bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced glycation end products (AGEs) involvements in the development of frank Alzheimer’s disease (FAD)
Authors: Oghenekevbe Vincent , Olughor O
Published: January 2025

Background

AGEs is one of the Maillard’s reaction products (MRPs) found in over‐processed common diets, causing food‐nutrients abnormal modifications. Some MRPs are potentially toxic or carcinogenic. MRPs present in stages: initial, intermediate and final. The aim of this presentation is to state roles played by AGEs in the development of AD as recent findings.

Method

Through threaded literature review

Result

1) MRPs and disease causing associations were first recognized by Swedish scientists in 2002 and involvement of AGEs in development of AD in 2010; 2) MRPs include: N'fructoselysine (furosine), 5‐ Hydroxymethyl furfural (HMF), acrylamide, heterocyclic amines and melanoidins; 3) some neurotransmitters are modified amino acids, known as monoamines; 4) some other neurotransmitters are unmodified amino acids; 5) certain short chain amino acids (peptides) function as neuromodulators, by being able to alter a neuron’s response to a neurotransmitter, or block its release; 6) a neurotransmitter’s effect depends upon its concentration, the types and numbers of receptors and ion channels on the receiving cells' membranes; 7) neurotransmitters affect each other’s levels, the same neurotransmitter can even have opposite effects on different types of cells; 8) AD is due to depleted Acetylcholine (Ach) neurotransmitter in the brain, causing imbalance. Ach coordinates functions in the brain by enhancing nerve transmission in a horizontal direction and also inhibiting transmission in a vertical direction; 9) Ach can both inhibit and stimulate because it can bind two types of receptors: on basket cells (to decrease levels of GABA production and stimulate horizontal nerve transmission) and on bipolar cells (to increase GABA production and strengthen the inhibition of vertical transmission).

Conclusion

How AGEs disrupts some of these functions to contribute to the development of AD (typified by ‘forgetfulness and difficult‐thinking’) will be discussed.
A/T(N) Status Biomarkers Associate with Polymorphisms in Purinergic Signaling Genes
Authors: Costa Luciana Rocha , de Bastiani Marco Antônio , Machado Luiza Santos , Borelli Wyllians Vendramini , Benedet Andrea , Zimmer Eduardo R. , Souza Diogo O. , de Souza Débora Guerini
Published: January 2025

Background

Purinergic signaling is vital in various cellular processes like neuroinflammation, synaptic transmission, Aβ clearance, and tau phosphorylation regulation. This study aims to examine if SNPs in purinergic signaling genes are associated to A/T(N) status biomarkers in Alzheimer’s Disease through Genome Wide Association Studies.

Method

The SNPRelate package was used to analyze SNPs in genes related to purinergic signaling and A/T(N) markers. We included 152 cognitively unimpaired and 359 cognitively impaired individuals from the ADNI cohort. Generalized linear models were applied to investigate associations between independent variables (SNPs, APOE4 status, sex, age, education, and diagnosis), and A/T(N) markers, specifically tau status (CSF/Plasma ptau181), amyloid status (CSF Aβ and AV45‐PET ratio of cortical grey matter/whole cerebellum), and neurodegeneration status (average FDG‐PET metaROI). We also conducted a voxel‐wise linear regression testing the association between [18F]FDG metabolism and SNP carriership, corrected by sex and age. The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t>3.11, p<0.001, df = 495).

Result

We identified 13 SNPs in the intronic region of purinergic signaling genes that had a significant association with A/T(N) status biomarkers (Table 1). CSF Aβ levels were associated with polymorphisms in the adenosine deaminase 1 (ADA1) and 2 (ADA2) genes. AV45‐PET binding was associated with SNPs in ADA2, ADORA1, and P2×1 genes. CSF ptau181 levels were associated with polymorphisms in the ADORA1, NTPDase‐2/CD39L1, and pannexin 1 gene. Increased FDG uptake was associated with a polymorphism in the ADORA2B gene. Finally, a polymorphism in the ADORA1 gene presented a positive association with [18F]FDG metabolism in the parietal lobe white matter (tmax = 3.97, p<0.0001) (Figure 1).

Conclusion

Multiple SNPs within genes related to purinergic signaling have been identified to be linked with A/T(N) status markers. These results underscore the significance of purinergic signaling in cellular processes relevant to brain homeostasis, suggesting potential implications for Alzheimer’s disease (AD). Consequently, these findings highlight promising cellular mechanisms underlying the development of dementia.
Assessing the Impact of Gepirone on Major Depressive Disorder ‐ A systematic review and meta analysis
Authors: Khalifa Mostafa A. , Salaheldin Abdelmoneim Osama , Elsead Jana Ahmed , Aboud Fatama Azzam , Korim Basmala Mohamed , Abdalsttar Shehab Sherif , Mahmoud Abdalla Ahmed
Published: January 2025

Background

Major depression has been affecting more than 280 million of the general population, and this number continue to rise. Thus, impairing daily life activities. Research on Major depression has been since the 19th century for the sake of elevating symptoms with less side effects. The aim of our study is to assess the impact of a potential game changer in treatment of Major depression, Geprione

