Method

The project aims to recruit a total of 75 participants from the Hospital Clínic de Barcelona, including healthy controls (with normal values of plasma pTau), mild cognitive impairment due to AD (MCI), and AD Dementia (AD) confirmed by CSF biomarkers (Figure 1). All subjects will complete a comprehensive neuropsychological battery and Altoida digital assessment. Sleep‐wake phenotypes will be assessed by sleep questionnaires (Pittsburg Sleep Quality Questionnaire, PSQI, and Epworth Sleepiness Scale, ESS) and 2‐week actigraphy (Motion Wath 8 device). Noradrenaline levels and neuroinflammation markers in CSF will be measured. Immune phenotyping (cytometry, immune activation assays, scRNA/TCR sequencing) of peripheral blood mononuclear cells (PBMC) will be performed. In addition, selected participants will participate on the study's Advisory Board.

Result

To date, we have recruited 25 healthy controls, 25 MCI, and 23 AD participants who performed a total of 67 neuropsychological testings, 47 Altoida assessments, 34 CSF noradrenaline measurements, 65 actigraphy monitoring, and 59 isolation of PBMC. There were no age or gender differences between groups (Table 1). As expected, MMSE was lower in MCI/AD than controls (p<0.01). PSQI and ESS showed no differences, but preliminary analyses of 28 (10 HC, 14 MCI, 4 AD) actigraphy recordings showed that MCI and AD had a greater sleep latency than controls (p<0.05). As expected, preliminary analyses of 34 participants, including 21 MCI and 13 AD, showed similar noradrenaline levels. Further analyses will be performed, including the correlation between immune/noradrenaline markers and clinical data in an increased sample size.

Conclusion

Sleep questionnaires might have a poor performance in identifying sleep alterations in MCI/AD individuals. Digitally assessed sleep‐wake patterns might help to detect sleep alterations. A deeper understanding of the role of biological mechanisms, such as immunologic profiles or noradrenergic dysfunction, driving sleep alteration is warranted.
Spousal care partners have increased levels of anxiety, depression and blood short chain fatty acids
Authors: Zuo Zhiyi , Arbab Zunaira , Shan Weiran , Jain Avani , Gallagher Virginia , Reilly Shannon , D’Abreu Anelyssa , Manning Carol A
Published: January 2025

Background

Spousal care partners to people with dementia (PWD) have a higher rate of depression and anxiety when compared to similar age controls. Previous studies have suggested a role of gut microbiota in the pathophysiology of neuropsychiatric symptoms and Alzheimer’s disease (AD). Thus, our study aims to: (1) determine the presence and severity of depression and anxiety in care partners of PWD, and (2) determine the concentrations of short chain fatty acids (SCFA), which are mainly produced by gut microbiota and are important in mediating gut microbiota effects, in the blood of care partners of PWD.

Methods

Three groups of participants were recruited for this cross‐sectional study: healthy controls, patients with AD and their spousal care partners. We used the Beck Depression Inventory (BDI‐II) to assess the presence and severity of depression, the State‐Trait Anxiety Inventory to evaluate care partner distress, and repeatable battery for the assessment of neuropsychological status (RBANS) for cognitive assessment. Their blood and feces were harvested.

Results

We recruited 53 participants: 15, 21 and 17 participants in the control, care partner and AD groups, respectively. Patients with AD had lower mean (SD) total RBANS scores [69 (16)] than controls [110 (11)] (P < 0.001) and care partners [111 (13)] (P < 0.001). Patients with AD and their care partners had higher state and trait anxiety scores than controls (Fig. 1). Care partners had the highest BDI scores (Fig. 2). Care partners had higher concentrations of acetic acid, propionic acid and butyric acid in the blood than those in the control group (Fig. 3).

Conclusions

Spousal care partners had evidence of increased levels of depression, anxiety, and concentrations of SCFAs relative to controls. Our results suggest that care partners to PWDs have gut microbiota different from that of controls, which may be related to their elevated anxiety and depression.
Polygenic risk for schizophrenia predicts dopamine‐related grey matter volume alterations in people with Alzheimer’s disease and psychotic symptoms
Authors: Manca Riccardo , Venneri Annalena
Published: January 2025

Background

Psychotic symptoms may manifest in Alzheimer’s disease (AD), especially in advanced disease stages and in patients with higher polygenic risk scores for schizophrenia (SCZ‐PRS). Such genetic risk seems also to influence grey matter volume (GMV) alterations in patients with psychosis. Since multiple neurotransmitter systems, namely dopamine (DA) and serotonin (5‐HT), have been implicated in psychosis, the aim of this study was to investigate whether a SCZ‐PRS may explain variance in the association between GMV and the cerebral distribution of DA and 5‐HT.

Method

Eight‐hundred ADNI participants with genetic data were selected for this study: 203 cognitively unimpaired (CU) and 597 people with AD. Patient were divided into psychotic (PT‐PS, n = 121) and non‐psychotic (PT‐NP, n = 476) based on available NPI‐Q data. A SCZ‐PRS was calculated for each participant using a Bayesian approach. T1‐weighted MRI scans were pre‐processed with SMP12 and JuSpace to extract Fisher’s z‐transformed individual correlation coefficients between GMV and PET atlases for DA and 5‐HT receptors/transporters. General linear models were used to test the association between the SCZ‐PRS and GMV‐neurotransmitter correlation coefficients (p < 0.05). Analyses were replicated in a sub‐sample of amyloid‐positive participants.

