bluuebunny/crossref_metadata_2025 huggingface dataset:
TNFα‐mediated inflammation in mouse models of VCID
Authors: Krick Katelynn E , Sudduth Tiffany L , Johnson Sherika , Rogers Colin B , Weekman Erica M , Wilcock Donna M.
Published: December 2023

Background

Tumor necrosis factor alpha (TNFα) is a prominent pleiotropic cytokine with dichotomous effects. Primarily produced in the brain by glial cells, TNFα interacts with two subtypes of TNF receptors (TNFRs) that dictate the cellular response, be that pro‐ or anti‐inflammator. The diverse cellular responses include cell survival, cell death, proliferation, and angiogenesis. Due to the critical role inflammation plays in the pathogenesis of Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID), understanding the specific roles of pleiotropic cytokines like TNFa in dementia‐causing diseases will provide mechanistic and therapeutic insights. Both inhibition of soluble TNFα (sTNFα) and deletion of pro‐inflammatory TNF receptor 1 (TNFR1) have been shown to decrease severity of amyloid deposition in AD models. However, similar studies have not been conducted regarding VCID outcomes.

Method

This study sought to examine gene and protein expression of TNFα and the two receptors, TNFR1 and TNFR2, within two mouse models of VCID; the hyperhomocysteinemia (HHcy)‐induced VCID co‐morbid with amyloid deposition and aged Tg2576 with severe cerebral amyloid angiopathy (CAA)‐associated VCID. Measures were taken via qPCR for mRNA assessment and Meso Scale Discovery assays (MSD) for protein quantification.

Result

In HHcy‐induced VCID, TNFα mRNA levels were significantly increased regardless of the presence of amyloid deposition. Similarly, protein levels of TNFα trended higher in HHcy groups compared to their controls regardless of amyloid presence. Levels of TNFR1 mRNA trended lower in the HHcy model but was significantly increased in HHcy‐amyloid co‐morbid mice. When investigated in aged Tg2576 mice with CAA, TNFR1 protein expression increased at older timepoints compared to younger, and against wild type controls. Anti‐inflammatory and innate immune‐associated TNFR2 was increased at 20 months in CAA mice when compared to age‐matched controls.

Conclusion

These findings display differences in gene and protein expression of TNFa and its receptors in two models of VCID. The unique expression in these models merits further research into the differences in TNF‐mediated inflammation in VCID. Further research is also necessary to determine potential therapeutic advantages of drugs such as TNFα inhibitors in cases of VCID with and without amyloid deposition.
Pseudo‐temporal models of Alzheimer’s Disease progression across brain‐derived transcriptomics, proteomics, and metabolomics
Authors: Heath Laura M , Batra Richa , Cary Gregory A. , Wiley Jesse C , Poehlman William L. , Linden Abby Vander , Krumsiek Jan , Arnold Matthias , Kaddurah‐Daouk Rima F. , Carter Gregory W , Greenwood Anna K
Published: December 2023

Background

We applied a pseudo‐temporal model to multi‐omic data from individuals with heterogeneous neuropathology to examine molecular changes across the spectrum of Alzheimer’s Disease (AD) progression.

Methods

Manifold learning algorithms ‘order’ samples based on similarity of expression or abundance patterns to calculate a ‘trajectory’ of disease progression. We applied this approach to RNAseq (N = 1078), TMT‐proteomics (N = 602), and metabolomics (N = 500) profiles of human postmortem brain samples from the ROS/MAP study within the Accelerating Medicine Partnership‐AD consortia (AMP‐AD); 318 individuals were included in all three ‐omics datasets. Analyses were stratified by sex. We examined associations between pseudotime, a quantitative measure of progress along each trajectory, and neuropathological and clinical endpoints. We calculated differential expression or abundance along each trajectory. For transcriptomic and proteomic data, we used gene set enrichment analyses to identify significant GO terms changing along the trajectory and grouped them into 19 distinct AD‐relevant biological domains. We similarly annotated changing metabolic pathways along metabolomic trajectories.

Results

Pseudotime estimates were significantly associated with AD status such that “early” (low pseudotime) samples were enriched for controls, and “late” (high pseudotime) samples were enriched for cases, in all ‐omics. Omic‐specific pseudotimes were weakly correlated with each other (Pearson’s r for: RNAseq vs proteomics: 0.39; RNAseq vs metabolomics: 0.28; proteomics vs metabolomics: 0.41). Proteins involved in mitochondrial metabolism and synaptic function were downregulated in early stages in both sexes, while transcriptomic trajectories indicated early sex‐specific differences in synaptic function and immune response. In both sexes, metabolic amino acid and lipid pathways were perturbed in early stages, though specific pathways were different; early Phosphatidylcholine and Leucine, Isoleucine, and Valine Metabolism perturbations were especially prominent in women, while early Glutathione Metabolism perturbations were more prominent in men.

