bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between MTA visual scale scores and hippocampal volume measured by a medical device in patients from a multicentric memory clinic population
Authors: Longo Clarisse , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Schwarz Adam J. ,   MEMENTO Study group
Published: June 2023

AbstractBackgroundThe medial temporal lobe (MTL), including the hippocampus, undergoes atrophy in patients with Alzheimer’s disease (AD). Visual rating of medial temporal lobe atrophy (MTA) is often performed in the assessment of patients with cognitive impairment. Calculation of hippocampal volumes (HV) can also be achieved by multiple automated and semi‐automated methods using T1‐weighted MR images. The current study investigated the relationship between HV and z‐scores calculated by an automated method, included in the QyScore® medical device, and visual MTA rating scores using Scheltens’ scale in a multicentric memory clinic population at baseline.Method1959 participants from the MEMENTO cohort (Age 71.02 +/‐ 8.61, 1218 Female, MMSE 27.95 +/‐ 1.91) had 3DT1 MRI scans analyzed with QyScore®, an FDA‐approved and CE‐marked image analysis software. HV are reported in mL, corrected for % Intra Cranial Volume (ICV), and in z‐scores calculated relative to a cognitively normal population. 814 had amyloid status from CSF or PET, of which 216 were Amyloid+. Correlation between MTA scores and quantitative HV measurements was ascertained by Spearman’s rank correlation.ResultThere was a significant negative correlation between MTA scores and HV in %ICV (Left ‐0.62, p<0.001; Right ‐0.59, p<0.001) and z‐scores (Left ‐0.47, p<0.001; Right ‐0.43 p<0.001) for the total sample, as well as in Amyloid+ individuals HV in %ICV (Left ‐0.63 p<0.001, Right ‐0.58 p<0.001) and z‐scores (Left ‐0.50 p<0.001, Right ‐0.47 p<0.001). The correlation was also strong when separated by clinical diagnosis: patients with Subjective Cognitive Complaint (SCC, N = 306, AGE: 69.82 +/‐ 8.03, 196 female, MMSE: 28.86 +/‐ 1.17) and MCI (N = 1646, Age: 71.23 +/‐ 8.71, 1018 Female, MMSE: 27.79 +/‐ 1.95) presented MTA scores correlated both with HV in %ICV (Right = ‐0.47 p<0.001, Left = ‐0.50 p<0.001 for SCC; Right = ‐0.60 p<0.001, Left = ‐0.63 p<0.001 for MCI) and z‐scores (Right = ‐0.26 p<0.001, Left = ‐0.33 p<0.001 for SCC; Right = 0.44 p<0.001, Left = ‐0.49 p<0.001 for MCI).ConclusionThe automated quantification of ICV‐corrected HV and z‐scores were well‐correlated to MTA scores. QyScore® z‐scores may improve specificity in patients with cognitive impairment, by providing automated quantification of hippocampal atrophy directly compared with healthy ageing.
Seizures exacerbate excitatory‐inhibitory imbalance and tau seeding effects in 5XFAD mice
Authors: Barbour Aaron J , Gourmaud Sarah , Stewart David A , Li Xiaofan , Zebrowitz Sydney E , Ferrigno Sarah , Lee Virginia M.‐Y. , Talos Delia M , Jensen Frances E 
Published: June 2023