Result

The SCZ‐PRS was negatively associated with correlations coefficients between GMV and the D2 dopaminergic receptor (D2r) in the whole sample (β = ‐0.016, p = 0.023) and in the PT‐PS group (β = ‐0.037, p = 0.030). However, the latter association was significant only when analyses were restricted to amyloid‐positive participants (Figure 1). In the PT‐NP group, the SCZ‐PRS was negatively associated with correlations coefficients between GMV and two 5‐HT receptors (5‐HT1b: β = ‐0.014, p = 0.027; 5‐HT2a: β = ‐0.013, p = 0.038). No between‐group differences in SCZ‐PRSs were found.

Conclusion

The SCZ‐PRS was differentially associated with GMV alterations linked to either DA, in PT‐PS, or 5‐HT, in PT‐NP, that are both neurotransmitters previously implicated in psychotic symptoms. However, the influence of SCZ‐PRS on DA‐related GMV loss appears to be primarily relevant to psychotic manifestations in AD. These findings suggest that future innovative pharmacological interventions targeting the DA system may be beneficial to treat psychosis in AD.
Plasma p‐tau231 in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross‐sectional and longitudinal cohort study
Authors: Malotaux Vincent , Ashton Nicholas J. , Öhrfelt Annika , Chen Yinghua , Su Yi , Garcia Gloria , Guzman Claudia F , Villegas‐Lanau Andres , Giraldo‐Chica Margarita M. , Aguillon David Fernando , Tirado Victoria , Baena Ana Y. , Muñoz Claudia , Acosta‐Baena Natalia , Pruzin Jeremy J. , Ghisays Valentina , Ríos‐Romenets Silvia , Vila‐Castelar Clara , Martinez Jairo E. , Giudicessi Averi , Tariot Pierre N. , Zetterberg Henrik , Lopera Francisco , Blennow Kaj , Reiman Eric M. , Quiroz Yakeel T.
Published: January 2025

Background

Plasma tau phosphorylated at threonine 231 (p‐tau231) is a promising novel biomarker of emerging Alzheimer's disease (AD) pathology. We aimed to characterize cross‐sectional and longitudinal plasma p‐tau231 measurements and estimated ages of biomarker onset in an exceptionally large number of presenilin (PSEN1) E280A (Glu280Ala) mutation carriers and age‐matched non‐carriers from the Colombian autosomal dominant Alzheimer’s disease kindred.

Method

We included a cohort of 722 PSEN1 E280A mutation carriers (mean age 36.36± 12.43 years; 399 females) and 640 non‐carriers (mean age=37.29±13.29 years; 350 females) with baseline assessments from the Alzheimer’s Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia); of these participants, longitudinal measures were available for 164 mutation carriers and 132 non‐carriers (with a mean follow‐up of 4.8±3.1 and 5.6±3.2 years respectively). We used an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p‐tau231 developed at the University of Gothenburg. Using log‐transformed data, we examined the relationship between plasma p‐tau231 levels and age to establish the earliest age at which p‐tau231 concentrations begin to diverge between mutation carriers and non‐carriers. Rates of change in p‐tau231 levels were also compared between the two groups. Data were modeled using Linear Mixed Effects Models, a restricted cubic spline, & Hamiltonian Markov chain Monte Carlo analyses.

Result

Carriers had higher levels of plasma p‐tau231, compared to non‐carriers (9.05±7.44 vs. 5.21±3.37, p<0.001). Plasma p‐tau231 measurements were significantly correlated with age in both groups (r=0.63 in carriers vs. r=0.19 in non‐carriers, p<0.001) and began to differentiate carriers from non‐carriers at age 23 (21 years before the estimated median age at mild cognitive impairment [MCI] onset for this kindred). In population with longitudinal data, PSEN1 E280A mutation carriers had a higher rate of change in p‐tau231 levels compared to non‐carriers (0.03±0.02 vs. 0.01±0.01, p<0.001) and began to differ from non‐carriers at age 19, 25 years before the carriers’ estimated median age of MCI onset.

Conclusion

Our findings support the promise of plasma p‐tau231 as a biomarker for the detection and tracking of AD pathology, the identification of potential candidates for clinical trials and the evaluation of disease‐modifying therapies.
Longitudinal Variations in Retinal and Neuronal Degeneration in Cognitively Normal Older Adults using Peripapillary Optical Coherence Tomography Angiography
Authors: Woo Joshua , Fekrat Sharon , Joseph Suzanna , Robbins Cason B , Haystead Alice , Stinnett Sandra , Grewal Dilraj S
Published: January 2025

Background

Despite an aging population, it remains challenging to reliably differentiate between loss of cognitive function associated with normal aging and cognitive decline associated with pathologic processes. With growing interest in using retinal and optic nerve biomarkers to diagnose neurodegenerative diseases, characterization of the velocity of normal retinal age‐related changes will further our understanding. We evaluated longitudinal microvascular changes in cognitively normal older adults using optical coherence tomography (OCT) and OCT angiography (OCTA).