Method

we have conducted a comprehensive search, including key databases such as Cochrane, PubMed, SCOPUS, and ScienceDirect, to ensure thorough coverage of all relevant literature, using appropriate key mesh terms. Search date ranged from 1987 to 2024. Randomized controlled studies published between that studied Patients with Major Depressive Disorder (MDD) diagnosed based on standardized criteria such as DSM‐5 with Geprione only as administration while comparing it to a placebo reflected as reduction in depressive symptoms for outcome were included. Exclusion criteria included populations with induced major depression such as substance abuse and breast‐feeding women, studies assessing other drugs from azapirones family than Geprione, with comparison to any drug other than placebo, and randomized controlled studies with incomplete outcome data. This systematic review was registered with PROSPERO [CRD42024510595] and followed PRISMA guidelines. Risk of bias was assessed using Cochrane library tool RoB 2 (revised tool for Risk of Bias in randomized trials). Data syntheses will be performed through Rev‐Man program

Result

Seven Randomized controlled trails (n = 7) were included from 203 identified titles, after excluding duplicates (n = 13) and not fulfilling the inclusion and eligibility criteria (n = 183). A pilot study was conducted on 4 of these papers, revealing that all studies demonstrated that Gepirone is a potential treatment for major depression disorder and Our systematic review is currently in progress and is expected to be completed by the end of 2024

Conclusion

The study views Gepirone as a potential treatment for major depression disorder with regard to fewer side effects and higher efficacy compared to standard treatment e.g., atypical antidepressants and tricyclic antidepressants. We encourage further research across variable populations for more robust evidence.
Associations between CYP4F2 missense variant rs3093105 A>C and Alzheimer’s disease phenotypes
Authors: Noor Shiropa , Mori‐Fegan Daniel K , Wong Yuen Yan , Wu Che‐Yuan , Roman Richard J. , Taha Ameer Y. , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

20‐hydroxyeicosatetranoic acid (20‐HETE) is a potent vasoconstrictor synthesized by the CYP4F2 enzyme. The CYP4F2 missense variant rs3093105 A>C (W12G) has been implicated in hypertension and stroke, risk factors for Alzheimer’s disease (AD), and with decreased 20‐HETE activity. To explore the potential role of the CYP4F2/20‐HETE pathway and AD, this study investigated associations between the rs3093105 variant and AD phenotypes.

Method

Participants from the Alzheimer’s Disease Neuroimaging Initiative with amyloid‐beta 42 positive PET status and a diagnosis of AD or mild cognitive impairment were selected. Linear regressions explored the relationship between rs3093105 C‐allele carrier status (AC/CC vs AA) and cognition, assessed as executive function and memory composites and Rey Auditory Verbal Learning Test (RAVLT) scores; and brain volumetric measures at baseline, obtained using FreeSurfer on MRI T1‐weighted images. Longitudinal associations (up to 48 months) were explored via interactions between carrier status and time in mixed effects models. Covariates included baseline age, sex, APOE e4 status, years of education, intracranial volume, and Mini Mental State Exam score.

Result

The rs3093105 variant was present at a minor allele frequency of 19.2% in 315 individuals (mean age 73.3 ± 7.57, 43.2% women). At baseline, C‐allele carriers had higher executive function composite scores (B = 0.315, SE = 0.119, p = 0.009, n = 315) and RAVLT immediate (sum of trials 1‐5) scores (B = 2.46, SE = 1.24, p = 0.048, n = 315), and larger whole brain volume (B = 14.19, SE = 6.84, p = 0.039, n = 310). Over time, carriers had higher memory composite scores (B = 0.116, SE = 0.052, p = 0.027, n = 183) and RAVLT learning (trial 5 minus trial 1) scores (B = 0.484, SE = 0.207, p = 0.021, n = 179), and retention in hippocampal volume (B = 4.19, SE = 1.71, p = 0.016, n = 127).

Conclusion

Altogether, rs3093105 C‐allele carriers show better performance on memory tests and retention of hippocampal volume. These findings suggest a potential role of the CYP4F2/20‐HETE pathway in AD progression and warrants replication studies in other cohorts.
Characterization of GPR3 function in astrocytes in a preclinical AD mouse model
Authors: Osorio Carlos Alberto Ayhllon , Espinosa Diego Rolando Hernandez , Huang Yunhong , Guimarães Thais Rafael , Thathiah Amantha
Published: January 2025

Background

Alzheimer’s Disease (AD) is neuropathologically characterized by the accumulation of Amyloid‐β (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. GPR3 is a G protein‐coupled receptor (GPCR) that has been implicated in Aβ pathogenesis via β‐arrestin 2 (βarr2)‐mediated intracellular signaling. Genetic deletion of Gpr3 reduces the Aβ plaque burden and cognitive decline in AD transgenic mice. However, Gpr3 deficiency is also associated with adverse effects, e.g., increased anxiety‐ and depression‐like behavior. Recently, our lab demonstrated that selective inhibition of GPR3‐mediated βarr2 signaling maintains the beneficial physiological functions of GPR3‐mediated G protein‐signaling while reducing the Aβ plaque burden in the AppNL‐G‐F
AD knockin (KI) mouse model. We also determined that GPR3 is more abundantly expressed in astrocytes relative to neurons and microglia. Nevertheless, GPR3 function in astrocytes has not been investigated to date.

