bluuebunny/crossref_metadata_2025 huggingface dataset:
Lexical access failure in Alzheimer’s Disease through the lens of semantic knowledge
Authors: Banerjee Anamika , Khan Azizuddin
Published: January 2025

Background

Lexical access refers to the generation or retrieval of conceptual representation. Representation of concepts or semantic knowledge involves the organization of concepts in an associative manner building up the mental lexicon. Several studies have pointed out an early presence of lexical access failure in Alzheimer’s Disease(AD). While lexical access deficit is rampant among patients with AD, the underlying processes involved in retrieval failure remain debatable. Some findings suggest that the difficulty in lexical access can be due to a deterioration in the conceptual representation. Therefore, to understand the nature of the difficulty underlying lexical access failure among people with AD, the current study aims to understand the involvement of semantic knowledge in lexical access.

Method

In this study, three groups of participants will be recruited, Healthy Controls (HC), Mild Cognitive Impairment (MCI) and Dementia with AD. According to apriori sample size calculation, a total sample size of 54 would be required for the present study, with 18 participants per group. In the current study, the semantic priming task is used to understand the ongoing debate about the involvement of semantic knowledge in Lexical access. The experiment consists of 4 tasks to probe their semantic knowledge and visual perception. Each trial consists of a prime‐ image or word, presented for some duration followed by a related or unrelated target. The participant needs to report whether the target was related to the prime or not.

Result

The lexical retrieval is expected to be differentiated along the different phases of the disease as a function of semantic priming. It is expected that the lexical retrieval in the HC group would be least impacted across the three conditions and AD with Dementia to be the most impacted. The performance on each condition could be differentiated across each disease severity group, along with a difference in the prime type, that is, primes related to the target would show better performance than unrelated primes across all the conditions in each of the groups.

Conclusion

The findings from this study would contribute towards understanding processes underlying lexical access failure among people with Alzheimer’s Disease.
Altered T and B lymphocyte subtype abundance in the blood of APP/PS1 mice at 6, 9 and 12 months old
Authors: Sun Jiaqi , Low Yi Ling Clare , Huang Xin , Kagawa Yoshiteru , Masters Colin L. , Jin Liang , Pan Yijun
Published: January 2025

Background

Mounting evidence support the involvement of adaptive immune system in the pathogenesis of Alzheimer’s disease (AD). The current study investigated the age‐dependent changes in the abundance of B and T cell subtypes in APP/PS1 mice, a commonly used model for AD.

Method

Peripheral blood was collected through cardiac puncture from 6‐, 9‐, 12‐month‐old APP/PS1 transgenic (TG) mice (APPsw+ and PSEN1dE9+, n = 8‐12) and their wildtype (WT) littermates (C57BL/6J, n = 12‐15). Flow cytometry (BD FACSCalibur™) was employed to quantify B and T lymphocytes and their subtypes. Surface markers such as CD19, Gl7, CD93, CD3, CD4, CD8 and CD25 were used for identifying early and activated B cells, as well as helper T cells, cytotoxic T cells and regulatory T cells, respectively.

Result

A 3‐fold increase in the abundance of early B cells were observed in 6‐month‐old TG mice compared to WT, while their abundance decreased (42.4% P = 0.0106, and 46.2% P = 0.0431) in 9‐ and 12‐month‐old TG mice compared to WT. The abundance of activated B cells was significantly decreased in 6‐, 9‐, and 12‐month‐old TG mice compared to WT (54.3% P = 0.0499, 36.7% P = 0.0071, 45.6% P = 0.0082). A significant reduction in helper T cells (10.6%, P = 0.0056) was observed only in 6‐month‐old TG mice compared to WT. The abundance of cytotoxic T cells was found increase in 9‐ and 12‐month‐old TG mice compared to WT (1.25‐fold P = 0.0001, 1.20‐fold P = 0.0252, respectively). A significant decrease in regulatory T cells (34.5% P = 0.048) was noted in TG mice compared to WT at 12‐month‐old but not at earlier age.

Conclusion

The study on APP/PS1 mice revealed an age‐dependent alteration in the abundance of B and T cell subtypes, supporting the involvement of adaptive immune system in AD. Future studies could address how these changes are related to AD pathological changes and confirm these changes in human blood samples.
Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, Ivabradine, attenuates brain mitochondrial oxidative stress without reducing cognitive impairment in Dox‐induced chemobrain
Authors: Pintana Hiranya , Apaijai Nattayaporn , Sripusanapan Adivitch , Piriyakunthorn Chotrawee , Chunchai Titikorn , Jinarat Damrongsak , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Doxorubicin (Dox), a chemotherapeutic agent, is known to cause chemobrain leading to cognitive decline and brain mitochondrial dysfunction. Ivabradine (Iva), hyperpolarization‐activated cyclic nucleotide‐gated channel blocker used for angina and arrhythmia, has been shown to be an anticonvulsant, antioxidant, and neuroprotective agent. However, the effects of Iva on cognitive function, and brain mitochondrial function in Dox‐induced chemobrain are still not determined. This study aimed to investigate whether Iva attenuates Dox‐induced brain toxicity in male rats by affecting cognitive dysfunction, synaptic dysplasticity, and brain mitochondrial dysfunction.

Method

Twenty male Wistar rats were divided into 4 groups: vehicle‐treated control, Iva‐treated control, vehicle‐treated Dox, and Iva‐treated Dox. The control rats were received normal saline, while the Dox‐treated rats were received Dox at a dose of 3 mg/kg/day intraperitoneally on days 0, 4, 8, 15, 22, and 29. Iva (10 mg/kg) was administered by oral gavage from day 0 to day 29. On day 30, novel object location (NOL) test was performed to assess cognitive function. Hippocampal‐synaptic plasticity and brain mitochondrial function were measured after euthanasia.