Methods

Participants over 50 years old without history of neurodegenerative disease or cognitive impairment were enrolled. Exclusion criteria included retinal/optic nerve pathology, glaucoma, and diabetes, among others. The Zeiss Cirrus HD‐OCT 5000 with AngioPlex was used to obtain OCT and OCTA images at baseline and two years later. OCTA parameters measured were optic nerve head‐centered capillary perfusion density (CPD) and capillary flux index (CFI). OCT was used to measure retinal nerve fiber layer (RNFL) thickness. Generalized estimating equations were used to account for measurements obtained from two eyes of the same subject.

Results

189 eyes of 111 cognitively normal older adults were analyzed (average age at baseline, 69.3 ± 5.8; average Mini‐Mental State Examination score, 29.54 ± 0.71; 86 women [77.5%]). Average follow up was 2.1 ± 0.5 years. After controlling for sex, CPD (p<.001), CFI (p<.001), and RNFL thickness (p=0.005) decreased with increasing age at both cross‐sectional time points. Over the follow‐up period, rate of change in CPD, CFI, and RNFL thickness was not significantly correlated with age; however, rate of change in CPD (p=.038) and RNFL thickness (p=0.008) was slower in females compared to males. Average CPD was higher among females at both time points compared to males (p=.002), with no significant differences in CFI and RNFL thickness.

Conclusions

In cognitively normal adults, there is a significant reduction in peripapillary CPD, CFI, and RNFL thickness associated with aging beyond 50 years old. Females had higher CPD values with slower rates of change in CPD and RNFL thickness. With prior studies documenting microvascular alterations associated with Alzheimer’s disease, these values provide benchmarks of normal aging and help detect accelerated rates of decline in neurodegenerative diseases.
White matter free water: a sensitive biomarker of small vascular disease for VCID research
Authors: Maillard Pauline , Lu Hanzhang , Arfanakis Konstantinos , Gold Brian T , Kramer Joel H. , Wang Danny JJ , Seshadri Sudha , Satizabal Claudia L , Rosenberg Gary A. , Singh Herpreet , Schwab Kristin , HELMER Karl , Greenberg Steven M. , Decarli Charles , Arvind Caprihan
Published: January 2025

Background

In recent efforts to improve early identification, staging, and prediction of risk of persons at risk for vascular contributions to cognitive impairment and dementia (VCID) in relation with small vessel disease (SVD), the MarkVCID consortium has worked to identify and validate fluid‐ and imaging‐based biomarkers for SVD associated with VCID. Free water (FW) measured derived from diffusion tensor imaging and one of the selected neuroimaging biomarker “kits”, has been demonstrated to have excellent instrumental validity and to be a sensitive biomarker of cognitive performances. We sought to further examine FW clinical relevance by investigating whether FW predicts cognitive worsening over time.

Method

This study included 275 individuals from the MarkVCID‐1 cohort who received baseline MRI and clinical assessment, as well as a follow‐up clinical examination (mean time±SD: 1.31±0.49 years, Table 1). Our goal was to evaluate whether baseline mean FW (mFW) predicts change UDS3‐EF, a validated executive function composite score derived from the Uniform Data Set (v3.0). We used a linear mixed‐effect regression with EFC score as the outcome variable and time, baseline mFW, age, sex and education, as well as interactions between time and other variables as fixed effects, along with a random subject‐specific intercept and time slope (M1). In secondary models, we also adjusted for presence of diabetes, hypertension (M2) and white matter hyperintensities (log‐transformed, normalized for intracranial volume, M3) to estimate the added contribution of mFW above vascular risk factors and to and a classic SVD marker.

Result

We found a significant effect of time and mFW on EFC scores (b=‐0.63, p=0.0092 and b=‐0.22, p<0.0001 respectively, Table 2), indicating that IRT scores decrease with time and increased baseline mFW. The significant interaction between time and mFW (b=‐0.079, p=0.00075), indicated that increased baseline mFW is associated with accelerated EFC decline. Adding VRF and WMH burden to model M1 did not change these relationships (Table 2).

Conclusion

Our study revealed that baseline FW can predict cognitive worsening over a period as short as of 18 months, providing additional evidence of the clinical relevance of FW as a biomarker of SVD in the context of VCID research.
Assessment of the Correlation and Diagnostic Accuracy between CSF and Plasma AD Biomarkers: A Comparison of the Lumipulse and Simoa Platforms
Authors: Piñol‐Ripoll Gerard , Dakterzada Faride , Cipriani Raffaela , Ortega Ricard López , Arias Alfonso , Llena Iolanda Riba , Julián Maria Ruiz , Huerto Raquel P , Tahan Nuria , Matute Carlos , Capetillo‐Zarate Estibaliz
Published: January 2025

Background

Alzheimer’s disease (AD) plasma biomarkers related to amyloid (A), tau (T), and neurodegeneration (N) can potentially be used to identify these pathological features of the disease, as shown in recent studies. Our objective was to compare the clinical and analytical performance of plasma AD biomarkers measured using the single‐molecule array (Simoa) and Lumipulse platforms.

Method

We quantified ATN and AT plasma biomarkers in 127 patients with mild cognitive impairment (MCI) (n = 81), AD (n = 30), and non‐AD dementia (n = 16) using a Simoa HD‐1/HD‐X analyser (Quanterix) and a Lumipulse G600II automated platform (Fujirebio Europe NV).