Conclusions

Despite differences in the biological nature of the data used to order trajectories, pseudotime was associated with multiple measures of AD progression across all three ‐omics. Each analysis provided a unique snapshot of molecular change across AD progression. Sex‐specific differences, especially those noted early in disease trajectories, may provide crucial insights into key processes driving disease in women and men.
Do the benefits of education for late‐life cognition change across birth cohorts? Assessing period effects in the Health and Retirement Study
Authors: Eng Chloe W. , Glymour M. Maria , Rehkopf David
Published: December 2023

Background

Education consistently predicts late‐life cognition, but studies rarely consider the transformation of education that current older adults experienced across the 20th century. We assess whether the relationship between education and late‐life cognition remains constant across birth cohorts spanning over 40 years of changing social investments and progress.

Method

US Health and Retirement Study participants (age 50+) were enrolled at multiple points between 1998 and 2018, allowing for the study of participants of different birth years at the same age (n = 28,299 participants and 151,514 visits across all available data collection waves). US‐born participants with at least one memory measurement were stratified into eight birth cohorts of approximately five years each, spanning more than 40 years. Mixed models with random intercepts for each participant investigated the presence of effect modification across birth cohorts for the education‐dementia relationship. Age was not evenly distributed across birth cohorts; therefore models were additionally run restricted to ten‐year age groups. Secondary analyses investigated whether period effects further existed by race and gender. All models adjusted for age, quadratic age, gender, race, cognitive practice effects, childhood census region, and parental education.

Result

Earlier birth cohorts showed larger associations between education and late‐life cognition, with each additional year increase in schooling associated with a 0.10 SD (95% CI: 0.09, 0.11) higher memory score in the earliest cohort compared to the latest (interaction p‐value <.0001). Findings were consistent when restricting analyses to age groups. Effects of education across cohorts also slightly differed by gender, with increased education being associated with larger gender disparities in memory of 0.04 SD (95% CI: 0.02, 0.06) more per year of schooling in the latest cohort compared to the earliest (interaction p‐value <.0001), and by race, with a narrowing of racial disparities in later cohorts for the cognitive benefits of increased education (interaction p‐value <.0001).

Conclusion

Each year increase in attained education had overall larger effects among earlier cohorts, though this may differ across sociodemographic and age groups. Future research is needed to examine whether differences arise from historical transformations of the educational experience or from changes in downstream economic opportunities across time periods.
White Matter Hyperintensity Growth/Regression quantification: MarkVCID multi‐site Instrumental Validation
Authors: Bahrani Ahmed A , Abner Erin L , Powell David K , Gold Brian T. , Wilcock Donna M. , Jicha Gregory A , Ali Doaa
Published: December 2023

Background

White matter hyperintensities (WMH) are one of the main recognized biomarkers for the small vessel diseases related to the vascular contributions to cognitive impairment and dementia (VCID). WMH found to be dynamic, increasing in volume, but also stability or even decreasing in volume over time. The ability to measure and track such longitudinal change over periods of time, as short as one‐year, is critical for both mechanistic discoveries and for the informed future use of biomarkers to track disease modification in clinical trials of VCID. The NINDS‐funded MarkVCID Consortium engaged to test such a protocol for cross‐site inter‐rater and test‐retest reliability to establish instrumental validation of this candidate biomarker for VCID.

Method

T1 and 3D FLAIR MRI acquisitions were collected longitudinally and analyzed across six independent sites, using a unique post‐acquisition processing protocol. The analytic platform was built within a Singularity Container to provide the necessary software tools for rigorous uniform co‐registration and intensity corrections that enabled precise measurement of WMH change in regard to growth, stability and regression over a one‐year interval. Baseline and 12‐month follow‐up scans were acquired across MarkVCID sites and pooled to generate the validation dataset used for cross‐site inter‐rater reliability (n = 30). To evaluate test‐retest reliability, two baseline scans (acquired approximately one‐week apart) were independently co‐registered to the 12‐month follow‐up scan (n = 18). Cross‐site inter‐rater and test‐retest reliability were assessed using intraclass correlational analyses (ICC).

Result

ICC values for test‐retest reliability of WMH growth and regression were 0.97 and 0.94 respectively. Mean ICC values for cross‐center WMH masks were 1.0 for both time points, see Fig. 1 and 2, and WMH growth and regression were 0.99 for both see Fig. 3 and 4.

Conclusion

The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one‐year period as measured by cross‐site inter‐rater and test‐retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.
Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period
Authors: Robb W Hudson , Gogniat Marissa A. , Zhang Panpan , Shah Krish U , Houston Michelle L , Pechman Kimberly R. , Liu Dandan , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L.
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.

Methods

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.

Results

In main effect models, neither CSF Aβ42 (p‐values>0.31) nor p‐tau (p‐values>0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values>0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values<0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).

Conclusions

Results linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation.

Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082
Cellular Energy Metabolism is Altered in the Trem2R47h NSS Mouse Model of AD
Authors: Bishop Joseph , Vu Michael M , Malhas Rond , Cheema Amrita K , Milinkeviciute Giedre , MacGregor Grant R , Green Kim N , Tenner Andrea J , LaFerla Frank , Mapstone Mark , Consortium MODEL AD
Published: December 2023

Background

Human GWAS have identified variants of the triggering receptor expressed on myeloid cells 2 (TREM2) gene as a major genetic risk factor for Alzheimer’s disease (AD). TREM2 is necessary for maintaining microglial metabolic fitness and may be critical for providing cellular energy demands for microglial‐dependent β amyloid phagocytosis. Here, we examine the plasma metabolome of Trem2 R47H NSS mice in the presence of β amyloid plaques to examine alterations of cellular energy metabolites.

