bluuebunny/crossref_metadata_2025 huggingface dataset:
Macro and microarchitectural features of sleep in Alzheimer’s dementia and mild cognitive impairment in a large clinical cohort
Authors: Pathmanathan Jay , Zheng Kevin , Little David , Laberinto Kim , Sadeghi Kolia , Tjipterto Dhany , Arslan Alexander , Patino Angelica , Kleinschmidt David , Alday Phillip , Puryear Corey , Westover M Brandon , Donoghue Jacob
Published: December 2023

Background

Recent work has characterized polysomnographic changes in Alzheimer’s Dementia (AD) that correlate with disease severity and precede clinical diagnosis. However, relatively small sample sizes and a paucity of studies examining sleep microarchitecture have been limitations. In this study we examined sleep micro‐ and microarchitectural features in large cohorts of patients with AD and mild cognitive impairment (MCI).

Method

Using a database of over 15,000 clinical PSGs with associated clinical metadata, 125 and 173 subjects were identified with mild AD and MCI, respectively. 260 age and sex matched subjects without neurological disease were identified as healthy controls (HC). Sleep staging results were based on AASM criteria, and micro‐architectural features were assessed using an algorithm trained to predict wake (1) or sleep (0) using spectral data from 3 seconds of EEG from a unique healthy adult cohort (Wake EEG Similarity Index, WESI).

Result

Sleep fragmentation was apparent in both the MCI and AD cohorts (relative to healthy controls), with AD subjects demonstrating significantly more severe PSG disturbances. Healthy controls demonstrated 400 minutes of total sleep time, in contrast to 374 minutes for MCI subjects and 362 minutes for healthy controls. Healthy subjects demonstrated 33 minutes of wake after sleep onset (WASO), compared to 60 and 67 minutes for MCI and AD subjects, respectively. As has been previously reported in smaller cohorts, wakeful bouts and N1 durations were significantly prolonged for AD and (to a lesser extent) MCI subjects, while N2, N3, and REM durations were reduced (with a pronounced reduction in AD N3 percentage). Sleep microarchitectural features assessed using WESI demonstrated that AD and MCI subjects had markedly higher relative wakefulness in all sleep stages except for N3, which showed the same sleep depth as HC.

Conclusion

We confirm increased sleep fragmentation and loss of deeper sleep stages, correlating to disease severity. Spectral features of all sleep stages EXCEPT N3 appear more wakeful in AD and MCI subjects ‐ suggesting microarousals or impaired sleep maintenance contribute to sleep pathology. While N3 duration was markedly reduced, depth of sleep was comparable between populations. PSG findings offer promise as early diagnostic and therapeutic targets.
Immunohistochemical detection of amyloid beta and tau proteins in the Monodelphis domestica brain
Authors: Perez Ismael , Le Truc , Barnes Brooklyn , Alaniz Esperanza I , VandeBerg John L , Gil Mario
Published: December 2023

Background

Animal models have been important for the understanding of Alzheimer’s disease and related dementias (ADRD). However, most of the research involving these diseases has been with rodents. Researchers have raised awareness about the need for alternative and feasible animal models in order to understand these types of diseases. To increase the knowledge of alternative animal models for the study of ADRD, the current study proposed the use of the Monodelphis domestica animal model to detect the presence of amyloid beta and tau proteins.

Method

Fixed brains from young adult Monodelphis were used in the present study. A standard immunohistochemistry (ABC‐DAB) staining protocol was used to detect amyloid beta and tau proteins. To detect the presence of amyloid beta, a 1:100 anti‐amyloid primary dilution was used; for tau protein, a 1:1000 anti‐tau primary dilution was utilized. Only the hippocampal region was selected for description and quantification. An Axioscan Z.1 microscope system was utilized to capture images, and image analysis was performed using ImageJ software.

Result

The area of the hippocampus of the first coronal section was 30262602.934 um2. The results from an amyloid‐beta dilution of 1:100 detected amyloid beta in a number of neurons in the hippocampus. Amyloid beta was also detected in the hippocampus of another brain section (total area: 7048008 um2). The negative control tissue did not reveal positive signal in neurons in the hippocampal area, suggesting low levels of non‐specific binding. The results for tau antibody are pending.

Conclusion

Our study revealed that in Monodelphis domestica animal model brain tissue, a 1:100 dilution resulted in identification of positive amyloid beta protein. However, no abnormal amyloid beta plaque formation was found with this animal model. A possible explanation was that a natural, non‐induced animal model was used in the study.
Ultra High‐Plex Spatial Proteogenomic Investigation of Giant Cell Glioblastoma Multiforme Immune Infiltrates Reveals Distinct Protein and RNA Expression Profiles
Authors: Bonnett Shilah , Rosenbloom Alyssa , Ong Giang , Conner Mark , Newhouse Daniel , New Felicia , Sato Hiromi , Phan Chi , Ilcisin Saskia , Lyssand John , Geiss Gary , Beechem Joseph M.
Published: December 2023

Background

The advancement of spatially resolved, multiplex proteomic and transcriptomic technologies has revolutionized and redefined the approaches to complex biological questions pertaining to tissue heterogeneity, tumor microenvironments, cellular interactions, cellular diversity, and therapeutic response. Most spatial technologies yield single analyte proteomic or transcriptomic datasets from separate formalin‐fixed paraffin‐embedded (FFPE) tissues sections. Multiple studies have demonstrated a poor correlation between RNA expression and protein abundance owing to transcriptional and translational regulation, target turnover, and post‐translational protein modifications. Therefore, a workflow that accurately measures RNA and protein simultaneously within a single tissue section with distinct spatial context is critical to a more complete biological understanding of cellular interactions and activities. Such multimodal omic datasets of protein and DNA or RNA have been termed “spatial proteogenomics”.

