bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial proteomic analysis of single amyloid plaques in brain tissue using laser capture microdissection and mass spectrometry
Authors: Jiao yun 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of pathological amyloid protein deposits in the brain. Analyzing the proteomic composition amyloid plaques is essential for advancing biomedical research on Alzheimer’s disease. Laser capture microdissection (LCM) is a technique that enables precise isolation and collection of specific cells or structures from tissue samples. In this study, we developed a method utilizing LCM to capture single amyloid plaques from fresh frozen brain tissue for subsequent profiling using Data‐independent acquisition (DIA) proteomics.Methods1: Tissue sections (10‐12 µm) were collected from fresh frozen mouse and human brain tissue and stored at ‐80°C.2: Fresh frozen tissue sections were fixed with 70% alcohol and stained for plaques using X‐34 dye with series dehydration. 3: One plaque and one non‐plaque areas from the same section were captured using LCM (approximately 50 µm diameter). 4: Perform proteomic analysis using a modified LC‐MS/MS method.Results1: We developed an optimized method for isolating single amyloid plaques from fresh frozen brain tissue samples. 2: We established a proteomic platform for analyzing single plaque samples at a sub‐microgram level, representing one of the studies with the deepest coverage of single plaque proteome. This platform utilized liquid chromatography and tandem mass spectrometry (LC‐MS/MS) in conjunction with data‐independent acquisition (DIA) proteomic profiling. 3: Due to the low protein level in plaques (∼5ng/plaque), we use 0.2%DCA as a lysis buffer. This buffer can precipitate upon acidification, eliminating the need for a desalting step and minimizing sample loss. Finally, ∼20,000 peptides and ∼5,000 proteins have been identified from ∼5ng initial protein per sample. 4: Notably, we observed several key proteins, such as Abeta, Apoe, Mdk, and Ntn1, consistently appeared in the plaque areas. The enriched protein pathways and protein‐protein interaction modules were also reported.ConclusionOur approach provides an optimized platform for conducting in‐depth profiling of LCM‐captured single amyloid plaque in Alzheimer’s disease. This method enables a comprehensive understanding of the proteomic composition of these plaques, contributing to the advancement of Alzheimer’s disease research.
Exploring the Potential Link between Occupational Circadian Rhythm Dysfunction as a Risk Factor for Alzheimer’s Dementia: A novel hypothesis
Authors: El‐Satar Youssef M. Abd , Mohamed Hazim , Ismail Youssef A. , Haitham Youssef , Walid Mohammad 
Published: January 2025

AbstractBackgroundThe circadian rhythm controls physiological functions across by responding to environmental light cues. fluctuations in this rhythm, such as those induced by irregular work schedules, have been associated with adverse health outcomes, this study aims to assess the increased likelihood risk of developing Alzheimer’s dementia for workers with irregular work schedules.MethodsExploring and referencing studies on Alzheimer disease (AD) which had proved an undeniable relationship between dopamine levels with AD onset, this study showcases the relationship of dopamine levels and circadian rhythm and its effect indirectly on Alzheimer as a predisposing factor of AD.Discussion and ResultTraditionally thought to be the result of neurodegenerative processes, disturbances of the circadian rhythm and sleep‐wake cycle are common symptoms seen in people with AD. However, there may be a possible reciprocal association between circadian abnormalities and the development of AD, suggesting that they may also be risk factors. Circadian rhythms significantly influence dopamine levels throughout the day. This is demonstrated by in vivo studies that show heightened dopamine neuronal firing during the day (7:00‐11:00 h) and at the start of the night (19:00‐23:00 h), with significantly fewer spikes firing in between (11:00‐15:00 h). Furthermore The dopaminergic system has been implicated in the pathogenesis of Alzheimer’s disease and its progression, with patients who suffer from Alzheimer showing low dopamine levels.ConclusionConsidering the influence of circadian rhythm on dopamine levels, there seems to be a potential interplay between circadian disruptions and neurological health, warranting further investigation into the relationship between circadian rhythm disturbances and the risk of Alzheimer’s dementia onset.