Method

We examined the abundance of plasma metabolites obtained from homozygous Trem2 R47H NSS (Jax #034036), 5xFAD x Trem2 R47H NSS, 5xFAD hemizygous, and control (WT) mice (n = 10 each group) at 4 months of age. We measured 762 lipids and 204 polar metabolites from peripheral plasma using liquid chromatography mass spectrometry (LC‐MS). We conducted differential abundance (DA) analysis for the individual metabolites and compared the groups using FDR correction (q < 0.05). We used DA metabolites in pathway analysis to examine which metabolic pathways were impacted by TREM2 R47H and the presence of amyloid (5xFAD hemizygous background).

Result

Homozygous Trem2 R47H NSS mice, both in the presence and absence of amyloid plaques (i.e. 5xFAD hemizygous or non‐transgenic background), had significantly lower abundance α‐D‐glucose and lactate compared to their relevant control groups (q’s < 0.05). 5xFAD x Trem2 R47H NSS mice also showed significantly lower phosphatidylethanolamine (PE) abundance relative to 5xFAD hemizygous mice (q’s < 0.05) and this was especially apparent for female mice (q’s < 0.05). KEGG pathway analysis using DA features revealed enrichment on Glycerophospholipid Metabolism and Glycolysis/Gluconeogenesis pathways.

Conclusion

We report lower levels of the entry substrate to glycolysis (Glucose) and an end product metabolite (Lactate) in homozygous Trem2 R47H NSS mice, especially in the presence of amyloid. The depletion of these energy metabolites in circulating blood may reflect failure of the immunometabolic switch from oxidative phosphorylation to glycolysis in support of increased energy demands of activated microglia. We also find significant depletion of glycerophospholipids in Trem2 R47H NSS mice, which was more pronounced for female mice. These results suggest cellular energy dyshomeostasis associated with microglial activation which can be measured in peripheral blood.
Cerebral amyloid angiopathy and neuritic plaques impact tangle burden and cognitive decline in a heterogeneous clinical population
Authors: Godrich Dana , Pasteris Jeremy , Martin Eden R. , Schellenberg Gerald D. , Pericak‐Vance Margaret A. , Cuccaro Michael L. , Scott William K. , Rundek Tatjana , Kukull Walter A. , Montine Thomas J. , Beecham Gary W.
Published: December 2023

Background

Alzheimer disease (AD) presents with two primary pathologies: neurofibrillary tangles (NFT) and neuritic plaques (NP). However, these hallmark pathologies typically co‐occur with pathologies from AD‐related dementias like cerebral amyloid angiopathy (CAA) [Godrich, 2022; PMID: 35142102]. While CAA is known to impact cognitive impairment, the role of CAA in AD dementia is still not well described [Rabin, 2022; PMID: 35759327]. Here we present an analysis of CAA, NP, and NFT to assess the interplay of these pathologies with cognitive decline and genetic risk factors for AD.

Method

Data come from 4,915 autopsied individuals from the National Alzheimer’s Coordinating Centers (NACC). NFT, NP, and CAA were measured ordinally. We used ordinal logistic regression to model and compare independent and interactive effects of CAA and NP on NFT and cognitive decline while adjusting for sex, AAD, and APOE. We also evaluate models with an APOE and NP interaction as a comparison to gauge whether it is more informative than CAA. Finally, we replicate causal mediation analysis from Rabin et al. and extend the path model to include APOE, stratifying both models by NP severity (Fig.1).

Result

The model with CAA and NP interactions best explained NFT burden outcome (per AIC, pseudo‐R2, and F‐test), even when compared to models with APOE. We replicated Rabin et al. findings that CAA does not directly affect cognitive decline but rather indirectly via NFT mediation, but only in individuals in the high NP group. We saw this in a larger clinical cohort with ordinal measures of neuropathology, which are more commonly obtained than linear ones. We also extended the mediation analysis to include APOE and findings held.

Conclusion

We replicated the relationship between CAA, AD pathologies, and cognitive decline [Rabin, 2022] and extend the findings to a more heterogeneous clinical population. Even when accounting for APOE, CAA still had an indirect effect on cognitive decline in the high NP group as mediated by NFT severity, showing that the findings are likely not due to APOE confounding. These findings continue to underscore the importance of the consideration of co‐occurring neuropathologies like CAA when developing novel AD therapeutics.
Relationships between CYP450‐sEH oxylipins, small vessel disease markers, and regional neuroimaging in Alzheimer’s disease and mild cognitive impairment
Authors: Lin William Z. , Yu Di , Xiong Lisa Y. , Anita Natasha Z. , Liang Nuanyi , Shen Qing , Ozzoude Miracle , Fischer Corinne E. , Frank Andrew R , Freedman Morris , Kumar Sanjeev , Pollock Bruce G. , Tang‐Wai David F. , Tan Brian , Haddad Seyyed M. H. , Nanayakkara Nuwan D. , Ramirez Joel , Symons Sean , Arnott Stephen R. , Lou Wendy , Rabin Jennifer S. , Taha Ameer Y. , Swardfager Walter
Published: December 2023

