bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulated bioenergetics pathways in the Alzheimer’s mouse brain
Authors: Raju Raghavan Pillai , CAi Lun P , Tyagi Alpna , Pugazhenthi Subbiah
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common cause of dementia in the aging population. The pathological characteristics include extracellular senile plaques and intracellular neurofibrillary tangles. In addition, mitochondrial dysfunction, oxidative stress, and neuroinflammation contribute to AD pathogenesis.

Method

RNA‐seq analysis was done to compare the transcriptome in the brain of 5XFAD mice to the WT brain.

Result

There was significant changes in the expression of genes related to pathways such as, oxidation‐reduction, oxidative phosphorylation, innate immune response, ribosomal protein synthesis, and ubiquitin proteosome system. The most striking feature was the alteration of the oxidation‐reduction process with changes in the expression of a large number of mitochondrial genes. We also observed an upregulation of several immune response genes. Gene interaction network of oxidation‐reduction related genes further confirmed a tight “Gordian knot” of mitochondrial genes. Furthermore, gene interaction analysis of all the 1288 genes showed at least three distinct interaction clusters, with the predominant one relating to cellular energetics

Conclusion

We identified 1288 genes distinctly different in the 5XFAD brain compared to the WT brain and found cellular energetics to be the most distinct gene cluster in the AD mouse brain compared to the WT.
Predictive biomarkers for cognitive decline in patients with idiopathic REM sleep behavior disorder
Authors: Wang Ruihan , Cai Hanlin , Gao Hui , Qin Linyuan , Yang Feng , Chen Qin
Published: December 2023

Background

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is regarded as an early stage of the synucleinopathy, which may precede the onset of cognitive impairment or parkinsonism. Biomarkers for cognitive decline in patients with iRBD would be helpful to early intervention. Our aim was to identify biomarkers for predicting the cognitive deterioration risk in patients with iRBD.

Method

We involved patients with polysomnographically confirmed iRBD who has at least 2 visits from the Parkinson’s Progression Markers Initiative (PPMI) database. Progression of cognitive state to MCI or dementia during follow‐up was defined as the endpoint. Baseline clinical features, biofluid and genetic biomarkers were compared between iRBD with or without progression of cognitive decline. Predictive biomarkers were identified with Kaplan‐Meier and Cox proportional hazards analysis, adjusting for age, sex, and years of education.

Result

A total of 38 patients with iRBD were enrolled (average age: 69.53 ± 5.54, male: 84.21%) . During follow‐up (median 5.45, IQR 4.08‐7.1 years), Progression of cognitive decline occurred in 57.89% (22/38) patients with iRBD. Baseline clinical features including hallucinations and psychosis (HR = 13.783, p = 0.022) and higher confidence abnormalities consistent with a neurodegenerative parkinsonian syndrome (HR = 2.258, p = 0.017) increased the risk. Patients with a lower loge‐transformed the ratio of Aβ 1‐42 in cerebrospinal fluid (CSF) to ΝfL in serum (Aβ/NfL, HR = 0.375, p = 0.044) and t‐tau in CSF to ΝfL in serum (t‐tau/NfL, HR = 0.277, p = 0.044) had a higher risk of cognitive decline. Genetic biomarkers consisting of GBA rs75548401(HR = 13.783, p = 0.022), STK39 rs1955337 (HR = 11.882, p<0.001), and COMT rs4680 (HR = 2.376, p = 0.021) variants increased the risk, while MCCC1 rs12637471 (HR = 0.408, p = 0.024), COMT rs165656 (HR = 0.451, p = 0.033), COMT rs4633 (HR = 0.421, p = 0.021), and COMT rs165599 (HR = 0.427, p = 0.023) variants decreased the risk. A model combining age and variables with p<0.05 exhibited above presented the best predictive performance, with an AUC of 0.963 (95% CI 0.896–1.000, p<0.001).

Conclusion

Our findings provide potential biomarkers to evaluate the risk of progression to MCI or dementia in patients with iRBD. Combination of clinical features, biofluid and genetic biomarkers performs optimal predicting accuracy.
Isoform‐ and cellular metabolism‐specific apolipoprotein E (ApoE) lipidation in astrocytes
Authors: Lindner Karina
Published: December 2023

Background

Apolipoprotein E (ApoE) is the major lipoprotein in the brain and connects the metabolic interactions between astrocytes and neurons. The E4 variant (APOE4) affects this function and represents a genetic predisposition for Alzheimer’s disease (AD), but the molecular mechanisms remain unclear.

Method

We have integrated cell‐free in vitro assays, a new cell system based on isogenic iPSC‐derived astrocytes and lipidomics to study ApoE lipidation, and how this is affected by genetic polymorphism.

Result

We show that ApoE produces different types of lipoprotein particles via distinct lipidation pathways. ApoE forms high‐density lipoprotein (HDL)‐like, cholesterol‐rich particles via the ATP‐binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress‐associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol‐rich lipoprotein particles, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10‐20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. Fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion.

