bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross‐scale functional connectivity patterns of the aging brain learned from the multi‐cohort iSTAGing study
Authors: Zhou Zhen , Li Hongming , Tran Chau B , Ma Yuncong , Srinivasan Dhivya , Abdulkadir Ahmed , Wen Junhao , Erus Guray , Mamourian Elizabeth , Nasrallah Ilya M. , Bryan Nick , Wolk David A. , Beason‐Held Lori L , Resnick Susan M. , Shou Haochang , Davatzikos Christos , Fan Yong
Published: December 2023

Background

Brain functional connectivity (FC) measures derived from resting‐state fMRI (rsfMRI) data have advanced our understanding of the brain organization. However, most existing studies investigate the brain functional networks (FNs) at a specific scale, ignoring potentially complementary FC information at different levels of spatial granularity as well as the cross‐scale information. Given that the brain is a multi‐scale, hierarchical system, FCs between FNs at different spatial scales may provide complementary information to those measured within‐scales for characterizing the aging brain.

Method

We computed multiscale FNs to capture their FC measures across multiple scales and investigated the associations between cross‐scale FCs and the brain aging based on rsfMRI data of a diverse cohort (n = 4186, aged 22 to 97 years) from seven sites of the iSTAGING study [1]. For each subject, we computed the FNs at seven scales, yielding seven sets of k (k = 17, 25, 50, 75, 100, 125 and 150) FNs, same as our previous study [2‐3]. We estimated FC measures between the 542 FNs using Pearson’s correlation, yielding the cross‐scale FC matrices that were harmonized across sites in the tangent space using ComBat‐GAM [4] with sex and age as covariates. The harmonized FC measures were used as features to build an age prediction model using Ridge regression as illustrated in Figure 1. The brain age prediction model was compared with that built on harmonized FC measures between FNs of the same scales, with the performance estimated with a nested five‐fold cross‐validation.

Result

The cross‐scale FC measures performed significantly better than the within‐scale FC measures for the brain age prediction, as summarized in Table 1. Figure 2 shows the most informative FC measures for the brain age prediction. Specifically, FC measures computed both cross‐ and within‐scales between the visual, somatomotor, and frontoparietal networks provided relatively more useful information for the brain age prediction than FC measures between other FNs.

Conclusion

Our study demonstrated that the cross‐scale FC measures provided complementary information to the within‐scale FC measures for predicting the brain age, facilitating enhanced understanding of aging related changes of the brain functional organization.
Stable Isotope Labelling Kinetics: Models and methods to evaluate APP production rates with Posiphen treatment in the DISCOVER clinical trial
Authors: Elbert Donald L , Galasko Douglas R. , Farlow Martin R. , Aslanyan Vahan , Pa Judy , Lucey Brendan , Honig Lawrence S. , Moghekar Abhay , Bateman Randall J. , Momper Jeremiah , Rissman Robert A , Balasubramanian Archana , Maccecchini Maria L. , Feldman Howard H. ,   ADCS DISCOVER Study Group
Published: December 2023

Background

Posiphen has been reported to decrease translation of beta amyloid precursor protein (APP) mRNA, resulting in decreased production of Aβ.1 The pharmacodynamics of Posiphen require further clarification to better assess its therapeutic potential.

Method

The DISCOVER phase 1b placebo controlled RCT enrolled patients with MCI or mild AD dementia (age 55‐89, MMSE 17‐30, CDR = 0.5‐1.0, CSF Aβ42/40 < 0.131 by mass spectrometry) at five centers.2,3 Patients were randomized to sequential dose cohorts of oral Posiphen (60 mg; once (QD), twice (BID) or three times (TID) per day for 21 days) or placebo. SILK studies were performed during a confinement on day 22. Lumbar and venous catheters were placed and 13C6‐leucine infused for 9 hours with dosing of placebo or Posiphen according to assigned study arm. CSF and venous blood were collected every two hours over 36 hours. Pharmacodynamics of APP were evaluated via a recently described mathematical model of APP and Aβ kinetics.4

Result

APP production rate was calculated for a total of 14 subjects (less than study design due to COVID) by the model in Figure 1. Nonparametric analysis of group differences was not significant (p = 0.08) with n = 1‐5 per group (Figure 2A). A trend towards lower CSF Aβ40 concentrations (indicative of lower intrinsic APP production rates) prior to drug exposure was noted in the higher dose groups (Figure 2B). The calculated APP production rate was thus controlled for pre‐drug CSF Aβ40 concentrations, which showed a downward trend with increasing dose (95%CI:(‐2209.58, 147.79, p = 0.08; Figure 3) but was not significant.

Conclusion

This study provides preliminary evidence that the rate of production of APP may be measured by the SILK method in Aβ lowering drug trials. Variability in APP productions rates in the population suggest that CSF Aβ concentration should be considered as part of study randomization.
Associations between NTproBNP and 10‐year cognitive decline in The Irish Longitudinal Study on Ageing (TILDA)
Authors: De Looze Celine , Feeney Joanne , Fitzpatrick Annette L. , Kenny Rose Anne , O’Halloran Aisling M ,   The Irish Longitudinal Study on Ageing
Published: December 2023

Background

NT‐proB‐type Natriuretic Peptide (NTproBNP) is a hormone released in response to changes in pressure inside the heart often related to heart failure and other cardiac problems. Early evidence shows significant correlations between brain structure and markers of heart failure including ejection fraction and NTproBNP. We sought to investigate if levels of this biomarker are related to cognitive decline over 10 years in older adults participating in the Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged 50 years and older residing across Ireland.