Background

Cytochrome P450 (CYP450) derived epoxides are vasoactive lipid mediators that may confer neuroprotective and anti‐inflammatory effects. CYP450 epoxides are degraded by soluble epoxide hydrolase (sEH) into diols. This study investigated relationships of these CYP450‐sEH “oxylipins” with regional small vessel disease (SVD) markers, atrophy, and white matter microstructural integrity in people with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.

Method

Participants with clinical AD or MCI were identified from the Ontario Neurodegenerative Disease Research Initiative. Fasting serum oxylipins were quantified using ultra‐high performance liquid chromatography‐tandem mass spectrometry. White matter hyperintensities (WMH), lacunes, perivascular spaces (PVS), and brain parenchymal fraction (BPF) were quantified using structural magnetic resonance imaging. Fractional anisotropy (FA) and mean diffusivity (MD) were measured using diffusion tensor imaging. Spearman correlations were performed between oxylipin species and imaging measures, controlling for demographic factors, ApoE4 status, glucose, cholesterol, systolic blood pressure, and waist circumference. Results were corrected for multiple comparisons using a 5% false discovery rate.

Result

In both the AD (n = 73) and MCI (n = 28) groups, fatty acid epoxide concentrations were generally associated with higher FA. Diol concentrations were generally associated with lower FA in AD, but with higher FA in MCI. Epoxide concentrations were associated with greater MD in AD but with less MD in MCI. There were multiple associations between diols and greater regional BPF in AD that were less pronounced and less widespread in the MCI group; however the trend was consistent between AD and MCI for the left middle inferior frontal region (greater diols, greater BPF). In AD, it is notable that the 14(15) arachidonic acid epoxide was associated with lower WMH volumes (Spearman’s ρ: ‐0.234 to ‐0.577); the 9(10) linoleic acid epoxide was associated with greater temporal lobe BPF (Spearman’s ρ: 0.204 to 0.499).

Conclusion

Differential correlations between plasma oxylipin concentrations and regional neuroimaging measures between AD and MCI suggest that the involvement of the CYP450‐sEH pathway may differ across stages of AD progression.
Optimizing Subjective Cognitive Concern Assessment to Predict Cognitive Decline in Motoric Cognitive Risk Syndrome: Results from the Einstein Aging Study
Authors: Nester Caroline O. , Gao Qi , Wang Cuiling , Emmeline Ayers , Katz Mindy J. , Derby Carol A. , Lipton Richard B. , Verghese Joe , Rabin Laura
Published: December 2023

Background

Motoric Cognitive Risk Syndrome (MCR) is a predementia condition that combines slow gait speed and subjective cognitive concerns (SCC), and predicts incident dementia in diverse global populations. MCR status is simple and inexpensive to ascertain, facilitating assessment in low resource settings. Though the slow gait component of MCR diagnosis is well operationalized, there is no standardized approach to SCC assessment. We hypothesized that in older adults with slow gait, the SCC questions that best predicted cognitive decline would most successfully operationalize SCC.

Method

Einstein Aging Study participants (n = 324; Mage = 70.4; Meducation= 15; 67%women; 46.3%White) completed the Cognitive Change Index Supplement (CCI‐40) as part of a comprehensive neuropsychological assessment (which included the Clinical Dementia Rating Scale [CDR]) at baseline and over up‐to‐5 annual follow‐ups (Mwave= 1.48). The CCI‐40 queries SCC across cognitive domains, including memory (21 items), language (4), executive functioning (5), attention/concentration (4), visuospatial functioning (2), calculation (1), mental clarity (2), and orientation (1). Slow gait was diagnosed based on established MCR criteria (1 SD below age/sex adjusted means). We used linear mixed effects models (LME) for continuous, and generalized LME for binary longitudinal cognitive outcomes, to examine how various definitions of SCC at baseline predict cognitive changes in older adults with slow gait, adjusting for covariates including age, sex, education, race/ethnicity, and depression. We report the interaction terms between SCC and time. The final sample included 43 participants (13%) who met slow gait criteria at baseline.

Result

Among participants with slow gait, the CCI‐40 total score was associated with decline on neuropsychological measures of attention/processing speed (β = ‐0.09, p = 0.05), verbal fluency (β = 0.03, p = 0.01), and a global dementia rating scale (β = 0.04, p = 0.02). Item‐by‐item analysis revealed a subset of items that were significantly associated with decline in key neuropsychological domains, including executive functioning, language, and memory.