Methods

We performed bulk RNAseq analysis of cortical brain samples from AppNL‐G‐F; hemagglutinin‐tagged (HA)‐GPR3 (AD KI) and AppNL‐G‐F; G protein‐biased HA‐GPR3 (Biased AD KI) mice at 6‐months of age. We are currently utilizing flow cytometry to analyze Biased AD KI relative to AD KI brains at 6‐, 12‐, and 18‐months of age (early‐, mid‐, and late‐stage pathology). We are labeling Aβ plaques in vivo with a fluorescent Congo‐red derivative, methoxy‐X04 (MX04). Three hours after MX04 administration, the mice are euthanized. One brain hemisphere is dissociated and analyzed by flow cytometry for ACSA2+/MX04+ astrocytes, GFAP+/MX04+activated astrocytes, and markers of proliferation (Ki67).

Results

We determined that astrocytes exhibit increased hypertrophy and expression of Gfap in Biased AD KI mice. In accordance with these findings, we observe differential expression of several cytokines (e.g., Il‐1β, Il‐5, and Chil3/5), chemokines (e.g., Ccl6, Ccl9, and Cxcl9), and growth factors (e.g., Fgf3, Pdgfd, and Vegfd) in Biased AD KI mice, suggesting that GPR3 is involved in the crosstalk between astrocyte, microglia, and neurons. Preliminary FACS analysis also indicates differential expression of markers of astrocyte activation in astrocytes isolated from our Biased AD KI mice.

Conclusion

These studies provide strong evidence for the astrocytic function of GPR3 in AD, which has therapeutic potential to reduce neuroinflammation and AD pathology and counteract neurodegeneration.
Qualitative use of the RE‐AIM/PRISM framework for adaptation of a primary care educational program on the care of persons with behavioral and psychological symptoms of dementia
Authors: LeCaire Tamara J. , Schroeder Molly , Paniagua Uriel , Stone Jonathan A , Albrecht Tammi , Houston Stephanie , Schrager Sarina , Carlsson Cynthia M. , Walaszek Art
Published: January 2025

Background

Primary care clinicians report limited self‐efficacy for managing complex behavioral and psychological symptoms in persons with dementia (BPSD). Complementary approaches, the academic detailing model and the DICE ApproachTM, improved self‐efficacy for memory clinic clinicians and their teams to identify and manage BPSD. Methods guided by the RE‐AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) / PRISM (Practical, Robust, Implementation and Sustainability Model) framework are shared for pre‐implementation adaptation of this program for generalist primary care.

Methods

A stakeholder‐engaged qualitative study with both current and future program stakeholders was used to identify a) gaps in BPSD management, and b) multi‐level barriers and facilitators to the academic detailing model. Framework guided semi‐structured interview topics included contextual factors impacting program reach, reasons for adoption and program effectiveness, and barriers and facilitators for implementation. The team completed 14 interviews; 7 with clinicians practicing in primary care integrated memory clinics with prior academic detailing participation (Champions) and among 7 clinician colleagues with no or minimal program experience (Novices). Inductive and deductive qualitative thematic analysis approaches were used, the latter organized by RE‐AIM domains and multi‐level context.

Results

A sample of themes and adaptations for shaping program access and fit (Reach) are shared. 1) Applied learning supports knowledge and self‐efficacy for BPSD care. Case‐based, experiential learning fits for both experienced and inexperienced clinicians. Champions acknowledge experiential learning builds confidence (facilitator), while Novices note having limited direct care experience (barrier). Adaptations for Novices will include more extensive introduction to identifying and managing BPSD and emphasize building confidence. 2) Improve access to education and materials. Champions noted the challenge to “keep tools at your fingertips” could be overcome with reference materials or templates while Novices highlighted needing access to more structured resources in light of numerous guidelines to follow in primary care. In response, user‐friendly BPSD management resource guides to support clinical decisions have been developed.

Conclusions

We provide a novel qualitative application RE‐AIM/PRISM with both current and future stakeholders to inform adaptations pre‐implementation. This approach will aid identifying contextual barriers and facilitators to reach, adoption, implementation, and effectiveness of academic detailing for delivery to generalist primary care teams.
Spatial Dissection of the Distinct Cellular Reponses to Normal Aging and Alzheimer’s Disease
Authors: Gong Yun , Haeri Mohammad , Zhang Xiao , Li Yisu , Liu Anqi , Wu Di , Zhang Qilei , Yan Xiaoxin , Jazwinski S. Michal , Jiang Lindong , Chen YiPing , Swerdlow Russell H , Shen Hui , Deng Hong‐Wen
Published: January 2025

Background

Aging significantly elevates the risk for Alzheimer’s disease (AD), contributing to the accumulation of AD pathologies, such as amyloid‐β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease.

Method

In this study, for the first time, we employed a cutting‐edge spatial transcriptome platform, SpaTial Enhanced Resolution Omics‐sequencing (Stereo‐seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls.

Result

Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD‐associated disruptions in laminar architecture, and identified changes in layer‐to‐layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non‐neuronal cells, compared to cells distant from the source of stress. Notably, the cell‐cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell‐type specific gene co‐expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD.