Conclusion

The molecular mechanisms discussed here provide a new model explaining the interaction between genetic polymorphism and environmental factors, such as dyslipidaemia or aging, in the aetiology of late‐onset AD, as well as inspire possible new strategies for therapeutic intervention.

Graphical abstract from https://doi.org/10.1016/j.celrep.2022.110435.
Targeted proteomic profiling in cerebrospinal fluid and plasma identifies biomarkers for Alzheimer’s disease
Authors: Ye Yuanqing , Saxena Satya , Michael Nagle , Stomrud Erik , Janelidze Shorena , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Devanarayan Viswanath , Sachdev Pallavi , Hansson Oskar
Published: December 2023

Background

In the ATN (Amyloid b, Tau, Neurodegeneration) biomarker research framework proposed for Alzheimer’s Disease (AD), a critical need is the identification of robust markers of neurodegeneration (“N”) for more accurate disease state diagnosis and prognosis. Targeted proteomic profiling can be highly valuable for identifying such markers.

Method

We reanalyzed Olink™ data from 270 CSF and plasma samples from the Swedish BioFINDER study (Whelan et al. 2019) using additional normalization and adjustments to reduce technical variation and inter‐subject heterogeneity. These include 1) plate‐level quantile normalization, 2) adjustment for age, gender, BMI, and anti‐inflammatory drugs, and 3) first principal component as a covariate to account for heterogeneity in control subjects from different cohorts. Our analysis cohort included 140 Aβ+ cognitively normal (ApCN), 65 Aβ+ mild cognitive impairment (ApMCI), and 138 Aβ + AD (ApAD) subjects. Proteins with false discovery rate < 5% and Cohen’s D ≥ 0.5 were considered statistically significant. Multiscale Embedded Gene Co‐expression Network Analysis (MEGENA) was used to identify co‐expressing network modules and hub proteins.

Result

Our analysis identified significant alterations of 65 CSF and 94 plasma proteins comparing different pairs of ApAD, ApMCI and ApCN groups. AUC ranged from 61% to 86% for differentiating ApAD vs ApCN. MMP‐10 was found to be significantly altered in all CSF comparisons, but not in plasma. We identified many significantly altered proteins not reported by Whelan et al (2019), including TFF3, EFNA4, and CTSC that are known to be associated with neurodegeneration or neuroinflammation. MEGENA analysis identified 10 network modules for CSF and 17 network modules for plasma. The most significant CSF modules were represented by IGFB‐2 and PLC hub proteins and enriched for positive regulation of cellular function. The most significant plasma modules were represented by SIRT2 and LAT and enriched for cellular response to stimulus.

Conclusion

Targeted proteomic profiling of matching CSF and plasma samples along with co‐expression network analysis can yield additional markers in the ATN framework for early detection and screening for AD.
Odor Identification Moderates Relationship Between Cognitive Training and Cognitive Decline
Authors: Deehan Emily G. , Phillips Julia , Qian Min , Doraiswamy P. Murali , Goldberg Terry E. , Devanand D. P.
Published: December 2023

Background

Olfactory deficits have been shown to predict cognitive decline. Recent findings suggest that computerized cognitive training may reduce the risk of cognitive decline and dementia. However, the impact of olfaction deficits on cognitive training outcomes is unclear. In this study, we investigate how lower odor identification may moderate the relationship between treatment assignment (cognitive games versus crossword puzzles) and cognitive outcomes in older adults diagnosed with mild cognitive impairment (MCI).

Method

Data were drawn from the Cognitive Training and Neuroplasticity in Mild Cognitive Impairment (COG‐IT) Trial (NCT03205709). In this two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, Computerized Cognitive Training (CCT) or computerized Crossword Puzzle Training (CPT), followed by six booster sessions. 106 patients received neuropsychological and olfactory assessments through the 11‐item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS‐Cog) and the 40‐item University of Pennsylvania Smell Identification Test (UPSIT). In linear mixed‐model analyses, the effect of baseline UPSIT score on change in the ADAS‐Cog score from baseline over 78 weeks by treatment group, adjusted for age and baseline ADAS‐Cog, was assessed.

Result

Among 106 older adults (n = 50 [games]; n = 56 [crosswords]), higher baseline UPSIT scores predicted improved ADAS‐Cog performance at week 78 for all patients randomized to CPT (beta coefficient, 0.15, 95% confidence interval [CI], 0.02 to 0.27; P = 0.02). Greater baseline UPSIT score predicted improved ADAS‐Cog performance at weeks 12, 52, and 78 for early MCI patients randomized to CPT (Week 12: beta coef. 0.26, 95% CI 0.09 to 0.43; Week 52: beta coef. 0.23, 95% CI 0.05 to 0.40; Week 78: beta coef. 0.22, 95% CI 0.05 to 0.39). This was not shown in early MCI patients randomized to CCT. Higher baseline UPSIT predicted significant improvement in ADAS‐Cog for late MCI patients randomized to CCT at week 78 (beta coefficient, 0.24, 95% CI 0.05 to 0.42; P = 0.01).