Conclusion

Our findings suggest that attention to SCC assessment in older adults with slow gait may provide key insight into individuals at greatest risk for cognitive decline. SCC in MCR may be best operationalized through comprehensive assessment across broad cognitive domains. Future work will develop a brief SCC screen optimized to predict cognitive decline in this population.
Associations between brain TSPO and [18F]FDG‐PET signals in neurodegenerative disorders
Authors: Machado Luiza Santos , Vidor Pedro , Limberger Christian , de Carvalho Lavínia Perquim , Machado Leonardo , Carvalho Guilherme Da Silva , da Rocha Andreia Silva , Bellaver Bruna , Soares Carolina , Ferreira Pamela C.L. , Pascoal Tharick A. , Rosa‐Neto Pedro , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Zimmer Eduardo R.
Published: December 2023

Background

Recent evidence indicates that activated microglial cells contribute to the brain FDG‐PET signal changes in neurodegenerative disorders. Radiopharmaceuticals targeting the 18‐kDa translocator protein (TSPO) have been used to measure microglial activation. The combination of FDG‐PET and TSPO‐PET allows for assessing, in‐vivo and non‐invasively, whether they associate in brain regions vulnerable to neurodegeneration. So far, multiple studies have used FDG‐PET and TSPO‐PET concomitantly, but to our knowledge, no systematic evaluation has been conducted to assess whether they are associated. We aimed to systematically summarize the current data on brain TSPO‐PET and FDG‐PET signals in individuals with neurodegenerative disorders.

Method

Studies performing TSPO‐ and FDG‐PET in neurodegenerative disorders were searched in PubMed and Web of Science. Included articles must have performed PET images concomitantly with both tracers in healthy controls and individuals presenting with neurodegenerative disorders. This review complied with PRISMA (2020) guidelines and was registered at PROSPERO (CRD42022354523).

Result

A total of 272 articles were found after a search on PubMed and Web of Science, with eight meeting the inclusion criteria. We included clinical studies with individuals presenting Alzheimer’s Disease (AD), Parkinson’s Disease (PD), corticobasal syndrome and progressive supranuclear palsy, behavioral variant frontotemporal dementia, and progressive nonfluent aphasia. In AD, five studies presented negative associations, and one presented a positive association between TSPO and FDG signals in brain regions vulnerable to AD. In PD (3 studies) and the other related neurodegenerative disorders (2 studies) evaluated, we found a negative correlation between FDG‐PET and TSPO‐PET signals in vulnerable regions.

Conclusion

All studies presented associations between FDG‐ and TSPO‐PET signals. These findings suggest that microglia, indexed by TSPO binding, negatively impacts brain glucose metabolism indexed by FDG‐PET. Further studies are needed to address associations between TSPO‐PET and FDG‐PET in the asymptomatic and early stages of neurodegenerative disorders.
Adults with Down syndrome show quantitative sleep electroencephalogram patterns similar to those observed in patients with Alzheimer’s disease
Authors: Giménez Sandra , Clos Susana , Serna Leidy Y. , Carmona‐Iragui Maria , Benejam Bessy , Rojas Monica , Bejanin Alexandre , Arranz Javier , Videla Laura , Barroeta Isabel , Aranha Mateus Rozalem , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Mañanas Miguel Angel , Lleo Alberto , Romero Sergio , Fortea Juan
Published: December 2023

Background

Down syndrome (DS) is a genetic form of Alzheimer’s disease (AD) with a preclinical AD biomarker changes similar to euploid forms of AD. In sporadic AD, sleep electroencephalogram (EEG) changes have been related to cognitive decline and AD progression. However, whether DS follows a similar pattern of sleep EEG changes has not been investigated. Here, we aimed to quantify sleep EEG pattern in adults DS using spectral analysis and entropy changes.

Method

Cross‐sectional study, 67 adults with DS (41.1±11.4 yo) without signs of AD cognitive decline, and 24 euploid adults (58.3±12.4 yo) performed a polysomnography with extended 19 channels EEG setup. For data analysis, EEG was segmented into 5s epochs and preprocessed by an automatic artifact rejection procedure based on amplitude and kurtosis. Power spectra at the common EEG bands were calculated separately for wake, for NREMS: N1, N2, N3 stages, N2 stage, slow wave sleep (SWS:N3 stage) and REM stage. Sample entropy was also calculated for each epoch. Differences in EEG power across sleep stages between groups were calculated and represented by statistical percentage differences in one channel (Fz‐derivation) and by statistical topographic maps in all 19 EEG channels. For the dynamic of the EEG spectrum, the average of delta and entropy activity was calculated in Fz for each NREM cycle, and for sigma activity in NREM‐REM cycles.

Result

As compared to the control group, subjects with DS presented overall and significant increments in the delta and theta band for all sleep stages, and across sleep cycles(p<0.01). Topographic maps showed also a generalized increase in the beta band (13‐35Hz) compared to controls, mainly for N2 and N3 stages. A general decrease in the sample entropy (p<0.01) was also observed for all the sleep stages, implying that Down subjects have more regular and deterministic EEG rhythms.

