bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between sleep restlessness and neuroimaging biomarkers of Alzheimer’s Disease in mid‐life to older adults and patients
Authors: Kholghi Mahnoosh , Fazlollahi Amir , Lupton Michelle K , Bourgeat Pierrick , Zhang Qing , Martin Nicholas G , Breakspear Michael , Fripp Jurgen ,   PISA (Prospective Imaging Study of Aging: Genes, Brain and Behaviour)
Published: June 2023

AbstractBackgroundRecent research demonstrates a bidirectional relationship between sleep and Alzheimer’s Disease (AD) pathology, with supporting evidence that changes in sleep pattern occurs from the preclinical stage of AD. The cooccurrence of sleep disturbances and amyloid‐beta (Aβ) accumulation suggests the importance of monitoring sleep patterns in adults that are at high‐risk of developing AD later in life. We first investigated whether resting heart rate (RHR) and nocturnal sleep restlessness (NSR) are different in cognitively impaired (CI) and cognitively unimpaired (CU) mid‐life to older adults. We also examined any association of these sleep characteristics with hippocampus volume (HV) and Aβ, as neuroimaging biomarkers of AD, regardless of the cognitive status.Method107 middle to old age (46‐75 years old) adults (age 61.5±6.5, 74 Females, 64 APOE ε4 carriers, and 88 CU) underwent 3T MRI and PET scans as part of the Prospective Imaging Study of Ageing (PISA) study. A ballistocardiograph sleep monitoring device was used to track their RHR and NSR for approximately 5 months after their PET scan. NSR was quantified by total time in bed, total duration and number of bed‐exits, and multi‐episodic sleep. HV was normalised using total intracranial volume, and Aβ load was calculated in Centiloid scale (CL) with Aβ positivity defined as CL>20. Generalised Linear Models were used to examine the relationship between sleep and imaging biomarkers. Age, gender, BMI, APOE, and years of education were used as independent covariates.ResultCIs spent more time in bed (p = 0.002) and had more bed‐exits (p = 0.009) than CUs. However, no significant difference was found on RHR and multi‐episodic sleep between CUs and CIs. Individuals with higher Aβ load, regardless of their cognitive status, had lower RHR (p = 0.04) and more bed‐exits (p = 0.04), and spent more time in bed (p = 0.01). Also, individuals with smaller HV frequently exited the bed during the night (p = 0.03) and spent more time in bed (p = 0.003).ConclusionIndividuals with cognitive impairment experienced higher levels of NSR with frequent bed‐exits and more time in bed. Also, these sleep characteristics were significantly associated with the Centiloid value, Aβ status, and HV, regardless of the cognitive status.
Microglia show distinct tau associated subpopulations along tau spreading in human Alzheimer’s disease
Authors: Wachter Astrid , Woodbury Maya E. , Abdourahman Aicha , Bennett Rachel E , Lin Gen , Kwon Taekyung , Liao Fan , Pastika Timothy , Tamm Joseph A. , Venkat Nandini , Yanamandra Kiran , Grinberg Yelena , Kummer Markus P. , Das Sudeshna , Dellovade Tammy L. , Karran Eric H , Langlois Xavier , Ried Janina S , Serrano‐Pozo Alberto , Talanian Robert V. , Biber Knut , Hyman Bradley T. 
Published: June 2023

AbstractBackgroundIn Alzheimer’s disease (AD) progression, amyloid beta load uniformly increases across the brain cortex, while neurofibrillary tangles progressively spread in a stereotypical pattern from entorhinal to visual cortex. AD is known to have a strong genetic link to microglia and recently, expression profiling at single cell resolution has identified disease‐associated microglia populations with differential amyloid‐beta vs. tau pathology association in human AD brain. However, prior human studies focusing on microglia included a limited number of donors and/or cells per donor, and how microglial transcriptomes change with progression of tau pathology remains largely unknown.MethodUsing single nuclei RNA sequencing, we profiled 337,512 microglia from 32 donors across 4 pathology groups (no to severe pathology) and five brain regions along the tau spreading pathway (entorhinal cortex, Brodmann Area 20, Brodmann Area 46, secondary visual cortex, and primary visual cortex) to investigate their cellular heterogeneity as a function of disease progression. Phospho‐Tau231 and HT7‐HT7 aggregated tau levels of adjacent tissue were assessed for quantification of tau pathology.ResultWe confirmed previously described microglial populations across all profiled regions and identified cluster associations with tau levels, which mirrored the expected stereotypical progression across brain regions. Integrative analysis showed high similarity of microglia subtypes across regions, but interestingly also revealed entorhinal cortex and late tau pathology enriched clusters. Genes upregulated in early vs. late tau‐affected regions at severe pathology stage, but not in healthy brain, were found to be enriched in DNA repair and replication processes as well as immune response activation, while downregulated genes corresponded to glial cell differentiation and gliogenesis.ConclusionThis study constitutes a high‐quality resource of microglia phenotypes in a previously unmet sample size with regard to both donors and cells per donor, well characterized by quantitative readouts for tau pathology association across tau spreading regions. We foresee this study will contribute to a better understanding of how microglial phenotypes can be targeted during the progression of tau pathology in AD, while further work is required to distinguish causality from consequence.
Expression of proteins involved in mitochondrial fusion, fission and energy production is altered by age, sex and Alzheimer’s disease
Authors: Aeschlimann Pascale C , Lane Emma L , Gee Julia M , Kidd Emma J 
Published: June 2023