Conclusion

Our results are consistent with literature, suggesting that impaired olfaction moderates memory decline. Our preliminary results show that individuals with less impaired olfaction may experience greater cognitive improvement following cognitive training.
Relationship between plasma cortisol with the neuropathology of patients across the Alzheimer’s disease continuum
Authors: Souza Laura Willers , Bieger Andrei , Borelli Wyllians Vendramini , Antônio De Bastiani Marco , Bauer‐Negrini Guilherme , DuBois Jonathan M. , Zimmer Eduardo R. , Lab Zimmer Neuroimaging
Published: December 2023

Background

The relationship between high cortisol levels and brain atrophy in patients across the Alzheimer’s disease (AD) continuum has been relatively unexplored. Thus, this study sought to investigate the association between plasma cortisol levels and brain cortical thickness in patients across the biological and clinical continuum of AD.

Method

Participants with baseline plasma cortisol concentrations (n = 544), structural MRI, and CSF Aβ1‐42 and CSF p‐tau181 were selected from the ADNI database. Three general linear models (GLMs) were constructed to assess the association between cortical thickness and cortisol levels (Freesurfer’s v7.1.1): (1) cortisol as an independent variable; (2) cortisol, cognitive status, and interaction; (3) cortisol, neuropathology (measured by Aβ1‐42 and p‐tau181 positivity), and interaction. These analyses were corrected for multiple comparisons through cluster formation (p<0.01) and permutation (Monte Carlo simulation of 10,000 iterations).

Result

Demographics are depicted in Table 1. The cortical thickness showed a negative correlation with plasma cortisol concentrations in the following clusters (first GLM; Figure 1 and 2): left hemisphere – superior parietal (pcc = ‐0.13; p = 0.0002); superior frontal (pcc = ‐0.13; p = 0.0004); superior parietal (pcc = ‐0.13; p = 0.013); precentral (pcc = ‐0.12; p = 0.02); isthmus cingulate (pcc = ‐0.13; p = 0.02); caudal middle frontal (pcc = ‐0.11; p = 0.031); fusiform (pcc = ‐0.12; p = 0.046); right hemisphere – inferior parietal (pcc = ‐0.13; p = 0.0004); precuneus (pcc = ‐0.12; p = 0.0014); superior frontal (pcc = ‐0.12; p = 0.003); parahippocampal (pcc = ‐0.12; p = 0.003); superior parietal (pcc = ‐0.12; p = 0.041). Interestingly, no interactions between cortisol and AD cognitive status and neuropathology were identified (second and third GLMs – data not shown).

Conclusion

This cross‐sectional study identified a negative correlation between plasma cortisol concentrations and cortical thickness in brain regions typically affected by AD, which was found to be independent of AD diagnosis and neuropathology. This finding suggests that high peripheral cortisol levels may create a vulnerability that is independent of AD neuropathology in regions commonly affected by the disease, which may accelerate disease progression.
Mass spectrometry identifies tau C‐terminal phosphorylation signature of neuronal hyperexcitation
Authors: Schneeweis Amanda , Lama Tsering , Ma Junfeng , Pak Daniel T.S.
Published: December 2023

Background

Tau pathology has been reported to be exacerbated during hyperexcitation, a characteristic of AD.

Method

Primary hippocampal cultures (DIV20) were treated with 100µM picrotoxin for 24hrs. Tau was isolated from cultures using immunoprecipitation. Unbiased mass spectrometry was performed to identify specific tau sites phosphorylated during hyperexcitation. Subsequently, we transfected primary hippocampal neurons with these identified tau sites mutated to phosphor‐mimetic or phosphor‐null sites. We used fluorescent microscopy to identify any changes associated with tau localization, neuronal morphology, and spine morphology.

Results

Sites S409, S412, S413, T414, S416, S422, and T427 are uniquely phosphorylated during hyperexcitation. When all identified sites contain the phosphonull mutation, PSD‐95 intensity is significantly higher compared to control levels, and the mutated tau levels are significantly higher in dendrites compared to control levels.

Conclusion

There are unique sites of tau phosphorylated during hyperexcitation. These sites regulate PSD95 levels and tau localization.
Validation of a Video Adaptation of the UDSv3 Cognitive Battery (VCog): Study Design and Preliminary Participant Satisfaction Results
Authors: Sachs Bonnie C. , Latham Lauren , Craft Suzanne , Barnes Lisa L. , Clark Lindsay R. , Dodge Hiroko H , Duff Kevin , Farias Sarah Tomaszewski , Fischer Eric , Gaussoin Sarah A. , Goldstein Felicia C , Hampstead Benjamin M. , Jayadev Suman , Jicha Gregory A , Kaye Jeffrey A , Kukull Walter A. , O'Connell Abigail H , Mechanic‐Hamilton Dawn , Neugroschl Judith A. , Papp Kathryn V. , Saykin Andrew J. , Sewell Margaret , Rapp Stephen R.
Published: December 2023

Background

The Uniform Data Set Neuropsychological Battery, Version 3 (UDSv3) was designed for face‐to‐face assessment of cognition within Alzheimer’s Disease Research Centers (ADRCs) in the USA. However, there are many reasons research participants may be unable to meet face‐to‐face for assessments. This inter‐ADRC, multi‐site study will validate a video‐administered adaptation of the UDSv3 battery in a diverse sample of ADRC participants. Here, we present study methods and summarize preliminary participant satisfaction ratings with VCog procedures.