Method

Here we present a novel spatial proteogenomic (SPG) assay on the GeoMx® Digital Spatial Profiler platform with NGS readout that enables ultra high‐plex digital quantitation of proteins (147‐plex) and RNA (whole transcriptome,>18,000‐plex) from a single FFPE sample. We demonstrated high concordance, R>0.85, and minor change in sensitivity (<11%) between the SPG assay and the single analyte GeoMx Whole Transcriptome Atlas and GeoMx NGS Protein assays. We used the SPG assay to interrogate 23 different glioblastoma multiforme samples across 4 pathologies.

Results

We observed clustering of both RNA and protein based on cancer pathology and anatomic location. The in‐depth investigation of giant cell glioblastoma multiforme (gcGBM) revealed distinct protein and RNA expression profiles compared to that of glioblastoma multiforme (GBM). Spatial proteogenomics allowed simultaneous interrogation of critical protein post‐translational modifications alongside whole transcriptomic profiles within the same distinct cellular neighborhoods.

Conclusions

Within our dataset, we observed >2‐fold higher protein expression levels of phospho‐GSK3β (Ser9) in gcGBM compared to GBM. Inactivation of GSK3β through phosphorylation has been shown to enhance proliferation of GBM cells. We also observed differential protein expression phosphorylated Tau variants. Phospho‐Thr231 Tau was >2‐fold higher in GBM compared to gcGBM. Associated with neurodegenerative Alzheimer’s disease, changes in Tau expression and phosphorylation have also been observed in glioblastoma. Our study exemplifies the utility of the SPG assay in expanding our understanding of glioblastoma multiforme molecular pathology.
Interaction of Amyloid Beta with Mitochondrial RNAs
Authors: Yurttaş Zuhal , Çamoğlu Tugay , Dursun Erdinc , Gezen‐Ak Duygu
Published: December 2023

Background

Despite mitochondrial RNA’s (mt‐RNA) polycistronic origin, research has shown that a number of post‐transcriptional mechanisms can control transcription. The amyloidogenic proteins such as prion and aSyn are known to bind RNA. However, the main peptide responsible for the pathogenesis of Alzheimer’s disease (AD), amyloid beta 1‐42 (Aβ1‐42), is not known to interact with RNA. It is well known that Aβ1‐42 is an alpha‐helix in monomer form. However, by attaching zinc, Aβ1‐42 achieves sheet folding. Aβ’s new conformation resembles zinc finger transcription factors. Furthermore, using randomly generated RNA molecules, it has been shown that the Aβ peptide domain that interacts with metals may also interact with RNA. As a result, Aβ has the potential to interact with mtRNAs, and this possible interaction may be linked to malfunctioning mitochondria in AD. Aβ1‐42, on the other hand, may affect the LRP130 protein, which is implicated in the mtRNA post‐transcriptional processes. In the current study, we seek to determine whether Aβ1‐42 may interact with mtRNA and whether Aβ1‐42 treatment affects LRP130’s ability to bind to mtRNA.

Method

In our study, the possible interaction of Aβ1‐42‐mtRNA and whether LRP130’s binding capacity to mtRNA was changed due to 0,1µM of Aβ1‐42 peptide treatment was investigated by RNA immunoprecipitation (RNA‐IP) and qRT‐PCR in differentiated LUHMES cells.

Result

Aβ – RNA IP experiment revealed that certain specific mtRNA binding signals were detected in untreated cells, albeit at a low level. Compared to untreated cells, the administration of Aβ1‐42 dramatically reduced LRP130’s affinity for mtRNAs.

Conclusion

Aβ1‐42, the major peptide of AD, may be able to influence post‐transcriptional mitochondrial expression. When we consider the significance of RNA‐protein interactions in neurodegenerative processes, we determine that our research can offer a current strategy for AD biomarker research and the generation of therapeutic RNA aptamers. This study is supported by The Scientific and Technological Research Council of Turkey (TUBITAK) (Project ID:219Z179).
miRNAs peripheral biomarkers for early diagnosis of AD in Latinamerican population
Authors: Orellana Paulina , Caviedes Ariel , Gonzalez Carolina , Salcidua Stefanny , Henriquez Fernando , Cabello Victoria , Lillo Patricia , Villagra Roque , Cerda Mauricio , Zitko Pedro , Thumala Daniela , Gonzalez Christian , Ibanez Agustin , de la Cruz Rolando , Slachevsky Andrea , Duran‐Aniotz Claudia
Published: December 2023

Background

Timely diagnosis of Alzheimer’s disease (AD) is a critical first step in clinical care treatment. However, the availability of diagnostic tools for these conditions is either unavailable or unaffordable, especially in Latin American and the Caribbean (LAC) countries. In this scenario, microRNAs (miRNA) have recently emerged as promising cost‐effective and noninvasive biomarkers since they can be readily detected in different biofluids such as plasma bound to protein or inside exosomes. Our aim is to identify new blood biomarkers to calculate the risk to develop AD in the early stages using machine learning based on exosomal miRNAs detection and different cognitive domains.