AbstractBackgroundAge is the biggest risk factor for Alzheimer’s disease (AD) but being female also increases risk with ∼63% of AD patients being female. This sex difference could partly be explained by menopause‐related oestrogen deficiencies during ageing. Oestrogen is neuroprotective and it is highly probable this deficiency after the menopause affects neuronal survival and contributes to the onset of AD. Oestrogen receptors are found in mitochondria and evidence suggests that the neuroprotective effect of oestrogen involves supporting mitochondrial function. The clear link between mitochondrial dysfunction and the pathophysiology of AD suggests a decrease in the beneficial effects of oestrogen on mitochondrial function after the menopause would have serious consequences. We hypothesise that alterations in oestrogen, due to ageing and the menopause, affect mitochondrial function and contribute to the increased susceptibility of women to AD.MethodLevels of mitochondrial proteins, dynamin‐related protein‐1 (DRP‐1), mitofusin‐1/2 (Mfn1/2), mitochondrial dynamin‐like GTPase (OPA1) and the electron transport chain (ETC) complexes 1‐5, were measured using immunoblotting in frontal cortical brain samples from young (20‐36), middle‐aged (40‐53) and old (64‐99) men and women with no history of dementia and in AD patients (Braak stage 5/6, 69‐92 age).ResultIn female AD brains a significant decrease was observed in Mnf1 and DRP‐1 compared to age‐matched females and in OPA1 in male AD compared to old male brains. Mnf2 and ETC complex 3 (cytochrome reductase) were significantly increased in female AD compared to male AD brains. DRP‐1 was significantly decreased in old males compared to middle‐aged males, while ETC complex 2 (succinate dehydrogenase) was significantly increased in old females compared to young females.ConclusionWe demonstrate for the first time age, sex and disease differences in the expression of proteins involved in various aspects of mitochondrial function including fusion, fission and energy production. These changes could underlie previous findings showing a range of mitochondrial abnormalities in AD brains and support the ‘mitochondrial cascade hypothesis’ that mitochondrial dysfunction is the primary event causing β‐amyloid deposition, synaptic degeneration, and NFT formation (Swerdlow et al., J. Alz. Dis. 2010 20:Suppl 2, 265‐79.). Our findings could partly explain female vulnerability to AD development.
Objective assessment of sleep parameters using multimodal AX3 data in older participants
Authors: Kalantari Elaheh , Monica Ciro Della , Revell Victoria Louise , Atzori Giuseppe , Hilton Adrian , Skeldon Anne C , Dijk Derk‐Jan , Kouchaki Samaneh 
Published: June 2023

AbstractBackgroundSleep disturbances are both risk factors for and symptoms of dementia. Current methods for assessing sleep disturbances are largely based on either polysomnography (PSG) which is costly and inconvenient, or self‐ or care‐giver reports which are prone to measurement error. Low‐cost methods to monitor sleep disturbances longitudinally and at scale can be useful for assessing symptom development. Here, we develop deep learning models that use multimodal variables (accelerometers and temperature) recorded by the AX3 to accurately identify sleep and wake epochs and derive sleep parameters.MethodEighteen men and women (65‐80y) participated in a sleep laboratory‐based study in which multiple devices for sleep monitoring were evaluated. PSGs were recorded over a 10‐h period and scored according to established criteria per 30 sec epochs. Tri‐axial accelerometers and temperature signals were captured with an Axivity AX3, at 100Hz and 1Hz, respectively, throughout a 19‐h period, including 10‐h concurrent PSG recording and 9‐h of wakefulness. We developed and evaluated a supervised deep learning algorithm to detect sleep and wake epochs and determine sleep parameters from the multimodal AX3 raw data. We validated our results with gold standard PSG measurements and compared our algorithm to the Biobank accelerometer analysis toolbox. Single modality (accelerometer or temperature) and multimodality (both signals) approaches were evaluated using the 3‐fold cross‐validation.ResultThe proposed deep learning model outperformed baseline models such as the Biobank accelerometer analysis toolbox and conventional machine learning classifiers (Random Forest and Support Vector Machine) by up to 25%. Using multimodal data improved sleep and wake classification performance (up to 18% higher) compared with the single modality. In terms of the sleep parameters, our approach boosted the accuracy of estimations by 11% on average compared to the Biobank accelerometer analysis toolbox.ConclusionIn older adults without dementia, combining multimodal data from AX3 with deep learning methods allows satisfactory quantification of sleep and wakefulness. This approach holds promise for monitoring sleep behaviour and deriving accurate sleep parameters objectively and longitudinally from a low‐cost wearable sensor. A limitation of our current study is that the participants were healthy older adults: future work will focus on people living with dementia.
Re‐evaluation of the genetic role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late‐onset Alzheimer disease
Authors: Fan Kang‐Hsien , Aslam Muhammad Muaaz , Francis Lily , Bedison Margaret A , Lawrence Elizabeth C , Acharya Vibha , Snitz Beth E , Ganguli Mary , DeKosky Steven T , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas 
Published: June 2023