Conclusion

Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome‐wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.
End‐to‐End 3D CycleGAN Model for Amyloid PET Harmonization
Authors: DONG XUANZHAO , Wang Yalin , Shah Jay , Ghisays Valentina , Luo Ji , Chen Yinghua , Lee Wendy , Li Baoxin , Chen Kewei , Reiman Eric M. , Wu Teresa , Su Yi
Published: January 2025

Background

Amyloid PET (Positron Emission Tomography) is crucial in detecting amyloid burden within the brain. However, the diversity of amyloid tracers and the scarcity of paired data significantly challenge the collaboration between cross‐center studies. In this research, we introduce a novel patch‐based 3D end‐to‐end image transformation model. This model works as a harmonization strategy, transferring the amyloid PET images from one tracer type to another.

Method

51 florbetapir (FBP) and 604 PiB images from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. 3D Cycle‐Consistent Generative Adversarial Networks (CycleGAN) was used to learn the end‐to‐end 3D image transformation using adversarial training strategies in conjunction with Resnet generators and multilayer discriminators within different tracer domains. Data augmentation techniques were applied to process the FBP images to balance the training samples and patch‐based learning was used throughout the experiment. The trained CycleGAN model was then applied to an independent dataset with 46 paired images from www.gaain.org/centiloid‐project for performance evaluation. Correlation analyses were conducted voxel‐wise and on mcSUVR, comparing the FBP/synthetic PiB to the true PiB data. The Structural Similarity Index Measure (SSIM) and Peak Signal‐to‐Noise Ratio (PSNR) were also evaluated between the synthetic and real PiB SUVR images.

Result

The synthetic PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.942 between FBP and real PiB to 0.958 between the virtual and real PiB SUVR image (p < 0.0001). The agreement of mcSUVR improved from r = 0.909 to r = 0.954 (p<0.001) in the independent test dataset. The SSIM and PSNR between synthetic and real PiB are 0.762 and 25.370 in the independent dataset.

Conclusion

We proposed a novel end‐to‐end image transformation model for 3D PET image synthesis. The model finds the nonlinear mapping between different tracers and eliminates the requirement for paired training images. The result was confirmed using an independent dataset to demonstrate its effectiveness.
Long‐term mortality in the SPRINT cohort
Authors: Jaeger Byron C , Gaussoin Sarah A. , Williamson Jeff D. , Pajewski Nicholas M. , Reboussin David M.
Published: January 2025

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) showed intensive blood pressure (BP) control, defined by systolic BP goal of < 120 mm Hg, reduced cardiovascular morbidity and mortality. However, a secondary analysis that incorporated approximately 4‐years of observational follow‐up found that mean BP levels increased after the trial and the benefit of intensive BP control on cardiovascular and all‐cause mortality attenuated. We re‐examined these findings using an updated version of the observational data that includes approximately 8‐years of follow‐up.

Methods

SPRINT included patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke. The SPRINT intervention ended on August 20, 2015, and trial close‐out visits occurred through July 2016. Extended observational follow‐up for mortality was obtained via the US National Death Index from 2016 through 2023.

Results

Among 9361 randomized participants, the mean (standard deviation) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a maximum follow‐up of 13 years, 2597 all‐cause and 907 CVD mortality events occurred (Figure). During the trial, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49‐0.89) and all‐cause mortality (HR, 0.83; 95% CI, 0.68‐1.00). During the 8‐year observational period, the benefit of intensive BP control attenuated for both outcomes (CVD mortality HR: 1.02; 95% CI, 0.84‐1.24; all‐cause mortality HR: 1.08; 95% CI, 0.94‐1.23). Overall (i.e., combining trial and observational periods), intensive BP control was beneficial for CVD mortality (HR, 0.84; 95% CI, 0.74‐0.96) but not all‐cause mortality (HR, 0.96; 95% CI, 0.89‐1.04).

Conclusions

Intensive BP control reduced CVD mortality risk during the trial and overall, but its benefits were less evident during the observational period. Given increasing BP levels during the observational period, maintaining BP control may be essential for sustaining long‐term benefit.

Figure: Cumulative incidence of cardiovascular and non‐cardiovascular mortality by treatment group
How Low Should We Go to Prevent Brain Aging Associated with Exposure to Ambient Fine Particles?
Authors: Wang Xinhui , Chen Jiu‐Chiuan , Salminen Lauren , Petkus Andrew J , Millstein Joshua , Espeland Mark A. , Braskie Meredith N , Thompson Paul M. , Gatz Margaret , Resnick Susan M. , Kaufman Joel D. , Rapp Stephen R. , Tooze Janet A , Shumaker Sally A. , Younan Diana
Published: January 2025

Background

Late‐life exposure to PM2.5 is a risk factor for Alzheimer’s disease (AD) and related dementias. Accelerated brain aging associated with PM2.5 exposure likely takes place at preclinical stage. In Feb.2024, US EPA lowered the annual standard for fine particulate matter (PM2.5) from 12‐ to 9‐µg/m3. Whether the new exposure standard is sufficient to protect the aging brain is unclear.

