bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shotgun proteomics for the discovery of protein biomarkers for cerebral amyloid angiopathy
Authors: Vervuurt Marc , Kuiperij H. Bea , de Kort Anna M. , Kersten Iris , Wessels Hans , Gloerich Jolein , Van Nostrand William E , Verbeek Marcel M. 
Published: December 2023

AbstractBackgroundOftentimes, the search for novel (protein) biomarkers starts in transgenic animal models, to minimize inter‐individual variation and confounding influences. In our search for novel biomarkers for cerebral amyloid angiopathy (CAA), we have executed shotgun proteomics analyses aimed at identifying novel biomarker candidates on the cerebrospinal fluid (CSF) of rodent models for CAA type I, and compared relative expression of proteins with wild‐type controls. Additionally, we have attempted to validate these candidates by comparing selected biomarker levels in CSF of human sporadic CAA patients (sCAA) compared to Alzheimer’s patients and control subjects.MethodA Bruker TIMS‐ToF‐MS/MS instrument was used to analyze CSF samples of rTg‐DI and wild‐type rodent samples, following trypsin digestion. Protein identification was inferred from the Uniprot unreviewed rodent database using Bruker Daltonics Data Analysis. Identified biomarker candidates were additionally researched in human CAA and Alzheimer’s Dementia (AD) patients, and controls in CSF in independent validation attempts using targeted analyses including ELISA, or enzyme activity assays.ResultDifferential expression levels in rodents were discovered for cathepsins B (CatB; p < 0.001 and p = 0.05) and S (CatS; p < 0.001 and p = 0.06), and hexosaminidase B (HexB; p = 0.003 and p = 0.17) for uncorrected and corrected results respectively. Human CatB and CatS CSF levels measured by ELISA did not differ significantly between CAA, AD patients or controls (p = 0.77 and p = 0.09). Analytical sensitivity of the CatB and CatS activity assays was too low to quantify activity in human CSF, whereas total hexosaminidase (as a measure of HexB activity) and HexA activity analyses in human CSF did show (a trend) in significant decreases in CAA patients compared to controls (p = 0.07 and p = 0.05 respectively).ConclusionBiomarker candidates identified from untargeted protein screenings do not directly correspond to validation efforts in human biomarker studies. Increased HexB expression levels in rodents contrastingly appear to be reflected in decreased hexosaminidase activity in CSF in human CAA, but would need to be further validated in studies with greater power.This study was funded in the NIH CAFÉ project (5R01NS104147‐02).
Eliciting evidence on linguistic perspectives for Subjective Cognitive Impairment, Mild Cognitive Impairment and Alzheimer’s Disease: A cross‐sectional study
Authors: Kaltsa Maria , Tsolaki Anthoula , Lazarou Ioulietta , Mittas Ilias , Papageorgiou Mairi , Papadopoulou Despina , Tsimpli Ianthi Maria , Tsangalidis Anastasios , Tsolaki Magda 
Published: December 2023