AbstractBackgroundA rare missense APOE variant (L28P; APOE*4Pittsburgh) has been reported to be a risk factor for Alzheimer’s disease (AD). However, sinceL28P has been observed only among APOE*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect.MethodSamples were derived from three sources: University of Pittsburgh, Alzheimer’s Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE*4‐background and 3/4 is the most common genotype containing the APOE*4 allele.ResultA total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80.ConclusionEven with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology.
The APOEε4 allele exacerbates the transcriptomic responses to Aβ plaques and neurofibrillary tangles in Alzheimer’s disease
Authors: Li Zhaozhi , Wachter Astrid , Alla Srinija , Noori Ayush , Abdourahman Aicha , Tamm Joseph A. , Woodbury Maya E. , Talanian Robert V. , Biber Knut , Karran Eric H , Das Sudeshna , Hyman Bradley T. , Serrano‐Pozo Alberto 
Published: June 2023

AbstractBackgroundMicroglia, astrocytes, and neurons undergo profound functional alterations in response to amyloid‐β (Aβ) plaques and neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD). Recent studies using human induced pluripotent stem cell‐derived glial cells and neurons, APOE knock‐in mice, and human brain bulk RNA‐seq have implicated the APOE genotype in these changes, but lack spatial information with respect to Aβ plaques and NFTs. Here we tested the hypotheses that (1) transcriptomic differences between AD and control subjects are maximum within and near Aβ plaques and NFT‐bearing neurons; (2) Aβ plaques and NFTs are associated with distinct transcriptomic changes; and (3) the APOE genotype differentially impacts the transcriptomic changes associated with Aβ plaques and NFTs in the AD brain.MethodLaser capture microdissection (LCM) in cryostat sections was performed from superior temporal gyrus (BA22) cortex of human AD (n = 10, including n = 5 APOEε4/ε4, n = 4 APOEε3/ε3, and n = 1 APOEε3/ε4) and age‐ and sex‐matched controls (n = 8). Thioflavin‐S‐positive Aβ plaques, the 50 µm halo around them, NFTs with the 50 µm halo around them, and areas far (>50 µm) from plaques and NFTs were laser‐capture microdissected and subjected to RNA‐sequencing to identify differentially expressed genes (DEGs).ResultAβ plaques had a greater impact on the transcriptome than NFTs (i.e., higher number of DEGs, both upregulated [logFC>0, unadj. P‐value<0.05: 2,623 vs. 1,230 genes; adj. P‐value<0.05: 1,152 vs. 0 genes] and downregulated [logFC>0, unadj. P‐value<0.05: 2,563 vs. 1,056 genes; adj. P‐value<0.05: 827 vs. 0 genes]) relative to control cortex. Aβ plaques were characterized by upregulated microglial and downregulated neuronal genes, whereas NFTs had primarily downregulated neuronal genes. A gradient of Aβ plaques > plaque halo > NFTs > far areas was evident, with upregulation of neuroinflammation and downregulation of synaptic neurotransmission and energy metabolism‐related gene sets. Comparing APOEε4 and APOEε3 age‐ and sex‐matched homozygotes revealed greater changes in APOEε4 homozygotes across locations.ConclusionAβ plaques and, to a lesser extent, NFTs, concentrate the bulk of transcriptomic changes in the AD cortex. The APOEε4 allele is associated with greater microglial and neuronal transcriptomic responses to Aβ plaques and NFTs, compared to APOEε3 carriers. These findings will inform future spatial transcriptomics studies.
Brain reserve is associated with cognition in AD and MCI patients with different vascualr risk factors status
Authors: Lee Wei‐Ju , Chen Ting‐Bin , Chen Hung‐Chieh , Yang Yu‐Hsiu 
Published: June 2023