Method

miRNAs were extracted from plasma circulating exosomes samples of Subjective Cognitive Complaint subjects belonging to the GERO cohort in two different times (T1 = baseline and T2 = 18 months, n = 50). miRNAs were sequencing to identify the expression levels. Dysregulated miRNAs were analyzed and correlated with neuropsychological evaluations to create machine learning algorithms. miRNAs obtained from algorithms were validated in a new population of subjects at both stages (T1 and T2, n = 50), using qRT‐PCR and correlation analysis with neuropsychological tests.

Result

For algorithm development, we classified subjects into stationary and progressive impairment. Algorithms were trained using the sequenced miRNAs, neuropsychological tests and neuroimaging. As possible predictors of progression of cognitive impairment, the best performing algorithm was Random forest using only miRNAs data. In a new group of subjects, three miRNAs selected by the algorithm and four miRNAs obtained from the literature were validated and the ROC curves were constructed. The combination of these miRNAs (algorithm and literature miRNAs), were the best predictor of the progression of cognitive impairment.

Conclusion

This study could be used in the initial phases of the diagnostic process of AD because it is minimally invasive, low cost and accessible to a large number of patients in Latin American and the Caribbean (LAC) countries.
Role of Social, Clinical, and Contextual Factors in Explaining MRI Markers of White Matter Injury and Change in Objectively‐Assessed Cognition by Race/Ethnicity: The Multi‐Ethnic Study of Atherosclerosis
Authors: Jimenez Marcia Pescador
Published: December 2023

Background

Racial and ethnic disparities in Alzheimer’s disease and related dementias (ADRD) are well documented. The mechanisms through which race and ethnicity as markers of systemic racism are associated with brain health are lacking.

Method

We used data from the Multi‐Ethnic Study of Atherosclerosis (MESA) and a causal mediation framework to determine whether the association between race/ethnicity (measured in Exam 1, 2000‐2002) and brain health is mediated through pathways represented by social (education level, health insurance (yes/no)), clinical (hypertension, diabetes, and depression symptoms), and contextual factors (neighborhood socioeconomic status) measured in Exam 1. Brain health was measured by 3T magnetic resonance imaging (MRI, N = 966) and change in cognitive scores (N = 2002). Participants completed the Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive tests in Exams 5 (2010‐2012) and 6 (2016‐2018). Participants underwent MRI in 2018‐2019 to assess white matter (WM) injury assessed by WM hyperintensity volume (WMHV) and fractional anisotropy (FA). All models were adjusted for age, gender, education, marital status, income, and for WMHV models, total intracranial volume.

Result

Mean (SD) age at baseline was 58 (9) years, 29% participants self‐reported Black, 17% Hispanic, 11% Chinese and 43% White. Black and Hispanic participants experienced a larger decrease in CASI (‐3.3 points (95%CI: ‐4.1, ‐2.5); ‐4.7 (‐5.7, ‐3.7) respectively), DSC (‐2.2 (‐3.6,‐0.8); ‐5.3 (‐7.0,‐3.6)), and DS scores (‐0.4 (‐0.7,‐0.2); ‐1.1 (‐1.4,‐0.8)) from Exam5 to 6 than White participants, after accounting for covariates and baseline cognitive score. Black participants had greater WMHV (21% (1%, 50%)), and lower FA (‐.006 (‐0.01,‐0.002)) than White participants. We observed that the association between race/ethnicity as markers of racism and CASI change was mediated by education (proportion mediated 13% (1%, 21%)), and that the association with DSC change was mediated by health insurance (proportion mediated 9% (4%, 24%)) but not by any other social, clinical or contextual factor. The association between race/ethnicity and WM injury markers and change in DS was not mediated by social, clinical nor contextual factors.

Conclusion

Education and health insurance appear as factors that may partially explain the association between race/ethnicity and cognitive decline.
Estimates of diagnosed dementia prevalence and incidence among diverse beneficiaries in Traditional Medicare and Medicare Advantage
Authors: Haye Sidra , Thunell Johanna , Joyce Geoffrey , Ferido Patricia , Tysinger Bryan , Jacobson Mireille , Zissimopoulos Julie M
Published: December 2023

Background

Approximately half of Medicare beneficiaries are enrolled in Medicare Advantage (MA) ‐ a private plan alternative to Traditional Medicare (TM). Yet little is known about diagnosed dementia rates among Medicare Advantage enrollees, limiting population estimates.

Methods

100% claims of Medicare beneficiaries using Encounter data for MA and claims for TM were used to quantify diagnosed dementia prevalence and incidence rates in MA, compare rates to TM, and provide estimates for the entire Medicare population and for different racial/ethnic populations.

Result

Dementia incidence and prevalence among MA beneficiaries was 2.54% (95%CI 2.53‐2.55) and 7.04% (95%CI 7.03‐7.06). Comparison to TM adjusted for sociodemographic and health differences among beneficiaries in MA and TM; the prevalence of diagnosed dementia among beneficiaries in MA was lower (7.1%; 95%CI 7.12‐7.13) than in TM (8.7%; 95%CI 8.71‐8.72). Diagnosed dementia incidence rate was also lower in MA (2.50%; 95%CI 2.50‐2.50) compared to TM (2.99%; 95%CI 2.99‐2.99). There were lower rates in MA compared to TM for men and women and White, Black, Hispanic, Asian, American Indian/Alaska Native persons. Diagnosed dementia prevalence and incidence for the entire Medicare population was 7.9% (95%CI: 7.91‐7.93) and 2.8% (95%CI: 2.77‐2.78).

