bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐Modal Structural Covariance Patterns Predictive of Dementia Ratings and Geriatric Depression Severity
Authors: Nickerson Lisa D , McManus Kaitlin R. , Kumar Poornima , Frederick Blaise deB , Harper David G. 
Published: December 2023

AbstractBackgroundMore than 6 million Americans suffer from Alzheimer’s disease (AD), the most common age‐associated, neurodegenerative dementia, characterized by progressive cognitive decline and the sporadic emergence of neuropsychiatric symptoms (NPS). We applied linked independent component analysis (LICA), a unsupervised learning approach for data fusion, to identify multi‐modal gray matter patterns of covariation that were predictive of dementia ratings and depression symptoms to understand the brain circuitry underlying both.MethodPublicly available data from 277 participants (177 healthy controls, 61 mild cognitive impairment, and 39 AD (aged 58 – 93) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset were used to conduct secondary analyses.T1‐weighted MR images were used to compute spatial maps of cortical thickness (CT) and pial surface area (PSA) using Freesurfer and grey matter (GM) density maps using FSLVBM. CT, PSA and GM maps for each modality were concatenated across participants into 4D data files that were analyzed using FSL Linked ICA to estimate 25 multi‐modal spatial components and subject loadings quantifying the strength of each component pattern per participant. Random forest regression with 5‐fold cross validation was used to predict CDR and GDS from the resulting subject loadings (with age, sex and site).ResultTwo LICA components (Fig 1) had highest feature importance in predicting CDR (R2 = 0.41). The same two patterns (Fig1) plus two additional patterns (Fig 2) were most important in predicting GDS (R2 = 0.08).ConclusionGreater CDR was predicted by larger (Fig 1A) decreased GM and CT of widespread temporal lobe regions and (Fig 1B) of reduced GM of entorhinal cortex/mesial temporal lobe with nodes of the default mode network, implicated in disease progression. Greater GDS was also predicted by these two patterns as well as a pattern (Fig 2A) reflecting decreased GM in nucleus accumbens, amygdala and a cerebellar‐thalomocortical (CTC) circuit strongly implicated in cerebellar cognitive affective syndrome (CCAS) and another (Fig 2B) comprised of CT decreases in cortex and temporal regions and GM decreases in frontoparietal regions resembling areas of the frontopariatal functional connectivity network. These multi‐modal brain‐behavior mappings could be translated to better understand dementia and neuropsychiatric symptoms of AD.
The Complex CPAP and Oxygen Therapies and Quality of Life in Alzheimer Patients
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich 
Published: December 2023

AbstractBackgroundCPAP, as a method of artificial pulmonary ventilation by constant positive pressure, improves oxygen supply to organs and tissues, including the cells of the cerebral cortex. This effect increases when CPAP and oxygen therapy are combined.MethodWe followed 11 female patients, ages 65 to 75, with Alzheimer’s disease. They were treated for Alzheimer’s disease according to accepted standards. All of them had COVID‐19, and in the rehabilitation program, they were prescribed CPAP therapy in combination with oxygen therapy, which was performed at night when the patients were sleeping, for one month. When they went to bed at a fixed time, a helmet was put on their heads, which allowed them to perform CPAP and oxygen therapy in their sleep. One patient could not get used to sleeping in the helmet, so she was treated differently and was excluded from our study. We also changed the oxygen content of the air in the helmet every three days. The patients themselves also filled out a Quality of Life Rating Scale every two weeks.ResultAfter the sessions, the patients subjectively evaluated their condition as being more rested, stronger, and able and willing to do something. Objectively, there were no improvements in patients' activity during the first two weeks of therapy. Already, after a week of therapy, a fixed bedtime led to better sleep. Also, the best effect was observed when the concentration of oxygen in the supplied air was between 35 and 40 percent. After one month of therapy, patients rated their health as good on the Quality of Life Rating Scale, whereas at the beginning of therapy, they rated their health as poor. After one month of therapy hedonic was evaluated as having joy in life, as opposed to a lack of joy in life, at the beginning of therapy. Also, all the patients themselves associated these changes with the CPAP and oxygen therapy.ConclusionComplex CPAP and oxygen therapy can be recommended as part of a comprehensive therapy for Alzheimer’s disease to improve their quality of life.
Serine racemase expression in the pyramidal layer of the hippocampus of rat in the hypertensive encephalopathy modeling
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich 
Published: December 2023

