bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety profile of semaglutide in people aged 55 years and over: pooled data from the PIONEER, SUSTAIN and STEP phase 3 clinical programmes
Authors: Sabbagh Marwan , Boschini Cristina , Cohen Sharon , Fugger Magnus , Jessen Frank , Martino Gabriel Gerardo , Pedersen Sue D. , Tarazona Luis Rafael Solís , Aroda Vanita R. 
Published: December 2023

AbstractBackgroundThe risk of Alzheimer’s disease (AD) increases with age. The glucagon‐like peptide‐1 analogue semaglutide, approved for type 2 diabetes (T2D) and overweight/obesity, is being investigated in the phase 3 evoke and evoke+ trials in people with early AD aged 55‐85 years. There is a need to summarise semaglutide weight loss efficacy and safety data in older populations. We investigated the safety of semaglutide in people with T2D and/or overweight/obesity ≥55 years using data from the phase 3a PIONEER, SUSTAIN and STEP clinical programmes.MethodSafety data for participants ≥55 years were pooled for: people with T2D receiving once‐daily oral semaglutide 3, 7 or 14 mg versus comparator (active or placebo) for 26‒78 weeks in PIONEER 1‒5 and 7‒10 (PIONEER pool, N = 4186); people with T2D receiving once‐weekly subcutaneous semaglutide 0.5 or 1 mg versus comparator (active or placebo) for 30‒56 weeks in SUSTAIN 1‒5 and SUSTAIN Japan (NCT02207374 and NCT02254291; SUSTAIN pool, N = 2825); and people with overweight/obesity (with/without T2D) receiving once‐weekly subcutaneous semaglutide 2.4 mg versus placebo for 68‒104 weeks in STEP 1‐6 (STEP pool, N = 1584).ResultData from 8595 participants were included. At baseline in the PIONEER, SUSTAIN and STEP pooled datasets, mean (standard deviation [SD]) age was 64.3 (6.4), 63.5 (6.1) and 62.0 (5.6) years, respectively, and mean (SD) body mass index was 30.8 (6.2), 31.0 (6.2) and 35.6 (6.2) kg/m2 (Table 1). The percentages of participants with adverse events (AEs) leading to treatment discontinuation in the semaglutide arms of PIONEER, SUSTAIN and STEP were 10.2, 9.1 and 7.7%, respectively, versus 5.2, 3.9 and 3.3% for the comparator arms (Table 2). Gastrointestinal disorders were the most frequently reported AE system organ class, with nausea, diarrhoea, constipation and vomiting the most frequent gastrointestinal AEs in the semaglutide arm of each pooled dataset (Table 2). Weight loss was greater with semaglutide versus comparator in all trials, with a tendency to plateau over time (Figure 1).ConclusionThe safety profile of semaglutide in participants ≥55 years is similar to that observed in the overall population, supporting the evaluation of semaglutide in an older population with early AD in evoke.
Bio‐Hermes: A study to assess the relationship of blood and digital biomarkers with Aβ PET scans in older persons with normal cognition, MCI or mild AD
Authors: Beauregard Douglas W. , Mohs Richard , Dwyer John , Hollingshead Sarah , Smith Katy , Bork Jason , Kerwin Diana R. 
Published: December 2023