Conclusion

Lower diagnosed dementia rates in MA compared to TM may exacerbate racial/ethnic disparities in diagnosed dementia. Rates tracked over time will provide understanding of impact on dementia diagnosis of 2020 MA risk adjustment for dementia.
Impact of a Hybrid Dementia Education Program for College Students: New Friends
Authors: Paniagua Uriel , Nuttkinson Bonnie L. , Spensley Sheryl , Schroeder Molly , Kelble Laura M. , Eastman Alexis M. , Young Zoe X. , LeCaire Tamara J. , Morhardt Darby J. , Walaszek Art , Carlsson Cynthia M.
Published: December 2023

Background

“New Friends” at the University of Wisconsin‐Madison pairs undergraduate and graduate students with mentors living with mild cognitive impairment or dementia due to Alzheimer’s disease or other related dementias (ADRD) and their caregivers. The 7‐month program aims to improve student understanding of living with memory loss, cultivate relationships beyond clinical practice, and bolster interest in dementia care. Modeled on Northwestern University’s Buddy Program, the in‐person program transitioned to a virtual format during the COVID‐19 pandemic. We sought to evaluate program impact following this transition.

Methods

Throughout the program, students met with mentors monthly in‐person, by phone, or virtually, and documented their experiences. Student presentations were led by various guest speakers.

Students were tested on dementia knowledge before and after the program, and asked to rate improvement in understanding, including academic and psychosocial knowledge (1 = minimal; 5 = great). Mentors completed a reflection survey about their experience and its impact on self‐esteem, self‐efficacy and quality of life. Findings before and after the format transition were summarized.

Results

From 2014‐2019, 72 students enrolled in the program, compared to 115 from 2020‐2022 during the virtual/hybrid format. Student knowledge increased for both in‐person and virtual/hybrid formats (p‐value<0.01). Self‐rated academic and psychosocial knowledge gains were similar between formats (mean 3.9 and 4.2, respectively, for in‐person participants, and 3.6 and 3.8, respectively, for virtual/hybrid participants). Two‐thirds (66%) of in‐person and 77% of virtual/hybrid respondents indicated having had misconceptions on ADRD challenged. Mentors were satisfied and rated improvements owing to the program with both formats. Many mentors have participated for multiple years.

Conclusion

The “New Friends” transition to a virtual/hybrid format provided increased flexibility, access and was well received by participants. The program had a positive impact on student knowledge and misconceptions. Many participated in the program because of their interest in aging, geriatrics, or dementia. Extending the program to students, whether virtually or in‐person, may broaden their approach to treating patients with memory loss and increase the number of students pursuing work in the field of dementia care. Further efforts to evaluate the longitudinal impact of this program are underway.
Targeting the Interactions of Small GTPase ARF with C9ORF72:SMCR8:WDR41 Complexes Implicated in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
Authors: Azimian Fereshteh , Chen Yan‐Hua , Lu Qun
Published: December 2023

Background

C9ORF72 plays important roles in many cellular processes, including autophagy, membrane trafficking and immune response. The C9ORF72 mutation is the most common cause of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) which is attributed to both gain‐ and loss‐of‐function mechanisms. C9ORF72 forms a complex with SMCR8 and WDR41, which was reported to regulate signaling of small GTPases such as Rab and ARF proteins. Developing small molecules that modulate interfacial C9ORF72:SMCR8:WDR41 (CSW) and small GTPase interactions will aid in understanding their mode of actions and the potential roles of GTP‐dependent signaling in ALS/FTD. Since the C9ORF72 complex has been shown to elicit prominent GTPase activating protein (GAP) activity on ARF, a major regulator of membrane traffic, we aimed to develop novel small molecules that interfere with the binding between the C9ORF72 complex and ARF1.

Method

To identify novel ligands to interfere with the binding between CSW complex and ARF1, we applied in silico virtual screening methods. To this end, the crystal structure of the CSW in complex with ARF1 (PDB: 7MGE) was used for screening of 40,183,714 chemicals available in Mcule database to find hit compound (s).

Result

We defined the binding pocket in the interface of ARF1 and CSW complex including all essential amino acid residues. For filtering the compounds, stringent criteria such as the number of rotatable bonds and the number of heavy atoms were applied. The top 100 hits were identified using this structure‐based virtual screening which show various interactions with the defined binding site of target. Next, the prepared library (the 100 identified Hits) was used as input for virtual screening using Schrodinger software. Flexible docking was performed using Glide program running under LINUX operating system. Based on vina scoring function, 10% of most active compounds that showed the best docking scores were identified and kept for further analysis.

Conclusion

Rational design, computer‐aided, and in silico screening help developing pharmacological modulators to regulate C9ORF72‐ARF signaling and investigate their potential roles in ALS/FTD.