AbstractBackgroundAlzheimer’s Disease (AD) neuropathology is largely driven by two pathological proteins, tau, and ß‐amyloid, both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Central to the progression of AD is the spread of tau along neuronal networks likely via neuronal activity. Our previous work suggests a bidirectional relationship between AD and epilepsy with seizures inducing AD pathology and vice versa (Gourmaud et al. Brain, 2021; awab268). Additionally, there is evidence of excitatory‐inhibitory (E:I) imbalance in AD reminiscent of E:I imbalances involved in epileptogenesis. Thus, we hypothesized that seizures can exacerbate E:I imbalance in AD models and that this enhanced hyperexcitability promotes the propagation of pathological tau.MethodWe utilized the Five times familial AD (5XFAD) model and an established pentylenetetrazol (PTZ) kindling method to induce seizures in these and WT littermates. To model pathological tau spread seen in AD, a cohort of animals also underwent intracerebral injection of human AD‐derived tau (AD‐tau) into the hippocampus and overlying cortex prior to seizure induction. Western blots were performed for the Cl− transporters, K+‐ Cl−cotransporter 2 (KCC2) and Na+‐K+‐Cl− cotransporter 1 (NKCC1), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunits, GluA2 and GluA1, and GABAAR subunits α1 and α3, given their roles in E:I balance. AD‐tau injected mice were also examined by western blot for phospho‐tau AT8 [Ser202; Thr205] and phospho‐tau AT180 [Thr231] in sites proximal (hippocampus) and distal (frontal cortex) to injection site to determine the effects of seizures on tau propagation.ResultPTZ‐kindling enhanced the dysregulation of Cl‐ transporters, NKCC1 and KCC2 (p<0.05, n = 12‐19) and GluA2/GluA1 ratios (p<0.05, n = 12‐19) in 5XFAD mice, while 5XFAD mice showed decreased GABAARα1 (p<0.05, n = 12‐19). No significant changes were seen in the hippocampus for AT8 nor AT180, but seizure induction elevated AT8 levels in the frontal cortex across genotypes (p<0.05, n = 5‐9).ConclusionOur data suggest that seizures exacerbate E:I imbalance in 5XFAD mice and tau propagation in both WT and 5XFAD mice. Thus, drugs targeting mechanisms involved in E:I balance or controlling seizures with antiseizure medication shows therapeutic efficacy for AD patients with comorbid seizures.
Lighter sleep and obstructive sleep apnea associate with higher enlarged perivascular spaces 15 years later
Authors: Baril Andree‐Ann , Pinheiro Adlin A , Himali Jayandra Jung , Sanchez Erlan , Pase Matthew P. , Seshadri Sudha , Demissie Serkalem , Romero Jose Rafael 
Published: June 2023

AbstractBackgroundEnlarged perivascular spaces (ePVS) and sleep disturbances have been associated with incident dementia. While healthy sleep is suggested to promote glymphatic clearance in the brain, poorer sleep may be associated with higher ePVS burden (representing impaired perivascular drainage), which may contribute to sleep’s role in dementia risk. We assessed the association between sleep characteristics measured with polysomnography and subsequent ePVS burden.MethodWithin the Framingham Heart Study, 522 participants (age: 46.1±9.0 years; 50.4%M) underwent a full‐night in‐home polysomnography. Sleep variables measuring sleep architecture (total sleep time, wake after sleep onset, sleep efficiency), sleep stages (N1, N2, N3 and REM sleep in absolute minutes and percent of total sleep time), and obstructive sleep apnea severity (apnea‐hypopnea index, obstructive sleep apnea categories [mild, moderate, severe], sleep time <90% SaO2) were extracted. On average 16.7 ± 2.6 years later, participants underwent magnetic resonance imaging. ePVS were rated in the basal ganglia and centrum semiovale, and dichotomized for analyses: low burden (<20 counts, grade 1 and 2) or high burden (>20 counts, grade 3 and 4). Logistic regressions analyses relating sleep characteristics to ePVS burden were used, adjusted for age, sex, time interval between polysomnography and magnetic resonance imaging, APOE4 allele carrier status, hypertension, and smoking.Results21 participants had high ePVS burden in basal ganglia, and 68 participants in the centrum semiovale. Longer time spent in N1 (minutes and % of total sleep time; OR[95%]: 1.02[1.00‐1.04], p = 0.026; 1.11[1.03‐1.19], p = 0.008 respectively), shorter time spent in N3 (minutes; OR[95%]: 0.99[0.98‐0.99], p = 0.029), and longer time spent <90% SaO2 (OR[95%]: 1.03[1.00‐1.05], p = 0.025) were associated with higher ePVS burden in the centrum semiovale. No other associations between sleep characteristics and ePVS ratings were observed.ConclusionLighter sleep, as characterized by longer N1 sleep and shorter N3 sleep, as well as the hypoxemia component of obstructive sleep apnea are associated with higher ePVS burden in subsequent brain magnetic resonance imaging. If replicated, these findings suggest a role for sleep disturbances in glymphatic clearance and cerebral small vessel disease, which may be implicated in the association between sleep and dementia risk.
Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Gibson Erin , Beg Mirza Faisal , Popuri Karteek , Mackenzie Ian R , Rosen Howard J. , Kantarci Kejal , Boeve Brad F. , Boxer Adam L , Tartaglia Carmela , Hsiung Ging‐Yuek Robin ,   the ALLFTD Consortium
Published: June 2023