Method

Remote video cognitive assessments (Vcog) are being administered 4‐8 weeks before or after annual in‐person UDSv3 cognitive assessments, in counterbalanced order, to 500 participants from 12 ADRCs. Participants were previously classified as having normal cognition (NC), MCI, and mild dementia. Participant ratings of satisfaction, acceptability, and preference for test modality are being obtained, and psychometric characteristics of the video battery relative to face‐to‐face administration evaluated. Concordance between adjudicated outcomes (NC, MCI, dementia) between modalities is also being examined.

Result

Of currently enrolled participants from four sites (N = 29 (NC = 14, MCI = 13 and dementia = 2); age: 72.9 (8.9) years; education: 16.2 (2.5) years; 62.1% female; 82.8% non‐Hispanic white), 85% report using video‐conferencing platforms more frequently because of COVID‐19 and 83% of that group anticipate continued use in the future. Participants reported (1 = very easy/likely to agree; 5 = very difficult/likely to disagree) that the testing was convenient (M = 1.14 (.44)), visits were very easy to initiate (M = 1.34 (.72)), technology was very easy to use (M = 1.00 (.00)), and task instructions were easily understood (M = 1.28 (.80)). Seventy‐six percent found video testing to be more convenient than in‐person testing and 24% found it equally convenient. Forty‐eight percent said they would choose video sessions in the future, 21% chose either video or in‐person, and 31% chose in person.

Conclusion

Video‐based remote neuropsychological assessments have the potential to greatly benefit research and reduce participant burden. Initial findings from this large validation study of the UDSv3 suggest that older adults of varying cognitive statuses find the video‐adapted UDSv3 cognitive battery to be convenient and easy to use. Additional available data regarding participant satisfaction data will be reviewed.
Microtubule‐associated protein tau (MAPT) in the lens of the eye in non‐transgenic and transgenic tau mutant (P301S) mice
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E
Published: December 2023

Background

We previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule‐Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model. Here we investigated whether tau protein was expressed in non‐transgenic mouse lenses and in a transgenic tau mutant (P301S) mouse model. We also studied whether cataracts may develop in this P301S tau mutant mouse model.

Method

P301S tau mutant transgenic and non‐transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice were sacrificed throughout their lifespan at ages 3‐12 months. Mice were perfused with phosphate buffer saline, lenses were isolated and then imaged under two different sources of light using a D70 digital Nikon camera and a custom‐adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western Blotting using tau antibodies.

Result

P301S transgenic and non‐transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non‐transgenic mice. No cataract phenotype was observed in transgenic or non‐transgenic mouse lenses.

Conclusion

There was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non‐transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.
Analytical Validation of Novel microRNA Panel for Risk Stratification of Cognitive Impairment
Authors: Kunwar Arzu , Ablordeppey Kenny K , Mireskandari Alidad , Sheinerman Kira S. , Kiefer Michael , Umansky Samuil R. , Kumar Gyanendra
Published: December 2023

Background

We have been developing a novel approach to identify risk of early cognitive impairment in patients by profiling of brain‐enriched and inflammation‐associated microRNA (miRNA) biomarkers, isolated from the plasma of cognitively normal and cognitively impaired patients. Here, we present the analytical validation of a miRNA panel, (CogniMIR®), for the expression of 24 miRNAs for large‐scale testing of plasma specimens in a clinical laboratory

Method

miRNA from plasma specimens was isolated using the MagMAX mirVana kit (ThermoFIsher). 24 synthetic miRNAs oligos (IDT) werecombined and diluted to create quantification markers for making standard curves. RT was performed using miRCURY LNA RT kit. qPCR for miRNA profiling was carried out using custom plates (Qiagen), pre‐plated with lyophilized miRCURY LNA‐based primers for 24 miRNAs of the (CogniMIR®) panel. qPCR was perfomred on a Quantstudio 7 Flex instrument.

Result

Synthetic RNA dilution series for 24 miRNAs (200,000 copies, 20000 copies, 2000 copies, 200 copies and 20 copies in a qPCR reaction) were tested on two different days. Average slope of the standard curves for all 24 miRNAs were determined to be in ‐3.3 to ‐3.7 range, and average R2 was 0.99 to 1. The data demonstrates that all 24 synthetic miRNAs of the (CogniMIR®) panel can be reliably and consistently detected even if the sample input is 20 copies in a qPCR reaction.

Intra‐run repeatability analysis, using plasma samples from four subjects was tested by two operators on two different days. The data demonstrated that both operators generated repeatable and consistent Cts in both replicates on both days as seen by R2 value of 0.94 to 0.99. The inter‐run data analysis, using the same four samples tested by two operators on two different days, showed that reproducible Ct data were obtained by both operators when the experiment was repeated on the next day as demonstrated by R2 value of 0.96 to 0.97.