AbstractBackgroundRecently developed blood and digital biomarkers may enable the identification of persons with amyloid deposits in the brain. While these biomarkers are promising, most haven’t been evaluated in populations like those screened for clinical treatment trials or in populations with racial and ethnic diversity similar to the US population. The Global Alzheimer’s Platform Foundation® (GAP) completed its biomarker study (Bio‐Hermes) comparing results of blood and digital biomarker tests with brain amyloid PET scans and traditional cognitive tests. The trial enrolled 1,002 participants in three cohorts: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Mild AD.MethodWithin 18 months, 17 sites enrolled 1,002 participants (60‐85 y/o) in clinically defined cohorts of: CN (N = 417), MCI (N = 312), and Mild AD (N = 273). Traditional and digital cognitive testing, amyloid PET imaging, biospecimen collection, and speech analytics were performed. A subset of participants received a retinal exam. Blood biomarkers included, Aß 42/40, p‐Tau181/217/231, NfL, GFAP, full genome sequencing, including APOE status, and proteomics. Digital biomarkers included memory recall, executive functions, and drawing‐based and speech elicitation tasks. Blood biomarkers’ relationship to amyloid PET was measured using Spearman’s rank correlation. A ROC curve analysis will assess the sensitivity and specificity of each biomarker and combination of biomarkers compared with amyloid positivity from PET.ResultStatistical models to be competed in April 2023 for presentation.24% of participants were from underrepresented populations (URP) either African American, Hispanic or other. The CN cohort was 61% female, with 21% amyloid PET Positive; the MCI cohort was 54% female with 34% amyloid PET Positive; the Mild AD cohort was 51% female with 62% amyloid PET Positive. Penalized multiple regression will be used to predict amyloid level (continuous) and amyloid positivity status. Candidate predictors include cohorts, blood‐based biomarkers, cognitive assessments (rating scales and digital), retinal measurements, and speech recognition digital biomarkers.ConclusionBio‐Hermes generated a unique, well‐characterized, diverse sample set that determined the utility of several promising biomarkers. Validation of these biomarkers will expedite AD clinical trial enrollment by quickly identifying appropriate participants while reducing the variability and burden of screen failures from high‐cost brain scan procedures.
Electrophysiological effects of mitochondria‐derived extracellular vesicles: implications for memory dysfunction in neurodegenerative disorders
Authors: D'Acunzo Pasquale , Argyrousi Elentina K , Ungania Jonathan M. , Kim Yohan , DeRosa Steven , Pawlik Monika , Goulbourne Chris N. , Arancio Ottavio , Levy Efrat 
Published: December 2023

AbstractBackgroundMitovesicles are a newly identified subtype of small extracellular vesicles (EVs) of mitochondrial origin. We recently developed a method to separate mitovesicles from other EVs after their isolation from the extracellular space of murine and human brain tissues. This method permits the study of the roles of mitovesicles in physiology and disease.Given their origin, we hypothesized that mitochondrial dysfunction, a hallmark of both Alzheimer’s disease (AD) and Down syndrome (DS), could induce alterations in mitovesicles, thus perturbing brain homeostasis and contributing to propagation of pathology. Therefore, we studied mitovesicle components and functionality after their isolation from the brain of a mouse model of DS (hereafter Ts2) as compared to diploid (2N) controls, as well as from frontal cortices of individuals with DS as compared to their age‐matched 2N controls.MethodBrain mitovesicles were isolated and analyzed by Western blotting, electron microscopy, nanotrack analysis, and monoamine neurotransmitter degradation assay as recently described (D’Acunzo, et al., 2022, PMID: 35962195). Coronal hippocampal slices from wild‐type mice were perfused with different subtypes of brain EVs, pretreated or not with clorgiline and pargyline (1 μM each), irreversible inhibitors of the monoamine oxidases type A and B (MAO‐A and MAO‐B), respectively. Long‐term potentiation (LTP) was induced at the level of the Schaeffer collateral fibers through a theta‐burst stimulation (Fà, et al., 2014, PMID: 24643165).ResultMitovesicle number is higher in brains of DS individuals and of Ts2 mice and contain a higher MAO‐B protein amount and enzymatic activity as compared to diploid controls, suggesting a potential mitovesicle‐dependent impairment of neuroamine homeostasis in DS. In agreement with that, Ts2 (but not 2N) mitovesicles stimulated a decreased LTP in recipient hippocampal slices as compared to vehicle control (Fig. 1; mtVs: mitovesicles). This biological activity was abolished when MAO‐B (but not MAO‐A) was blocked. The other EV subtypes of both genotypes, microvesicles and exosomes, did not trigger an effect on LTP. DS changes were found to be sex independent.ConclusionPathogenic mitovesicles are previously undescribed active players of the brain extracellular milieu by regulating LTP via MAO‐B, and potentially contribute to memory formation deficiencies typically found in AD and DS.
Evolution of language abilities over the course of the disease in a large cohort of patients with lvPPA: More than a repetition impairment
Authors: Lavoie Monica , Tastevin Maud , Sablonnière Justine De La , Poulin Elizabeth , Carrier‐Auclair Julie , Laforce Robert 
Published: December 2023