AbstractBackgroundMost descriptions of the clinical and cognitive features of Alzheimer’s Disease (AD) highlight deficits mainly in memory ability, while the in‐depth understanding of the language deficits of people with AD remains limited with most data reported as heterogeneous (see Eyigoz et al., 2020; Kavé & Dassa, 2018). The overarching goal of DemLENS project (https://demlens.enl.auth.gr/) is to investigate the key linguistic characteristics of native speakers with cognitive impairment and the decline of language skills.MethodThe study integrates the clinical evaluation, the neuropsychological assessment and thorough linguistic profiling via language production data from 168 native speakers of Greek. Specifically, we examine the lexical, syntactic and content complexity of spoken language elicited through sentence repetition, single picture description, picture sequence narratives and personal narratives. We tested young healthy adults (yHC = 35), cognitively intact elder healthy adults (eHC = 31), speakers with Subjective Cognitive Decline (SCD = 32), speakers with Mild Cognitive Impairment (MCI = 33) and speakers with mild to moderate AD (AD = 38).ResultThe data analysis focuses on the annotated data at the microstructure level – e.g. POS, syntactic complexity, internal state terms – and at the macrostructure level – e.g. information content units, narration length and narration density and revealed that depending on the cognitive severity stage, language subsystems deteriorate at different stages in the progression of AD. Lexical access difficulties, reduced informational content (e.g. narration density: F
(4,164) = 6.514, p<.001; yHC,eHC>SCI,MCI>AD) and syntactic complexity of speakers’ production appear to drive linguistic decline. Note also that sentence repetition was shown to have high discriminatory value in the development of AD (e.g. accuracy index: F
(4,164) = 92.632, p<.001; yHC>eHC,SCI>MCI>AD (Figure 1).ConclusionLanguage performance exposes subtle early signs of progression to AD that can shed light on the early detection of cognitive decline, thus facilitating the clinical process. Consequently, a language‐based AD assessment is ecologically valid and one of the least intrusive ways to assess symptoms of AD.
References
Eyigoz, E., Mathur, S., Santamaria, M., Cecchi, G., & Naylor, M. (2020). Linguistic markers predict onset of Alzheimer’s disease. EClinicalMedicine, 28, 100583.Kavé, G., & Dassa, A. (2018). Severity of Alzheimer’s disease and language features in picture descriptions. Aphasiology, 32(1), 27‐40.
Assessing a universal neocortical mask for Centiloid quantification
Authors: Bourgeat Pierrick , Dore Vincent , Rowe Christopher C , Benzinger Tammie L.S. , Tosun Duygu , Goyal Manu S. , LaMontagne Pamela J. , Jin Liang , Weiner Michael S. W. , Morris John C , Masters Colin L , Fripp Jurgen , Villemagne Victor L ,   the Alzheimer’s Disease Neuroimaging Initiative, OASIS3, and the AIBL research group
Published: December 2023

AbstractBackgroundThe Centiloid (CL) project was developed to harmonise the quantification of Aβ‐PET scans to a unified scale. The CL neocortical mask was defined using 11C‐PiB, overlooking potential differences in regional distribution among Aβ tracers. We created a universal mask using an independent dataset of 5 Aβ tracers, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.MethodUsing data from the ADOPIC study (AIBL, ADNI and OASIS3), age‐matched pairs of mild Alzheimer’s disease (AD) (MMSE = 20‐24;CL>25) and healthy controls (MMSE> = 28;CDR = 0;CL<15) were selected: 18F‐Florbetapir (FBP:147 pairs), 18F ‐Florbetaben (FBB:22 pairs), 18F ‐Flutemetamol (FLT:10 pairs), 18F ‐NAV (NAV:42 pairs), 11C‐PiB (PIB:63 pairs). The PET images were smoothed to a uniform 8mm resolution to reduce the influence of different scanner sharpness on the derived masks. The images were then spatially normalised using the SPM CL pipeline and transformed into SUVR (whole cerebellum). For each tracer, the mean AD‐HC difference image was computed and mirrored. The threshold for each difference image was optimised to maximise the overlap with the standard CL mask. The Universal mask was defined as the intersection of all 5 masks. It was then used to recalibrate each tracer into Centiloids. The Universal mask and associated transforms were evaluated on the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement and variance in the young controls (YC). They were also evaluated on the baseline ADOPIC dataset (N = 3565) with the effect‐size between HC/AD and HC/MCI.ResultThe overlap between each tracer specific mask was high (mean Dice = 0.82). The Universal mask was 26% smaller than the Standard one, but the overlap was high (Dice = 0.74). The Universal mask led to a small reduction in the variance of the YC in most tracers (‐3.4%) and a small increase in the R2 between each of the 11C‐PiB/18F‐tracer pairs (+0.24%). In ADOPIC, it led to a higher effect‐size between HC/AD (1.43 vs 1.42) and HC/MCI (0.71 vs 0.70).ConclusionThe universal CL mask led to an increase in inter‐tracer agreement and group separation. Those increases were however relatively small indicating that the existing standard CL mask is suitable for the quantification of all Aβ tracers.
Neuroprotective Potential of Silymarin against Rotenone induced motor deficits in Wistar Rats
Authors: Agrawal Mohit , Chaudhary Hema , Singhal Manmohan 
Published: December 2023