Result

We found a strong correlation between the Simoa and Lumipulse methods, although there were systematic differences between biomarker values measured by each method. Concerning the clinical diagnosis, Simoa Ptau181/Aβ42 (AUC 0.739, 95% CI 0.592–0.887) and Lumipulse Aβ42 and Ptau181/Aβ42 (AUC 0.735, 95% CI 0.589–0.882 and AUC 0.733, 95% CI 0.567‐0.900) had the highest discriminating power. However, their power was significantly lower than that of CSF Aβ42/Aβ40, as measured by Lumipulse (AUC 0.879, 95% CI 0.766–0.992). Similarly, Simoa Ptau181 and Lumipulse Ptau181/Aβ42 were the markers most consistent with the CSF Aβ42/Aβ40 status (AUC 0.801, 95% CI 0.712–0.890 vs. AUC 0.870, 95% CI 0.806–0.934, respectively) at the ≥2.127 and ≥0.084 cut‐offs, respectively.

Conclusion

The Simoa and Lumipulse plasma AD assays showed comparable clinical and analytical performance. However, the performance of these biomarkers is weaker than that of CSF AD biomarkers. Interestingly, both platforms identify plasma Ptau181/Aβ42 as a promising biomarker for AD. At present, the analysed AD plasma biomarkers may be useful for screening to reduce the number of lumbar punctures in the clinical setting. However, the use of these markers as diagnostic tools requires further investigation.
Investigating the role of gut microbiome in associations between fast food consumption and cerebrospinal fluid biomarkers of Alzheimer's disease in a cognitively unimpaired cohort
Authors: Peter Darby , Heston Margo B. , Hong Qilin , Agarwal Puja , Ulland Tyler K. , Johnson Sterling C. , Asthana Sanjay , Knight Rob , Kaddurah‐Daouk Rima , Zetterberg Henrik , Blennow Kaj , Rey Federico E. , Bendlin Barbara B.
Published: January 2025

Background

Emerging evidence underscores the significant influence of diet on risk for Alzheimer’s disease and related dementias (ADRD). In particular, a Western dietary pattern associates with increased risk for ADRD, with proposed mediation via inflammatory mechanisms, among others. Although a Western dietary pattern associates with gut microbiome alterations, it remains unclear whether microbial alterations mediate Western diet‐associated inflammation and neurodegeneration. To begin to investigate these relationships, this study assessed whether the gut microbiome mediates associations between fast food consumption and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, glial activation, and Alzheimer’s disease (AD).

Method

Cognitively unimpaired adults (n=86, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center) underwent lumbar puncture, provided a stool sample, and reported average weekly fast food consumption over the past year via questionnaire. Participants were an average of 67 years of age and 62% of participants (n = 53) were female. Fecal microbiome composition was characterized using 16S rRNA sequencing. A QIIME2/Phyloseq pipeline was used to complete denoising, feature classification, filtration of rare taxa and agglomeration at each taxonomic rank. CSF biomarkers were quantified using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Multiple regression tested associations between fast food consumption and CSF biomarkers of neurodegeneration, glial activation, and AD. Phylogenetically‐informed mediation (PhyloMed; Hong et al, 2021) was performed at each taxonomic rank to identify bacterial clades mediating the relationship between fast food and the CSF Aβ42/40 amyloid pathology test.

Result

A significant association between fast food and CSF Aβ42/40 was observed, such that more frequent fast food consumption associated with lower levels of CSF Aβ42/40 (Figure 1), but no significant mediating effects of gut microbiome were observed (Table 1). No significant associations between fast food consumption and other CSF biomarkers were observed (Table 2).

Conclusion

While associations between fast food consumption and CSF biomarkers were expected to be partially mediated by gut microbial alterations, few individuals reported consuming fast food more than once each week. Further evidence is needed to characterize the influence of fast food and its nutritional components on neurodegeneration and development of AD pathology preclinically.
Cross‐Sectional Comparison of Structural MRI Markers of Cognitive Impairment in an Ethno‐racially Diverse Cohort
Authors: Wisch Julie K. , Petersen Kalen , Millar Peter R , Abdelmoity Omar , Meeker Karin L. , Braskie Meredith N , Toga Arthur W. , O'Bryant Sid E. , Ances Beau ,   the HABS‐HD Study Team
Published: January 2025

Background

Structural MRI can describe neurodegeneration associated with aging and Alzheimer Disease (AD). Brain age gap (BAG) quantifies the difference between chronological age and predicted “brain age” and can be estimated using many published algorithms. Higher BAG indicates accelerated brain aging. Regional estimates of volume and thickness detect structural differences in AD signature regions (e.g., hippocampus, tempo‐parietal regions). This project aimed to identify the structural MRI measure that had the best correspondence with Clinical Dementia Rating (CDR) in an ethno‐racially diverse sample.

Method

We compared structural MRI measures in the Health & Aging Brain Study–Health Disparities (691 non‐Hispanic Black (NHB), 1094 Mexican‐American (MA) and 1085 non‐Hispanic White (NHW) participants). We calculated BAG using DeepBrainNet (BAGDBN) and BrainAgeR (BAGBAR). We derived Freesurfer‐based cortical thickness (meta‐ROI) and hippocampal volume (normalized for intracranial volume). We applied ANOVA followed by post‐hoc Tukey tests to assess differences in the interaction of self‐identified race/ethnicity and CDR, correcting for age, gender, and scanner. We performed ordinal regression to predict CDR using the same covariates, except CDR.