Method

Levels of NTproBNP were measured in 4,105 participants, mean age 61.5 years and 53.8% women, from blood drawn at baseline (Wave 1: 2009‐2011). Verbal memory (10‐word immediate and delayed recall) and verbal fluency/ executive function (animal naming) were measured every two‐years over a 10‐year follow‐up (Wave 1 – 6) and were used to create a composite score at each wave which served as a measure of global cognitive function. Linear mixed effect models with adjustment for covariates were performed. Model 1 included age, age^2, sex, education; Model 2 included Model 1 + cardiovascular diseases (heart failure, heart attack, stroke, tia, hypertension, diabetes), lifestyle factors (smoking, alcohol, physical activity, waist‐hip ratio) and depression.

Result

NTproBNP was significantly and negatively associated with cognitive function at Wave 3 (B = ‐0.13, 95%CI = ‐0.20, ‐0.05), Wave 4 (B = ‐0.24, 95%CI = ‐0.31, ‐0.16), Wave 5 (B = ‐0.25, 95%CI = ‐0.32, ‐0.17) and Wave 6 (B = ‐0.26, 95%CI = ‐0.34, ‐0.17) (p<.001) (Figure 1). After further adjustment, the associations remained significant.

Conclusion

These results suggest that NTproBNP may be useful as an early indicator of cognitive decline in older adults for those with and without current cardiovascular diseases.
Improving dementia phenotype prediction with functional mapping of genetic data in non‐European ancestries
Authors: Fu Mingzhou , Pasaniuc Bogdan , Vossel Keith , Chang Timothy S
Published: December 2023

Background

Many common genetic variants have been associated with dementia, but their ability to predict dementia prospectively is unknown, especially in non‐European ancestral populations. We sought to optimize dementia risk prediction models with machine learning in individuals of diverse genetic ancestries.

Method

Samples were selected from the University of California Los Angeles Health System with their electronic health records (EHRs) and linked genetic data. Dementia phenotype was defined using diagnosis codes and mapped phecodes. Polygenic risk scores (PRSs) were built using summary statistics of different population‐based genome‐wide association studies (GWASs). Independent significant and functionally mapped single nucleotide polymorphisms (SNPs) were identified using the FUMA tool. Logistic regression models were built with 1) APOE status, 2) a single PRS, or 3) multiple PRSs. The model with age and sex only was built as the baseline model. We trained LASSO models to determine dementia risk SNPs from weighted SNP‐level genetic data. We compared the predictive performance of these models after five‐fold cross‐validation with area under precision‐recall curve (AUPRC) and area under receiver operating characteristic (AUC). Finally, identified risk SNPs were mapped to genes for biological interpretation.

Result

There were 975 individuals included in the final Hispanic Latinx American ancestry sample, of which 9.44% (N = 92) were dementia cases. The model with LASSO‐selected functional mapped SNPs from multiple neurodegenerative diseases GWASs outperformed all other genetic risk score models (AUPRC: 0.39, AUROC: 0.87), resulting in a 19.6% increase in AUPRC from the best PRS model, and a 26.9% increase from the baseline model. The best‐performing LASSO model included nine SNPs, mostly located in the 19q13, 4p15, and 17q21 regions. Results of mapped genes not only revealed well‐known risk genes of dementia but identified risk genes from other neurodegenerative diseases.

Conclusion

We demonstrated that building genetic risk scores with trans‐ancestry GWAS and selecting potential causal SNPs can be beneficial for dementia prediction in non‐European ancestry populations. Further training using machine learning methods with functionally mapped SNP‐level genetic data showed significant improvement in predictive power compared to PRS models. Genetic risks of multiple neurodegenerative diseases may contribute to the predisposition to dementia.
Blood co‐expression network analysis identifies molecular pathways involved in cognitive resilience
Authors: Tsai Wei , McNiff Caitlin E. , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Nho Kwangsik , Allen Mariet , Heckman Michael G. , Kantarci Kejal , Mielke Michelle M. , Petersen Ronald C. , Saykin Andrew J. , Carrasquillo Minerva M. , Ertekin‐Taner Nilufer
Published: December 2023

Background

Two major risk factors of Alzheimer’s disease (AD) are advanced age and the APOE‐ε4 risk allele. However, despite having these risk factors, some individuals escape from developing AD or have slower cognitive decline. In this study we hypothesized that “resilient” individuals, defined as those who remain cognitively normal despite being >80 years‐old and carrying at least one copy of the APOE‐ε4 allele, have concerted changes in their blood transcriptomes that are associated with resilience to AD.