Method

This current study examined whether PM2.5‐associated brain aging is present at lower‐level exposures. We used longitudinal data from older women (n = 421; aged 77.3±3.5) enrolled in the Women’s Health Initiative Memory Study MRI‐1 (2005‐6) and MRI‐2 (2009‐10), living at locations with PM2.5 below 12‐µg/m3 (including 130 complying with EPA’s new standard) and without MCI, dementia or stroke prior to MRI‐1. PM2.5 exposures at residential locations were estimated as 3‐year annual averages prior to MRI‐1, based on validated regionalized universal kriging models. AD pattern similarity (AD‐PS) scores, developed by supervised machine learning and validated with ADNI data, were used to assess AD‐related neurodegeneration. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex were summed to define the regional volume of medial temporal lobe (MTL). We used linear regressions to estimate exposure effects on 5‐year changes in the AD‐PS scores and atrophies of MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics.

Result

During 5 years of follow‐up, on average AD‐PS scores increased by 0.16±0.15, while MTL volume shrank by 0.42±1.02 cm3. Among older women with PM2.5 <12‐µg/m3, each 1‐µg/m3 increment was associated with increased AD‐PS scores (βAD‐PS = 0.013, 95%CI = [0.003, 0.021], p<0.01) and additional MTL shrinkage (βMTL = ‐0.079, 95%CI = [‐0.138, ‐0.019], p = 0.01; primarily affecting PHG), equivalent to 3.0%‐3.6% higher dementia risks. PM2.5 exposure < 9‐µg/m3 remained significantly associated with progressive PHG atrophy (βPHG = ‐0.087, 95%CI = [‐0.169, ‐0.005], p = 0.04), but the associations with increased AD‐PS score or progressive MTL atrophy had less precise effect estimates. Further restricting the analyses to older women who remained cognitively normal at MRI‐2 did not materially change the results.

Conclusion

Our study supports EPA’s new decision to lower PM2.5 standard, but could not rule out the possibility of neurotoxic effects on aging brain with PM2.5 <9‐µg/m3.
Discovery of dementia type specific biomarkers with untargeted CSF proteomics
Authors: Stokkel Marijke E. , Vermunt Lisa , Knol Jaco , Piersma Sander , Pham Thang V. , Gagestein Berend , de Haas Richard R. de Goeij , Lemstra Afina Willemina , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M. , Teunissen Charlotte , Jimenez Connie R.
Published: January 2025

Background

Different pathologies can cause dementia, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia. Understanding the biological mechanisms underlying these diseases is important in order to develop therapies. Here we performed cerebrospinal fluid (CSF) proteomics in AD, DLB and FTD in order to study proteomic changes and identify novel potential biomarkers.

Method

Individuals from the discovery (n = 80) and validation (n = 77) cohort were selected from the Amsterdam Dementia Cohort based on clinical diagnosis and availability of a CSF sample. Single shot nano‐LC‐MS/MS was performed using a data independent acquisition (DIA) method in a QExactive HF (Qe) mass spectrometer. Additionally, the validation cohort was remeasured on a newly acquired EVosep‐TimsTOF‐HT (Bruker) allowing for deeper proteomic profiling. For each cohort, protein intensities were log2 transformed, and scaled according to the mean and standard deviation of the SCD group. Next, all groups were compared to each other on the levels for each protein with linear regression models, including age and sex as covariates. We performed Gene Ontology enrichment analysis for the differentially expressed proteins in the TimsTOF dataset.

Result

In total we identified 3501 unique proteins, 803 in the discovery cohort, 1296 in the Qe measurements of the validation cohort, and 2873 in the recent TimsTOF remeasurements of the validation cohort (Figure 1A). We identified 37, 30, and 34 differentially expressed proteins in AD, DLB and FTD, of which 11, 3 and 8 replicated in the Qe measurements cohort (Figure 1B‐D). Proteins that replicated between cohorts included ALDOA, SMOC1, CHI3L1 and PKM for AD, NPTX2 and VGF for DLB and SERPINA3 and CHI3L1 for FTD. Investigation of the most statistically enriched biological terms shows processes related to synaptic signaling to be downregulated in AD, DLB and FTD. Similar to literature (Bader et al., 2020), metabolic processes were found to be upregulated in AD. In contrast, upregulation of adaptive immune responses in DLB and complement activation and fibrinolysis in FTD have not been previously observed (del Campo et al., 2023; van der Ende et al., 2019)

Conclusion

Improvements in mass spectrometers enable deeper proteome profiling, essential for uncovering novel processes underlying disease.
Improved Precision and Sensitivity: Refinement of a Homebrew Simoa Assay for Detecting pTau181 in Plasma and Serum
Authors: Vanbrabant Jeroen , Bayoumy Sherif , Antwi‐Berko Daniel , van der Flier Wiesje M. , Verberk Inge M.W. , Teunissen Charlotte , Stoops Erik
Published: January 2025

Background

Plasma tau phosphorylated at Threonine181 (pTau181) has been extensively studied as an accessible biomarker of amyloid pathology and is compared in various studies with other pTau epitopes. ADx has developed a Quanterix Homebrew Simoa assay using a highly pTau181 specific capture mAb (ADx252) and an N‐terminal tau detector ADx204 demonstrating high clinical performance (Janelidze et al., 2023; Ashton et al., 2022; Bayoumy et al., 2021). Nevertheless, measuring pTau181 in samples from young adults or serum that have lower levels remains challenging due to limited sensitivity and precision in the low calibrator range. This work describes an updated Homebrew assay for detection of pTau181 in human plasma and serum with increased precision and sensitivity compared to the previously published ADx pTau181 Simoa assay.