Result

After correction for multiple comparisons, BAGDBN significantly differed between CDR 0 and CDR 0.5 in MA (pcorrected=0.045) and NHB (pcorrected=0.017) but not NHW (pcorrected=0.110). The other measures significantly differed between CDR 0 and CDR 0.5 for NHW only (Figure 1). For individuals with a 1 Z‐score elevation in BAGDBN (6.1 years), NHW have 1.21 (95%CI: 1.18, 1.26) times the odds of being CDR 0.5, while NHB significantly greater risk (OR = 1.31, 95%CI: 1.27, 1.36). MA have 1.26 times the odds (95%CI: 1.22, 1.31). In contrast, for individuals with a 1 Z‐score decrease in cortical thickness, there is no difference in odds ratio by ethno‐racial group (NHW=1.21, 95%CI: 1.17, 1.27; NHB=1.30, 95%CI: 1.24, 1.37; MA=1.28, 95%CI: 1.24, 1.33) (Figure 2).

Conclusion

The neurodegeneration measures with the strongest correspondence to CDR varied by ethno‐racial group. BAGDBN may display greater sensitivity to the subtle changes that occur as individuals transition from CDR = 0 to 0.5 in underrepresented cohorts. Further work is needed to understand what features BAGDBN captures, but this suggests care should be taken when choosing neurodegeneration markers.
Determining aging trajectories though hyperbolic embeddings of MEG brain networks
Authors: Ramirez Hugo , Tabarelli Davide , Brancaccio Arianna , Belardinelli Paolo , Marsh Elisabeth B , Funke Michael E , Mosher John C , Maestú Fernando , Xu Mengjia , Pantazis Dimitrios
Published: January 2025

Background

Investigating age‐related changes in MEG brain networks offers significant potential for comprehending aging trajectories and unveiling anomalous patterns associated with neurodegenerative disorders, such as Alzheimer's disease. In this study, we extended a deep learning model called Fully Hyperbolic Neural Network (FHNN) to embed MEG brain connectivity graphs into a Lorentz Hyperboloid model for hyperbolic space. Through these embeddings, we then explored the impact of aging on brain functional connectivity across multiple decades.

Method

We analyzed data from 587 participants enrolled in the Cambridge Centre for Ageing and Neuroscience (Cam‐CAN) longitudinal study. Notably, we introduced a unique metric—the radius of the node embeddings—which effectively proxies the hierarchical organization of the brain. We leveraged this metric to (i) assess whether we can decode age‐related information, and (ii) characterize subtle hierarchical organization changes of various brain subnetworks attributed to the aging process.

Result

Our decoding results revealed that the hyperbolic radius carries substantially more age‐related information compared to all other conventional graph‐theoretic measures examined, underscoring the effectiveness of employing hyperbolic embeddings to characterize the aging process. An examination of hyperbolic radius alteration patterns across decades exposed numerous subnetworks showcasing a decline in hierarchy during aging, with some displaying gradual changes and others undergoing rapid transformations in the aging brain (illustrated in Figure 1cde).

Conclusion

Overall, our study presented the first evaluation of hyperbolic embeddings in MEG brain networks, introduced a novel measure of brain hierarchy, and used this measure to highlight aging trajectories in the large cohort of the Cam‐CAN dataset. A prominent finding was the reduction of hierarchy across a substantial number of subnetworks throughout the aging brain. This hierarchy reduction could imply a shift in the brain network configuration impairing cognitive processes.
Effect of Refrigeration on Alzheimer’s Disease Biomarker Measurements in Plasma
Authors: Reyes Ramiro Eduardo Rea , Wilson Rachael E , Keske Elysse , Marshall Martie , Jensen Cindy , VandenLangenberg Monica , Lange Kate , Jeffers Beckie , Fredricks Aaron , Williams Victoria J. , Okonkwo Ozioma C , Bendlin Barbara B. , Engelman Corinne D. , Gleason Carey E. , Hogan Kirk J. , Chin Nathaniel A. , Carlsson Cynthia M. , Jonaitis Erin M. , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik
Published: January 2025

Background

Mobile phlebotomy is an attractive option for the study of Alzheimer’s disease (AD) in rural and underserved populations, but logistics of collecting, and shipping these samples outside clinical settings can introduce additional sources of variability. Knowledge is limited on the impact of field collection on blood‐based Alzheimer’s disease biomarkers, especially protein stability when dry ice is not available during shipping. Our study looks into the effects of holding plasma samples under refrigeration prior to freezing on AD biomarker concentrations compared to samples that were frozen within one hour of collection as is standard practice.

Method

We used plasma samples from 30 participants (58‐93 yo, mean age = 72.23, SD = 7.31; 18 females, 12 males) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Center, with aliquots from each of them undergoing three different treatments: a reference condition frozen immediately at ‐80°C, and two treatments involving refrigeration at 2‐8°C for either 48 or 72 hours before freezing. We measured the concentration of five AD blood biomarkers (ALZpath pTau217, GFAP, NfL, Aβ40, and Aβ42) using the Quanterix HD‐X platform. Finally, we evaluated biomarker stability by comparing refrigeration treatments to the aliquots frozen immediately, via repeated measures ANOVAs and ICC analysis.