Method

We generated blood RNA‐sequence data from 105 APOE‐ε4 carriers from the Mayo Clinic Study of Aging (MCSA) who remained cognitively normal after age 80 (resilient), or who developed mild cognitive impairment (MCI) or AD (non‐resilient). Weighted gene co‐expression network analysis (WGCNA) was performed to evaluate the association of the blood co‐expression network with primary phenotypes of resilience and memory scores. To validate our findings, we constructed a consensus co‐expression network using both MCSA and a replication cohort of blood microarray data from 91 Alzheimer’s Disease Neuroimaging Initiative (ADNI) study participants who had a similar demographic profile. We annotated the consensus modules for their enrichment of cell types, biological processes, genes within previously published genome‐wide significant (GWS) AD‐associated loci, and genes that reside in consensus modules built from seven brain regions across three different autopsy cohorts. To identify genetic variants regulating blood consensus module co‐expression, we performed module quantitative trait locus (modQTL) analysis.

Result

We found co‐expression modules significantly (q<0.05) correlated with the memory phenotype, logical memory delayed recall, across both MCSA and ADNI cohorts. Some of these modules were enriched with blood cell types and biological processes, including telomere maintenance, mitochondrial functions, and immune response. We found 1 module significantly (q<0.05) enriched with genes near GWS AD‐associated loci and 4 modules with genes in brain consensus modules. Lastly, we found 8 modQTLs significantly (Bonferroni‐p<0.05) associated with the co‐expression of 5 different modules.

Conclusion

We identified blood co‐expression modules, biological pathways and specific genetic variants associated with cognitive resilience in the presence of AD risk factors. This study provides novel insights into the potential role of peripheral blood in the development of and resilience to AD.
Deep trans‐omic network fusion for altered functional interactions underlying Alzheimer’s Disease
Authors: Xie Linhui , Raj Yash , Varathan Pradeep , He Bing , Nho Kwangsik , Salama Paul , Saykin Andrew J. , Yan Jingwen
Published: December 2023

Background

Multi‐omic data like genotype, gene expression and protein expression have been increasingly explored in post‐GWAS era to interpret GWAS findings and to gain more insight of the Alzheimer’s disease (AD) mechanism. However, each ‐omics data type is usually examined individually and identified genetic variations, genes and proteins are not necessarily functionally related.

Method

We used GWAS genotype, RNA‐Seq gene expression, and protein expression data from 133 subjects of ROS/MAP Project for original study and 121 subjects of Mount Sinai Brain Bank (MSBB) for replication (Fig. 1a). The multi‐omic data pre‐processing steps were shown in Fig. 1b. We proposed a new interpretable deep neural network MoFNet, extended from Varmole [1], to jointly model the prior knowledge of functional interactions using ROS/MAP cohort (Fig. 1c). It aimed to identify a subnetwork of functional interactions from prior knowledge that are both predictive of AD and evidenced by multi‐omic data. Particularly, prior functional interaction network was embedded into the architecture of MoFNet in a way that it resembles the information flow from DNA to gene and protein.

Result

The proposed model MoFNet significantly outperformed all other state‐of‐art classifiers when evaluated using multi‐omic data from ROS/MAP cohort (Table 1). It yielded three major multi‐omic sub‐networks related to innate immune system, clearance of mis‐folded proteins, and neurotransmitter release respectively (Fig. 2a). One subnetwork includes all the major members of the SNARE complex, an essential mediator of synaptic vesicle fusion. Majority of our identified genes/proteins are related to synaptic activities in neuronal, astrocyte and microglial cells. Differential expression analysis show MoFNet returned more genes and proteins due to functional connections (Fig. 2b). Around 50% of these findings were replicated in another independent cohort (MSBB).

Conclusion

Our identified gene/proteins are highly related to synaptic vesicle function. Altered regulation or expression of these genes/proteins could cause disruption in neuron‐neuron or neuron‐glia cross talk and further lead to neuronal and synapse loss in AD. Further investigation of these identified genes/proteins could possibly help decipher the mechanisms underlying synaptic dysfunction in AD, and ultimately inform therapeutic strategies to modify AD progression in the early stage. [1] Nguyen et al., Bioinformatics, 2021.
AMYLOID‐Β AND PHOSPHORYLATED‐TAU ACCUMULATION IN RETROSPLENIAL CORTEX OF YOUNG ALZHEIMER’S MODEL
Authors: Mondragón‐Rodríguez Siddhartha
Published: December 2023

Background

Our aim in the present study was to evaluate molecular and functional alterations in the retrosplenial cortex (RSC) of very young Alzheimer’s transgenic mice (3xTg‐AD). The RSC is a cortical area that functions as a key component of the core network of brain regions involved in cognitive functions such as episodic memory, navigation, and planning.

Method

Electrophysiology: Local field potentials were recorded using borosilicate electrode (2‐6 MΩ). Integrated theta‐band power was calculated in 5 s binds over a period of 2‐10 min and the mean spectrum was taken as the grand mean of each animal.

Immunohistochemistry: For immunofluorescence, antibodies: pS396 and BAM10 were used. The brain areas were visualized using an epifluorescence microscope (Axioplan2, Zeiss).

Result

Our results show significant accumulation of intracellular amyloid‐β (Aβ) and hyperphosphorylated tau (pTau) in principal neurons from 1‐month‐old 3xTg‐AD mice, which correlates with GSK3β activation and tau phosphorylation at serine 396. Coincidently, oscillatory activity from the RSC is altered in the young 3xTg‐AD mice. Specifically, we found that theta frequency is significantly higher in the transgenic animals.