Conclusion

These results indicate the utility of the (CogniMIR®) panel for miRNA profiling, and demonstrate that our miRNA detection technology is reliable, reproducible, and operationally friendly to test a large scale of specimens in any CAP/CLIA certified clinical laboratory.
Uncovering Novel Modifiers of Tau Aggregation and Pathology using a Proximity Proteomics Approach (BioID)
Authors: Lee Jannifer H , Morderer Dmytro , Khalil Bilal , Smith Courtney L , Wren Melissa C , Tsai Chih‐Wei , Liu Feilin , Croft Cara L , Carlomagno Yari , DeTure Michael , Dickson Dennis W. , Cook Casey N. , Golde Todd E , Petrucelli Leonard , Rossoll Wilfried
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs), comprised primarily of microtubule‐associated protein tau. NFTs are defining hallmarks of AD and its accumulation into pathological oligomers and fibrils has been associated with cognitive decline in AD and other tauopathies. Despite its pivotal role in the disease process, we still have a poor understanding of how their formation, toxicity, and spread across brain regions is regulated via tau‐associated proteins that regulate the oligomerization, pathological accumulation, and seeding of tau in affected cell types and vulnerable brain regions.

Method

We have established two proximity‐dependent biotin‐identification (BioID) models as novel approaches to identify the composition and proximal molecular environment of tau aggregates. Using an in vitro and ex vivo model approach coupled with mass spectrometry, we have identified proteins that were primarily associated with mutant tau aggregates vs. soluble wildtype tau and stratified them based on significance, molecular pathway and druggability. Immunoblotting and immunofluorescence were performed to assess the interaction of endogenous and overexpressed top candidates with tau, along with visualization with NFTs in the context of human AD pathology to assess their impact on tau‐aggregate formation and toxicity.

Result

To determine the physiological and aggregate specific interacting partners of tau, we are comparing wild type tau (TauWT) with mutant tau (Tau3xMUT) carrying three tauopathy‐associated mutations (A152T/P301L/S320F). The proteomic analysis from our combined proteomic datasets revealed that significantly changed proteins included candidates involved in RNA processing, as well as protein ubiquitination and proteasome degradation. We have begun validating proteins that are enriched in mutant tau in human tissue of AD, as well as primary tauopathies, that may be druggable targets for tauopathies.

Conclusion

This study provides novel insights into cellular pathways and molecular mechanisms of neurodegeneration, by identifying in the context of living neurons and brain tissue different functional classes of tau‐associated proteins with relevance for AD pathophysiology. These are expected to include proteins that may mediate the toxic effect of NFTs, facilitate the formation or degradation of pathological tau aggregates, and catalyze posttranslational modifications of tau oligomers and associated proteins.
Mapping cognitive trajectories in older adults with essential tremor
Authors: Dargie Samantha A. , Chapman Silvia , Nguyen Diep , Berry Diane S. , Ghanem Ali , Powell Allison , Rizer Sandra , Tsapanou Angeliki , Huey Edward D. , Louis Elan D. , Cosentino Stephanie
Published: December 2023

Background

Older adults with essential tremor (ET) are at increased risk for Alzheimer’s disease (AD) and related disorders. Examining cognitive trajectories within this population will enable better identification of individuals who evidence accelerated rates of change. Here we examine how variability in baseline cognitive performance affects trajectories of cognitive change within three subgroups of cognitively normal older adults: 1) those whose baseline neuropsychological scores were entirely within normal limits (WNL); 2) those with at least one low score considered to have unlikely clinical significance (UCS); and 3) those with at least one low score considered to have possible clinical significance (PCS).

Method

Older adults with ET completed comprehensive neuropsychological testing and clinical interviews, and 159 received a consensus diagnosis of cognitively normal. Participants were then subdivided into one of three categories defined above: WNL (N = 66, 75.38 ± 8.96 years of age), UCS (N = 54, 76.35 ± 10.25 years), and PCS (N = 37, 80.22 ± 9.00 years). Generalized estimating equations (GEE) were used to compare rates of change in global cognition, memory, executive function, attention, visuospatial, and language z‐scores over time across these groups. Participants were seen for two to four visits (24.98 ± 20.29 months). Models were adjusted for age, gender, and years of education.

Result

All three groups, WNL (β = ‐.005, p = .028), UCS (β = ‐.006, p = .011), and PCS (β = ‐.012, p = .002), evidenced decline in their memory performance over time, with the latter groups declining faster than the WNL group. Relative to the WNL and UCS groups, the PCS group also declined faster over time in overall cognition (β = ‐.010, p = .029) and in language (β = ‐.024, p = .035).