Result

We found consistent concentrations of pTau217 [F(1.78, 44.49) = 0.16, p = .829; ICC(3,3) = 0.987, p < 0.001], NfL [F(1.45, 39.14) = 2.84, p = .086; ICC(3,3) = 0.992, p < .001], and GFAP [F(1.63, 43.89) = 1.66, p = .205; ICC(3,3) = 0.996, p < 0.001] for up to 72 hours of refrigeration. However, both Aβ42 and Aβ40 levels in plasma significantly declined after refrigeration [Aβ40: F(1.22, 33.07) = 27.38, p < 0.001; ICC(3,3) = 0.537, p < .001; Aβ42: F(1.16, 31.34) = 15.35, p < .001; ICC(3,3) = 0.713, p < .001].

Conclusion

Our results highlight the sensitivity of plasma Ab to the storage conditions, and show pTau217, GFAP, NfL as candidates to study when ideal handling conditions for plasma samples are not easily accessible. Their resilience under refrigeration can provide flexibility to access more remote communities and increase representation in AD research.
Innovative Dementia Care Practices in Japan: Exploring Logical, Lateral, and Integrative Care Approaches
Authors: Tanaka Takahiro , Akune Kenichi , Vernon Andrew
Published: January 2025

Japan’s aging demographic is witnessing a sharp rise in dementia cases, projected to reach 7.3 million by 2025 and 9.66 million by 2045. This increase not only foresees substantial economic strains, with social costs expected to hit 22.5 trillion yen by 2045 and 24.3 trillion yen by 2060, but also exerts pressure on the labor force as more individuals leave jobs for caregiving roles. Additionally, safety concerns are escalating with the rising number of people living with dementia reported missing. In response, innovative dementia care practices are essential.

The Housenka Group, based in Osaka, Japan, has pioneered three innovative approaches to dementia care: Logical Care (Fact Acceptance‐Based Aid), Lateral Care (Reality Affirmation‐Based Aid), and Integrative Care (Comprehensive Aid). Logical Care is centered around enhancing clarity and structure in communication to help people living with dementia understand and come to terms with their situation. A prime example of this method is seen when a daughter clearly explains to her mother the need to transition to a care facility. In contrast, Lateral Care is tailored for those people living with dementia who struggle to comprehend objective realities. It encourages caregivers to empathize with and validate the residents' personal perceptions of reality. A notable instance of this method in action involves caregivers addressing a resident using her former professional title, ‘President’, thereby significantly aiding her adjustment to a new environment.

Integrative Care blends elements of both Logical and Lateral Care, tailoring to individual requirements and behavioral responses. A significant implementation of this approach involved using pictograms to help a resident locate essential facilities, addressing issues like confusion and disorientation.

These approaches collectively aim to offer person‐centered, compassionate support to people living with dementia, valuing both their cognitive limitations and emotional well‐being. They provide a potential framework for effective dementia care applicable globally, especially in aging populations. The study highlights the critical need for flexible and understanding care practices in enhancing life quality for people living with dementia and their caregivers, marking a significant stride in dementia care innovation.
Circulating proteins associated with rate of cognitive decline based on APOE genotype
Authors: Fohner Alison E , Brody Jennifer A. , Sitlani Colleen , Xue Diane , Longstreth W.T. , Odden Michelle , Austin Thomas R. , Gerszten Robert Edgardo , Trittschuh Emily H. , Psaty Bruce M. , Seshadri Sudha
Published: January 2025

Background

APOE genotype is the most important genetic risk factor for Alzheimer’s disease (AD), but whether it affects the proteins associated with AD risk is unclear. Circulating proteins may reveal biology underlying pathologic processes.

Methods

We evaluated log2 standardized levels of 4979 proteins quantified using modified aptamer technology [SomaScan] in plasma from 2725 participants in the Cardiovascular Health Study who were free of dementia and stroke. Participants were recruited from 4 sites in the United States and plasma samples were obtained in 1992/1993. Cognitive decline was measured with annual modified mini mental state exams (3MSE) and digit symbol substitution tests (DSST) over 7 years. APOE genotype was classified as e4 carrier, e2 carrier, or non‐carrier. Adjusting for sex, age, race, education, and study site, we used linear mixed effects modeling to evaluate whether the association of each protein with rate of cognitive decline differed based on APOE genotype. We ran two models: one comparing APOE e4 to the other genotypes and another comparing APOE e2 to the other genotypes. A p‐value of 2.1x10‐5 was considered significant.

Results

Mean age of participants was 74 years, 61% were female, 15% were Black, 25% were APOE e4 carriers, 17% were APOE e2 carriers, and mean cognitive follow‐up was 5.2 years. For 3MSE, 38 proteins had significant interactions with time and APOE e4 carrier status (Table 1) and 15 proteins with APOE e2 carrier status (Table 2). For DSST, only 3 proteins had significant interaction with time and APOE e4 carrier status and none with APOE e2. Proteins included those involved in lipid transport, neuronal differentiation, immune response, and cell signaling.