Method

The ADx pTau181 assay was updated using re‐engineered formats of ADx252 (RD‐070) and ADx204 (RD‐073). Antibody conjugation to beads was optimized by C‐terminal incorporation of a tag to enhance antibody conjugation efficiency and robustness. The assay was further optimized using alternative diluents resulting in a linear curve over the full calibrator range. The clinical performance of the assay format was compared to the previous pTau181 assay version using plasma from 50 AD patients (defined by CSF biomarker profile) and 50 cognitively healthy donors from the Dutch Brain Research Registry (Hersenonderzoek.nl). Paired plasma and serum from a prospective collection of healthy donors (n = 50) were also analyzed using the optimized pTau181 assay.

Result

The optimized assay showed a higher AUC of 0.96 (95% CI 0.92‐0.99) compared to 0.88 (95% CI 0.82 – 0.95) for the previous version (ΔAUC = 0.08, DeLong’s p = 0.047). Furthermore, our optimized assay was able to measure serum pTau 181, exhibiting a strong correlation of the analyte between plasma and serum and with pTau217 levels. Additionally, precision and sensitivity were improved (no vs. 18 plasma samples with CV%>20 on duplicate measurements; mean plasma sample S/N increased from 4.3 to 9.8).

Conclusion

Our study illustrates the successful development of an optimized Homebrew pTau181 assay, with enhanced analytical and clinical performance achieved by an improved sensitivity and precision at measuring pTau 181 in plasma and serum samples.
APOE genotype, polygenic risk for Alzheimer’s disease, and plasma cytokines in participants of the multisite SuperAging Research Initiative
Authors: Huentelman Matt , Piras Ignazio , Naymik Marcus , Stark Bobbi , Bonfitto Anna , Taguinod Francis , Schafer Rhiana , Martersteck Adam , Maher Amanda Cook , Geula Changiz , Rogalski Emily J ,   The SuperAging Research Initiative
Published: January 2025

Background

The SuperAging Research Initiative (SRI) seeks to identify factors that promote cognitive healthspan. SuperAgers are defined as individuals aged 80 and older with episodic memory performance that is at least average for people who are two to three decades younger. A goal of the SRI is to identify the genomic contributors to SuperAging and herein we describe the interim results of DNA‐ and plasma protein‐based analyses.

Method

Biospecimens were collected in concert with in‐person cognitive assessments. Genomic DNA (n = 125 SuperAgers) was isolated from PAXGene DNA tubes using a Promega Maxwell instrument. Genome‐wide SNP genotypes were generated using the GSA BeadChip (Illumina) and imputation was performed via TOPMed. Polygenic risk scores (PRS) for Alzheimer’s disease (AD) were generated using the summary statistics from the AD GWAS reported by Lambert et al. Plasma samples (n = 59 SuperAgers and 52 Controls) were analyzed using a Luminex panel that included 24 cytokine and inflammatory markers.

Result

APOE allele and genotype frequencies were found to be similar to neuropathologically‐assessed control samples from the “TGen II” AD GWAS cohort (e4 allele frequency; SuperAgers = 9.8%. Controls = 10.8%). AD PRS distributions in the SuperAger samples were also similar to the TGen II Controls; however, three SuperAgers were noted to have AD PRS values that were significantly high risk. Two cytokines demonstrated association with SuperAging, IL‐7 (increased in SuperAgers; p = 0.003) and Interferon‐gamma (increased in SuperAgers; p = 0.04). However, after multiple hypothesis correction, neither remained significant.

Conclusion

These results suggest that SuperAgers are not at lower risk for AD based on their APOE genotypes and AD polygenic risk scores. However, this does not account for all SuperAger participants as 15% are e4 allele carriers and 3% demonstrate AD PRS scores that are significantly elevated. Lastly, immune system profiling suggests that IL‐7 and Interferon‐gamma may be elevated in SuperAger plasma, suggesting that immune system function may be associated with SuperAging. This interim analysis of the SRI cohort supports the concept that the propensity to be a SuperAger is likely heterogenic. SuperAgers with high genetic risk for dementia may represent unique opportunities to search for resilience factors.
Perception of change in sexual activity and sexual satisfaction in Alzheimer’s Disease: views of people with dementia and their spouse‐carers
Authors: Nogueira Marcela Moreira Lima , Lacerda Isabel , Baptista Maria Alice , Belfort Tatiana , Dourado Marcia C. N.
Published: January 2025

Background

The progression of dementia may be followed by decreased sexual activity for People with Alzheimer’s Disease (PwAD) and their spouse‐carers. We designed this study to investigate the perception of change in sexual activity and sexual satisfaction among couples whose spouses were diagnosed with Alzheimer’s Disease (AD).