Acknowledgement: This study is supported in part by NIH GM146257 on ALS² Initiative and by The Wooten Foundation.
Sleep and electroencephalography biomarkers in preclinical Alzheimer’s Disease
Authors: Dude Jason , Boyd Jill , Hamilton Raiyan , Ju Yo‐El
Published: December 2023

Background

Accumulating evidence supports a bi‐directional relationship between sleep and Alzheimer’s Disease, including sleep disruptions in preclinical Alzheimer’s Disease (pAD), prior to onset of overt cognitive symptoms. Subsequently, sleep phenotypic variables and electroencephalography (EEG) features are attractive noninvasive biomarkers for pAD. The Biomarkers of Alzheimer’s Disease in Sleep and EEG (BASE) study seeks to develop such sleep‐EEG biomarkers for pAD.

Method

Community‐dwelling participants (n = 52, mean age: 70.8 ± 4.5 years) underwent cognitive testing including Montreal Cognitive Assessment (MOCA, general cognition), Craft Story 21 (CS21, memory), and Trails A and B (visuospatial, executive); performance was z‐scored by age, sex, and education. Objective measures of sleep quality were obtained using actigraphy over 4‐14 (mean 9.1) days at home: wake time after sleep onset (WASO), number of awakenings (NoA), and sleep efficiency. In‐lab overnight polysomnography was performed, and EEG features were extracted during NREM sleep from F3, F4, C3, and C4 channels: relative slow and fast delta power (RSDP, RFDP), spindle density, and slow wave density. The following morning (9‐10AM), CSF was obtained by fasted lumbar puncture, and assessed for amyloid‐b‐42 and tau; pAD was determined by tau/amyloid‐b‐42 ratio. Correlations between cognitive performance and EEG /sleep variables were performed using linear models, adjusted for age, sex, education, and sleep apnea status. Interaction between pAD status and correlations were assessed.

Result

There were 36 biomarker‐negative healthy controls (HC) and 16 with pAD; groups did not significantly differ demographically. RSDP and WASO were negatively associated with CS21 (RSDP: p = 0.040; WASO: p = 0.034). RFDP and NoA interacted with pAD status for MOCA (RFDP: p = 0.010; NoA: p = 0.026), and RFDP interacted with pAD status for CS21 (p = 0.017).

Conclusion

We assessed objective sleep quality and sleep‐EEG features against cognitive performance, and any interaction with pAD status. Worse sleep quality was associated with worse memory performance. Among the EEG features assessed, RFDP was strongly negatively correlated with memory performance in those with pAD, suggesting neurophysiological aberrations of NREM sleep in this cohort.
Targeted Proteomics in Parkinson’s Disease
Authors: Vasanthakumar Aparna , Kulkarni Ameya S
Published: December 2023

Background

Identifying biomarkers associated with neurodegenerative diseases and their progression may enable patient enrichment and improve clinical trial designs.

Method

Genomic studies have revealed correlations between genetics, transcriptomics, and epigenetics with disease pathology and diagnosis in the brain and peripheral blood. For example, previous studies have showed that rate of cognitive decline estimated by slopes of cognitive scores associated with change in DNA methylation.

Result

Several of these genomic marks point to proteomic changes, especially given the chromosomal location of these differentially expressed or methylated marks. Moreover, since proteins represent a key class of biomolecules that will help illustrate real‐time human biology, we tested a targeted proteomic analysis using the Olink platform.

Conclusion

Data from the analysis of targeted proteomic analysis in the context of clinical data as well other omics datasets for the same participants will be discussed at this session.
Neuroimaging of new and novel Alzheimer’s Disease (AD) mice from the MODEL AD Consortium
Authors: Obenaus Andre , Stark Craig E.L. , Wu Yu‐Chien , Territo Paul R
Published: December 2023

Background

The ability of preclinical neuroimaging in rodent models of Alzheimer’s Disease and Related Dementia (ADRD) to assess the progression of disease is increasingly providing novel insights into AD, like human AD imaging. Preclinical studies have the advantage of being able to directly correlate findings to the observed neuropathology. Recently, University of California Irvine and Indiana University School of Medicine along with Jackson Laboratories were awarded funding to design and phenotype relevant mouse models of late onset AD (LOAD), forming the MODEL AD consortium (https://www.model‐ad.org/). Imaging cores from these will utilize existing state of the art translationally relevant medical imaging methodologies as well as ascertain feasibility of emerging imaging methods for increased diagnostic sensitivity.

Methods

Two primary imaging modalities will be utilized: high‐field MRI (9.4T and 17.6T) and PET/CT. Deep MRI phenotyping are based on the accepted human‐AD standards like ADNI (Structural T2W, FLAIR, diffusion, perfusion (PWI), susceptibility, and functional MRI and MR spectroscopy). Novel histological vessel painting combined with PWI will assess vascular modifications. PET imaging will evaluate brain metabolism (18F‐FDG), regional perfusion (64Cu‐PTSM), amyloid (18F‐AV45), tau (18F‐AV1451), neuroinflammation (18F‐CPPC and 18F‐GSK1482160), and astrogliosis (18F‐FEBU) markers in new mouse models.