Conclusions

Large‐scale proteomic profiling identified circulating proteins differentially associated with cognitive decline based on APOE genotype. Many of the proteins are involved in pathways previously implicated in AD risk. Replication and other characterization are needed to clarify how APOE genotype may affect mechanisms involved in cognitive decline and AD risk.
Prostatic malignancy with paraneoplastic subacute encephalitis with unique imaging characteristics
Authors: Singh Mridula , Sahu Suman Kumar , Kushwaha Suman , Maheshwari Siddharth , Panda Ashwin Kumar , Mustafa Alisha
Published: January 2025

Background

Prostatic malignancy with paraneoplastic subacute encephalitis –A rare syndrome

Method

We present a case of 76 year old male without any previous comorbidity and addiction who manifested a rapid neuropsychiatric decline with a frontotemporal syndrome over a period of 6 months. He was anemic and cerebrospinal fluid study showed 10 cells with lymphocytic predominance. The extensive workup of csf for infection, malignancy revealed nothing. His workup for metabolic, neuroinfection and stroke came out negative. His PSA came 4 times the upper limit and MRI brain showed T2 hyperintensity in left temporal lobe with punctate contrast enhancement and atrophy of right temporal lobe with enlarged temporal horn. His MRI pelvis showed PIRADS 4 lesion highly suggestive of malignancy. His paraneoplastic markers came negative. As our institute being neuropsychiatric one, we had to refer the patient to multispecialty hospital. The patient succumbed to illness within two months after referral from our institute while undergoing treatment for the malignancy.

Result

Prostatic malignancy causing paraneoplastic rapidly progressive dementia with unusual MRI features.

Conclusion

Limbic encephalitis presents with short term memory loss, complex partial seizures and neuropsychiatric complaints. Our case presented subacutely as frontotemporal syndrome. The signal abnormalities in the mesial temporal lobes without contrast enhancement are the typical MRI findings. In our case patient had extensive involvement of temporal lobe with contrast enhancement, so likey an overlap between limbic encephalitis and encephalomyelitis. To the best of my knowledge none of the case in past had this MRI feature.
ATN system and disease‐modifying treatment eligibility in a hospital‐based cohort
Authors: Cecchetti Giordano , Canu Elisa , Rugarli Giulia , Coraglia Federico , Basaia Silvia , Calloni Sonia Francesca , Vezzulli Paolo Q. , Spinelli Edoardo G. , Santangelo Roberto , Caso Francesca , Falini Andrea , Magnani Giuseppe , Filippi Massimo , Agosta Federica
Published: January 2025

Background

This study aims at applying the AT(N) classification to a cohort of patients with Alzheimer’s disease (AD) and related disorders, and to investigate how many cases would be eligible for the emerging disease‐modifying treatments.

Method

We conducted a retrospective evaluation of 429 patients referred to the Memory Center of IRCCS San Raffaele Hospital in Milan. Patients underwent clinical/neuropsychological assessments, lumbar puncture, structural brain imaging, and positron emission tomography (FDG‐PET). Patients were stratified according to AT(N) classification, group comparisons were performed and the number of eligible cases for anti‐β amyloid monoclonal antibodies was calculated.

Result

Sociodemographic and clinical features were similar across groups. Although the clinical presentation was similar, the A+T+N+ group showed more severe cognitive impairment in memory, language, attention, executive, and visuospatial functions compared to other AT(N) groups. Notably, T+ patients demonstrated greater memory complaints compared to T‐ cases. FDG‐PET outperformed MRI and CT in distinguishing A+ from A‐ patients. Although the 60.8% of the observed cases were A+, only the 17.2% were eligible for amyloid‐targeting treatments.

Conclusion

The AT(N) classification is applicable in a real‐world clinical setting. The classification system provided insights into clinical management and treatment strategies. Low cognitive performance and specific regional FDG‐PET hypometabolism at diagnosis are highly suggestive for A+T+ or A‐T+ profiles. This work provides also a realistic picture of the proportion of AD patients eligible for disease modifying treatments emphasizing the need for early detection.

Funding: Foundation Research on Alzheimer Disease. Next Generation EU/National Recovery and Resilience Plan, Investment PE8‐Project Age‐It.
Microstructural assessment of the locus coeruleus‐entorhinal cortex pathway and association with ATN markers in patients with cognitive impairment
Authors: Aiello Marco , Borrelli Pasquale , Cavaliere Carlo , Marizzoni Moira , Ribaldi Federica , Garibotto Valentina , Scheffler Max , Jelescu Ileana O , Jovicich Jorge , Salvatore Marco , Frisoni Giovanni B. , Pievani Michela
Published: January 2025

Background

This study investigated microstructural features of the locus coeruleus to entorhinal cortex pathway (LC‐EC) in relation to amyloid (A), tau (T), neurodegeneration (N) markers and cognitive impairment in memory clinic patients.

Method

124 participants were recruited from the Geneva Memory Clinic (n=30 cognitively unimpaired – CU; n=80 MCI and n=14 dementia ‐ CI) and underwent clinical assessment, 3T MRI scan including diffusion weighted imaging, amyloid PET, and tau PET. Diffusivity indices (fractional anisotropy ‐ FA, mean, axial and radial diffusivities ‐ MD, AxD, RD) were assessed in the LC‐EC pathway using a probabilistic atlas. A, T, N markers were assessed both as continuous and dichotomous measures. Differences in LC‐EC microstructure according to ATN markers and diagnosis were assessed with ANOVA models (FDR correction). Linear regression models were used to test whether LC‐EC pathway microstructure predicted cognitive impairment independently of ATN markers.