Understanding apathy: behavioral and neural correlates of apathy in neurodegenerative disorders
Authors: Nsor Neke , Brown Casey 
Published: January 2025

AbstractBackgroundApathy, a common neuropsychiatric symptom of neurodegenerative disorders, involves a lack of motivation and reduced interest in positive activities, along with diminished concern for others. Deficits in basic aspects of emotional functioning including difficulties recognizing emotions (emotion recognition) and generating positive or negative emotions (positive and negative emotional reactivity) may underpin neuropsychiatric symptom clusters like apathy. Neural systems (i.e., anterior cingulate cortex, putamen, ventral striatum) that support emotional functioning may also be implicated in apathy. This study examined the behavioral and neural correlates of apathy in dementia.MethodThe study included 434 care‐recipients with a variety of neurodegenerative disorders (n = 275), individuals at risk of transitioning to a neurodegenerative disease (n = 123), and healthy controls (n = 36). Care‐recipients underwent neuropsychological testing, neuroimaging, and clinical interviews to obtain a diagnosis. Caregivers reported on their care recipient’s emotional functioning using a well‐validated questionnaire and apathy was assessed using a clinical interview. We first tested whether the three aspects of emotional functioning (emotion recognition, positive emotional reactivity, and negative emotional reactivity) were associated with apathy using a linear regression. Then we examined the neural correlates of apathy with voxel‐based morphometry.ResultGreater apathy correlated with diminished positive emotional reactivity and emotion recognition, even after accounting for a number of covariates (i.e., care recipient age, gender, education, race, cognitive impairment, and diagnosis). Apathy was not significantly associated with negative emotional reactivity. At the neural level, increased apathy was associated with reduced grey matter in the ventral striatum and anterior cingulate cortex, while reduced emotion recognition was associated with reduced grey matter in the temporal cortex (Fusiform Gyrus & Temporal Pole). We did not find any significant association between grey matter volume and positive reactivity.ConclusionFindings suggest that the abilities to recognize emotions and generate positive emotions are linked to apathy symptoms. Apathy in dementia may be associated with deficient activation in brain regions involved in reward and salience detection, whereas deficits in emotion recognition were linked to regions involved in face perception and social cognition. Further disentangling the associations between emotional functioning and neuropsychiatric symptoms may improve differential diagnosis and promote more targeted interventions.
Acute cerebrovascular injury drives chronic reactive heterogeneity of microglia in a mouse model of mixed etiology dementia
Authors: Dimas Sophia H , Roberts Jill , Goulding Danielle S. , Saito Kai , Cryer Carlie , Wendell Ben , Whitnel‐Smith Laura , Morganti Josh M. 
Published: January 2025

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) results from cerebrovascular injuries, significantly contributing to age‐related cognitive decline, and coexists with Alzheimer’s disease (AD) in excess of 70% of AD patients. These co‐occurring neuropathological subtypes are referred to as mixed‐etiology dementia (MED). Despite the prevalence of MED little is known regarding the neuroinflammatory responses of microglia in the context of vascular injury in tissues already containing AD‐related cerebral amyloidosis. In order to begin to understand the susceptibility of microglia in this MED environment we generated a mouse model of MED combining transient stroke in the 5xFAD mouse model of cerebral amyloidosisMethodMale 5xFAD mice received sham or tandem CCA/MCA unilateral occlusion surgery to induce transient cerebral hypoperfusion model of MED. Post‐surgical intervals spanning sub‐acute (7 days) and chronic (28 days) were examined using histological techniques in tandem with single cell RNA sequencing and spatial transcriptomics.ResultMED drives progressive cerebral amyloid angiopathy (CAA) accumulation as a function time resulting in a shift of amyloid plaque load from parenchymal domains to significantly higher vascular loads at 28 days. Microglial reactivity is markedly changed due to MED with disruptions in markers associated with homeostatic‐ like reactivity (e.g. P2ry12) towards accumulation of disease‐associated reactivity (e.g. Clec7a). Similarly, we demonstrate that MED drives differential accumulation of vascular injury‐reactive subsets of microglia at both single cell and spatial transcriptomic levels beyond the DAM signatures present in the sham mice and varying as a function of post‐injury intervalConclusionMED drives chronic microglial heterogeneity beyond classic DAM signatures, highlighting potential new mechanistic and targetable routes underlying MED neuropathological sequelae
The role of Peak width Skeletonized Mean Diffusivity in AD disease progression