Results

MODEL AD consortia will utilize platform mice (Table 1) across their lifespans and effects after being fed a high fat diet. Known and emerging GWAS risk variants for AD will be added to these platform mice to better replicate human AD. Neuroimaging data will be presented from PET/CT and MRI, focusing on exemplars from relevant AD mouse models including platform mice. A long‐term goal of the MODEL‐AD Imaging cores is to co‐register MRI, PET/CT and vascular measures to concordant histopathological and spatial RNA data. The cores have developed state‐of‐the‐art analytical pipelines to process imaging data to support spatial and temporal localization of ADRD.

Conclusions

The MODEL AD consortium (UCI/IUSM/Jax) will develop new and novel AD mouse models and the imaging cores will deeply phenotype these models using existing and emerging neuroimaging methods and analytic approaches, using MRI and PET/CT. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).
Neuroticism, cognition and depression: do those with greater neuroticism have more cognitive decline among depressed elderly individuals?
Authors: Kahtalian Lais Lundstedt , Ribeiz Salma Rose Imanari , Neubern Patricia Cardoso Buchain , Filho Geraldo Busatto , Gonçalves Eduardo C Q , Marques Fernanda Mariotti
Published: December 2023

Background

Neuroticism is a multidimensional personality characteristic related to a predisposition to experience psychological distress and negative mood states, and it may be an indicator of worse cognitive and mood outcomes in older adults. It is one type of personality trait described by Costa and McCrae on the Five‐Factor Model of Personality. Evidence shows that higher neuroticism scores contribute to chronic stress response that induces neuronal dysfunction, increasing susceptibility to cognitive decline and dementia. However, few studies were conducted previously evaluating associations between neuroticism, depression and cognitive decline.

Method

Subjects consist of 76 elderly depressed individuals who were treated over 24 weeks at the Institute of Psychiatry of the Faculty of Medicine in the University of São Paulo. The study subjects were selected from a pool of outpatients and were included in the study if they met the DSM‐5 criteria for major depression and were at least 60 years old at baseline enrollment. Those with evident cognitive impairment (Mini Mental State Examination <13) were excluded.

At baseline, subjects received standardized clinical assessments administered by a geriatric psychiatrist, including: Mini Mental State Examination; CAMCOG, translated and adapted for Brazilian population; and Montgomery–Asberg Depression Rating Scale (MADRS). The personality assessment was performed using the NEO‐FFI inventory. Correlations will be performed using Pearson’s linear coefficient for correlations of numerical variables and Spearman’s for ordinal variables.

Result

The sample was predominantly female, with a mean age of 69.1 ± 6.6, low education (70.4% studied up to elementary school), and 45.7% lived with a partner. To understand the relationship between personality factors and cognition parameters, correlations will be conducted and controlled by age and sex.

Conclusion

The evaluation of neuroticism is relevant as this personality trait may impact therapeutic interventions, leading to poorer outcomes and worsening cognitive and functional disabilities.
High‐density lipoprotein particle size distribution among patients with Alzheimer’s disease, mild cognitive impairment, and age‐matched controls
Authors: Zheng Jack Jingyuan , Hong Brian V. , Agus Joanne , Tang Xinyu , Guo Fei , Lebrilla Carlito B. , Harvey Danielle J. , Jin Lee‐Way , Maezawa Izumi , Zivkovic Angela M.
Published: December 2023

Background

High‐density lipoproteins (HDL) are protective against several chronic diseases, including Alzheimer’s disease (AD). The size distribution of HDL particles is one of the determining factors of HDL function since HDL of various sizes subgroups play unique roles. Yet not much is known about HDL particle size distribution in the context of AD.

Method

In this study negative‐stained transmission electron microscopy (NS‐TEM) was used to explore the particle size distribution of isolated HDL samples from 194 subjects with AD (n = 71), mild cognitive impairment (MCI, n = 40), or no cognitive impairment (n = 83). HDL particles were isolated using density‐adjusted ultracentrifugation followed by size exclusion chromatography and analyzed by NS‐TEM followed by image analysis using the software ImageJ. Individual particle diameter data were obtained, grouped into different size‐based categories and the relative abundances of each subgroup were compared among diagnostic groups and across clinical parameters.

Result

Patients with AD and MCI had a significantly higher percentage of 7‐8 nm HDL particles and a lower percentage of 9‐10 nm, 12‐13 nm, and 13‐14 nm particles. Body mass index, clinical dementia rating score, and white matter hyperintensity volume were positively correlated with the percentage of 7‐8 nm particles and negatively correlated with the percentage of 9‐10 nm particles, whereas executive score, semantic memory score, and verbal memory score were negatively correlated with the percentage of 7‐8 nm particles, and positively correlated with the percentage of 9‐10 nm particles.

Conclusion

These findings show that specific alterations in HDL particle size distribution in patients with AD and MCI are linked with measures of cognitive function and may be a promising direction for the discovery of new biomarkers and therapeutic targets in AD.
Leptin peptides and the Implications on Alzheimer’s Disease
Authors: CALIO MICHELE LONGONI , Massinhani Fernando H , Porcionatto Marimelia Aparecida , Marinho Darci Souza
Published: December 2023

Background

Obesity and neurodegeneration are growing health problems worldwide. Alzheimer’s disease (AD) is the most prevalent cause of progressive dementia in the elderly population. AD is characterized by the combined presence of extracellular plaques formed by β‐amyloid peptide and intraneuronal neurofibrillary tangles of abnormally hyperphosphorylated Tau protein. Several studies have shown that obesity is a risk factor for dementia. Leptin, initially described as the hormone responsible for controlling food intake and energy expenditure, also has other important physiological functions related to neuronal activity, proliferation and protection. With the discovery that neurogenesis persists in the brain of adult mammals, including brain regions affected by AD, many studies aim to stimulate this physiological process in various areas of the brain for the treatment of neurodegenerative diseases to repair and/or prevent neural loss. These regions also express the long form of the LepRb leptin receptor and are the first regions to be affected by chronic neurocognitive deficits.