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.
Systemic and central nervous system metabolome changes associated with Ginkgo biloba treatment in non‐demented subjects
Authors: Clark Christopher , Popp Julius 
Published: June 2023

AbstractBackgroundIn order to characterize the biochemical changes associated with Ginkgo biloba treatment, at metabolite and pathway level, we used a state‐of‐the‐art untargeted metabolomics approach in a well characterized cohort of healthy non‐demented subjects, with or without Ginkgo biloba treatment.MethodWe analysed data including cerebrospinal fluid (CSF) and peripheral blood measurements of proteomics, metabolomics, the methionine pathway, lipidomics, minerals, miRNAs, sterols and neuroinflammatory markers in samples obtained from both groups, covering over 2500 analytes and/or molecules.ResultData analysis at individual metabolic levels revealed differences in the expression of 15 analytes at CSF level and 25 analytes in peripheral blood, including 13 unidentified miRNAs. Pathway enrichment revealed these changes were associated with an overrepresentation of insulin signalling, platelet degranulation and hemostasis in peripheral blood and with growth factor signalling at CSF levels.ConclusionThese results demonstrate the ability of this approach to uncover metabolic changes in patients undergoing a Ginkgo treatment. In further steps, we will perform enrichment analysis in CSF samples and build multivariate models accounting for potential confounders and a multi‐omics model, to assess the interactions between different biological pathways and levels; these approaches will require the recruitment of additional participants for the gingko group. This will also allow targeted omics approaches to further explore these alterations and relate them with the clinical evolution of participants over time, including cognitive decline and non‐cognitive symptoms at follow‐up visits.
Random forest selected transcripts from multiple neurodegenerative diseases reveal common affected cellular processes
Authors: Huseby Carol J. , Delvaux Elaine , Brokaw Danielle L. , Coleman Paul D. 
Published: June 2023

AbstractBackgroundNeurodegenerative diseases such as Alzheimer’s disease are associated with changes in specific molecular pathways involving metabolomic and biological processes active in both the central nervous system and vascular peripheral system. Each disease results in neurodegeneration in vulnerable regions and cell types specific to that disease and are expressed in whole blood as disease progresses. Machine learning can be applied to the entire blood transcriptome of neurodegenerative diseases providing information for a pathophysiological relationship and gives us the advantage of using the vast knowledge of gene expression to analyze pathways affected thereby guiding insight into possible treatment strategies. We applied our unique machine learning algorithm to public data sets for selection of transcripts that guide our discovery of affected pathways.MethodsWe used large public blood microarray mRNA expression datasets, with platforms of more than 30,000 probes covering 10,000 genes, to discover disease transcripts using a novel Random Forest algorithm which selected supervised predictors for six different neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), behavioral variant frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and Friedreich’s ataxia (FRDA).ResultsOur machine learning selection of transcript disease classifiers reveals that neurodegenerative diseases have common themes as well as unique individual differences. Molecular components which overlap across diseases might be considered neurodegeneration generalities or a result of mixed pathology, while differential components identified by selected feature transcripts may represent unique dysfunctions.ConclusionOur Random Forest algorithm selected important features hidden in mRNA expression values from blood of affected individuals of six neurodegenerative diseases compared to healthy controls. For each of the six diseases studied here, the selected features were categorized by pathway analysis into eight main functional groups. The dysfunction of any or multiple functional groups combined can lead to synapse and cell loss in these neurodegenerative diseases each with specific vulnerabilities in particular tissue and cell types. Vulnerability is usually associated with those cells vulnerable to the disease pathology and are often first to exhibit cell death from cytotoxic events such as neuroinflammation, mitochondrial dysfunction, transcription alterations, apoptosis, protein synthesis dysfunction, cytoskeletal changes, and ubiquitylation/proteasome stalls.
Hypogyrification in midlife women with surgical menopause, a population at risk for late life Alzheimer’s
Authors: Gravelsins Laura , Brown Alana , Almey Anne , Gervais Nicole J , Duchesne Annie , Rieck Jenny , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Witt Suzanne Tyson , Classon Elisabeth , Lykke Nina , Theodorsson Elvar , Ernerudh Jan , Lundqvist Elisabeth Åvall , Kjølhede Preben , Morrison India , Novembre Giovanni , Engström Maria , Bernardini Marcus , Foulkes William , Rajah Natasha , Grady Cheryl , Einstein Gillian 
Published: June 2023