Conclusion

Despite the wide consensus that Aβ deposition in a variety of AD transgenic mice, including 3xTg‐AD, is detected after several months of age, this study shows the first evidence of intracellular Aβ accumulation in pyramidal cells as early as 30 days of age, which does not seem to be related to any cognitive compromise. Thus, early Aβ and pTau accumulation was correlated with altered oscillatory activity from the RSC. In sum, our results indicate that very early accumulation of intracellular Aβ may impact the excitability of the RSC network, possibly due to changes in pTau throughout GSK3β activation.
Neuropsychological Profile of Internal Frontal Hyperostosis
Authors: Oliveros‐Cid Antonio , Lorente Victoria Celorrio , Oliveros‐Juste Antonio , Cimorra Belen Delgado , Luque Laura Cano , Lopez Maria Angeles Cid , Martinez Esther Sierrra , Moreno Lisbed Rondon , Izaguerri Cristina
Published: December 2023

Background

In 1765 Giovanni Morgagni described internal frontal hyperostosis syndrome (IFH), obesity and hirsutism. Stevart (1928) and Morel (1930) added the presence of neurological and neuropsychiatric involvement, constituting the definition of Morgagni‐Stewart‐Morel Syndrome (MSM). There are cases of HFI with absence of the rest of symptoms.

Method

Clinical, neuropsychological and neuropsychiatric evaluation of 5 patients treated for cognitive and behavioral impairment in whom neuroimaging neuroimaging showed internal frontal hyperostosis, apparently of sufficient entity to be associated with frontal lobe compression. Independent evaluation of the rest of the clinical and and family history that could indicate the presence of the constellation of constitutive symptoms of MSM.

Result

The neuropsychological battery showed as fundamental findings: depressive mood, attentional deficit, deterioration of working and recent memory, loss of concentration. No productive psychotic symptoms. Difficulty in complex tasks or complex skills. Anhedonia. No obsessive or compulsive symptomatology, nor anxiety as a predominant symptom. Irritability and irascibility. Mnesic process of inactive profile, difficulty in the change of mnesic strategy or language, or inhibition of irrelevant stimuli, problems with calculation, reasoning, sequencing or mental organization. Reduced verbal and non‐verbal fluency and disordered self‐regulation. Attention was drawn to the discordance between the significant functional impairment of the patients and the relatively preserved performance on neurocognitive battery.

Conclusion

The presence of psychiatric and neurocognitive symptomatology associated with HFI has a characteristic profile, a varied constellation of deficits attributable to frontal lobe dysfunction, but should be actively investigated, because of its difficult until it significantly affects the patient’s performance.
Understanding social network and cognitive function among Korean immigrant older adults in the United States
Authors: Han Hae‐Ra ,   PLAN trial team
Published: December 2023

Background

Social networks provide benefits to older adults, including some positive impact on cognitive health. Immigrant older adults with limited English proficiency in the United States (US) may experience the disruption of social network change resulting from their relocation compounded with language barriers. Despite the central role of social networks in older adults’ cognitive function, little information is available about actual social network size among immigrant older adults in the US and how social network sizes are associated with their cognitive status.

Method

Korean American (KA) older adults represent one of the fastest growing, yet some of the most vulnerable groups in the US due to their limited English proficiency. PLAN—Preparing health aging through Dementia literacy And Navigation—is an ongoing, multi‐site clinical trial involving KA older adults (65+ years) with probable dementia with a goal of promoting their linkage to dementia care. Potential participants go through cognitive screening using Mini‐Mental State Exam (MMSE) to confirm eligibility. Part of the screening process involves a survey about social network using Lubben Social Network Scale‐6 as availability of a caregiver is part of eligibility criteria. Using eligibility screening data, we investigated social network among community‐dwelling KA older adults and its association with MMSE status after controlling for age, sex, and education.

Result

A total of 747 KA older adults (mean age = 77 years, 28% male, and 61% ≤high school) were included in the analysis. More than one third (35%) of the sample had a score <12 on the Lubben scale, indicating being “at risk for social isolation.” Logistic regression analysis revealed that KA older adults who were at risk for social isolation had more than twice higher odds (adjusted odds ratio = 2.007, p = 0.002) of being MMSE positive (i.e., cognitive decline) than those who were not, after controlling for age, sex, and education.

Conclusion

Social network analyses have potential to present much needed information in relation to older adults’ health status. Our findings suggest the urgent need for social support resources in this socially disadvantaged group of immigrant older adults. Future research should investigate effective strategies to enable access to the resources of wellness in the population.
Depression is associated with dementia and accelerated cognitive decline in African Americans
Authors: Lachner Christian , Craver Emily C , Crook Julia E. , Lucas John A. , Ferman Tanis J , Graff‐Radford Neill R. , Day Gregory S.
Published: December 2023

Background

African Americans (AA) represent 12% of the United States population ≥65 years‐old, but 19% of persons with dementia. Inequalities in social determinants of health may influence access to healthcare resources contributing to increased dementia risk. Modifiable risk factors, including vascular risk factors and depression, may contribute up to 40% of dementia risk and are overrepresented in AA. Accordingly, risk factor modification in AA may improve disparities and decrease dementia risk.