Authors: Jarholm Jonas Alexander , Tecelao Sandra , Pålhaugen Lene , Kirsebom Bjørn‐Eivind , Bjornerud Atle , Fladby Tormod , Selnes Per 
Published: January 2025

AbstractBackgroundCerebral small vessel disease (CSVD) is common in Alzheimer’s disease (AD), but it is unclear how CSVD affects cognition and disease progression. Peak width of Skeletonized Mean Diffusivity (PSMD) is a Magnetic Resonance Imaging (MRI) marker of global white matter integrity, believed to reflect both total vascular burden and the cognitive impact of CSVD. We examined the relationship between PSMD and memory, processing speed and executive function, and to assess the predictive value of PSMD on clinical progression.Method265 cases and controls between 40‐80 years old were recruited from the Norwegian multi‐center study DDI (Dementia Disease Initiation), with 2‐5 follow ups (0.7‐8 years). Subjects were according to the Clinical Dementia Rating (CDR), with 0 as cognitively unimpaired (CU) if, 0,5 as mild cognitive impairment (MCI) if CDR, and ≥ 1 as dementia. Amyloid status was determined from Amyloid‐PET or from amyloid‐β42/40. PSMD was obtained from 6 MRI scanners and harmonized for scanner effects in R using ComBat, with age, sex, staging and amyloid status at baseline as covariates.The relationship between PSMD and cognitive scores was assessed using a general linear model, with age, sex, education and an PSMD‐amyloid interaction variable as covariates. Subjects were classified into the following groups: A‐ low PSMD, A+ low PSMD, A‐ low PSMD, A+ high PSMD high, where PSMD high or low signifies above or below the group median. Survival analysis was performed in 195 subjects, using the “survival” package from R, with progression from CU to MCI/dementia or from MCI to dementia as the events of interest. Hazard ratios were assessed with the Cox proportional‐hazards model with age and A status/PSMD at baseline and sex as covariates.ResultThere was a significant relationship (p<0.01) between PSMD and TMT A and B, but not with CERAD recall. PSMD low A+ subjects had 5.5 times higher risk of cognitive decline (p<0.01) than PSMD low A‐, while PSMD high A+ had 14.3 times higher risk.ConclusionWe found that high PSMD load increases the risk of AD disease progression, but is not significantly associated with delayed recall, the core cognitive biomarker of AD.
Role of the Gut Microbiome in Cognitive Health of Puerto Ricans: A Novel Perspective for Understanding Alzheimer’s Disease
Authors: Herrero‐Rivera Carlos Alberto , Morales Hiram , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Olivieri‐Henry Gerianne , Godoy‐Vitorino Filipa , Sepulveda Vanessa 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) comprise over 70% of dementia cases in the United States (US), characterized by progressive neurodegenerative symptoms. In the US and Puerto Rico (PR), AD is the sixth and fourth leading cause of death, respectively. The Gut‐Brain Axis is a bidirectional communication mechanism between the central nervous system and microbes that reside in the gastrointestinal tract. Research shows that neuroactive metabolites influence neurological responses and inflammatory pathways. Even though a correlation between gut microbiome and some neuropsychological diseases (e.g., Parkinson’s) has been described, its association with AD is understudied. This study compared the gut microbiome of Puerto Ricans with AD to healthy controls to help elucidate the role of gut microbiota as a possible contributing factor for the high prevalence in this population.MethodThe study evaluated 100 participants: AD (n = 50) and controls (n = 50) with a medical history, physical exam, ApoE genotype, and cognition using the Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR). Stool for genomic DNA extractions and microbiome characterization using 16S rRNA genes (V4 region) via Illumina MiSeq.ResultMicrobial Alpha Diversity showed no significant difference between AD and controls. Microbial Beta Diversity showed a significant difference between groups (P‐value = 0.034). Phyla‐level taxa tendencies in AD showed a higher relative abundance of Actinobacteria, Verrucomicrobia, and Euryarchaeota. Taxonomic profiling also showed reduced levels of neuroprotective genera Faecalibacterium and Bacteroides, and increased levels of pro‐inflammatory opportunistic Eggerthella. Regarding CDR testing of AD groups, there were significant differences in alpha diversity among normal CDR with mild and severe dementia. The microbial richness of controls declined with their cognitive status based on MoCA. One variant of ApoE4 was present in 92% of AD patients (46/50) and 94% in controls (47/50). Only one subject had E3E3 phenotype while 30.4% E3E4, 2.9% E4E4, and 5.9% E2E3.ConclusionThis study, the first of its kind in PR, suggests that microbial diversity and richness are associated with cognitive status. Furthermore, it showed possible bacterial dysbiosis in AD patients compared to controls which paves the way for identifying microbial biomarkers and modulation‐based interventions.