Method

Using a cross‐sectional design, we compared 74 dyads of people with Alzheimer´s disease (PwAD) and their spouse‐carers, and 21 elderly dyads control. We assessed sexual satisfaction with Questionnaire on Sexual Experience and Satisfaction (QSES), cognition using a Mini‐Mental State Examination (MMSE), disease severity using a Clinical Dementia Rating scale (CDR), awareness of disease with Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), functionality with Pfeffer Functional Activities Questionnaire (FAQ), depressive symptoms with Cornell Scale for Depression in Dementia (CSDD), quality of life using a Quality of Life in Alzheimer’s Disease Scale (QoL‐AD), and burden using a Zarit Burden Interview (ZBI). Univariate and multivariate regression analyses were conducted to identify the factors that influenced couples’ sexual satisfaction.

Result

We found a significant difference between the perception and no perception of change in sexual activity of PwAD (p < 0.001), spouse‐carers (p < 0.01), and controls (p < 0.05). Moderate to severe sexual dissatisfaction was observed in 36.5% of PwAD, 65% of spouse‐carers, and 31% of controls. PwAD sexual satisfaction was related to cognitive impairment (p < 0.05). Spouse‐caregivers sexual satisfaction was related to gender (p < 0.05) and the presence of sexual activity (p < 0.001).

Conclusion

The perception of change and consequent interruption of sexual activity, with higher sexual dissatisfaction, were higher in PwAD and their spouse‐carers, in comparison with control group. We also found that spouse‐carers experienced lower levels of sexual satisfaction than PwAD and healthy elderly couples. Moreover, PwAD sexual satisfaction was related to the level of cognitive impairment and spouse‐carers’ sexual satisfaction was related to gender and the presence of sexual activity.
MRI‐visible perivascular space volume: An in vivo marker of post‐mortem vascular pathology
Authors: Silbert Lisa C , Lahna David , Schwartz Daniel , Roese Natalie E , Hurworth Justin , Wall Rachel C , Krajbich Victoria , Woltjer Randall
Published: January 2025

Background

MR‐visible perivascular space (PVS) burden is associated with clinical and MRI features of cerebrovascular disease. Its utility as an in vivo biomarker of post‐mortem pathology is uncertain.

Method

Eighteen older adults (age at death 98.0, sd 5.5; 83% female) with autopsy consent were followed longitudinally in the Oregon Alzheimer’s Disease Research Center with MRI and cognitive assessments until death. In vivo MR‐visible white matter (WM) PVS volumes were derived using an automated segmentation algorithm based on T1 intensity thresholding and morphological constraints. Basal ganglia (BG) PVS were hand‐traced on a single axial T1 slice with highest number of PVS. WM and BG PVS volumes were summed and normalized to brain volume to create a PVS score. General linear models (GLM) examined relationships between whole brain PVS score and: 1) cognition, and 2) post‐mortem vascular pathologies. Models were adjusted for age, sex, and time between MRI and death when applicable.

Result

In vivo MRI PVS score was associated with greater post‐mortem deep microvascular lesions (p = 0.002), arteriolosclerosis (p = 0.004), and atherosclerosis (p = 0.002). In separate models, PVS score was associated with worse performance on Trails B (p = 0.006) and MMSE (p = 0.02), but not memory (p = 0.6).

Conclusion

Greater whole brain in vivo PVS burden is associated with worse cognitive performance in domains commonly associated with cerebrovascular disease and multiple post‐mortem cerebrovascular pathologies. Findings support the use of in vivo PVS as a candidate “V” marker in A/T/N classifications of older individuals
Gray matter microstructural changes due to cognitive aging in healthy cohort
Authors: Singh Kavita , Barsoum Stephanie , Schilling Kurt , An Yang , Ferrucci Luigi , Benjamini Dan
Published: January 2025

Background

Cognitive impairment with age remains undetected until it interferes daily life activity or presents dementia symptoms. In the US, 61% of dementia population is not diagnosed, which is in part due to limited sensitivity of clinical neuroimaging modalities in assessing early gray matter (GM) changes. Here we look at microstructural changes in GM using mean apparent propagator (MAP‐MRI) in cognitively underperforming (CU) and healthy aging (HA) cohorts, grouped according to their cognitive performance based on the NIH Toolbox.

Methods

725 subjects aged 36 to 90 years were included in this study using the Human Connectome Project‐Aging (HCP‐A) imaging dataset (T1w, multi‐shell diffusion ‐dMRI). Nine NIH Toolbox measures were used to classify CU and HA population groups (Figure 1). Each test score was z‐normalized and subjects in the lower and upper 50th percentile in all 9 tests were considered as CU and HA, respectively. Diffusion data was processed using TORTOISE dMRI processing package. Corrected DWIs were processed using MAP‐MRI, which yielded the following parameters: return to origin/axis/plane probability (RTOP, RTAP, RTPP), non‐Gaussianity (NG), and propagator anisotropy (PA) (Figure 2a). The T1w images were processed generating 125 SLANT cortical and subcortical regions of interest (Figure 2b). Two‐way ANOVA was used to investigate group differences while accounting for age, sex, education and site. All statistical analysis was done in Matlab2022b.

Results

The list of tests and respective scores of the two groups is provided in Figure 1. Zero‐displacement probabilities were more sensitive in detecting group differences compared to NG and PA. The two groups displayed notable differences in the following brain regions: the operculum, involved in visuospatial cognition; the precuneus, key to memory retrieval; and the posterior cingulate, which plays a role in processing speed, executive function, and memory. Additionally, the auditory and sensory‐related areas exhibited significant variations, aligning with expectations. These group differences are shown in Figure 3.