Result

Dox‐treated rats showed a decreased % preference index of a new location in the NOL test, decreased % of field excitatory postsynaptic potential (fEPSP), and impaired brain mitochondrial function as indicated by increased mitochondrial ROS, impaired brain mitochondrial membrane potential change, and caused mitochondrial swelling (Figure 1A‐G). Iva‐treated control rats showed no effects on the NOL, % fEPSP, and brain mitochondrial function compared to vehicle‐treated control rats. Iva‐treated Dox rats exhibited a decrease in brain mitochondrial reactive oxygen species (ROS), but showed no significant difference in NOL, % fEPSP, brain mitochondrial membrane potential change, and mitochondrial swelling compared to vehicle‐treated Dox rats (Figure 1A‐G).

Conclusion

Dox‐induced chemobrain manifested in cognitive impairment, synaptic dysplasticity, and brain mitochondrial dysfunction. Iva treatment showed a reduction in brain mitochondrial ROS, with no improvement in mitochondrial membrane potential changes and swelling in Dox‐induced chemobrain. Iva did not improve cognitive function and hippocampal‐synaptic plasticity in Dox‐treated rats. These findings suggest the antioxidant properties of Ivabradine in chemobrain, but this dose of Iva was not enough to protect brain injury in Dox‐induced chemobrain.
Regularity of blood transfusion influences the severity of systemic iron burden, cognitive decline, and gut dysbiosis in thalassemia patients
Authors: Suparan Kanokphong , Trirattanapa Kornkanok , Sriwichaiin Sirawit , Kerdphoo Sasiwan , Tantiworawit Adisak , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Thalassemia is a hereditary disease with impaired red blood cell production, resulting in cumulative systemic iron burden. The life‐long therapeutic blood transfusion with or without iron chelators in those patients leads to the development of early‐onset neurocognitive decline. However, the effects of regularity of blood transfusion on the severity of iron burden, cognitive decline, and gut dysbiosis in thalassemia patients are still unclear.

Method

Sixty participants, including 20 transfusion‐dependent (TDT) patients, 20 non‐transfusion‐dependent (NTDT) patients, and 20 healthy controls, underwent evaluation for neurocognitive function using the Montreal Cognitive Assessment (MoCA). The current systemic iron burden was determined by the levels of serum ferritin. Amplicon‐based sequencing of the bacterial 16s rRNA V3‐V4 regions of stool DNA was employed to delineate profiles of gut microbiota.

Result

The TDT patients showed greater severity of systemic iron burden, cognitive decline and gut dysbiosis than the NTDT patients. The TDT group was particularly afflicted with systemic iron burden as indicated by the highest levels of serum ferritin (Fig. 1A). Compared to the controls, the TDT and NTDT groups had significantly lower MoCA scores (Fig. 1B). In addition, there was a negative correlation between MoCA scores and the levels of serum ferritin (Fig. 1C). The thalassemia patients also exhibited gut dysbiosis, with microbial compositions among the three groups being distinct from each other (Fig. 1D and 1E). Interestingly, an increase in abundance of Paraclostridium was associated with cognitive decline.

Conclusion

These findings suggest that the severity of systemic iron burden, based on the regularity of blood transfusion, impacts on the magnitude of cognitive decline and gut dysbiosis in thalassemia patients. It is possible that systemic iron potentially serves as a dose‐dependent factor in the pathogenesis of neurodegeneration through gut dysbiosis. Therefore, therapeutic approaches via well‐control of systemic iron levels and balanced gut microbiota could prevent early‐onset cognitive decline in thalassemia patients.
Association of long‐term blood pressure variability with plasma neurofilament light underlies the comorbidity of Alzheimer's Disease and cerebral small vessel disease
Authors: Li Qin , Li Xiaofeng
Published: January 2025

Background

Alzheimer’s disease (AD) frequently coexists with cerebral small vessel disease (CSVD) is common in the aging population, yet the underlying mechanisms are not yet fully understood. Both long‐term blood pressure variability (BPV) and plasma neurofilament light (PNFL) were identified as potential biomarkers for AD and CSVD. This study aims to understand the mechanisms of comorbidity between AD and CSVD by investigating the associations among BPV, PNFL, and comorbidity. The severity of CSVD was visualized as white matter hyperintensities (WMH).

Method

Data was collected from the Alzheimer’s Disease Neuroimaging Initiative database. Participants with cognitively normal and mild cognitive impairment were included in the data analyses as clinical dementia rating (CDR) = 0 and 0.5. Aβ status was determined by cerebrospinal fluid Aβ levels and the WMH burden was defined by adjusting the WMH volume for intracranial volume. The differences in BPV and PNFL levels among participants with different Aβ status and varying WMH burdens were compared. Causal mediation analyses were conducted to explore whether the relationships of BPV with brain structural changes and cognition were mediated by PNFL.

Result

Aβ positive participants with high WMH burden had higher BPV and PNFL compared to Aβ negative individuals with low WMH burden. Systolic BPV (estimate [est] = 0.022, p = 0.004) was associated with WMH volume, and diastolic BPV (est = ‐0.053, p = 0.002) was associated with hippocampal volume. Both systolic BPV and diastolic BPV were associated with memory and executive function. Moreover, systolic (est = 0.013, p<0.001) and diastolic BPV (est = 0.012, p < 0.001) were associated with PNFL independent with average blood pressure. Mediation analyses revealed that PNFL mediated the association between systolic BPV and both WMH volume and executive function. PNFL also mediated the relationship between diastolic BPV and both hippocampal volume and memory function.