AbstractBackgroundWomen with early ovarian hormone deprivation due to bilateral salpingo‐oophorectomy (BSO; ovarian and fallopian tube removal) are at risk for later life Alzheimer’s disease (AD), but estradiol therapy (ET) may be protective (Rocca et al., 2007). Working memory (WM), temporarily maintaining and manipulating information in mind, depends on structural integrity of fronto‐parietal brain regions (Burzynska et al., 2012). WM declines have been observed in midlife women with BSO not taking ET (Gervais et al., 2020), however, structural brain–WM relationships in this midlife population remain unexplored. This study aimed to: 1) Investigate fronto‐parietal cortical thickness and gyrification (folding) changes in younger women after early BSO and their relationship to WM, and 2) Explore whether ET ameliorates these changes.MethodWomen with early BSO taking ET (BSO+ET: M±SDage = 45±5.1; n = 26), or not taking ET (BSO: M±SDage = 46±5.0y; n = 26) were compared to premenopausal, age‐matched controls (AMC: M±SDage = 44±2.9y; n = 42) from Toronto and Montreal, Canada, and Linköping, Sweden. T1‐weighted scans were acquired on Siemens Prisma/Philips 3T scanners. WM was measured using Digit Span Backwards (Wechsler, 1945) maximum span and Digit Ordering Task (Petrides et al., 1993) errors. Average cortical thickness and gyrification of fronto‐parietal regions were calculated from CIVET (Ad‐Dab’bagh et al. 2005), adjusting for scanner and past cancer treatment.ResultLinear models showed no group differences in cortical thickness or WM. However, they showed BSO had significant hypogyrification (reduced cortical folding) in the supplementary motor area (SMA), part of the posterior prefrontal cortex, compared to AMC (adjusted for brain volume; FDR‐corrected p = 0.028). BSO+ET had intermediate SMA gyrification, and did not differ from either group. SMA gyrification was unrelated to WM, and gyrification–WM relationships did not differ by group.ConclusionWe found SMA hypogyrification in younger women with BSO compared to AMC and BSO+ET. The SMA supports WM manipulation and is an early area affected by age‐related gyrification declines (Madan, 2021). Moreover, hypogyrification may reflect reduced brain connectivity, and gyrification globally declines with AD severity (Liu et al., 2012). Although SMA hypogyrification in women with BSO was unrelated to WM, it may serve as an early sign of later life cognitive decline.
Imipramine treatment reduces Alzheimer’s disease neuropathologies in cerebral organoid models of Alzheimer’s disease and Down syndrome
Authors: Johnson Noah R , Dooling Breanna , Aghili Leila , Chial Heidi J , Potter Huntington 
Published: June 2023