Conclusion

This study underscores the common occurrence of cognitive aging among the healthy population and demonstrates that MAP‐MRI is a valuable tool for assessing GM microstructural changes, particularly when comparing these changes to those observed in resilient aging populations.
Modeling the influence of presenilin‐1 mutation position on primary outcomes of a gantenerumab trial: findings from the DIAN‐TU‐001 study
Authors: McCullough Austin A. , Cao Yuchen , Chen Charles D. , Gordon Brian A. , Cruchaga Carlos , Goate Alison M. , Hassenstab Jason J. , Ibanez Laura , Li Yan , Perrin Richard J. , Renton Alan E. , Xiong Chengjie , Salloway Stephen , Llibre‐Guerra Jorge J. , Clifford David B. , McDade Eric , Bateman Randall J. , Benzinger Tammie L.S. , Wang Guoqiao , Joseph‐Mathurin Nelly ,   DIAN study team
Published: January 2025

Background

In autosomal dominant Alzheimer disease (ADAD), the position of a pathogenic genetic variant within the presenilin‐1 (PSEN1) coding sequence influences how amyloid‐beta accumulates and how dementia progresses (Joseph‐Mathurin et al, 2024). In the first trial of anti‐amyloid monoclonal antibodies in individuals at risk for ADAD (Dominantly Inherited Alzheimer Network Trials Unit study 1 [DIAN‐TU‐001]), gantenerumab demonstrated target engagement but did not meet its primary clinical endpoint (Salloway et al, 2021). Whether the distribution of pathogenic genetic variants within the cohort may have influenced the trial results remains unclear. Here, we investigated the primary outcomes from DIAN‐TU‐001 as a function of mutation position.

Method

We evaluated 72 participants with a PSEN1 mutation who completed the DIAN‐TU‐001 study under the placebo (n = 29) and the gantenerumab (n = 43) arms. Both arms were grouped by the PSEN1 mutation position relative to codon 200 as precodon‐200 and postcodon‐200 (Table 1). Mixed models for repeated measures were adjusted for sex, baseline Clinical Dementia Rating® (CDR®) scores, and baseline EYO and estimated the effect of PSEN1 mutation position on the mean change from baseline PiB‐PET composite and baseline cognitive composite, as imaging and clinical outcomes, respectively. Significance of differences in least squares (ls) means on year 4 between pre‐codon 200 and post‐codon 200 mutation groups were calculated.

Result

Within each codon group, compared to placebo, the treated group had significant changes in PiB‐PET but not in cognitive composite (Figure 1). Placebo precodon‐200 group showed significantly faster amyloid accumulation rates (PiB PET composite SUVR) through year 4 than the placebo postcodon‐200 group (ls means diff. P‐value = 0.0065). However, no difference was observed between precodon‐200 and postcodon‐200 gantenerumab groups (ls means diff. P‐value = 0.45) through year 4. Difference in cognitive composite precodon‐200 vs. postcodon‐200 placebo groups was not significant (ls means diff. P‐value = 0.98). Differences in cognitive composite groups between treated groups trended toward significance (ls means diff. P‐value = 0.05).

Conclusion

These preliminary results show the potential influence of PSEN1 mutation position on the outcome of a monoclonal antibody targeting amyloid plaque removal. Further investigation into the potential effects of specific mutation type on trial results is warranted.
Attention‐Guided Deep Learning Discovers Brain Morphological Patterns of Alzheimer’s Disease from Structural MRI
Authors: Gu Ran , Li Hongming , Fan Yong
Published: January 2025

Background

Structural Magnetic Resonance Imaging (sMRI) is an invaluable tool for detecting brain morphological changes to aid in the diagnosis of Alzheimer’s Disease (AD). However, the heterogeneity of AD‐related neurodegeneration poses significant challenges for conventional image analysis techniques to accurately capture discriminative brain changes from whole‐brain sMRI data.

Method

We present a novel attention‐guided deep learning framework to automatically identify and focus on the most discriminative brain regions for robust AD diagnosis from sMRI scans (Figure 1). Our model leverages a 3D U‐Net as an attention generator to learn voxel‐wise attention weights to calibrate the original sMRI data via an attention mechanism, and the calibrated representation is subsequently passed to a classifier for AD diagnosis. This attention‐guided process enables the model to selectively focus on the most informative brain regions for feature learning and decision‐making. Our model has been evaluated on the ADNI dataset.

Result

A deep learning model was trained on the ADNI‐1 data and evaluated on the ADNI Go & 2 data. The model achieved an accuracy of 90.0%, precision of 82.3%, recall of 87.3%, and F1‐score of 84.7% in discriminating AD patients from cognitively normal individuals using sMRI data. The accuracy was better than an alternative model without the non‐attention‐guided model (with an accuracy of 87.6%), demonstrating the effectiveness of the attention‐guided mechanism. Visualization of the learned attention maps revealed salient regions localized in the hippocampus, ventricles, temporal lobes, and other areas known to be affected by AD (Figure 2).

Conclusion

The proposed attention‐guided deep learning framework demonstrated superior performance compared to traditional methods for AD diagnosis from sMRI scans. By explicitly learning to focus on discriminative brain regions, our model effectively captures AD related brain morphological patterns.