Conclusion

Heterogeneity in cognitive performance among cognitively normal older adults with ET predicts trajectories of cognitive decline longitudinally. Specifically, rates of decline were slowest in those with entirely normal test scores, and greatest in those whose scores were considered to have possible clinical significance. These preliminary results provide a starting point for further inquiry into the role of nuanced cognitive profiles in predicting rates of decline, impairment, and dementia in ET cases who may initially be labeled as “cognitively normal.”
Mitochondrial Mechanisms of Endothelial Cell Damage in Alzheimer’s Disease and Cerebral Amyloid Angiopathy
Authors: Parodi‐Rullan Rebecca M , Fossati Silvia
Published: December 2023

Background

Cerebrovascular endothelial cells (EC) are crucial regulators of cerebral homeostasis and function through the maintenance of the blood‐brain barrier (BBB). ECs damage and/or dysfunction may result in defects in brain clearance and perfusion, microhemorrhages, inflammation, and neurodegeneration. Damage to the ECs may result from cardiovascular risk factors (CVRF) such as high levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy). In Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), the presence of a CVRF may further exacerbate cerebrovascular function and neurodegeneration. EC do not rely highly on mitochondrial ATP production as they are glycolytic cells. Instead, EC mitochondria serve mostly as signaling organelles, which sense cellular damage and mediate downstream pathways such as inflammation. In this study, we aim to understand the mechanistic nature of endothelial mitochondrial dysfunction and its elicited pathways in Aβ‐ and mixed (Aβ+HHcy)‐mediated vascular pathologies. Understanding the mechanisms by which the mitochondria mediate EC inflammation, may pave the way to new roads for therapeutic advancements in the field.

Method

Human brain microvascular ECs were challenged with Aβ, Hcy, or the combination. Mitochondrial metabolic function, inflammatory cascades and signals, and EC barrier function were assessed.

Result

The presence of Aβ, but not Hcy, induced deficits in mitochondrial respiration and ATP production. In addition, there is evidence of mitochondrial fragmentation and the expression of fission proteins. Preliminary results further suggest a release of mitochondrial danger associated molecular patterns (mtDAMPs) that can promote an inflammatory cascade. The mitochondrial damage and subsequent inflammatory response are associated with an increase in EC barrier permeability and cytokine release, which is exacerbated in the presence of Hcy.

Conclusion

The EC dysfunction associated with Aβ is accompanied by severe deficits in mitochondrial metabolism and the release of mtDAMPS. The presence of Hcy exacerbates some of the detrimental effects of Aβ, particularly on mtDAMPS and BBB function, but Hcy does not appear to affect mitochondrial metabolic changes. Overall, our results reveal a novel role for mtDAMPs in vascular dysfunction in the presence of Aβ and/or Hcy.
The prevalence of young‐onset dementia in the Netherlands: a prospective study
Authors: Bodde Hanna E. , Kolman Guy , Bakker Christian , Peetoom Kirsten , van der Flier Wiesje M. , Raymond Koopmans , Verhey Frans R.J. , de Vugt Marjolein , Papma Janne M. ,   the PRECODE consortium
Published: December 2023

Background

Although dementia is often associated with old age, it also occurs below the age of 65. People with so called young‐onset dementia (YOD) have different needs compared to people with late‐onset dementia (LOD), however, most health care facilities are primarily directed at older patients. Accurate numbers of the prevalence of YOD are necessary to determine the required budget, set priorities by policy makers and ensure sufficient and appropriate health care.

Method

In this study we investigated the 1 year prevalence of YOD in two predefined catchment areas in the Netherlands: an urban and a rural area, together representative for the Dutch population. We recruited health care professionals working with individuals with YOD (case managers, neurologists, psychologists, psychiatrists and nursing home staff) and asked them to register each YOD patient they encountered. Cases were included if persons had a diagnosis of YOD before the age of 70 or displayed symptoms before the age of 65, and lived within the catchment area. The collection of minimal personal identifiers per patient resulted in a unique personal code, which was used to prevent double counting.

Result

Health care professionals registered 409 individuals with YOD within the urban area and 209 individuals within the rural area, which translates to respectively 41.5 and 36.6 per 100.000 population in the group aged 30 to 65 years. Alzheimer disease was the most common diagnosis (52,3% and 53,8%), followed by vascular dementia (26,3% and 11,2%) and frontotemporal dementia (7,3% and 8.6%). Other characteristics such as living situation, as well as cultural background will be analyzed.

Conclusion

Preliminary data point out that the prevalence of people with YOD in the Netherlands is between 36.6 and 41.5 per 100.000 population. This prospective case finding study also shed light on methodological issues in prevalence research. Advantages are a more accurate case finding. Disadvantages are higher costs and a great dependency on other health care professionals.
Altered cerebrovascular reactivity along functional networks in older adults with long COVID
Authors: Pommy Jessica , Cohen Alexander D , Patel Milan , Umfleet Laura Glass , Franczak Malgorzata , Brett Benjamin L , Obarski Shawn , Agarwal Mohit , Ristow Kelly , Swanson Sara J , Wang Yang
Published: December 2023

Background

Cerebrovascular reactivity (CVR), an indicator of neurovascular function associated with cognitive decline, relies on vascular and inflammatory processes, making it a potential mechanism of interest driving neurological changes in long COVID among older adults. Given the variability in symptoms associated with long COVID, distribution corrected z‐scores (DisCo‐Z), a subject‐specific abnormalities (SSA) approach more suited for heterogenous conditions, was employed to examine CVR and long COVID in older adults. Relationships between CVR, post‐COVID subjective cognitive decline (pcSCD), and cognitive function were examined.