AbstractBackgroundExcessive influence of glutamate on NMDA receptors mediates a cascade of biochemical changes leading to the development of intracellular acidosis, accumulation of free intracellular calcium and activation of a number of enzymes with the formation of free radicals. D‐serine acts as a co‐agonist of NMDA receptors and is involved in learning and memory under normal conditions. However, it has been suggested to play a role in glutamate damage in a number of CNS diseases. The formation of D‐serine in neurons and glial cells occurs with the participation of the enzyme serine racemase (SR) from L‐serine. An increase in the content of SR and the product of its enzymatic reaction, D‐serine, is considered as a process preceding excitotoxicity.MethodHypertensive encephalopathy was modeled on 12‐month‐old rats by the method of exposure to negative longitudinal g‐forces in the caudocranial vector with a force of 9 G for 5 minutes with an interval of 12 hours for 28 days. The following indicators were assessed: behavioral responses, cognitive and mnestic functions, the relative number of neurons with signs of damage, and the level of expression of serine racemase.ResultA morphometric study of the pyramidal layer of the hippocampus revealed a significant increase in the relative area of the immunopositive material in CA1 by 5.5% compared with the control (p<0.05). A feature of the expression of serine racemase in the experimental group was the translocation of immunopositive material, which was determined not only in the cytoplasm of perikaryons, but also in the dendrites of pyramidal neurons. In addition, the nature of expression changed in the experimental group to a moderately pronounced one, and in some pyramidal neurons to a pronounced one. Violation of the cytoarchitectonic of the CA1 zone was manifested in a less compact arrangement of pyramidal neurons, a pattern of spongiosis due to pericellular and perivascular edema, and the acquisition of increased tortuosity by neuronal dendrites.ConclusionHypertensive encephalopathy modeling demonstrates a sharp increase in the relative number of neurons with signs of damage, a decrease in the specific
Structural changes and features of heat shock protein HSP70 and HSP90 expression in the pyramidal neurons of the hippocampus of rat in the experimental discirculatory encephalopathy modeling
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich 
Published: December 2023

AbstractBackgroundThe heat shock protein (Hsp) system acts as intracellular chaperone molecules responsible for maintaining normal intracellular homeostasis by regulating the correct coagulation of newly synthesized peptides, as well as the transport and degradation of mature proteins. In addition to their role as chaperones, proteins of the Hsp family stabilize the cell membrane and inhibit the caspase‐dependent apoptosis cascadeMethodHypertensive encephalopathy was modeled on 12‐month‐old rats by the method of exposure to negative longitudinal overloads in the caudo‐cranial vector with a 9 G force for 5 minutes with 12 hours interval for 28 days. The behavioral responses, cognitive and mnestic functions, the relative number of pyramidal neurons with hyperchromic cytoplasm and shrunken perikariya, and the level of expression of heat shock proteins 70 kDa (Hsp70) and 90 kDa (Hsp90) were assessedResultAfter 28 days of exposure to 9 G negative longitudinal overloads, the rats showed functional and morphological manifestations characteristic of hypertensive encephalopathy. There was a decrease in the basic reflexes, disorders of the cognitive sphere, as well as decrease in memory and orientation‐exploratory activity. Morphological examination of the hippocampus against the background of pronounced edema revealed a significant increase in the relative number of pyramidal neurons with hyperchromatosis and perikaryon shrinkage in all zones of the pyramidal layer (p <0.01). These signs of reversible and irreversible damage were accompanied by a significant increase in Hsp70 expression, especially pronounced in the CA3 zone (p <0.01). A significant increase in Hsp90 expression was found in the CA1 zone (p <0.05)ConclusionDiscirculatory encephalopathy experimental modeling demonstrates signs of both reversible and irreversible alteration in all regions of the pyramidal layer of hippocampus. Differences in the ability of neurons of the pyramidal layer of different regions of the hippocampus to express Hsp70, Hsp90 were noted. In the CA1 and CA3 zones, compensatory reactions are more pronounced and are accompanied by a more pronounced expression of Hsp70, while in CA1, the expression of Hsp70 and Hsp90 is simultaneously enhanced
Age related neuropathology in a novel mouse model of Adult‐onset leukoencephalopathy
Authors: Shabestari Sepideh Kiani , Radhakrishnan Hamsi , Rothermich Winston Chang , Capocchi Joia Kai , Jullienne Amandine , Nguyen Jasmine , Tran Kayla Nhi , Pascual Jesse R. , Martini Alessandra Cadete , Head Elizabeth , Hume David A , Pridans Clare , Obenaus Andre , Stark Craig E.L. , Davtyan Hayk , Blurton‐Jones Mathew 
Published: December 2023

AbstractBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare human disease that is caused by mutations in CSF1R, a gene that is critical for the differentiation, proliferation, and survival of microglia. ALSP patients typically develop dementia, motor impairments, and seizures during their 30s or 40s. Upon autopsy, patients’ brains exhibit decreased numbers of microglia, white matter atrophy, astrocytosis, axonal spheroids, enlarged ventricles, and calcification. Two recent reports have further described rare cases of homozygous CSF1R mutations that lead to perinatal lethality, a complete absence of microglia, and an acceleration of ALSP pathologies. Unfortunately, there is currently no effective treatment for this devastating disease.MethodTo better understand the role of microglia in the development and progression of ALSP we utilized the ‘FIRE’ mouse model that harbors a homozygous deletion in a microglial‐specific enhancer within the CSF1R gene.ResultSurprisingly, at 2 months of age, despite absence of microglia, FIRE mice exhibit normal brain gross anatomy, minimal white matter alterations, and little to no pathology. However, by 10‐months of age FIRE mice exhibit many of the pathologies and symptoms observed in ALSP patients, including axonal spheroids, calcification, demyelination, seizures, and behavioral deficits. Importantly, postnatal transplantation of wildtype murine microglia prevents nearly all of these pathologies, demonstrating the importance of decreased microglial numbers on the development of ALSP. Additional ongoing examinations of 2‐ and 10‐month‐old FIRE mice are exploring the sex‐related impact of microglia absence on synaptic density and utilizing MRI imaging to examine white matter integrity and calcification.ConclusionTaken together, these data suggest that aged FIRE mice may provide a novel and informative, albeit rapidly progressing, model of human ALSP.
Deficit accumulation in relation to dementia and survival outcomes in residential care older adults
Authors: Song Xiaowei , Greeley Brian , Low Hilary , Hoang Jenny , Kelly Ronald , McDermid Robert 
Published: December 2023

AbstractBackgroundAs people age, they are more likely to accumulate health deficits leading to an increased risk of adverse outcomes, including dementia. In community‐dwelling older adults, even combining only the deficits traditionally unrelated to dementia predicts dementia. Previously, we reported an association between deficit accumulation and dementia in residential care. Here, our objectives are to 1) understand the profiles of deficit accumulation and the relationships between traditional and non‐traditional dementia risk factors in older residents with or without dementia and 2) investigate the impact of deficit accumulation on dementia and survival outcomes in residential‐care older adults.MethodWe analyzed the first full‐assessment data of older adults in InterRAI Residential Care (RAI‐RC MDS2.0) who enrolled in facilities under the care of Fraser Health Canada between 2010 and 2019 (female = 63.8%, mean age = 84.6±8.0 years). Dementia diagnoses (n = 18169), including pure Alzheimer’s disease (AD), mixed AD, other dementia, and no dementia (n = 11,589), were recorded at annual assessments. Two indices were constructed as the mean of the coded deficits between 0 (absent) and 1 (present), employing the same descriptive levels as in the original assessment. One index contained 20 traditional dementia risk factors (e.g., cognition, hypertension, and heart disease); the other contained 20 non‐traditional ones (e.g., vision, hearing, arthritis, and continence). Participants were followed until 2021. Relationships between the indices and their impact on survival were tested. Incidental dementia outcome was examined for the non‐demented sub‐sample.ResultOver 92% of residents had at least one daily‐living dependency. The two indices were highly correlated (R = 0.59, p<.001), and each positively related to mortality, regardless of dementia diagnoses. People with dementia accumulated more deficits and had a higher mean traditional risk index than those without dementia (F = 334.72, p<.001), while the latter group accumulated more non‐traditional risk factors on average (F = 135.39, p<.001). A higher level of the indices showed variable risks of incidental dementia at follow‐ups (p’s<.05).ConclusionOlder residents without dementia are dominated by dependent living with a distinct deficit accumulation profile than those with dementia. Deficit accumulation has negative impact on both dementia and survival outcomes in residential care.
APPLE‐Tree remote secondary dementia prevention; opportunities for scalable public health interventions to reduce dementia risk
Authors: Cooper Claudia , Barber Julie , Aguirre Elisa M , Whitfield Elenyd M , Parnell‐Johnson Sukey M , Martin Wendy M , Higgs Paul , Minihane Anne‐Marie , Poppe Michaela , Burton Alexandra , Marchant Natalie L , Bass Nicholas , Morgan‐Trimmer Sarah , Rapaport Penny , Kales Helen C , Huntley Jonathan D , Ritchie Karen , Hunter Rachael M , Walker Zuzana , Brodaty Henry , Lang Iain A , Petersen Irene , Rio Miguel , Wenborn Jennifer , Adeleke Mariam M , Walters Kate 
Published: December 2023