AbstractBackgroundDementia due to Alzheimer’s disease (AD) is the major type of dementias in the world. In addition to amyloid plaques and neurofibrillary tangles, cerebrovascular disease is another important pathophysiological cause of AD. Cerebrovascular disease is highly associated with vascular risk factors (VRFs). Well‐treated VRFs might decrease the risk and progression of AD. However, findings on the impact of VRFs treatment status on cognitive decline after the diagnosis of AD established are unclear, and there is no direct evidence supporting well‐treated VRFs can slow down the AD progression.MethodThis study recruited mild cognitive impairment (MCI) and mild AD patients (CDR = 0.5 or 1) with at least one VRF from at Taichung Veteran General Hospital. The treatment status of the VRFs was identified and all participants were evaluated by a standard neuropsychological test battery. We collected the participants’ brain MRI done within one year and performed Apolipoprotein E genotyping. FreeSurfer was used for structural MRI reconstruction and calculated total gray matter volume, hippocampus volume, and AD signature cortical thickness. Cerebrovascular lesions, including perivascular spaces in centrum semiovale, basal ganglia and presence of lobar cerebral microbleeds (LCMBs), and the volume of white matter hyperintensities were estimated by visual rating scales and Lesion Segmentation Tool for Statistical Parametric Mapping. We analyzed the relationships among the treatment status of VRFs, neuropsychological tests, and brain MRI.ResultWe recruited 61 patients in this study. Four patients refused to keep involving the study, 6 patients were not compatible with the criteria of MCI and AD after neuropsychiatric testing, and 4 patients’ brain MRI images cannot be analyzed after quality checked. The remaining 47 patients (15 MCI patients and 32 AD patients) constituted the final sample for analysis. The patients with well‐controlled VRFs present with similar cognitive function compared to the patients with partially‐controlled VRFs even though the more severe hippocampal atrophy was noted in the patients with well controlled VRFs. The severity of white matter hyperintensities and other cerebrovascular lesions are not correlated with the cognitive function in MCI and AD patients.ConclusionBrain reserve in the AD and MCI patients with well‐controlled VRFs might contribute cognitive function
Role of dopaminergic agonists on full‐length tau protein aggregation
Authors: Martic Sanela , Camilus Nayomi S 
Published: June 2023

AbstractBackgroundGlobally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. Dopamine receptor agonists have been used to target motor symptoms of AD [2] but there is a gap in knowledge on how these compounds play a role in tau protein aggregation.MethodHerein, we propose to evaluate the use of a unique class of multivalent inhibitors with various moieties (catechol, non‐catechol, biphenyl, piperazine, and thiazole) [3] as potential inhibitors for in vitro full‐length tau protein aggregation induced by heparin. Fluorescence aggregation assay, transmission electron microscopy and 4,4′‐Dianilino‐1,1′‐binaphthyl‐5,5′‐disulfonic acid dipotassium salt (Bis‐ANS) fluorescence spectroscopy were used to obtain IC50 values, characterize the aggregation morphologies and evaluate the hydrophobicity of tau aggregates, respectively.ResultThe catechol containing compounds, D‐519 and D‐520, prevented aggregation of tau whereas the non‐catechol and thiazole containing compounds (D‐264 and D‐636) were poor inhibitors. Based on the inhibitors’ density function theory calculations, effective aggregation inhibitors are characterized by their high polarity and polarizability.ConclusionData indicate that small molecule inhibitors may be useful therapeutics targeting tau aggregation related neurodegenerative diseases.
References:[1] a. Andronesi, O. C., Bergen, M. V., Biernat, J., Seidel, K., Griesinger, C., Mandelkow, E., & Baldus, M. (2008). Characterization of Alzheimer’s‐like paired helical filaments from the core domain of tau protein using solid‐state NMR spectroscopy. Journal of the American Chemical Society, 130(18), 5922‐5928.;b. Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E. M., & Mandelkow, E. (2008). Proline‐directed pseudo‐phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC‐1) conformation. Journal of Biological Chemistry, 283(46), 32066‐32076.[2] Martorana, A. et al. (2013). Dopamine D2‐agonist Rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacology, 64, 108‐113.[3] Ziu, I. et al. (2020). The multifunctional dopamine D2/D3 receptor agonists also possess inhibitory activity against the full‐length tau441 protein aggregation. Bioorganic & Medicinal Chemistry, 28(18), 115667.