AbstractBackgroundInitial language impairment in lvPPA causes naming and repetition difficulties along with phonological errors (Gorno‐Tempini et al., 2011). Little is known about the evolution of other language capacities with disease progression. This study aimed at exploring the full range of language impairments throughout the course of the disease, from onset to death.MethodWe performed a retrospective chart review on a large cohort of deceased lvPPA patients (n = 38; 18 M, 19 F; Mean age at onset = 69 years old). Presence or absence of impairment in various language abilities was determined via consensus by three experienced raters at 5 time points from onset to death.ResultAll 38 patients developed anomia, repetition impairment and writing difficulties throughout disease course (Figure 1). The overall prevalence of reading difficulties was also high (Figure 1), with impairment appearing more than two years post‐onset in most cases (Figure 2). Comprehension deficits were highly prevalent, appearing mostly in the first two years post onset (Figure 2). More than 75% of patients showed grammar difficulties (Figure 1), mainly in later stages of the disease (Figure 2). Semantic deficits also appeared later (Figure 2). Finally, apraxia of speech was quite infrequent (Figure 1).ConclusionIn addition to known language deficits in lvPPA (i.e., naming, repetition, reading and writing, see Brambati et al., 2009; Faria et al., 2013; Gorno‐Tempini et al., 2011; Sepelyak et al., 2011), our results suggest early impairments in comprehension as well as late grammar difficulties. To our knowledge, this is the first study which addresses the full range of language impairments in lvPPA over the entire course of the disease. We believe this is highly relevant for patients/families to better prepare for the future, as well as therapists to design more focused interventions.
The risk of sleep‐related cognitive impairment increases in middle‐age to older adulthood
Authors: Kim Hyun , Cohen Daniel E. , Levine Alina , Tucker Aren , Devanand Davangere P. , Lee Seonjoo , Goldberg Terry E. 
Published: December 2023

AbstractBackgroundThe association between sleep quality and cognition is widely established but the role of aging in this relationship has been unclear due to inconsistent findings with heterogeneous methods and a lack of studies in wide age ranges. The current study examined how age impacts the sleep‐cognition relationship using a large‐scale dataset with adults from young adulthood to older adulthood. Furthermore, we tested non‐linear effect of age to investigate the presence of age ranges in which the association between sleep and cognition is modified.MethodSample included 711 individuals (ages 36.00‐89.83, 59.66 ± 14.91, 55.7% female) from the Human Connectome Project‐Aging (HCP‐A). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and cognitive outcome measures included the NIH Toolbox fluid cognition (Dimensional change Card Sort Test, List Sorting Working Memory Test, Picture Sequence Memory Test, Pattern comparison Processing Speed Test, Flanker Inhibitory Control and Attention Test) and crystallized cognition composite scores (Oral Reading Recognition Test and Picture Vocabulary Test), the Trail Making Test (TMT) A and B, and the Rey Auditory Verbal Learning Test (RAVLT). The association between sleep quality and cognitive performance was measured using linear regression models, with sex, race, use of sleep medication, and years of education as covariates. Age moderation was tested via the interaction between sleep and age on cognition, with age as linear and non‐linear (quadratic) terms.ResultThere was a significant interaction term between the PSQI and non‐linear age term (age2) on TMT‐B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that the association between poor sleep quality and cognitive performance was moderated by age. Further analyses indicated that there were “critical age ranges” in which the sleep‐cognition association was more salient (ages 50‐75 for TMT‐B and 66‐70 for crystallized cognition).ConclusionThe association between sleep quality and cognitive performance may be modified by age. Individuals of the middle‐age to early older adulthood may be more vulnerable to sleep‐related cognitive impairment, indicating the clinical importance of detection and treatment of sleep disturbance in this particular age group.
Loss of Fatty Acid Degradation by Astrocytic Mitochondria as a Mechanism of Neuroinflammation and Neurodegeneration
Authors: Mi Yashi , Qi Guoyuan , Vitali Francesca , Shang Yuan , Raikes Adam C. , Wang Tian , Jin Yan , Brinton Roberta Diaz , Gu Haiwei , Yin Fei 
Published: December 2023