AbstractBackgroundNearly half of people aged 60+ experience memory impairments that infer an increased risk of dementia. The UK APPLE‐Tree (Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce) trial is evaluating a secondary dementia prevention intervention for people at increased dementia risk, delivered by group video call. It is potentially the first such intervention to be scalable to whole populations.MethodIn 2020‐22, We randomized 748 people aged 60+ with subjective or objective memory impairment, without dementia, 1:1 to the APPLE‐Tree intervention or usual care. In a visual ethnography sub‐study, we recruited intervention participants, purposively for diversity of background and experiences, to participate in photo‐elicitation interviews and workshops with a professional photographer/artist; where they created and shared photographs reflecting what they valued in their daily lives, their experiences of memory concerns, and the intervention. We used qualitative thematic methods to analyse interview, observational and visual data, exploring their experiences of active dementia prevention and the intervention.ResultsWe will present findings from our qualitative sub‐study. Nineteen intervention participants took part. We developed themes around: (1) connections to nature as a lifeline; (2) anchoring experiences within relationships to family; (3) reflecting on self‐growth: making active health and lifestyle changes intended to address memory concerns that were not perceived as inevitable. (4) exploring how enduring self‐identity underpinned a resilience to ageing stereotypes, and enabled adaptation and coping in response to challenges of memory concerns, ageing and the pandemic. We will describe the resulting co‐designed exhibition that was launched in London and exhibited at the Houses of Parliament.ConclusionWe describe experiences of the first group video‐call intervention which seeks to address key risk factors for dementia, including social isolation. The shift to remote delivery of psychosocial interventions has potential gains in terms of scalability and cost‐effectiveness, but risks increasing digital exclusion in vulnerable older people, especially those with memory concerns. We will discuss what our qualitative findings tell us about the effectiveness of our strategies to develop an inclusive, useful intervention.
A cell‐autonomous role of DNAJC5 in microglial‐mediated proteostasis in Alzheimer’s disease
Authors: Rosene Matthew J , Nykanen Niko‐Petteri , Brase Logan , Harari Oscar , Benitez Bruno A. 
Published: December 2023

AbstractBackgroundDNAJC5 encodes co‐chaperone cysteine‐string protein alpha (CSPα), a synaptic and endolysosomal protein whose mutations cause adult‐onset neuronal ceroid lipofuscinosis (ANCL). Characterized by endolysosomal dysfunction, microgliosis, synaptic loss, and protein aggregation, ANCL shares pathological features with Alzheimer’s disease (AD). The endolysosomal role of CSPα in non‐neuronal cell types has been understudied. Here, we aimed to address this gap and hypothesized that CSPα plays a yet undefined microglial role in AD.MethodAβ levels and plaques in human tissue were assessed through ELISA and immunohistochemistry, respectively. Bulk‐RNAseq data from two independent cohorts of AD and ANCL patients with controls (GSE5281; GSE15222) were analyzed. To assess cell‐autonomous expression, single‐nuclei RNAseq (snRNA‐seq) was mined from the parietal cortex of AD patients with APP and PSEN1 mutations (n = 16) along with sporadic AD (n = 31), non‐AD (n = 9), presymptomatic (n = 3), and control patients (n = 8). An independent cohort (GSE138852) was analyzed for rigor. Using Clue.io, candidate therapeutics projected to reverse the observed transcriptomic profile from DNAJC5 mutants in myeloid cells were identified. A cohort from iPSC‐derived microglia (GSE178317) was cross‐analyzed with the ANCL RNAseq.ResultIn tissue from ANCL patients, soluble or insoluble Aβ levels were nearly nonexistent and synaptic protein levels were reduced, but intraneuronal Aβ accumulation was increased, suggesting altered APP processing. In two independent RNAseq cohorts (GSE5281; GSE15222), DNAJC5 was reduced in AD patients versus controls. SnRNA‐seq from parietal cortex revealed higher DNAJC5 transcript levels in microglia versus neurons. RNAseq obtained from ANCL patients was cross‐referenced with dataset obtained from iPSC‐derived microglia, revealing 35 differentially expressed genes associated with proliferative microglia and 32 genes associated with the interferon/chemokine response. Analysis of ANCL transcriptomics in myeloid cell lines using Clue.io indicate HSP inhibitors (BIIB‐021, geldanamycin), an opioid receptor antagonist (BNTX), and a proteasome inhibitor (bortezomib) suggesting convergence in proteostasis in microglial cells. ANCL‐patient transcriptomics displayed reduced TSPAN14, which facilitates ADAM10 maturation, and elevated APH1B and GSAP, enzymes that promote γ‐secretase activity suggesting a shift towards amyloidogenic pathway.ConclusionDNAJC5 is implicated in AD pathogenesis modulating APP processing and amyloidogenesis. Furthermore, endolysosomal DNAJC5 might play a novel cell‐autonomous role in microglia under altered proteostasis.
Dihydroxytrimethoxyflavone possess memory improvement effects against scopolamine in mice via modulating multiple pathways: In‐silico and in‐vivo evidences
Authors: Singh Varinder , Singh Manjinder , Singh Thakur Gurjeet , Shri Richa 
Published: December 2023

AbstractBackgroundDementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.MethodsAnimals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.ResultsTreatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.ConclusionThese results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.