Method

Dementia risk factors were evaluated in community‐dwelling AA (n = 261) and non‐Hispanic White (NHW; n = 193) participants who completed ≥2 research visits in studies of memory and aging at the Mayo Clinic Florida Alzheimer Disease Research Center. The association between modifiable risk factors and cognitive impairment (global Clinical Dementia Rating® [CDR] ≥0.5), and rates of decline in impaired participants (measured using the CDR Sum‐of‐Boxes; CDR‐sb) were compared between AA and NHW, while controlling for demographics, APOEe4 status, and Area Deprivation Index.

Result

Modifiable dementia risk factors were common in AA and NHW participants. The ADI was higher in AA denoting greater socioeconomic and environmental deprivation [7.8 (2.3) vs. 4.0 (2.1); p<0.001]. History of stroke/transient ischemic attack (OR, CI95% = 2.52, 1.08‐5.83) was associated with an increased odds of dementia in AA participants only, while depression was associated with an increased odds of dementia in both AA (3.10, 1.52‐6.30) and NHW (3.46, 1.14‐10.48) participants. Moreover, depression (β, CI95% = 1.55, 0.5‐2.6), p = 0.004) was associated with a faster rate of decline (CDR‐sb) in cognitively impaired AA participants. AA participants with depression were disproportionately less likely to report use of antidepressant medications than NHW counterparts (40/45, 89% vs. 21/44, 48%); p<0.001).

Conclusion

Modifiable risk factors associated with dementia were common in AA and NHW participants. Depression was associated with dementia in both AA and NHW but uniquely associated with an accelerated rate of cognitive decline in AA participants. Disparities in use of antidepressant medications may contribute to these differences. Optimizing depression treatment in AA communities may improve cognitive trajectories and dementia risk in this population.
Apolipoprotein E polymorphism‐dependent effects on cellular function
Authors: Beyer Brittney A , Levine Zachary
Published: December 2023

Background

We have used a combination of cell‐based and biophysical approaches to investigate mechanisms by which apolipoprotein E (APOE) isoforms induce either protective or Alzheimer’s Disease (AD)‐associated pathological features.

Method

APOE polymorphism‐driven phenotypic and functional changes were investigated in both primary human astrocytes and central nervous system (CNS) cell types generated from a set of APOE isogenic hiPSC lines (APOE KO, E2, E3, E4). Using fluorescently‐labeled APOE, the transport of E2, E3 and E4 isoforms were tracked in live cells and changes in organelle co‐localization was assessed. Lipoprotein particles were isolated from conditioned media to investigate APOE polymorphism‐specific alternations in the assembly and secretion of high‐density lipoprotein (HDL) particles.

Result

We have identified APOE polymorphism‐specific changes in subcellular localization of APOE that are correlated with changes in cellular function, as well as the function of APOE as a major transporter of lipids and cholesterol in the brain.

Conclusion

Our results provide mechanistic insight into structure:function relationship of APOE in the context of pathological and protective isoforms.
Effect of disease‐associated variants in TREM2 on splicing and gene dosage
Authors: Korvatska Olena , Kiianitsa Kostantin , Lukes Maria E , Bird Thomas D. , Raskind Wendy H
Published: December 2023

Background

Loss‐of‐function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu‐Hakola disease (NHD) and behavioral variants of frontotemporal dementia (FTD), while heterozygous variants increase risk of late onset Alzheimer’s disease (AD) and FTD. In over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level, via premature termination codons or via aberrant splicing. The remaining ones are missense variants thought to inactivate the protein; however, the underlying pathogenic mechanism is less clear. In this work we tested whether disease‐associated TREM2 variants may contribute to the pathology via altered splicing

Method

SpliceAI prediction algorithm was used to screen 56 disease‐associated/risk‐modifying variants for potential effect on splicing. Variants scored by SpliceAI were tested in the splicing reporter assay with full‐length TREM2. Constructs with the common TREM2 variant or the spliceogenic SNP allele were nucleofected into THP‐1, HMC3 and BV2 cell lines. qRT‐/RT‐PCR and western blots were used to quantify the effect of variants at the transcript and protein levels. Nanostring nCounter analysis was used to measure TREM2 RNA in brains of NHD patients who carried spliceogenic variants.

Result

We demonstrated that multiple variants causative for NHD or associated with AD/FTD affect gene splicing reduced dosage of functional transcript and protein.

Conclusion

Our findings point to the complex character of pathogenicity of TREM2 variants, in which effects on post‐transcriptional gene regulation and protein function are often combined. This hidden layer of complexity necessitates inclusion of computational and experimental analyses of splicing and mRNA processing for better understanding of genetic variation in disease.
A transcriptome‐wide analysis of Alzheimer’s disease brain during systemic inflammation
Authors: Pegoraro Giulia , Smith Rebecca G. , MacBean Lachlan Ford , Smith Adam R. , Boche Delphine , Pishva Ehsan , Lunnon Katie
Published: December 2023

Background

The onset and progression of Alzheimer’s disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, many AD sufferers ultimately die with a systemic infection, and infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients. One of the aims of this study is to investigate the molecular mechanisms involved in the CNS response to systemic infections in AD through the analysis of gene expression changes.