AbstractBackgroundAstrocytes provide key neuronal support, and their phenotypic transformation is strongly implicated in neurodegenerative disorders including Alzheimer’s disease (AD). Metabolically, astrocytes possess modest mitochondrial oxidative phosphorylation (OxPhos) activity, yet the pathological role of astrocytic OxPhos in neurodegeneration remains to be defined.MethodWe generated the TfamAKO mice, in which the transcription factor A mitochondrial (Tfam) is deleted selectively in astrocytes. Behavioral, electrophysiological, immunostaining, transcriptomics, metabolomics, and magnetic resonance imaging analyses were employed to characterize AD‐relevant phenotypes of TfamAKO mice, which were further compared to an AD mouse model (5xFAD). Primary cell cultures and co‐cultures were used to determine the cell autonomous and non‐autonomous mechanisms by which disrupted astrocytic OxPhos induces astrocyte reactivity, neuroinflammation and neurodegeneration.ResultHere we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of AD including reactive astrogliosis, synaptic loss, microgliosis, demyelination, and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl‐CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid‐laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia via IL‐3 signaling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Moreover, the metabolic and transcriptional signatures of the hippocampus of TfamAKO mice highly overlap with that of 5xFAD mice.ConclusionWe reveal a lipid‐centric, AD‐resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
Evaluating aperiodic components of the spontaneous magnetoencephalograpic activity along AD continuum
Authors: Quivira‐Lopesino Adrián , Blazquez Guillermo , Maest Fernando , Cuesta Pablo 
Published: December 2023

AbstractBackgroundThe increase in life expectancy has resulted in a greater number of people developing disorders associated with aging such as Alzheimer’s disease. Mild Cognitive Impairment (MCI) is a prodromal stage that has been commonly assessed with the aim of finding biomarkers associated with the dementia progression. Previous literature has stated that MCI patients suffer a slowness of the basal oscillatory brain electrophysiological activity when compared to healthy controls. This slowness, reported with EEG and MEG, is mainly characterized by a diminished alpha power and enhanced theta and delta power. These results have been found when assessing the periodic component of the brain oscillations (i.e. evaluating the spectral power), whereas the aperiodic component has usually been ignored. Recently, researchers from UCSD have developed a toolbox (FOOOF) able to assess the aperiodic component of the spectral power, by computing the exponent of the 1/f‐like activity. This exponent is an aperiodic component that has been related to the integration of the underlying synaptic currents. Under this hypothesis, the exponent will be lower (flatter spectra) when the excitation‐inhibition (E/I) balance would reflect a higher excitation relative to inhibition, whereas the exponent will be higher (steeper spectra) when the E/I balance would reflect a higher inhibition relative to excitation.MethodIn this study, using a preexisting eyes closed resting state MEG database, we have assessed differences in the aperiodic exponent between healthy (N = 195) and MCI‐diagnosed (N = 79) individuals. To this end, we computed at the sources’ space (using a LCMV beamformer with a 1 cm spacing grid at MNI space) the exponent of the spectral power, and then performed a set of between groups statistics (ANCOVA with age as covariate) with a cluster‐based permutations methodology.ResultIn our results we observed an increased aperiodic exponent in the precuneus cortex of the individuals with MCI when compared to healthy participants.ConclusionThis result would be indicating a decreased E/I balance, hypothetically due to an increased inhibition. Further investigation will be needed to clarify the relevance and implications of these results.
Fully automatic deep‐learning based segmentation of Hippocampal subfields from standard resolution T1W MRI in Alzheimer’s Disease
Authors: Joules Richard , Wolz Robin 
Published: December 2023