Result

Lower FA (p=0.020) and higher MD, RD and AxD (p<0.005) was observed in participants with tau positivity in the EC (TEC+, Braak stage ≥1) compared to tau negative subjects (TEC‐). Higher MD, RD and AxD was observed in neurodegeneration positive (N+, medial temporal atrophy) versus negative (N‐) participants (p<0.001), and CI versus CU (p<0.016). There was no difference in LC‐TE microstructure between amyloid positive (A+) and negative (A‐) subjects (p>0.05) nor between tau positive (T+; Braak stage ≥4) and negative (T‐) subjects (p>0.05). The regression model showed that RD of the LC‐EC tract was associated with clinical diagnosis and mini mental state examination score independently of ATN markers (p<0.05).

Conclusion

Our results indicate that LC‐EC microstructural measures, specifically RD, are sensitive in detecting CI and provide complementary information over ATN biomarkers. Associations with T suggest that LC‐TE microstructural alterations show regional specificity in the EC.
Mapping culturally sensitive assessment and care for Moroccan migrants with dementia in Spain
Authors: Taiebine Mohamed
Published: January 2025

Background

Given the context of globalization, epidemiological and health disparities create socio‐cultural barriers to specialized and appropriate care for people living with dementia in non‐Western countries, particularly in Spain, where Moroccan migrants maintain their position as the largest registered foreign community. We aimed to map cultural, clinical, and linguistic challenges and facilitators of dementia assessment and care for this population.

Methods

We investigated articles published in English, Spanish, and Arabic in different medical, allied health, social, and human sciences databases that addressed assessment and care for Moroccan migrants with dementia (MMWD) and their caregivers in Spain. Demographic, epidemiological, clinical, linguistic, socio‐cultural, and socio‐economic features as well as facilitators and barriers to assessment and care were summarized.

Results

The main findings emphasized the importance of embracing the socio‐cultural values of the host country, as well as maintaining bi‐cultural and bilingual status. The principal challenges included lack of translating and interpreting services, paucity of neurocognitive tools in Moroccan Arabic, and dearth of bi‐cultural and bilingual practitioners, while the facilitators were mainly the training of healthcare staff about dementia and capitalizing on cross‐cultural translation and adaptation of best evidence‐based interventions and assessment tools in dementia in Moroccan Arabic and Spanish.

Conclusions

Enabling cultural appreciation, inclusion and cross‐cultural competency should encourage stakeholders, practitioners, caregivers, and clients to respond culturally and linguistically to the unique features of elderly Moroccan Arabic migrants or those who are well‐established as Moroccan‐Spanish citizens. Implementing person‐centered care and culturally salutogenic approaches might erase frontiers in language, care, culture, and place of origin.
MRI‐driven Analysis of EEG Connectivity in Alzheimer’s Disease and Behavioral Frontotemporal Dementia
Authors: Cecchetti Giordano , Basaia Silvia , Canu Elisa , Curti Davide G. , Cursi Marco , Spinelli Edoardo G. , Caso Francesca , Fanelli Giovanna F. , Bellini Anna , Magnani Giuseppe , Agosta Federica , Filippi Massimo
Published: January 2025

Background

Previous EEG studies highlighted the potential of analyzing neural oscillatory activity for differentially diagnosing Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We recently studied primary progressive aphasia (PPA) variants associated with AD and FTD, revealing distinctive patterns of alterations in linear lagged connectivity (LLC) values within the default mode network (DMN) and the salience network (SN). This study utilizes the same functional MRI‐driven model for source reconstruction to investigate LLC values across typical amnestic AD and the behavioral variant of FTD (bvFTD).

Method

In this cross‐sectional, single‐center study, we consecutively recruited AD, bvFTD, and healthy subjects from the Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Resting‐state 19‐channel EEG data were acquired, and LLC values estimated across 6239 voxels at the whole‐brain level using standardized low‐resolution brain electromagnetic tomography (sLORETA). Subsequently, LLC values were averaged within SN and DMN maps derived from functional MRI data of healthy controls using seed‐based analysis. Network‐based statistics (5000 permutations‐based adjustment) were employed to compare LLC values among study groups.

Result

39 bvFTD patients, 39 AD subjects, and 21 healthy controls were enrolled. AD patients exhibited elevated connectivity at delta frequency band in both DMN and SN (p<0.01), and decreased values at alpha2 band in both DMN (p = 0.04) and SN (p = 0.03) compared to controls. Furthermore, AD patients displayed higher LLC values at theta band than both bvFTD and healthy subjects within both DMN and SN (p = 0.01). BvFTD patients exhibited a significant increase in EEG connectivity at delta band compared to healthy individuals, specifically within SN (p = 0.05). No other significant differences were observed.

Conclusion

LLC findings in AD patients align with our previous studies, indicating a comprehensive disruption of neural oscillatory activity, with theta frequency band emerging as a potential biomarker of AD. Consistent with our study in PPA patients, FTD patients exhibited a connectivity alterations at delta band limited to anterior cerebral regions. EEG holds promise in the differential diagnosis between AD and bvFTD, suggesting a link with underlying pathology.

Funding: Foundation Research on Alzheimer Disease. Next Generation EU/National Recovery and Resilience Plan, Investment PE8‐Project Age‐It.