Significant Relationship Between Worsening Sleep and Declining Brain Metabolism in APOE4+ Individuals
Authors: Hogue Anne E. , Silverman Daniel H. 
Published: January 2025

AbstractBackgroundWe recently reported that subjects who had worsening sleep over time had a clear worsening of both memory and brain metabolism compared to subjects whose sleep improved over time, and metabolic decline was particularly significant in the posterior cingulate cortex (PCC) (Alzheimer’s Dement. 2023; 19(Suppl. 24):e082867), an area of the brain that metabolically declines in the earliest stages of Alzheimer’s disease. Here we investigate the impact of worsening sleep on regional metabolic decline in Apolipoprotein E epsilon 4 positive (APOE4+) subjects compared to APOE4‐ subjects.MethodA consecutive series of 2,005 cognitively normal and mildly impaired subjects from more than 50 North American sites participating in the first three phases of the Alzheimer’s Disease Neuroimaging Initiative were studied. Changes in cognition assessed through formal neuropsychological testing, and in regional cerebral metabolism assessed through brain PET using the radiotracer [F‐18]fluorodeoxyglucose were examined. Activities in 47 standardized volumes of interest (sVOI’s), as normalized to each subject’s pons activity, were longitudinally measured.ResultIn this consecutive series of subjects, 211 were found to have had a change in insomnia status during their participation: 83 who were documented to have insomnia at baseline that was subsequently alleviated (“improving sleep”), and 128 who were documented to have no insomnia at baseline but developed it during the study period (“worsening sleep”); of the 211, 62 (29%) underwent FDG‐PET scans during both baseline insomnia and subsequent insomnia‐free status, or both baseline normal sleep and subsequent insomnia status periods. Within this group, 27 subjects were APOE4+ and 35 were APOE‐, with 59% of the APOE4+ subjects belonging to the worsening sleep group, and 41% within the improving sleep group. In the worsening sleep group with APOE4+ status, there was metabolic decline in bilateral mesial temporal and right thalamic regions (p&lt;0.0001), but not among those with APOE4‐ status (p&gt;0.50).ConclusionWorsening sleep was associated with regionally specific cerebral metabolic decline, as described above, in APOE4+ but not APOE4‐ non‐demented subjects, suggesting that poor sleep status may pose especially heightened risk of decline for those bearing APOE4 alleles.
Operationalizing postmortem pathology‐MRI association studies in ADRD with MRI‐guided histology sampling: does closer proximity lead to stronger associations?
Authors: Athalye Chinmayee , Khandelwal Pulkit , Bahena Alejandra , Trotman Winifred , Ohm Daniel T , Emrani Sheina , Teunissen‐Bermeo Eric , Capp Noah , Lim Sydney A , Levorse Lisa M , Denning Amanda E , Ittyerah Ranjit , Schuck Theresa , Gabrielyan Marianna , Prabhakaran Karthik , Mizsei Gabor , Robinson John L. , Detre John A. , Lee Eddie B , Irwin David J , McMillan Corey T , Tisdall M. Dylan , Das Sandhitsu R. , Wolk David A , Yushkevich Paul A. 