Method

The cohort of patients selected for the study is composed of 238 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 68 samples affected by AD and 55 controls, all of whom died with an infection, and 62 AD patients and 53 controls who did not have an infection at the time of the death. The infections included in the analysis consists of respiratory infections (i.e. pneumonia), urinary and chest infections. Following RNA sequencing, a weighted gene correlation network analysis (WGCNA) and pathway enrichment analysis were performed.

Result

The results from WGCNA show a module of particular interest with a correlation with both AD and respiratory infections, which represent most of the cases of infection. The pathway enrichment analysis performed on the genes composing this module identified several relevant biological pathways. Among the ten most significant pathways, part of them is involved in immune responses, such as “leukocyte activation involved in immune response” and “cell activation involved in immune response”.

Conclusion

This analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include repeating the analysis focusing on respiratory infections only, to examine if this source of heterogeneity is limiting our findings. Ultimately this data will be combined with miRNA sequencing and DNA methylation data from the same individuals, the work for which is ongoing.
A systematic evaluation of cortical GABA levels in transgenic mouse models of amyloid
Authors: Ramos Vanessa G. , Carello‐Collar Giovanna , Bellaver Bruna , Ferreira Pamela C.L. , Mensch André Nunes , Pascoal Tharick A. , Rosa‐Neto Pedro , Zimmer Eduardo R
Published: December 2023

Background

Rodent models that overexpress mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes have been widely applied in Alzheimer’s disease (AD) research. These models classically present amyloid plaque deposition in cortical and hippocampal areas and neurotransmission changes. Although amyloid‐related glutamatergic abnormalities have been extensively described, little is known about its effects on the GABAergic system. Thus, we aimed to examine GABA levels in the cortex of two transgenic amyloid mouse models.

Method

We systematically reviewed the literature following the PRISMA 2020 guidelines. PubMed and Web of Science databases were searched for studies reporting GABA levels in the cortex of APPswe/PSEN1dE9 and Tg2576 mice. We opted to evaluate only animals with mature amyloid plaques in their cortices, according to each mouse model previous characterization.

Result

The search identified 3576 papers. Seven records met the inclusion criteria (Tg2576: n = 21, mean age ± standard deviation (SD) = 14.7 ± 3.7 months; controls: n = 21; APPswe/PSEN1dE9: n = 25, mean age ± SD = 8.5 ± 4.1 months; controls: n = 25). Five out of seven results reported non‐significant differences in the GABA levels in multiple cortical regions, such as the frontal, pre‐frontal, and rhinal cortices of the Tg2576 mouse model, but two studies described that GABA is significantly decreased. Furthermore, all studies with the APP/PSEN1 model consistently reported decreased cortical GABA levels. Figure 1 provides a summary of our findings.

Conclusion

Our results suggest that APP and PSEN1 mutations may contribute to the decrease in the levels of GABA in cortical regions of amyloid models. Future meta‐analyses and clinical studies are needed to ascertain the consistency of the reported results.
Exploring the Behaviour, Reliability, and Usability of a new Smartphone Version of Paired Associates Learning
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K
Published: December 2023

Background

PAL is a well‐known and trusted task with good sensitivity to deficiencies in memory capabilities. There has been considerable interest in a smartphone version of PAL, and Cambridge Cognition has now completed work on smartphone PAL. Parallel work has shown that this new version of PAL is of equivalent difficulty to the existing classic PAL, and this study addresses characteristics of the smartphone version alone, in a well‐powered within‐subjects study designed to assess test‐retest reliability, bias, and the usefulness of a familiarisation session, as well as exploring usability.

Method

We obtained three PAL scores over three consecutive days in 86 (31 m, 55 f) participants aged 55+ (M = 57.6, SD = 5.65) via the Prolific online platform. Each day participants used their own devices to complete the smartphone PAL task. We analysed adjusted error scores up to eight‐box problems, with participants showing extreme score fluctuations (M +/‐ 3xSD) excluded on the basis that the task was not taken under comparable conditions. We analysed test‐retest reliability using Pearson correlations of scores over the three days and analysed the effect of a familiarisation session by looking at mean scores over three days.

Results

There was some attrition of users due to technical issues in the prototype version of the task, but adherence was good, and participants reported high levels of task enjoyment and satisfaction. Test‐retest reliability between familiarisation and Day Two was good, r = .63, and very good between Day Two and Day Three, r = .7. Analysis of mean scores showed that the familiarisation session had a significant effect, with task learning between familiarisation and Day Two significantly greater than between Day Two and Day Three. Participants reported good enjoyment of the task, and overwhelmingly described usability characteristics in positive terms.

Conclusion

This study highlights the value of a familiarisation session in reducing learning effects, and, like classic PAL, shows good to very good reliability. Moreover, PAL on a smartphone was well‐liked by these older participants, supporting its use in older populations.
Effects of lithium on phosphatidylinositol‐3‐kinase signaling pathways in triple transgenic animals for Alzheimer' disease
Authors: Couto Caíque de Oliveira Portugal , Wagner Carlos , Forlenza Orestes Vicente , De‐Paula Vanessa V.J.
Published: December 2023

Background

Alzheimer’s disease (AD), a severe, progressive and multifactorial disease. Among the altered biological pathways, we have the phosphatidyl inositol 3 kinase (PI3K), an important cell signaling mediator that loses its function as a result of changes in the Tau protein and Aβ toxicity. Our aim is to determine the ontological pathways related to PI3K in 3xTg‐AD animals chronically treated with lithium at therapeutic and subtherapeutic doses. Also determine the unique, statistically significant proteins of the biological pathways in the ontological pathway altered in hippocampal tissue.