AbstractBackgroundFamilial Alzheimer’s disease (fAD) is a autosomal dominant, early‐onset form of AD caused by genetic mutations such as duplication of the amyloid precursor protein gene (APP) on one chromosome (APPdup) or point mutations in APP such as the London mutation (APPV717I), both of which cause overproduction of the amyloid‐beta peptide (Aβ). People with Down syndrome (DS) also have a form of fAD due to triplication of APP which resides on chromosome 21. By age 40, all people with DS develop AD brain pathology, including Aβ plaques and neurofibrillary tangles of phosphorylated tau (pTau), and most go on to develop early‐onset dementia. We previously identified imipramine by high‐throughput screening for novel inhibitors of apolipoprotein E (apoE), which is the strongest risk factor for AD other than age itself. Here, we developed and characterized new cerebral organoid (CO) models of fAD and DS and used them to study common pathological mechanisms and to evaluate imipramine as a novel AD treatment.MethodWe obtained human induced pluripotent stem cells (hiPSCs) from multiple donors with fAD (APPdup or APPV717I), DS, or healthy controls (HC), all with the APOE3/3 genotype, and generated COs using validated techniques. We treated COs beginning at 45 days in vitro with 1 or 10 μM imipramine in the culture medium, and we collected treated and untreated organoids after 120 days for analysis by immunoblotting, immunohistochemistry, and ELISA.ResultCOs from fAD or DS donors were significantly reduced in size compared to those from HC donors. Increased expression of APP, Aβ, pTau, and apoE were observed in fAD and DS COs relative to HC COs. Levels of Aβ and apoE were positively correlated in all COs. Imipramine treatment significantly reduced the levels of some neuropathologies in AD COs, but did not affect the size or cellular composition of HC COs.ConclusionWe characterized several new CO models of fAD and DS, which will be useful for identifying commonalities in disease mechanisms as well as for dissecting the roles of chromosome 21 genes other than APP. Our results indicate that imipramine and other therapeutics targeting the role of apoE are promising approaches to treating AD.
Synergic Electron and Defect Compensation Minimizes Voltage Loss in Lead‐Free Perovskite Solar Cells
Authors: Liu Gengling , Jiang Xianyuan , Feng Wenhuai , Yang Guo , Chen Xi , Ning Zhijun , Wu Wu‐Qiang 
Published: June 2023

AbstractSn perovskite solar cells have been regarded as one of the most promising alternatives to the Pb‐based counterparts due to their low toxicity and excellent optoelectronic properties. However, the Sn perovskites are notorious to feature heavy p‐doping characteristics and possess abundant vacancy defects, which result in under‐optimized interfacial energy level alignment and severe nonradiative recombination. Here, we reported a synergic “electron and defect compensation” strategy to simultaneously modulate the electronic structures and defect profiles of Sn perovskites via incorporating a traced amount (0.1 mol %) of heterovalent metal halide salts. Consequently, the doping level of modified Sn perovskites was altered from heavy p‐type to weak p‐type (i.e. up‐shifting the Fermi level by ~0.12 eV) that determinately reducing the barrier of interfacial charge extraction and effectively suppressing the charge recombination loss throughout the bulk perovskite film and at relevant interfaces. Pioneeringly, the resultant device modified with electron and defect compensation realized a champion efficiency of 14.02 %, which is ~46 % higher than that of control device (9.56 %). Notably, a record‐high photovoltage of 1.013 V was attained, corresponding to the lowest voltage deficit of 0.38 eV reported to date, and narrowing the gap with Pb‐based analogues (~0.30 V).
Atomic‐Scale Insights into the Interlayer Characteristics and Oxygen Reactivity of Bilayer Borophene
Authors: Li Linfei , Schultz Jeremy F. , Mahapatra Sayantan , Liu Xiaolong , Zhang Xu , Hersam Mark C. , Jiang Nan 
Published: June 2023

AbstractBilayer (BL) two‐dimensional boron (i.e., borophene) has recently been synthesized and computationally predicted to have promising physical properties for a variety of electronic and energy technologies. However, the fundamental chemical properties of BL borophene that form the foundation of practical applications remain unexplored. Here, we present atomic‐level chemical characterization of BL borophene using ultrahigh vacuum tip‐enhanced Raman spectroscopy (UHV‐TERS). UHV‐TERS identifies the vibrational fingerprint of BL borophene with angstrom‐scale spatial resolution. The observed Raman spectra are directly correlated with the vibrations of interlayer boron–boron bonds, validating the three‐dimensional lattice geometry of BL borophene. By virtue of the single‐bond sensitivity of UHV‐TERS to oxygen adatoms, we demonstrate the enhanced chemical stability of BL borophene compared to its monolayer counterpart by exposure to controlled oxidizing atmospheres in UHV. In addition to providing fundamental chemical insight into BL borophene, this work establishes UHV‐TERS as a powerful tool to probe interlayer bonding and surface reactivity of low‐dimensional materials at the atomic scale.