Conclusion

Elevated BPV was linked with axonal damage, hippocampal atrophy, WMH progression, and cognitive decline. This finding suggests that the same risk factor may result in pathological changes in different brain regions and cognitive decline, which in turn may be associated with the comorbidity of AD and CSVD.
Causal network analysis on multi‐omics data from Alzheimer’s brain reveals strong connection between mitochondria functions and AD outcomes
Authors: Sun Li , Sanjay Apoorva Bharthur , Isacson Ole , Shin So‐Youn , Latourelle Jeanne
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent type of senile dementia affecting more than 6 million Americans in 2023. Most of these AD cases are sporadic or late‐onset AD with unclear etiology. Recent clinical trials on antibody drug clearing Ab plagues in brain show modest benefits of slowing down cognitive decline. This indicates that a deeper and more comprehensive understanding of AD mechanism is needed for better therapeutic developments.

Method

Using Aitia’s proprietary REFSTM platform, Bayesian network models were built on clinical, demographic, and multi‐omic data from 287 postmortem brain samples of ROSMAP project. In silico perturbations were performed to assess causal effects among the variables. Hierarchical clustering was conducted to identify RNA‐ and protein‐ modules and to summarize a module‐level causal network, where a module‐level causal effect was computed as summated causal effects normalized to module sizes. For each module, gene ontology (GO) terms were annotated using Metascape.

Result

A total of 119 RNA‐ and 33 protein‐ modules were identified, of which 22 RNA‐ and 8 protein‐ modules were enriched with top genes driving AD outcomes identified through in silico perturbations. These modules were significantly over‐presented with various GO terms. Notably, three out of eight protein‐ modules are strongly related to mitochondria functions. Moreover, three pairs of RNA‐ and protein‐ modules identified for their similar enrichment patterns are related to synaptic signaling & neuron development, mitochondria translation, and complex I assembly.

The module‐level causal network highlighted that the paths from AD risk factors (e.g. age, sex, APOE4) to AD outcomes (e.g. MMSE, Braak, Cerad) were strongly connected through three protein modules annotated for mitochondria function and three RNA modules annotated for nervous system development, while the paths to the cognitive outcome only (e.g. MMSE) included two immune response related and one cytoskeleton related modules as well.

Conclusion

Clustering analysis based on in silico causal relationships of clinical and multi‐omic data revealed a strong connection of genes involved in mitochondria functions with cognition and AD pathology, reminiscing “mitochondria cascade hypothesis” of AD first proposed two decades ago.
Amyloid, iron and cerebrovasculopathy in a new mouse model combining hemochromatosis mutations and Alzheimer’s amyloidosis and the etiological and diagnostic implications for dementia subtypes
Authors: Milward Adrienne (Lz) , Aryal Ritambhara , Acquah Elvis , Johnstone Daniel
Published: January 2025

Background

UK Biobank data show mutations related to the iron disorder hemochromatosis can approximately double the risk of dementia, in particular clinically diagnosed vascular dementia. Insights into the etiology of this dementia may be provided by cerebrovasculopathy in our new “Aβ+Irondys” mouse model, which combines hemochromatosis‐related mutations and amyloidosis, with increases in soluble Aβ species and plaques. This was created by crossing an established APP/PS1 model of β‐amyloidosis with our reported Hfe‐/‐xTfr2mut model of hemochromatosis‐related mutations exhibiting brain iron dyshomeostasis (Heidari Mol. Psych. 2016).

Method

Deposition of amyloid and other Aβ species was visualized by Congo red, thioflavins and Aβ immunolabeling. Iron was visualized by diaminobenzidine (DAB)‐enhanced Perls’ or transcardially perfused DAB+Turnbull’s staining.

Result

Compared to regular APP/PS1 mice, Aβ+Irondys mice have extensive cerebrovasculopathy, sometimes severe, at 6 months and older. This is typically accompanied by iron deposition in vessel walls, sometimes co‐localizing with amyloid (Congo Red birefringence). Cerebrovasculopathy includes enlarged perivascular spaces, tortuosity, wall thickening, lumenal stenosis, microaneurysm, anastomosis and other changes in vessel profiles and diameter, wall rupture and microhemorrhage. Intense parenchymal staining for iron adjoining cortical vessels may arise from ruptured vessels.

Conclusion

Co‐deposition of iron and Aβ within blood vessels is exacerbated by hemochromatosis‐related mutations and can cause severe cerebrovasculopathy and amyloid angiopathy. This could lead to neuronal hypoperfusion and dysfunction throughout the brain in early disease stages and ultimately to neurodegeneraion. This has potential implications for understanding the etiology of dementia related to hemochromatosis mutations and for the clinical diagnosis of dementia subtypes.
Studying the Role of Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer’s Disease
Authors: Frasineanu Anca Gabriela , Gupton Stephanie L. , Gupton Stephanie
Published: January 2025

Background

In the last decade, we have demonstrated that the brain‐enriched E3 ubiquitin ligase TRIM9 regulates cytoskeletal dynamics, membrane remodeling, and netrin‐dependent signaling pathways in all stages of neuron development, including the maturation of dendritic spines and electrophysiological activity. Moreover, TRIM9 protein levels increase in the adult brain and are maintained throughout adulthood. In the adult mouse TRIM9 is enriched within the postsynaptic density (PSD), a proteinaceous rich region in the post synapse, containing neurotransmitter receptors, scaffolding proteins, and cytoskeletal elements. The PSD proteome is significantly altered in adolescent mice when TRIM9 is lost, which is linked to changes in synaptic function. Our published proximity labelling experiments to characterize the TRIM9 interactome identified several proteins implicated in synaptic function and Alzheimer’s disease (AD), including Tau.