Method

The animals' hippocampus (WT and 3xTg‐AD) were divided into three subgroups: Li0 (standard chow); Li1 (ration containing 1.0 g of lithium carbonate/Kg); and Li2 (ration containing 2.0 g of lithium carbonate/Kg). Primary cultures of hippocampal neurons were treated with doses of 0.02; 0. 2 and 2mM. The identified protein pathways will be compared by Gene Ontology, using ClueGO, a Cytoscape software plug‐in. The analyzes for comparison with neurons and subsequent tissue identification will be performed by ‘Benjamini & Hochberg False Discovery Rate’ (p≤0.05 setting) for test correction for ‘biological process’. Ethical committee (1293/09).

Result

Our results on PI3K showed enrichment of pathways: response to hormone, cell migration, cellular response to endogenous stimulus, positive regulation of response to stimulus and regulation of catalytic activity.

Conclusion

Initial results are promising for the pharmacological understanding of lithium as a neuroprotector for Alzheimer’s disease.
Next generation humanized mice to investigate how Traumatic Brain Injury interacts with ApoE4 genetic risk factor to accelerate dementia
Authors: Khasheeipour Khashayar TK , Brown Arthur , Prado Marco
Published: December 2023

Background

Traumatic brain injury (TBI) is among the leading causes of disability and has been strongly linked to Alzheimer’s disease (AD), the most prevalent cause of dementia. Patients with a history of repeated TBI can present pathologies and symptoms similar to AD: Tau protein neurofibrillary tangles, Amyloid Beta Plaques, and chronic inflammation. We propose that TBI triggers pathological processes that underlie AD development and thereby accelerates AD’s development and severity.

Apolipoprotein E4 (ApoE4) protein has been thought to play a central role in several processes underlying AD development. ApoE4 is one of the biggest genetic risk factors for AD, which is also linked to worse short‐term and long‐term outcomes after TBI. However, how ApoE4 mechanistically affects the development of AD‐pathology after TBI has yet to be understood

Method

To explore this gap, we will use mice with humanized genes which develop AD like pathology with age (Late‐onset AD). The humanized genes include amyloid precursor protein (hAPP) and microtubule‐associated protein tau (hMAPT) ‐ precursors to amyloid beta plaques and neurofibrillary tangles, respectively ‐ in addition to two copies of apolipoprotein E4 (ApoE4) or the control ApoE3 allele. Half of these mice will experience three mild TBIs modeled after human concussions, while the other half will only be anesthetized. All mice will undergo behavioral testing to measure cognitive deficits and molecular analyses to characterize the timing and severity of AD pathology. Cognitive testing will be carried out using the rodent touchscreen Continuous Performance Test (rCPT), which are widely used with AD patients to test attentional processes.

Result

Preliminary results from rCPT before TBI, reveal no significant differences between genotypes and sex at 6‐month of age.

Conclusion

We aim to uncover how TBI interacts with ApoE4 protein to accelerate AD pathology at the molecular and behavioral levels. To maximize the clinical relevance of this project, we use mice with human genes implicated in AD, a clinically relevant noninvasive model of concussion, and touchscreen cognitive testing identical to touchscreen testing in humans. We aim to bridge the gap between animal models and clinical settings to identify future therapeutic targets for TBI and AD.
An information‐sharing framework of patient label propagation method to reveal distinct blood biomarkers and signatures in Alzheimer’s disease subgroups
Authors: Huang Xiaoqing , Garfe Nur Jury , Reeves Cristian A Lasagna , Huang Kun , Zhang Jie
Published: December 2023

Background

Alzheimer’s Disease (AD) is a complex and heterogenous dementia and the early detection remains very challenging. Although progresses have been made to identify serum biomarkers associated with AD, it is still difficult to generalize the findings into clinical setting and trace back to learn how these AD biomarkers are progressed through the regulatory pathways and how they play the roles in the disease mechanisms. Furthermore, distinct patterns or signatures among atypical progressing subgroups has not been investigated.

Method

We defined four subgroups of AD patients based on the trajectories of tauopathy and cognitive decline. Using the blood transcriptomic data from ROSMAP and ADNI, we performed hierarchical clustering for the top 1000 variable genes to obtain the gene signatures in each group. An NMF‐based decomposition and network assisted label propagation method was applied. Finally, we use the inferred label for ADNI patients to assess the distinct progression patterns for each AD subtype and validate and uncovering the genes and their enriched pathways that are associated with flagged progression biomarkers.

Result

Our preliminary results show that two gene expression clusters exist for both ROSMAP and ADNI data. Our previous study identified the activation of calcium channel related pathway exhibits a detrimental role in AD, with representative genes such as TGFB1, and S100A12. We observe the same pattern for these two genes in a subset of patients from ADNI gene expression data with an enrichment in neovascularization processes. We are now propagating patient group labels with the prior evidence of the alignment between these two data sets and investigating the primary genes linked to specific biomarker progression patterns through longitudinal analyses.