Methods

15 older adults with long COVID (M age = 63.9, 6 males) and 24 healthy older adults (M age = 66.7, 6 males) performed a breath‐holding task while in the MR scanner to examine CVR. DisCo‐Z was used to examine the presence and size of extreme clusters of increased or decreased CVR (>100 voxels) within the 7 Yeo functional networks. Non‐parametric tests were used to examine group differences in presence and mean size of extreme clusters. Finally, relationships between: 1) extent of pcSCD and extreme cluster values in long COVID, and 2) cognitive testing scores and global “burden” (cluster size mean and sum) were examined.

Results

Groups did not differ significantly on gender (p = .323) or age (p = .324). Greater incidence of positive extreme clusters within Ventral Attention (p = .028) and Limbic (p = .049) networks were observed in long COVID (with minimal incidences of negative extreme clusters across networks). Group differences were observed for mean cluster size in the Ventral Attention network (p = .016), as well. Extent of pcSCD was positively correlated with DisCo‐Z values for the Ventral Attention network (p = .021) with a trending level of significance for the Limbic network (p = 0.053). Finally, within the full sample, global CVR burden was negatively correlated with memory test scores (p = 0.014).

Conclusions

Using the SSA approach, group differences in CVR were observed in older adults experiencing long COVID. In particular, differences were observed within functional networks thought to drive attention, executive function, and emotional control, which was correlated with pcSCD. Finally, global CVR burden was negatively correlated with memory. These findings, though preliminary, suggest CVR may represent a potential neurobiological mechanism driving pcSCD in older adults.
P301L‐Tau Expression Induces Skeletal Muscle Abnormalities in Mouse Model of Tauopathy
Authors: Alava Bryan , Esser Karyn , Abisambra Jose F. F
Published: December 2023

Background

Patients suffering from Alzheimer’s disease (AD) and related tauopathies often report signs of muscle weakness. The pathological accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD, yet it is unclear whether pathological tau impacts skeletal muscle. Proper muscle function is necessary for movement and consequently impacts quality of life in tauopathy patients, while concurrently contributing to the physiological maintenance of whole‐body endocrine and metabolic homeostasis. Skeletal muscle crosstalks with other organ systems; therefore, disruption of skeletal muscle health impacts whole‐body processes, such as the formation of pathological tau. The objective of this study was to determine the links between tauopathy and muscle function.

Method

I performed intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (N = 4 females, 7 males) or a control plasmid (empty or a yellow fluorescent protein construct) (N = 5 females, 6 males). At 3 months, I measured grip strength. I harvested the brain, soleus, and tibialis anterior (TA) muscles at 15 months, and measured muscle mechanics concurrently in the soleus and extensor digitorum longus (EDL) muscles. I biochemically detected soluble tau and visualized TA structure immunohistochemically.

Results

Grip strength was reduced at 3 months in the P301L tau‐expressing mice of both sexes. The intrinsic force production of the soleus, but not the EDL, was reduced in P301L tau‐expressing males at 15 months. At this same time point, soluble tau accumulated in the cortex but not the soleus. Aggregation of nuclei were found histologically in the TA of P301L tau expressing mice but not in controls.

Conclusion

Changes in grip strength preceded insoluble tau accumulation and cognitive decline typical of this model. Reductions in the soleus force production indicate that P301L tau overexpression in the brain impacts intrinsic muscle strength, and occurs independently of innervation. The nuclear clumps detected in the TA of P301L tau‐expressing mice suggest that AAV‐P301L‐tau injections in the brain promote an inflammatory response in muscle. Together these data suggest that pathological tau species that are expressed in the brain reach peripheral tissues and exert deleterious consequences such as skeletal muscle abnormalities.
Plasma Neurofilament Light and Markers of Sensorimotor Function in a Predominantly Hispanic Population of Older Adults in San Antonio, Texas
Authors: Kautz Tiffany F , Velarde Angel G. , Francis Lily , Bernal Rebecca , Goss Monica , LaRoche Ashley , Katragadda Haritha V. , Vasquez Erin Livia , Mathews Julia J , Muhammad Jazmyn A , Saklad Jared , Kivisäkk Pia , Singh Herpreet , Greenberg Steven M. , Alliey‐Rodriguez Ney , Maestre Gladys E. , Gonzales Mitzi M. , Jacob Mini E , Seshadri Sudha , Satizabal Claudia L.
Published: December 2023

Background

Sensorimotor and blood‐based biomarkers are promising dementia biomarkers with high accessibility and limited invasiveness. Although sensorimotor changes appear with aging, more severe changes may precede cognitive decline, dementia, and other neurological diseases. Additionally, blood‐based neurofilament light (NfL), a broad marker of neuroaxonal injury, is commonly elevated in many types of neurological disease. Prior studies have suggested that increased blood levels of NfL in conjunction with sensorimotor decline may allow for earlier neurological disease diagnosis and/or prediction of disease severity, but little is known about the correlation of these markers in the general population. We examined the association between NfL and sensorimotor markers in a predominantly Hispanic population in San Antonio, Texas.