Conclusion

Subjects with DS present a high activity in the low frequency bands, detected in all EEG channels and all sleep and wake stages. These results follow the same tendency observed in the sleep EEG changes in preclinical AD, which evidence the suitability of adults with DS to study sleep EEG changes as possible AD biomarker.
Regulation of meningeal lymphatic function by APOE
Authors: DELIVANOGLOU NIKOLETA , Todd Kennedi , Barber Megan J , Neves Sofia Pereira , Schrader Racquelle , Sanchez Guadalupe , Rego Shanon , Martens Yuka A , Bu Guojun , Fryer John D. , Mesquita Sandro Gabriel (Sandro Da Mesquita) Ferreira Da
Published: December 2023

Background

The meningeal layers form a unique interface between the central nervous and peripheral immune systems. The lymphatic vasculature that is present in the meningeal dura and drains cerebrospinal fluid (CSF) becomes dysregulated during aging and in models of neurodegenerative disorders such as Alzheimer’s disease (AD). Apolipoprotein E (APOE), and the isoform APOE4 in particular, increases the risk for late‐onset sporadic AD. However, it is still poorly understood whether changes in meningeal lymphatic morphology and drainage are mediating the deleterious effects of APOE4 expression. In the present study, we investigate the effects of human APOE3 or APOE4 on meningeal lymphatic function and immunity.

Method

We evaluated the morphology of lymphatic vessels in dural whole mounts of age‐matched wild type, Apoe‐KO, APOE3, and APOE4 mice at 2‐3, and 11‐12 months. This assessment was performed in both male and female mice. The drainage function of meningeal lymphatics is being assessed in the same mice by in vivo imaging of CSF‐derived fluorescent tracers into the deep cervical lymph nodes. We have also performed RNAscope and protein measurements using murine meningeal tissue to investigate the main cellular source(s) of Apoe, and single‐cell RNA sequencing to explore the cell‐specific transcriptomic signatures linked to the changes in meningeal lymphatic function.

Result

Lymphatic vessel length is increased in 11‐12‐month‐old APOE4 male mice, when compared to their APOE3 counterparts. Interestingly, the same was not detected in female mice. Dural myeloid cells, expressing Itgam (encoding for CD11b), are the main source of Apoe mRNA transcripts, and one of the main sources of apoE protein in the brain dura mater. APOE4 expression and age markedly alter the transcriptional profile of meningeal myeloid cells, which show overexpression of lysosomal, antigen presentation, and complement genes.

Conclusion

APOE4 expression leads to a sex‐dependent meningeal lymphatic vascular remodeling, which is associated with an exacerbated activation of meningeal macrophages. In future studies, we will test whether the changes in meningeal lymphatics observed in mice expressing APOE4 are mediated by myeloid cell derived APOE.
Visualizing Braak stages with deformation‐based morphometry in super‐sampled MRI
Authors: Shafiee Neda , Fonov Vladimir S , Collins D Louis
Published: December 2023

Background

Unlike MRI data, histological data collected post‐mortem can’t be used to study the longitudinal formation of neurofibrillary tangles (NFT) and corresponding brain changes over time for individuals. Although structural MRI offers the possibility of non‐invasive longitudinal antemortem imaging, its resolution is a limiting factor. Using image processing and super‐sampling techniques, we examined the possibility of employing structural MRI to observe the NFT footprints in the brain.

Method

Data included baseline MRI scans of 1473 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset including ADNI1, 2, and GO. Voxel size was super‐sampled to 0.5×0.5×0.5mm (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased symmetric MRI template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. For each subject, the sex‐ and age‐corrected z‐scored Jacobian maps were then calculated and averaged for each diagnostic group: normal subjects(CN), early MCI, late MCI, and AD. The average map for CN group was subtracted from the other average maps to show the AD‐stage differences.

Result

The Braak tau staging pattern (Braak & Braak, 1995) is seen in average Jacobian maps as the disease progresses. Subjects in the MCI groups showed on average more pronounced neurodegeneration in the transentorhinal and entorhinal region (Braak Stages 1‐2), followed by degeneration in the hippocampus (Stages 3‐4). Later on, this neurodegeneration progresses toward the neocortex (Stages 5‐6). Figure 1 illustrates these results: A) the template, B)EMCI vs CN, C) LMCI vs EMCI, D) LMCI vs CN, E) AD vs CN. Red color shows an increase and blue indicates a decrease in local volume.

Conclusion

Using novel image processing techniques, we were able to verify the staging of AD‐related neurofibrillary pathology progression in MRI data. This shows that structural MRI data, although limited in resolution, can still offer in‐depth insight into the brain antemortem which will in return allow the longitudinal and possible lifespan studies with an accuracy close to histological data.
Improving dementia prognostication in cognitively normal older adults: conventional versus novel approaches to modelling risk associated with neuropsychiatric symptoms
Authors: Ghahremani Maryam , Smith Eric E. , Ismail Zahinoor
Published: December 2023

Background

In persons with mild cognitive impairment (MCI) neuropsychiatric symptoms (NPS) are consistently associated with greater dementia incidence rates. However, in cognitively normal (NC) individuals, findings are inconsistent. Conventional approaches to NPS modeling are often cross‐sectional and silent on natural history of symptoms, introducing noise. Mild behavioral impairment (MBI) refines identification of risk by specifying that NPS must be later‐life emergent and persistent, increasing signal and reducing noise. Here, we explored associations of both MBI and conventionally‐measured NPS with incident dementia in persons with NC and subjective cognitive decline (SCD). We hypothesized greater dementia incidence in MBI, compared to NPS not meeting MBI criteria (NPS‐not‐MBI) and no NPS.