Method

Cross‐referencing this list with a published dataset of differentially expressed proteins (123) in the hippocampal PSD of 9 month old Tau P301S mice (PS19 AD model) versus non‐transgenic control, revealed a significant percent (56 proteins, 45.5%) overlap. Here we investigate the role of TRIM9 in tau‐mediated neurodegeneration, since TRIM9 is poised to interact with many AD‐associated proteins, and published work indicates that TRIM9 expression in HEK293T cells increased aggregated tau species. Four genotypes were compared (Trim9+/+, Trim9‐/‐, Trim9+/+:PS19, and Trim9‐/‐:PS19), and 3‐4 animals per genotype and sex were used in each experiment. We analyzed changes in dendritic spine density of six month old murine cortical and hippocampal neurons using the Golgi‐Cox staining method. We also investigated changes in pathological tau accumulation, microglia and astrocytes activation using multiplexed immunofluorescence imaging and biochemical analysis.

Result

Iba1 positive microglia were significantly enriched in the hippocampus and entorhinal cortex of six month old Trim9‐/‐:PS19 mice compared to the other genotypes. Pathological tau accumulation had an increase trend in the hippocampus of Trim9‐/‐:PS19 mice compared to PS19 only mice.

Conclusion

Deletion of Trim9 exacerbated the progression of Alzheimer’s disease in six month old PS19 mice. Future experiments will use primary cultured hippocampal neurons to further determine the mechanism through which Trim9 deletion increases pathological tau accumulation.
Mild inhibition of mitochondrial complex I improves glucose metabolism and energy homeostasis in a cellular model of Alzheimer’s disease
Authors: Nguyen Thi Kim Oanh , Trushin Sergey A , Ostroot Mark , Trushina Eugenia
Published: January 2025

Background

While disease‐modifying treatments that reduce Aβ have been recently approved by the FDA, the identification of novel therapeutic targets and strategies that target underlying mechanisms to delay the AD development are still needed. Abnormal brain energy homeostasis and mitochondria dysfunction are observed early in AD. Therefore, the development of treatments to restore these defects could be beneficial. We identified small molecule (code name CP2) as a mild and specific mitochondrial complex I (MCI) inhibitor. Application of CP2 improved brain energy homeostasis, restored synaptic and cognitive function in APP/PS1 and 3xTgAD mice. However, mechanistic relationship between MCI inhibition, glucose uptake/utilization and mitochondrial function remains to be determined.

Method

Cellular energy metabolism was assessed in the neuroblastoma SH‐SY5Y cells that express either mutant human APP protein (APPswe) or empty vector (control) treated with vehicle or CP2. A Seahorse Extracellular Flux Analyzer was used to measure glycolysis, oxygen consumption rate, and fatty acids β‐oxidation (FAO). Flow cytometry allowed determining the translocation of glucose transporters to the cell surface. Changes in protein expression in response to treatment were assessed using Western Blot analysis. Changes in mitochondrial morphology were monitored using electron microscopy. The non‐radioactive Glucose Uptake‐Glo™ assay was utilized for measuring glucose uptake in cells. Metabolic flux analysis was done using 13C D‐Glucose stable isotope‐labeling.

Results

APPswe cells have a significant decrease in glycolysis and spare respiratory capacity, an indicator of the mitochondrial ability to produce energy under stress conditions. These observations were consistent with decreased glucose uptake, which was compensated by an increased FAO to provide axillary fuel for ATP production. Mechanistically, at the concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, acute CP2 treatment increased glucose uptake and utilization through the translocation of glucose transporters to the plasma membrane while prolong CP2 treatment activated metabolic sensors and mitochondrial morphofunctional pathways (e.g., fission, fusion, biogenesis, and turnover) consistent with the improved cellular bioenergetics in the AMPK‐dependent pathway.

Conclusion

Data suggested that mild MCI inhibition activates multiple neuroprotective mechanisms improving cellular energy homeostasis and mitochondrial function in vivo and in vitro, representing promising strategy that target early AD mechanisms.
Relationships between locus coeruleus microstructural integrity, sleep, and 24‐h rest‐activity rhythm in the context of plasma markers of Alzheimer’s disease: a 7T MRI study of asymptomatic older individuals
Authors: Van Egroo Maxime
Published: January 2025

Background

The brainstem locus coeruleus (LC) is among the first sites of Alzheimer’s disease (AD) pathology, accruing hyperphosphorylated tau as early as in young adulthood. Animal studies indicate that the LC is crucially involved in sleep‐wake regulation, a recently established factor contributing to AD‐related pathophysiological processes. However, the associations between LC integrity and sleep‐wake phenotypes in the context of AD pathology remain poorly characterized in humans. Here, we examined the relationships between in vivo 7T MRI‐derived LC microstructural integrity and objective measures of sleep or circadian rest‐activity patterns at different levels of AD pathology.

Method

Thirty‐eight cognitively unimpaired older adults (mean age = 66.53±9.22y., 18 females, Table 1) underwent dedicated LC imaging combined with whole‐brain neurite orientation dispersion and density imaging (NODDI) at 7T to extract microstructural indices of neurite density (NDI) and orientation dispersion (ODI) within the bilateral LC. In addition, they performed 10 days of actigraphy from which objective measures of sleep (average sleep duration and proportion of wake after sleep onset (WASO%)) and 24‐h rest‐activity rhythm (intradaily variability (IV), interdaily stability (IS)) were computed. Plasma concentrations of GFAP and phosphorylated tau epitopes were derived from blood samples using Single molecule array technology (p‐tau181, p‐tau231) and the Meso Scale Discovery platform (p‐tau217).