Method

Our sample included older adults from our San Antonio MarkVCID and South Texas Alzheimer’s Disease Research Center (ADRC) cohorts (n = 152, mean age 71.2±7.63, 60.4% women, 79.5% Hispanic) with available plasma NfL, olfaction (B‐SIT age‐adjusted percentile), grip strength, and touch (monofilament) data (Table 1). NfL concentrations were log‐transformed to achieve a normal distribution. We used linear or logistic regression models, as appropriate, to assess the association between NfL and sensorimotor outcomes, adjusting for age, sex, race, ethnicity, and cognitive diagnosis.

Result

Higher plasma NfL was significantly associated with decreased olfaction score percentiles (Beta [95% Confidence Interval], β = ‐8.79; [95% CI ‐16.89; ‐0.12], p = 0.05), grip strength in either hand (left: β = ‐3.62; [95% CI ‐5.51; ‐1.74], p = 0.0002; right: β = ‐2.99; [95% CI ‐5.01; ‐1.03], p = 0.003), and impaired touch perception (Odds Ratio [95% CI], OR = 2.56; [95% CI 1.01; 6.48]; p = 0.05), independent of the potential confounders listed above.

Conclusion

These results highlight the association of plasma NfL with several markers of sensorimotor function, which may reflect central and peripheral neuroaxonal injury. Additional studies are needed in larger community samples to confirm these findings and explore the potential of NfL as a marker of functional decline in longitudinal studies. We plan to continue collecting these markers, as well as gait and balance, longitudinally to gain a better understanding of the link between neurodegeneration, sensorimotor markers, and neurological disease trajectory in our unique South Texas population.
Circadian genes in wake‐promoting neurons have a different pattern of expression in Alzheimer’s Disease, Progressive Supranuclear Palsy, and Healthy Controls
Authors: Pereira Felipe Luiz , Satpati Abhijit , Raju Anya , Soloviev Alexander , Mladinov Mihovil , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Ehrenberg Alexander J. , Neylan Thomas C. , Grinberg Lea T.
Published: December 2023

Background

Individuals with neurodegenerative disorders often experience sleep disturbances before showing any other symptoms. Our recent studies found a link between tau‐driven degeneration of wake‐promoting neurons (WPN) and sleep/wake dysfunction in Alzheimer’s disease (AD), which is a shift from the previously held beta‐amyloid centric models for sleep dysfunction. The circadian system regulates WPN, but little is known about the pattern of circadian dysregulation in WPN in AD and other tauopathies. Methodological limitation such as undefined borders and the small size of WPN nuclei makes it challenging to perform such studies. We performed gene expression analysis using the nCounter human neuropathology panel and circadian genes custom code set (Nanostring, USA) to map these changes and inform customized therapies.

Method

RNA was isolated from wake‐promoting areas: locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN) dissected from Formalin‐Fixed Paraffin‐Embedded (FFPE) postmortem brain tissue of 6 AD, 7 progressive supranuclear palsy (PSP), and 5 healthy controls (HC) cases with similar ages at death. RNA expression levels were determined using bead‐based hybridization technology and differential expression analysis was conducted using DESeq2 with Wald statistical test and adding sex as a confounding variable.

Result

We identified differentially expressed circadian genes in WPN across disease conditions vs. HC (Figure 1) and between AD and PSP. Clock/Npas2 genes only have differential expression in PSP (although in different directions in LHA vs. TMN). PER gene families had changes in AD and PSP, but only in LHA and TMN.

Conclusion

Expression of circadian genes is dysregulated in WPN in AD and PSP, but the pattern is considerably different, with some gene families showing opposite directions of regional expression even in the same disease (i.e Clock/Npas2 and Cry). Interestingly, circadian dysregulation in hypothalamic neurons is more significant than in LC, possibly reflecting direct connections between the suprachiasmatic nucleus, the circadian clock, and TMN and LHA. This study supports the utility of fixed‐tissue‐based RNA expression analysis to unveil the molecular basis of sleep dysfunction in neurodegenerative diseases, even considering the complex neuroanatomy of the sleep‐controlling regions. Validation of these findings using multiplex immunohistochemistry and clinicopathological correlations are ongoing.
CSF‐plasma albumin ratio differs by sex in community dwelling older adults
Authors: Yates Alexis , Zhang Panpan , Liu Dandan , Pechman Kimberly R. , Houston Michelle L , Davis L. Taylor , Landman Bennett A. , Gifford Katherine A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L.
Published: December 2023

Background

Blood‐brain barrier (BBB) permeability is associated with Alzheimer’s disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults.

Method

Vanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlb
interaction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume.

Result

Female sex was associated with lower QAlb (p<0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values>0.7) or neuroimaging outcomes (p‐values>0.2). Models stratified by sex were also null for neuropsychological (p‐values>0.93) and neuroimaging outcomes (p‐values>0.11).

Conclusion

Elevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings.

Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082