Method

National Alzheimer’s Coordinating Center (NACC) participant data were analyzed. MBI was operationalized as no history of psychiatric disorders (to satisfy the symptom emergence criterion) and NPS present at more than two‐thirds of pre‐dementia study visits (to satisfy the symptom persistence criterion). Kaplan‐Meier dementia‐free survival curves were generated for all three NPS groups. Cox proportional hazard models compared dementia incidence rates across groups, adjusted for age, sex, education, race, and APOE‐e4 status.

Results

The NC sample comprised 1,408 MBI (age = 75.2±9.5; 54.3% female), 5621 NPS‐not‐MBI (age = 71.6±8.8; 65.5% female), and 5078 no‐NPS participants (age = 71.2±8.9; 67.6% female). Persons with MBI had lower dementia‐free survival (p<0.0001, Table 1) and a 3.17‐fold greater dementia incidence rate compared to no‐NPS (CI:2.62‐3.84, p<0.001, Figure 1); no significant differences were found for NPS‐not‐MBI (HR = 1.07, CI:0.91‐1.27, p = 0.420). Similarly, in the SCD subsample (n = 3,555), persons with MBI had a 1.99‐fold greater dementia incidence rate versus no‐NPS (CI:1.46‐2.70, p<0.001); NPS‐not‐MBI did not differ (HR = 0.89, CI:0.68‐1.16, p = 0.375).

Conclusions

In both NC and SCD, persons with MBI had greater incidence of dementia than no‐NPS, while NPS‐not‐MBI did not. Operationalizing NPS‐related risk in accordance with the MBI criteria of later‐life emergent and persistent symptoms improves the prognostic utility of NPS over conventional approaches. This method of MBI operationalization can be applied to legacy datasets and ongoing cohort studies to identify a high‐risk group. This group can be assessed for neurodegenerative disease biomarkers in advance of the objective cognitive decline that is usually used to identify risk.
Advanced measures of cortical microstructural change and associations with cognitive and blood‐based biomarkers in autosomal dominant Alzheimer’s disease
Authors: Veale Thomas , Malone Ian B , Abel Emily , Ocal Dilek , Ferguson Damien , O'Connor Antoinette , Zhang Hui , Fox Nick C , Cash David M , Weston Philip SJ
Published: December 2023

Background

In Alzheimer’s disease (AD), dysfunction and loss of cortical neurons occurs prior to symptom onset. Diffusion tensor imaging, measuring mean diffusivity (MD), provides a metric of microscopic change but lacks specificity for different underlying microstructural processes. We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate specific cortical microstructural features across the disease course in autosomal dominant AD (ADAD).

Method

Sixty‐three ADAD family members (36 mutation carriers) (Table 1) underwent T1w and multi‐shell diffusion MRI (dMRI). Cortical thickness and cortical MD were estimated, with NODDI providing measures of tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) (a proxy measure of dendritic complexity). Imaging metrics were sampled across six cortical regions of interest (ROIs) known to be particularly vulnerable to early neurodegeneration. Associations between dMRI measures and 1) disease stage as measured by estimated years to onset (EYO), 2) AD blood biomarkers, and 3) cognitive measures were assessed.

Result

Across mutation carriers, ODI (Figure 1) and TF (Figure 2) demonstrated negative associations (p<0.05) with EYO in most ROIs, while MD demonstrated positive correlations. Most associations remained after adjusting for cortical thickness. The association between ODI and EYO in the supramarginal gyrus also remained after adjustment for MD (p = 0.002). In presymptomatic carriers, EYO appeared most prominently associated with ODI (p<0.05 in 3/6 regions). ODI, TF and MD showed widespread associations with MMSE and CDR sum of boxes. TF was negatively, and MD positively, associated with serum NfL across ROIs, but for ODI this was only the case in the supramarginal gyrus. ptau181 demonstrated significant associations with ODI in the supramarginal (p = 0.0089) and inferior parietal (p = 0.033) cortices, and with MD in the entorhinal cortex (p = 0.015).

Conclusion

Cortical dendritic complexity (modelled by ODI) and cortical tissue fraction decrease, while overall diffusivity increases as individuals approach symptom onset. ODI appears to be the metric most closely associated with presymptomatic disease stage, possibly reflecting early dendritic pruning, and is associated with ptau – a measure of early pathology – while MD and TF may be more sensitive to later larger scale changes, given their associations with serum NfL and cognitive measures.
Easing the burden: AD trials sharing data and samples through a national repository
Authors: Foroud Tatiana M.
Published: December 2023

The availability of biological samples accompanied by detailed clinical data have been essential to support research to understand the biology and underpinnings of Alzheimer’s disease and related dementias (ADRD). These samples have been fundamental to the identification of ADRD genetic risk factors, the pathways implicated in ADRD pathology, and the development of biomarkers of ADRD onset and progression. The broad sharing of samples as well as the data generated from these samples has accelerated the rate of discovery and in turn the development of effective therapeutics. Importantly, to share samples with researchers outside the study, participants must be appropriately consented.