Result

Multiple linear regression models adjusted for age, sex, BMI, and actigraphic recording duration showed that higher LC ODI was associated with longer sleep duration (t(32) = 3.93, p<.001) and lower WASO% (t(32) = ‐2.33, p = .03, Figure 1). Importantly, interaction models revealed a synergistic deleterious effect of displaying lower LC ODI and elevated levels of p‐tau217 on WASO% as well as cross‐over interactions between LC NDI or ODI and p‐tau181, p‐tau217, or GFAP on IV and IS (Figure 2).

Conclusion

These preliminary results suggest that poorer LC microstructural integrity is linked to worse proxy measures of sleep quality and circadian rest‐activity patterns, but only in individuals with elevated levels of AD pathology. Our findings therefore provide novel evidence of the involvement of the LC in sleep‐wake phenotypes in older adults in the context of AD pathophysiological processes, and have implications for the identification of individuals at higher risk for AD‐related sleep‐wake disturbances.
Association of Objective Sleep Measures and White Matter Limbic System Integrity in Community‐Dwelling Cognitively Unimpaired Older Black and White Adults
Authors: Bubu Omonigho Michael , Gills Joshua L , Cesar Oliver , Kovbasyuk Zanetta , Sogade Anamarie , Dominguez Joanna , Browne Laurel Y , Valkanova Elena , Mbah Alfred , Figueredo Luisa F , Kam Korey , Mullins Anna E , Parekh Ankit , Masurkar Arjun V. , Varga Andrew , Osorio Ricardo
Published: January 2025

Background

We examined racial differences between measures of limbic white matter tracts and objective sleep parameters in cognitively unimpaired older‐adults.

Method

This cross‐sectional study included 170 community‐dwelling cognitively unimpaired older‐adults (mean±SD: age = 67.2±5.2y) participating in NYU studies of sleep, aging, and memory. Subjects completed polysomnography (NPSG) and brain MRI. Sleep measures of interest included total sleep time (TST), NREM stages 2, 3 and REM sleep duration, sleep latency and fragmentation, slow sleep spindles (SSP), sleep spindle density (SPD), AHI4% and REM AHI4%. Microstructural properties of the cingulum, uncinate fasciculus (UF), and fornix were estimated using diffusional tensor imaging (DTI) metrics including radial kurtosis (RK), radial diffusivity (RD), and fractional anisotropy (FA). Adjusted Linear mixed‐effects regression models examined associations between race, sleep, race*sleep and DTI metrics.

Result

Participants were 44.1% Black with 16.8±2.5y of education. Subjects were relatively matched on AHI4%, age, BMI and educational level. In the cingulum, increased fragmentation was associated with higher RD β[Left] = 0.0026, p = 0.022), decreased RK (β[Right] = ‐0.0069, p = 0.039) in Blacks. Additionally, increased sleep latency was associated with reduced FA (β[Right] = ‐0.0010, p = 0.019), higher RD (β [Right] = 0.0010, p = 0.008) in Blacks. In the UF, increased fragmentation was associated with higher RD(β[Left] = 0.0052, p = 0.019) and lower RK (β[Right] = ‐0.0010, p = 0.039) in Blacks; increased AHI4%REM was associated with reduced FA β[Left] = 0.0007, p = 0.041), higher RD (β[Right] = ‐0.0007, p = 0.027) and lower RK (β[AHI4%, Left] = ‐0.0029, p = 0.001) in Blacks. Furthermore, higher SSP (βRight] = 0.00031, p = 0.045 and SPD (β[Right] = 0.045, p = 0.025) was associated with higher RK in Blacks. In the cingulum of white participants, higher AHI4%REM was associated with reduced FA β[right] = ‐0.0006, p = 0.013), higher RD β[Left] = 0.0005, p = 0.051), and reduced RK β[Right] = ‐0.00198, p = 0.008). Additionally, NREM stage‐2 sleep duration was associated with higher FA β[Right] = 0.0010, p = 0.037) and higher RK β[Right] = 0.0031, p = 0.040). In the UF, increased fragmentation was associated with reduced RK β[Left] = ‐0.017, p = 0.047) in Whites.

Conclusion

Cognitively‐unimpaired Black and White older‐adults showed sleep disruption associations with limbic white matter integrity, with race‐specific associations observed across various microstructural properties of the cingulum, UF, and fornix. Thus, highlighting possible sleep‐related underpinnings of racial differences in Alzheimer disease‐risk.
Sex‐associated differences in brain insulin signaling and energy metabolism uncover early pathological alterations driving Alzheimer’s disease neuropathology
Authors: Lanzillotta Simona , Tramutola Antonella , Paul Bindu D , Domenico Fabio Di , Perluigi Marzia , Barone Eugenio
Published: January 2025

Background

Biological sex influences Alzheimer’s disease (AD) development, particularly concerning brain insulin resistance (bIR) and early energy metabolism defects. Biliverdin reductase‐A (BVR‐A) plays a crucial role in insulin signaling, and its downregulation leads to bIR. However, the sex‐related differences in AD neuropathology and underlying mechanisms remain unclear. We aimed to identify early changes in brain insulin signaling in males and females, shedding light on pathological signs preceding overt bIR and AD neuropathology.

Method

C57BL/6J mice (WT or BVR‐A knock‐out, M and F, n = 10/sex/group) received a chow or a high‐fat diet (HFD, 60% kcal by fat) for 1 or 8 weeks. Peripheral metabolic measurements (fasting glucose, insulin, and OGTT) and cognitive tests (NOR and Y‐maze) were performed. Brain insulin signaling activation (basal and intranasal insulin‐induced), oxidative stress marker levels, mitochondrial activity, and AD neuropathology markers were evaluated in the hippocampus and cortex. Correlations were performed with peripheral metabolic measurements (fasting glucose, insulin, and OGTT) and cognitive tasks (spatial memory).