AbstractBackgroundHippocampal subfield volumes are of interest in Alzheimer’s disease (AD) as sub‐regions are affected at different points in the disease trajectory and may provide increased sensitivity as biomarkers compared to the whole hippocampus alone. Subfield volume estimation typically requires a high‐resolution T2‐weighted MRI to ensure accurate anatomical parcellation; however, this increases scan times and may not be present in historical datasets. Automatic methods exist for subfield segmentation from mono‐modal standard resolution T1W MRI, with deep‐learning approaches providing the most promising results to date. Here we extend such work employing deep learning approaches to provide flexible hippocampal subfield segmentation of standard resolution (1mm3) T1W MRI.MethodWe trained a collection of deep‐learning segmentation models to perform binary segmentation of the CA1‐3, CA4/DG, Subiculum, and whole Hippocampus, using a publicly available dataset of 25 subjects with manually segmented region labels on T1 MRI (1mm3). Multilabel segmentations were generated from combination of segmentation outputs.ResultTotal hippocampal and subfield multi‐label segmentations were generated for all test subjects in each cross validated loop and DICE overlap with the ground truth label computed. Preliminary results, computed using a 5‐fold cross validation, report mean DICE in whole Hippocampus = 0.904(std: 0.014), CA1‐3 = 0.842(std:0.019), CA4/DG = 0.767(std:0.04), and Subiculum = 0.791(std:0.033).Segmentation models were applied to 947 subjects with standard T1 MRI from the ADNI cohort and either a CN or MCI label. Subjects were selected with pre‐existing hippocampal subfield volumes, provided by ADNI, computed with the ASHS method using a multi‐modal T1 and hi‐res T2 MRI image. While the proposed method and ASHS employ subtly different parcellation schema we note significant correlation across similar regions between methods.Logistic regression of ICV corrected volumes and MMSE, correcting for age and sex, reveal both ASHS and the proposed method can significantly discriminate between CN and MCI groups (Table 1), with subfields areas providing greater discrimination that of the whole hippocampus.ConclusionHere we present preliminary results for a flexible deep‐learning approach to segmentation of hippocampal subfields from standard resolution T1 MRI alone; indicating comparable performance for group discrimination to an established multi‐modal standard.
Mendelian randomization study using paired SNPs as instruments supports casual protective effect of overweight on Alzheimer’s disease
Authors: Duan Hongzhe , Holmes Rachel , Arbeev Konstantin , Wu Deqing , Yashin Anatoliy I , Ukraintseva Svetlana 
Published: December 2023

AbstractBackgroundMendelian Randomization (MR) is a powerful method of detecting causal effects in observational studies. However, choosing an appropriate SNP as an instrumental variable (IVar) is challenging because of difficulties in satisfying all assumption criteria. We proposed a novel strategy of creating IVar using paired SNPs between genes of interest, and tested this strategy in MR study examining causal relationships between being overweight and onset of Alzheimer’s disease (AD).MethodWe performed MR in the Health and Retirement Study (HRS) subsample of participants aged 75+, using the following binary variables: (1) ‘overweight’ BMI 25‐30 vs. (0) ‘normal’ BMI 18.5‐25, at ages 65‐75, as exposure; and (1) no AD vs. (0) AD onset at ages 75+, as outcome. We found significant association between ‘overweight’ BMI and lower odds of AD in logistic regression, and used MR to test causality. For IVar, we selected eight obesity‐related genes from the literature (ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG), cross‐paired their SNPs, and used counts of minor alleles of the paired SNPs to create new ‘composite SNP’s. Analyses were stratified by sex and race, and non‐stratified. Initial models were estimated in SAS. Resulting summary statistics were used in R‐package MendelianRandomization. F‐value>10 criteria was applied to ensure the IVar strength. The causal effect was evaluated using weighted median, Inverse‐Variance Weighted (IVW), and maximum likelihood (ML).ResultBeing overweight at ages 65‐75 had significant causal protective effect on AD onset after age 75 in White females (logistic regression: OR = 1.99 [higher odds for ‘overweight’ individuals to be in ‘no AD’ group], p‐value = 8.26E‐5; MR: number of instrument ‘SNP’s = 13, weighted median causal estimate = 1.27, p‐value = 1.91E‐5; IVW causal estimate = 1.14, p‐value = 2.30E‐08; ML causal estimate = 1.20, p‐value = 7.67E‐7). No causal effects were detected using single SNPs in the same genes.ConclusionThe proposed novel strategy of creating IVar for MR analysis, based on pairing SNPs between candidate genes, substantially improves the critical step of MR analysis: choosing efficient instrument SNPs. We successfully tested this new strategy in HRS data, and confirmed causal relationship between BMI and AD, specifically, significant causal protective effect of being overweight on AD onset later in life in white females.