Method

Given the neurogenic potential of leptin, the main objective of this study is to analyze and compare the action of this hormone with synthetic peptides (PEP) on cell proliferation, differentiation and Aβ plaque formation in two of the main neurogenic niches in AD model mice.

Result

The expression of glial, neuoblast and Aβ markers were detected by immunohistochemistry. We observed that animals treated with PEP4 had a significant increase in the proportion of BrdU/DCX+ cells regardless the age and animal model. Our results also show that treatment with PEP4 was able to significantly decrease the amount of Aβ plaques in the hippocampus of AD model animals. However, it is observed that this decrease is significantly smaller than when compared to that produced by leptin, demonstrating that it is more effective in reducing the number of Aβ plaques in the hippocampus region.

Conclusion

We believe that a better understanding of the mechanisms of the pathological processes that cause AD and how altered leptin signaling affects these processes could lead to the development of early therapies for the treatment of Alzheimer’s disease.
Longitudinal adversity, mental health and cognition pre‐ and during Covid‐19
Authors: Bauermeister Sarah
Published: December 2023

Background

Our previous research shows that self‐report early adversity (EA) is associated with poorer cognition and mental health. Importantly, poor mental health is also associated with both cognitive decline and dementia. However, longitudinal work in understanding long term effects of early and adult adversity (AA) on cognitive change is limited. Disentangling adversity types is complex and the mechanisms underlying long term effect are still to be understood. Our aim in this project was to investigate the relationship between EA and AA, and longitudinal mental health and cognition. In this study we also include assessments during Covid‐19 to explore the effects of a high stress load experience on previous and existing longitudinal adversity and mental health.

Method

Our work was conducted using the English Longitudinal Study of Ageing (ELSA UK) and data from 15,355 individuals with a mean age of 64.56 years at timepoint 1 (wave 3), 66.01 years (wave 6) and 67.49 years (wave 9) at timepoints 2, 3 and 68.66 years (Covid wave), we applied a longitudinal panel structural equation model (SEM) to the data. We assessed the effects and interrelationships of EA (self‐report retrospective) measured at timepoint 1 and AA (partner relationship strain) at timepoints 1‐3 on depression and cognition measured at timepoints 1‐3 and on mental health during the Covid‐19 pandemic.

Result

EA (timepoint 1) was associated with increased incidence of AA at all longitudinal timepoints (p <.01), also with higher depression at timepoints 1 and 2 (p <,.01), poorer cognition (verbal fluency) at timepoint 3 (p <.05) and increased depression (p <.01) and anxiety (p <.05) during the Covid‐19 pandemic. AA was associated with higher depression at all timepoints (p <.001) and poorer cognition (verbal fluency and memory) at timepoint 3 (p <.01; p <.05).

Conclusion

The deleterious effect of life course adversity on longitudinal mental health and cognition are significant and during the Covid‐19 pandemic, the effect on depression was significant even when controlling for previous depression. Our results suggest that accumulative stress response may be implicated.
The impact of young controls in the detection of tau load in cognitively impaired and asymptomatic elderly
Authors: Macedo Arthur C. , Tissot Cécile , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Arias Jaime Fernandez , Wang Yi‐Ting , Aumont Etienne , Socualaya Kely Quispialaya , Lussier Firoza Z , Stevenson Jenna , Nazneen Tahnia , Hosseini Seyyed Ali , Karikari Thomas K , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick A. , Rosa‐Neto Pedro
Published: December 2023

Background

Neuropathological observations report incipient tau accumulation in the human brain starting in the third decade of life, with the proportion of individuals with some degree of tau deposition increasing with age. Given the high prevalence of tau positive cases among cognitively unimpaired (CU) older adults, one may question whether these individuals constitute an ideal reference group when assessing tau load in symptomatic population. Here, we compare tau biomarker levels of participants with Alzheimer’s disease (AD) and CU of different ages.

Method

We evaluated 35 CU young individuals (aged <26 years) and 124 amyloid‐beta (Aβ)‐ elderly, considered the two control groups. We also assessed 42 Aβ+ CU and 122 Aβ+ cognitively impaired (CI) individuals, diagnosed with either mild cognitive impairment or AD dementia. Participants were assessed with 18F‐MK6240 positron emission tomography (PET) and CSF and plasma pTau181, 217, 231 and 235. We used linear regression to perform voxel‐wise comparisons of tau‐PET signal between groups. We compared the standardized uptake value ratio (SUVR) in medial‐temporal and Braak‐like regions‐of‐interest (ROI) and fluid biomarkers levels using the Wilcoxon rank sum test.