Result

Male mice exhibited more pronounced alterations in brain insulin signaling, mitochondrial activity, oxidative stress, and AD‐related neuropathology compared to female mice after 8 weeks of HFD. These changes initially manifested in the cortex and subsequently in the hippocampus. Intriguingly, despite these molecular alterations, male mice showed better cognitive performances than female mice following 8 weeks of HFD. This evidence suggests that female mice are more susceptible to these metabolic alterations and that subtle changes promote worse outcomes on cognitive tasks. BVR‐A levels were found decreased in both cortex and hippocampus following HFD, and these changes were sex‐dependent. Loss of BVR‐A significantly correlated with the observed molecular alterations, as confirmed in BVR‐A knock‐out mice. Notably, knock‐out mice exhibited similar alterations observed in C57BL/6J mice after just 1 week on HFD, emphasizing the pivotal contribution of BVR‐A.

Conclusion

This study highlights the importance of identifying sex‐related differences as well as shared features in the progression of bIR in AD. Loss of BVR‐A is a common event, although temporal‐ and regional‐associated differences in males and females are observed. These observations warrant further investigations to unveil early pathological changes driving AD neuropathology.
Physical exercise upregulates Irisin in extracellular vesicles
Authors: De Felice Fernanda Guarino
Published: January 2025

Background

Physical exercise improves overall brain health, cognition, and stimulates the release of extracellular vesicles (EVs) in humans. Exercise upregulates irisin, a myokine derived from fibronectin type III domain‐containing protein 5 (FNDC5) previously shown to mediate the beneficial actions of exercise on memory in mouse models of Alzheimer’s disease (AD). Here, we investigated if physical exercise upregulates EVs. We further studied if EV’s cargo includes irisin and tested whether physical exercise protocols modulate its content in EVs.

Method

Individuals underwent a high intensity interval training exercise program. HIIT sessions were performed 3 times a week, over 6 weeks. Serum was collected before and the day after the last exercise session. Mice were submitted to a daily swimming exercise protocol, 5 times per week, over 5 weeks. Mice were terminated 1 hour after the last bout of exercise and plasma was collected. EVs concentration and number in humans and mice. EVs obtained from the cerebrospinal fluid (CSF) from cynomolgus and Rhesus monkeys at rest obtained by lumbar punctures were also studied. We further investigated if EV’s cargo includes irisin and tested whether physical exercise protocols modulate irisin content in EVs un mice and humans. FNDC5/Irisin in EVs was detected by Western blotting, Mass spectometry and ELISA.

Result

Our results indicate that irisin is associated with serum, plasma and CSF EVs from humans, mice and monkeys. Exercise upregulated EV‐associated FNDC5/Irisin in mice and humans, but did not alter circulating EV concentration. EV‐associated FNDC5/Irisin correlated positively with BDNF levels in serum obtained from humans post‐exercise.

Conclusion

These findings indicate a potential physiological role of exercise‐induced upregulation of EV‐associated irisin.
Aβ immunotherapy drives immune activation and cerebrovascular damage in a mouse model of Alzheimer’s Disease
Authors: Taylor Xavier , Noristani Harun , Fitzgerald Griffin , Oluoch Herold , Babb Nick , McGathey Tyler , Hole Justin T. , Lacor Pascale , DeMattos Ronald B. , Wang Yaming ,   Neuroscience Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
Published: January 2025

Background

Anti‐amyloid‐β (Aβ) immunotherapy trials have shown amyloid‐related imaging abnormalities (ARIA) as the most common and serious adverse events linked to pathological changes in cerebral vasculature. Nevertheless, the mechanisms underlying how amyloid immunotherapy triggers vascular damage, increases vascular permeability, and results in microhemorrhages remains unclear. Notably, activation of perivascular macrophages and infiltration of peripheral immune cells have been implicated in regulating cerebrovascular damage. However, further research is needed to understand the immediate downstream consequences of macrophage activation that exacerbate CAA‐related vascular permeability and microhemorrhages associated with amyloid immunotherapy.

Methods

This study investigates immune responses induced by amyloid‐targeting antibodies and CAA‐induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer’s disease (AD) mouse model of microhemorrhage.

Results

In the present study, we demonstrate anti‐Aβ (3D6) immunotherapy induces robust vascular inflammation and profound smooth muscle cell loss, leading to vascular damage and loss of blood‐brain barrier (BBB) integrity. Additionally, digital spatial profiling reveals robust recruitment of peripheral immune cells encompassing T and B‐ lymphocytes encircling vascular amyloid deposits. Finally, RNA in‐situ hybridization coupled with immunohistochemistry identifies 2 distinct subsets of macrophages encompassing tissue‐resident and monocyte‐derived macrophages around vascular amyloid deposits after Aβ immunotherapy demonstrating the multifaceted roles of immune activation and vascular damage in response to Aβ immunotherapy.