Published: January 2025

AbstractBackgroundHistopathological analysis of autopsied brains is the gold standard of diagnosis in neurodegenerative disorders. Co‐registered histology and MRI scans aid in understanding pathology and structural features. Previous studies focused on the medial temporal lobe (MTL) for atrophy patterns in phosphorylated tau (p‐tau) pathology and in whole hemisphere scans with contralateral semi‐quantitative p‐tau measures. Here, we extend this to study ipsilateral quantitative p‐tau and cortical thickness.MethodWe used 29 brain hemispheres from patients with Alzheimer’s Disease (AD) diagnosis. We identified 19 regions of interest (ROIs), spanning the cortex and MTL. The ROIs were manually marked on the T2‐weighted 7T hemisphere MRI (0.3mm3 isotropic). The MRI scans were used to build a 3D‐printed mold of the brain. This mold helped identify the slabs with ROIs for histological staining. We used LFB‐CV (Luxol fast blue cresyl violet) stain and AT‐8 antibody for p‐tau on each ROI slide, which were then registered to the whole hemisphere MRI scans in a semi‐automatic manner. We used a weakly‐supervised learning algorithm WildCat to get quantitative measures of p‐tau for each ROI in the histology. Regional cortical thickness at the ROI markers was measured as the diameter of the maximally inscribed sphere in the topologically‐corrected automated deep learning‐based segmentations. Separately, whole hemisphere‐based thickness measurements were derived using a surface‐based parcellation scheme.ResultOne‐sided Spearman rank test was performed to assess the correlation between p‐tau and cortical thickness measurements. For ipsilateral quantitative p‐tau, this test showed significant correlation in the posterior cingulate gyrus (r = ‐0.53, p‐value = 0.0072), anterior cingulate gyrus (r = ‐0.45, p‐value = 0.019), and the middle frontal gyrus (r = ‐0.41, p‐value = 0.025). We performed the same test with contralateral semi‐quantitative tau scores (Table 1). A generalized linear model showed significant correlations between whole hemisphere vertex‐wise thickness with regional measurements of neuronal tangles in the anterior cingulate (Figure 2).ConclusionPostmortem MRI‐guided ipsilateral quantitative p‐tau burden measures showed better correlation with cortical thickness, in absolute terms, than contralateral semi‐quantitative tau scores. Replication and understanding whether co‐localization or improved quantification are most responsible for this improvement will require larger brain donor cohorts.
Clinical Utility of U‐p53AZ as a prognostic biomarker for the prediction of progression rate, in individuals with early stages of Alzheimer’s Disease
Authors: Agus Shmuel , Piccirella Simona , Durrant Abe , Duncan Garrett B , Dickson Samuel P. , Hendrix Suzanne B. , Kinnon Paul 
Published: January 2025

AbstractBackgroundDespite recent success in AD clinical trials, many obstacles still prevent effectively halting disease progression. Many suspect that treating subjects earlier in the disease process will be key to providing more effective treatment. Better early diagnostics will aid the design and execution of prevention and early AD studies. Furthermore, early identification of rapid progressors may be valuable in treatment development, since imbalance of rapid progressors can disrupt the proper identification of effective treatment. We present the performance of U‐p53AZ (AZ284) to identify slow progressors and rapid progressors.MethodA total of 629 participants were randomly selected from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and the Alzheimer Disease Research Center (ADRC). 172 participants were classified as AD, 303 as cognitively normal, and 154 as MCI or other. U‐p53AZ measurements were taken at baseline and the prognostic value of U‐p53AZ was assessed through multiple analyses. Logistic regression models were fit to predict clinical diagnosis at time points up to 6 years and analyzed through receiver operating characteristic (ROC) analyses. Additionally, U‐p53AZ was used to predict “rapid progressors”. Rapid progressors were defined as patients that progressed in clinical diagnosis to AD within 2 years and as patients which progressed in clinical outcomes using a global statistical test (GST).ResultU‐p53AZ shows strong predictive performance as a standalone metric throughout both cohorts with an overall AUC of 0.956 when predicting clinical diagnosis at 6 years. Adding demographic variables in the AIBL study raises the AUC over 0.98. For modeling rapid progressors to a clinical diagnosis, U‐p53AZ returns an AUC of 0.887 between both studies. Using a GST of clinical outcomes to define rapid progressors results in an AUC of 0.914. In each case, U‐p53AZ returned a higher AUC compared to PET imaging or CSF.ConclusionU‐p53AZ can be used to improve prognostic accuracy of progression to AD over both 2 and 6 years, which will improve screening for AD patients in the clinic and in clinical trials. This prognostic accuracy will help obtain early treatment in those subjects and save resources among those unlikely to develop AD.