Result

In the voxel‐wise comparisons (Figure 1A‐E), CI participants presented more widespread cortical signal than control groups. Less signal in the parietal cortex was observed in the comparison with CU young. Higher t‐values were observed in Aβ+ CU individuals in the medial temporal region, compared to both control groups, and adjacent neocortex, especially compared to CU young. Temporal and Braak V‐VI SUVR were higher in CI but not in Aβ+ CU individuals compared to controls. Moreover, Braak I‐II and III‐IV SUVR and the fluid biomarkers levels were higher in both Aβ+ groups compared to controls (Figures 2A‐D; 3A‐G). Importantly, Braak I‐II SUVR and the CSF biomarkers levels were higher in CU old Aβ‐ versus young.

Conclusion

Here, we provide in vivo evidence that tau‐load in age‐matched Aβ‐ controls constitutes a bias for identifying tau pathology, particularly in individuals at early stages of AD pathophysiology. Age‐related tau load should be considered when selecting control groups to assess tau in symptomatic populations, especially those with early AD, and when defining criteria for tau abnormality.
The German S2k guideline: Informed consent of people with dementia to medical treatment
Authors: Pantel Johannes , Tesky Valentina Antonia , Haberstroh Julia
Published: December 2023

Due to demographic change, the medical care system will be confronted with a growing number of people with dementia (PwD). PwD are usually multimorbid, frequently suffer from other diseases in addition to dementia and are therefore regularly confronted with decisions on medical diagnostics, treatment, or palliative care measures. Since the ability of PwD to give informed consent is often called into question, representative decisions are frequently made. In many cases, PwD are even categorically judged incapable to consent based on their diagnosis. This deprives them of their right to autonomous decisionmaking which is, however, not in line with the demands oft the United Nations Convention on the Rights of Persons with Disabilities/UN‐CRPD. To make sure that legally effective informed consent has been given, the ability to consent must be assessed. Furthermore, PwD have to receive adequate information, and they have to be adequately supported by the application of suitable measures (e.g. enhanced consent procedures). Aim of the German S2k‐ guideline “Informed Consent of people with dementia to medical measures” is to provide assistance for medical professionals with respect to the above mentioned challenges, whereby S2k defines a standard of higher quality guidelines which use formalized methodological techniques for the consensus process. The guideline was developed under the auspice of the Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN), the Deutsche Gesellschaft für Neurologie (DGN) and the Arbeitsgemeinschaft Wissenschaftlicher Medizinischer Fachgesellschaften (AWMF) in Germany. Two of the authors (JP and JH) served as chairpersons for the guideline development. The guideline contains 33 recommendations and 31 legal requirements that were consented by 24 participating medical societies and institutions, including legal and bioehtical expertise. The patient perspective was provided by the German Alzheimers Associtaion (Deutsche Alzheimer Gesellschaft). The guideline is intended to provide a structured approach to ensure that people with dementia are able to act in terms of self‐determination when making decisions about medical measures. Structure and content oft the guideline that may serve as a template for the development of similar guidelines in other countries are presented at the congress.
ApoE variant associated with cognitive resilience alters AD associated hyperexcitability in dentate granule neurons
Authors: Berchulski Mariah R , Singh Surjeet , Martin Sophie L.A. , O'Connell Kristen MS , Kaczorowski Catherine C.
Published: December 2023

Background

Cognitive decline in Alzheimer’s disease (AD) differs based on background genetics even with similar pathology. Using genetic linkage analysis, we identified a coding variant in the receptor binding domain of ApoE that leads to changes in cognitive performance across a genetically diverse population harboring familial (FAD) mutations known as the AD‐BXDs (Neuner et al., 2019). Using CRISPR‐based gene editing, we developed a C57BL/6J (B6) mouse carrying the ApoE allele from the DBA/2J (D2) strain (ApoEE163D) and determined that ApoEE163D mice with 5XFAD transgene (ApoEE163D‐5XFAD) are susceptible to cognitive decline compared to B6‐5XFAD mice (Kaczorowski, et al., 2022).

Analysis of hippocampal RNA sequencing profiles from the hippocampus indicates robust transcriptomic changes in dentate gyrus (DG) granule cells associated with cognitive resilience to FAD mutations in the presence of the B6 ApoE genotype. Here we aim to evaluate the functional implications.

Method

We adapted the Patch‐Seq method (Cadwell et al., 2017) to investigate transcriptional and electrophysiological changes within the DG associated with both FAD mutations and ApoE genotype. Whole‐cell patch clamp was used to evaluate intrinsic excitability of granule cells from 14month old B6 mice carrying FAD mutations and ApoEE163D, compared to age matched controls. The cellular contents, including the nucleus, were collected after each recording to characterize the transcriptome, and the cells were filled and stained for downstream analysis of neuronal morphology.

Result

We observed a significant interaction of the 5XFAD and ApoE genotypes on DG granule cell excitability. Specifically, cells from ApoEE163D‐5XFAD required less current stimulus to both elicit a single action potential, and to fire in response to a current ramp (rheobase). Although input resistance was comparable across all 4 groups, the sag ratio of ApoEE163D‐5XFAD was also reduced.

Conclusion

Enhancement of DG excitability of ApoEE163D‐5XFAD mice may underlie increased seizure susceptibility that has been reported previously in FAD animal models on D2 genetic background and associated with increased risk of seizures in AD patients. Ongoing work will integrate DG excitability with single‐cell RNAseq, morphology, and behavior to dissect mechanisms underlying the modifier effect of ApoE genotype on susceptibility and resilience to cognitive deficits in FAD mutation carriers.