Conclusions

In summary, our study establishes a significant link between CAA‐Aβ antibody immune complex formation, macrophage activation, vascular damage leading to impairment of BBB integrity. Nevertheless, the full implications of this phenomenon on the susceptibility to microhemorrhages needs to be explored further. Therefore, additional investigations are needed to determine the potential preferential roles played by tissue‐resident and monocyte‐derived macrophages surrounding vascular amyloid deposits, unraveling the intricate interplay between immune activation, vascular damage and accelerated smooth muscle cell loss in response to Aβ immunotherapy.
Sex differences in locus coeruleus physiology
Authors: Rae Rosaria Josephine , McMahon Lori L
Published: January 2025

Background

Alzheimer’s disease disproportionately affects women in the U.S., with two‐thirds of individuals diagnosed being female. This gender disparity underscores the crucial role of sex as a significant risk factor for disease development. Recognizing the importance of this, it becomes imperative to investigate how Alzheimer’s disease presents differently between males and females, especially in the early stages when intervention is most potent. The locus coeruleus (LC) is the initial brain region affected by hyper phosphorylated tau in Alzheimer’s disease, preceding the accumulation of other pathological indicators. A deeper understanding of sex differences in this crucial region can provide insights into how Alzheimer’s disease related dysfunction manifests uniquely between the sexes

Method

In vivo electrophysiology under anesthesia was used to measure single unit activity of LC firing patterns in wild‐type Fischer male and female rats. Females have been estrous cycle tracked and stratification between estrus phases may uncover further differences within females. Recordings measured tonic firing and phasic firing in response to footshock. Spike sorting and signal processing differentiated LC principal neurons and interneurons, unique units, physiological features, and bursting patterns that were compared between groups.

Result

This data shows no significant differences in LC principal cell tonic firing between males and females. However during burst firing, females have an increased interspike interval, indicating decreased firing supporting sexually distinct physiology of the LC. Additionally, females have distinct waveform patterns from males including area under the curve and peak/valley energies, suggesting possible differences in intrinsic properties.

Conclusion

Sex influences LC phasic physiology which may contribute to AD disproportionately impacting women.
Comparison of cerebrospinal fluid and plasma oxidative stress biomarkers
Authors: de la Colina Adrian Noriega , Charisis Sokratis , Ntanasi Eva , Mamalaki Eirini , Skaperda Zoi , Kouretas Demetrios , Scarmeas Nikolaos
Published: January 2025

Background

Numerous studies have highlighted the role of oxidative stress in Alzheimer’s disease (AD) development. Yet, the alignment of systemic and central oxidative stress biomarkers is unclear across diverse populations in the AD continuum. This study aims to assess protein damage levels in plasma and cerebrospinal fluid (CSF) within the AD continuum.

Methods

One hundred forty participants without clinical dementia (47 with Mild Cognitive Impairment [MCI] and 93 cognitively unimpaired) from a memory clinic cohort underwent examination for central (CSF) and systemic (plasma) markers of oxidative stress. We measured Total Antioxidant Capacity (TAC), reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and reducing power (RP) using standard laboratory techniques and absorbance spectrophotometry (Hitachi U‐1500). Pearson’s correlations were employed to determine the congruence between the same biomarkers of oxidative stress in CSF and plasma. Factor analysis was performed to ascertain how many antioxidant dimensions they represent.

Results

Table 1 outlines participants' baseline characteristics. Pearson’s correlation analysis for the entire sample revealed no congruence between CSF and plasma in TAC (r = +.087) and GSH (r = .‐.161), while CSF and plasma RP (r = .+385*) and TBARS (r = ‐.216*) were correlated (Figure 1). Upon analyzing group‐level data, the cognitively unimpaired group showed congruence between CSF and plasma for GSH (r. = ‐.279*) and TBARS (r = ‐.287*) but not for TAC (r = +.191) and RP (r = +.202). In the MCI group, only RP (r. = +.640*) demonstrated congruence between CSF and plasma. Factor analysis with CSF biomarkers identified two components in the whole sample (Figure 2). Dimension 1 = GSH, and Dimension 2 = TAC, TBARS, and RP. Factor analysis with plasma identified as well two components: Dimension 1 = RP and GSH, Dimension 2 = TBARS and TAC. The factor analysis for the MCI group revealed the presence of a single component for CSF biomarkers, while there were two components for plasma: Dimension 1 = RP and TBARS, Dimension 2 = TAC and GSH.

Conclusion

Oxidative stress biomarker patterns differ across the AD continuum. RP demonstrates the most reliability, while TAC is the least. GSH and TBARS plasma and CSF measurements are negatively associated in the cognitively unimpaired, but not in the MCI population. Understanding oxidative biomarker evolution can enhance our comprehension of their role in AD and age‐related disorders.
Spontaneous and iatrogenic ARIA: Mechanistic insights from CAA‐related inflammation
Authors: Piazza Fabrizio , Lucia Davide Donato , Guzzi Francesca , Pascarella Rosario , DeBernardi Elisabetta , Antolini Laura , Basso Gianpaolo , Zedde Marialuisa ,   The CAA‐SINdem Study Group and The iCAB International Network Research Group
Published: January 2025

ARIA‐E/H (amyloid‐related imaging abnormalities‐Edema/Hemorrhage) is an umbrella term that defines the radiographic appearance of MRI images abnormality during treatments with Aβ‐lowering monoclonal antibodies (mAbs) for Alzheimer’s disease immunotherapy.

Today, it is well‐recognized that ARIA‐E events can also occur spontaneously in patients with cerebral amyloid angiopathy‐related inflammation (CAA‐ri), a rare autoimmune encephalopathy associated with raised cerebrospinal fluid (CSF) concentrations of spontaneous auto‐antibodies against Aβ (aAbs).

In this framework, the last years of research and experience of the iCAB international Network generated an increased consensus that therapy‐induced ARIA is the iatrogenic manifestation of CAA‐ri. Indeed, the natural history of CAA‐ri, the response‐to‐corticosteroid therapy outcomes, the regional and temporal co‐localization of radiographic ARIA‐E with microglial activation (both on neuropathology and in vivo with TSPO‐PET), the downstream negative effects on Aβ‐clearance pathways and the related risks for an ARIA‐H subsequent event, all provide remarkable supportive evidence that ARIA‐E associated with mAbs therapy is iatrogenic CAA‐ri.