Conclusion

We identified several altered pathways and genes that potentially render atypical AD progression patterns reflected by various biomarkers. Future work is undergoing to further explore the link between the gene signatures in each subgroup and the blood transcriptomic sub‐clusters, as well as the comparisons of the two blood transcriptomic data for potential longitudinal clinical information mapping between the two datasets.
Aβ accumulation associated with executive function decline and tau accumulation associated with memory decline in cognitively normal older people
Authors: Chen Xi , Juarez Alexis , Baker Suzanne L. , Harrison Theresa M. , Landau Susan M. , Jagust William J.
Published: December 2023

Background

The early accumulation of Aβ and tau in cognitively‐normal people is predictive of future cognitive decline. It has been difficult, however, to disentangle their effects. Aβ and tau target distinct regions in early stages. Frontal‐parietal regions are among the first to show Aβ accumulation and are important for executive control. Temporal regions, especially the medial temporal lobe, are early sites where tau accumulates and are critical for memory. Their differential vulnerability to Aβ and tau allows us to examine whether there are specific pathology‐cognitive associations, where faster decline in memory, beyond its expected level based on executive function, may be related to tau accumulation, and that faster executive function decline may be related to Aβ accumulation.

Method

78 cognitively‐normal older adults from the Berkeley Aging Cohort Study underwent longitudinal 11C‐Pittsburgh compound‐B (PiB) PET, 18F‐flortaucipir (FTP) PET, and cognitive assessments of executive function and memory (Fig‐1A). We used linear mixed‐effects models to estimate longitudinal change in Aβ (Fig‐1B), temporal tau (Fig‐1C), executive function (Fig‐1D), and memory (Fig‐1E). We focused on within‐individual variability in cognitive decline in different domains and computed two cognitive decline residual scores (executive function controlling for memory, Fig‐2A; memory controlling for executive function, Fig‐2B) to represent domain‐specific performance decline.

Result

Aβ accumulation across wide‐spread regions, especially frontal/parietal cortex, was associated with faster executive function decline, but not memory, even after controlling for meta‐temporal tau change (Fig‐3A). On the other hand, temporal tau accumulation, especially in the medial temporal regions, was related to faster memory decline, but not executive function, even after controlling for global Aβ change (Fig‐3B). Using raw cognitive slopes, instead of residual scores, yielded stronger associations with both pathologies but reduced the ability to detect specific pathology‐cognition relationships.

Conclusion

We found evidence supporting specific associations between accumulating pathology and domain‐specific cognitive decline. The “Aβ‐executive function, tau‐memory” association may reflect specific vulnerabilities in the executive control network and the memory network to different pathology, leading to cognitive decline in different domains. The variability of cognitive decline within the same individual across different domains provides unique information and may be used as behavioral markers for specific pathology.
Comparing the computerized and standard paper‐and‐pencil version of a novel test of memory in a community‐based geriatric sample
Authors: Beaulieu Ashleigh Nicole , Quintana Alan A , Ortiz Juliana , Ortega Alexandra , Hincapie Diana Maria , Curiel Rosie E , Loewenstein David A.
Published: December 2023

Background

Early and accurate diagnosis of Alzheimer’s disease (AD) is critical to improve illness management and outcomes, making neuropsychological measures an essential tool for clinicians. Research has demonstrated that proactive semantic interference (PSI) and failure to recover from PSI (frPSI) are sensitive to cognitive changes in early mild cognitive impairment (MCI) and preclinical AD determined by Aβ load using PET (Loewenstein et al., 2018; Matias‐Guiu et al., 2017; Curiel et al., 2019). These novel constructs are assessed by the LASSI‐L (Crocco et al., 2018; Crocco et al., 2020). The aim of the current study was to compare a new computerized version of this measure, the LASSI‐BC, to the standard paper‐and‐pencil version of the test.

Method

110 cognitively unimpaired (CU) older adults and 79 older adults diagnosed with amnestic MCI (aMCI) were administered the paper‐and‐pencil form of the LASSI‐L, whereas 62 CU and 52 aMCI participants were administered the LASSI‐BC. Their performance was compared to assess the validity of the LASSI‐BC to discriminate between different diagnostic groups.

Result

To assess the validity of the computerized version, both the aMCI and CU groups were compared using χ2 test for categorical variables and ANOVA for continuous variables, with adjustment for covariates such as degree of initial learning, sex, education, and language of evaluation. The performance of CU and aMCI groups using either form was relatively commensurate. Notably, sensitivity and specificity of measures of PSI and frPSI on both versions were calculated to assess diagnostic validity, yielding the following Results Sensitivity of 86.5%, Specificity of 88.1%, and Overall Classification of 87.4% for the LASSI‐BC relative to a Sensitivity of 65.0%, Specificity of 83.6%, and Overall Classification of 75.8% obtained for the paper‐and‐pencil LASSI‐L.

Conclusion

The LASSI‐BC displayed exceptionally high diagnostic validity which was comparable to the well‐established LASSI‐L. Notably, the advantages of the LASSI‐BC include a more standardized administration, suitability for remote assessment, and an automated scoring mechanism that can be verified by a built‐in audio recording of responses. These findings support the LASSI‐BC, a novel computerized assessment, as an exceptional tool for the early identification of individuals at risk of progressing to dementia.