Samples and data collected as part of clinical trials are important resources for further research discovery. However, trial participants are often not consented to allow their samples to be utilized for broader research goals. As a result, the samples from these well characterized research participants are not available to support additional, often collaborative, research.

NIA has developed infrastructure, including the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), to make the banking, sharing and distribution of samples easier. Uniform protocols and standard sample handling procedures has made it seamless to utilize samples collected across different studies. NIA has also developed infrastructure including the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the National Alzheimer’s Coordinating Center (NACC) and other data repositories to make the data generated from biological samples available to the research community.

During this presentation, we will discuss the importance of sample and data sharing and the advantages that can be gained from the ability to work across studies and trials. In addition, we will discuss challenges and important considerations when planning for future sharing with the research community.
One Form of tDCS Does Not Fit All: The intersectionality of severity level and expected tDCS benefit
Authors: Roncero Carlos Tyler , Chertkow Howard
Published: December 2023

Background

We investigated if a mixed group of people living with dementia (Alzheimer’s Disease (n = 16) or Frontotemporal dementia (n = 8)) would have faster response times on an N‐Back task (1‐back), a measure of working memory, after practicing the task with 20 minutes of tDCS, versus an analogous placebo condition. Crucially, half of these participants were slower than normal on the task at baseline, while the other half has normal response times. Our primary outcome measure was improvement on the MMSE task.

Method

Each participant practiced the n‐back in three separate nine‐session rounds, two months apart, with a different form of stimulation in each round: (1) 4mA unilateral stimulation, with one anode electrode over the left dorsolateral prefrontal cortex area and a cathode electrode over the occipital lobe area; (2) 4mA bilateral stimulation, using the same configuration, but with an extra active anode electrode over the right dorsolateral prefrontal cortex, and (3) SHAM stimulation.

Result

We found the condition x time x severity variable was significant (F (12, 264) = 2.17, p < .05), which suggests the results founds were dependent both of the tDCS montage received and the initial severity level of the participants. More specifically, as supported by post‐hoc tests, participants initially impaired on the N‐Back task improved on the MMSE when they received the bilateral tDCS montage, but those participants with normal response times improved on the MMSE when they received the unilateral tDCS montage.

Conclusion

Consistent with past studies, results suggest tDCS can be used to improve cognition in people living with dementia. Optimization, however, may depend both on the montage applied and the indiosyncratic nature of the participant. A bilateral montage, for example, that theoretically impacts a wider range of brain areas, may be superior to a unilateral one when people with dementia exhibit a greater degree of impairment.
Toxoplasma gondii‐induced amyloid reduction and neuroimmune responses in Alzheimer’s disease
Authors: Yanes Katherine Olivia , Tomasello Julia , Guanzon Nathaniel , Azevedo Ricardo , Wheeler Damian G. , Gandhi Sunil , Lodoen Melissa
Published: December 2023

Background

Toxoplasma gondii is a foodborne parasite that induces monocyte recruitment and microglial activation during infection of the brain. Similarly, in Alzheimer’s disease (AD), activated immune cells are often found in the brain and these localize near amyloid beta plaques. However, after infection with T. gondii in AD mouse models, there are fewer amyloid beta plaques in the brain, increased microglial activation, and decreased severity of AD symptoms. We hypothesize that T. gondii infection activates and enhances the phagocytic ability of microglia to clear amyloid beta.

Method

Female 5xFAD mice were infected with T. gondii or PBS treated, and their brains harvested after 6 weeks of infection. Brain tissue from these animals was analyzed for amyloid (Amyloglo) and immune cell markers for microglia, monocytes, and T cells (IBA1, CD68, CD11c, CD11b, CD45, CD3) by light sheet imaging, confocal microscopy, or flow cytometry. Mice were also fitted with headplates and cranial windows and injected with methoxy‐X04 (10 mg/kg) to enable longitudinal imaging of amyloid over the span of infection.

Result

Confocal microscopy of brain sections and light sheet imaging of intact brains from infected and uninfected 5xFAD mice have shown increased microglial activation markers (IBA1 and CD68) and decreased amyloid surface area and volume throughout infected brains in infected animals. Infected mouse brains also have increased co‐localization of amyloid and CD68 compared to uninfected mouse brains. Two‐photon imaging reveals that amyloid plaque area in vivo no longer increases in infected mouse brains as early as three weeks post‐infection and lasts as long as thirteen weeks post‐infection. Additionally, after six weeks of infection, we see an increase in Disease Associate Microglia (DAM) by flow cytometry, as well as an influx of other immune cells in the brain of infected mice as compared to PBS treated control mice.

Conclusion

Our data show that infection with T. gondii increases microglial markers associated with the DAM profile and these cells likely increase phagocytosis of amyloid beta. Infection with T. gondii appears to modulate the neuroimmune environment, including responding microglial cells, resulting in a neuroprotective phenotype.