In this talk, we will present and critically discuss the emerging new data supporting the potential of the assay for anti‐Aβ (auto)antibody CSF testing as a companion diagnostic and early biomarker for CAA‐ri and ARIA in real‐world clinical practice and immunotherapy trials. In this framework, we will also present the recently launched “ARIAisCAAri NET” project; an international, prospective, longitudinal, observational Registry and Biobank of patients with ARIA and CAA‐ri from the real‐world clinical practice aimed at fostering a precision medicine approach and biomarker research collaborations between the AD and CAA community.

Funding: Alzheimer’s Association Research Grant: 23AARG‐1030214 ‐ UncoveriNg Immune MechanIsms and Biomarkers of ARIA (UNIMIB‐ARIA Toolkit)

References:

Piazza F. et al. Association of Microglial Activation With Spontaneous ARIA‐E and CSF Levels of Anti‐Aβ Autoantibodies. Neurology, 2023

Kelly L. et al. Clearance of interstitial fluid (ISF) and CSF (CLIC) group‐part of Vascular Professional Interest Area (PIA), updates in 2022‐2023. Cerebrovascular disease and the failure of elimination of Amyloid‐β from the brain and retina with age and Alzheimer’s disease: Opportunities for therapy. Alzheimer’s and Dementia, 2023

Zedde ML et al. CAA‐ri and ARIA: Two Faces of the Same Coin? American Journal of Neuroradiology, 2023
Reactive astrocytes with reduced function of glutamate transporters in the AppNL‐G‐F knock‐in mice
Authors: Loera‐Valencia Raúl , Srivastava Ipsit , Goikolea Julen , Kaya Tamer Ayberk , Leal Maria Latorre , Iglesias Marta Pereira , Alvarez‐Jimenez Laura , Arroyo‐García Luis Enrique , Shimozawa Makoto , Nilsson Per , Fisahn André , Lindskog Maria , Maioli Silvia
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with synaptic and memory dysfunction. A pathological hallmark of the disease is reactive astrogliosis, with reactive astrocytes surrounding amyloid plaques in the brain. Astrocytes have also been shown to be actively involved in disease progression, nevertheless, mechanistic information about their role in synaptic transmission during AD pathology is lacking. Astrocytes maintain synaptic transmission by taking up extracellular glutamate during synaptic activity through astrocytic glutamate transporter GLT‐1, but its function has been difficult to measure in real‐time in AD pathology.

Method

In this study, we used an App knock‐in AD model (AppNL‐G‐F) carrying the Swedish, Arctic and Beyreuther mutations associated with AD and exhibiting AD‐like Aβ plaque deposition and memory impairment. Using immunohistochemistry, patch‐clamp of astrocytes, and western blot from tissue and FACS isolated astrocytes.

Result

We found that AppNL‐G‐F mice at 6‐8 months of age have astrocytes with clearly altered morphology compared to wild‐type (WT). Moreover, astrocyte glutamate clearance function in AppNL‐G‐F mice, measured as electrophysiological recordings of glutamate transporter currents, was severely impaired compared to WT animals. We suggest that the loss of function of GLT‐1 is not related to altered protein levels since no changes in GLT‐1 levels in synaptosomes nor FACS‐isolated astrocytes from AppNL‐G‐F mice were found. This phenotype can potentially alter synaptic transmission and/or contribute to glutamate excitotoxicity.

Conclusion

Our data suggest that astrocytic glutamate transporters are affected by excess Aβ42 in the brain contributing to synaptic dysfunction in the hippocampus. Thus, our data indicate that restoring astrocyte synaptic function could be a potential therapeutic strategy to treat AD.
Isoform‐dependent regulation of Tau function by phosphorylation
Authors: Naseri Nima N , Tomlinson Taylor L , Shimogawa Marie , Shalem Ophir , Petersson E. James , Rhoades Elizabeth
Published: January 2025

Background

Tau is a neuronal microtubule associated protein whose interactions with microtubules are regulated by phosphorylation. Tau has numerous putative phosphorylation sites, but it is unclear which combinations of Tau phosphorylation co‐occur in the normal state and precisely how they impact Tau function. Adding further complexity, there are six major Tau isoforms arising from alternative splicing. These isoforms are expressed in an age‐dependent manner: only 3R (3‐repeats in the microtubule‐binding domain) Tau is expressed in development, while both 3R and 4R (4‐repeats in the microtubule‐binding domain) Tau isoforms are present in adult brain.

Method

We applied time course studies in mice, sub‐cellular MT fractionation from human iPSC‐derived neurons as well as biophysical assays using recombinant Tau phospho‐mimics and purified tubulin to investigate the isoform‐specific impacts of phosphorylation to Tau‐tubulin/MT interactions. Significantly, we semi‐synthesized Tau, modified with bonafide site‐specific phosphorylation and a fluorescently labeled unnatural amino acid, to measure the impact of phosphorylation in the proline‐rich region to tau‐tubulin binding at the single molecule level.

Result

Our data reveal that in each of the platforms investigated, 3R Tau function is more dramatically altered by phosphorylation as compared to 4R Tau upon modification at the same residues. These isoform‐specific differences were most pronounced at phosphorylation sites in the proline‐rich region of Tau, and significantly less so in the C‐terminal tail.

Conclusion

Our findings highlight the possibility of differential regulation of Tau isoforms that reflect different roles for Tau in the developing and adult brains. Overall, our findings provide insight into functional regulation of Tau‐tubulin/MT interactions by phosphorylation, which is critical for ultimately understanding the significant increase in phosphorylated Tau found in pathology and whether specific phospho‐Tau forms can be targeted for therapeutic intervention.