AbstractBackgroundParkinson’s disease is a hypokinetic disorder characterized by selective loss of dopaminergic in substantia nigra pars compacta (SNPc) region of mid‐brain. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, neurons mitochondrial dysfunction and glutamate excitotoxicity etc. Silymarin was selected as an investigational drug, due to its numerous activities in current research, it possesses substantial antioxidant and neuroprotective functionalities and it has been reported to produce anti‐oxidant, anti‐inflammatory and neuromodulatory actions in previous studies.MethodIn the current study we have investigated the role of Silymarin against rotenone induced motor deficit and biochemical abnormalities in Wistar rats. Rats were treated with 1.5mg/kg rotenone subcutaneously for 35 days. Silymarin (50,100 and 200 mg/kg i.p.) was administered after 30 minutes of rotenone administration from day 7th to 35th day. Rotenone caused significant reduction in motor functions and body weight and produced elevation in striatal oxidative burden.ResultThe biochemical analysis revealed that there is reduction in the level of anti‐oxidants (GSH, Catalase, and SOD) in the animals following rotenone administration. Whereas Silymarin treated rats were stable and regained their body weight. In addition Silymarin significantly attenuated rotenone induced motor deficit and striatal oxidative stressConclusionOutcomes of the current study suggest neuroprotective potential of Silymarin and its ability to correct movement disability and thus could prove to be useful candidate molecule in the management of motor disorders.
Perivascular spaces in the brain enlarge over time; A three‐year longitudinal study
Authors: Bernal Jose , Menze Inga , Yakupov Renat , Kaya Pinar , Aki Cagla , Pfister Malte , Geisendörfer Jonas , Peters Oliver , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Wagner Michael , Ramirez Alfredo , Wolfsgruber Steffen , Kleineidam Luca , Jessen Frank , Schreiber Stefanie , Düzel Emrah , Ziegler Gabriel 
Published: December 2023

AbstractBackgroundPerivascular spaces in the brain can become enlarged (ePVS); their temporal dynamics remain under increasing debate. We studied automatic ePVS measurements obtained from 870 subjects along the AD continuum over the course of three years.MethodWe measured centrum semiovale (CSO) and basal ganglia (BG) ePVS volumes computationally in the multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) (Table 1; 870 subjects; 51% female, mean age 70.85 (SD 6.16), up to 4 annual time points; 2487 sets of T1w and FLAIR). We segmented ePVS using a multiscale Hessian‐based filtering method leveraging T1w and FLAIR imaging and validated segmentation against clinical visual ratings. We studied local longitudinal changes via the sandwich estimator toolbox and linear mixed‐effect modelling and tested for effects of age, hypertension, clinical diagnosis, ApoE4 status, pTau181, and Aβ42/40 on ePVS trajectories.ResultBG‐ePVS and CSO‐ePVS became more voluminous over time (Table 2 and Figure 1A‐C; BG: B = 0.04 [95%‐CI 0.03‐0.05], p<0.001; CSO: B = 0.02 [95%‐CI 0.00‐0.04], p<0.031).The age of the patient at baseline determined the baseline volume of ePVS in the BG (B = 0.13 [95%‐CI 0.09‐0.17], p<0.001), but not in the CSO‐ePVS (p = 0.245).WMH can form around ePVS (Figure 1D) and their progression was correlated with PVS enlargement (BG: B = 0.05 [95%‐CI 0.04‐0.07], p<0.001; CSO: B = 0.19 [95%‐CI 0.15‐0.22], p<0.001).No other predictors contributed significantly to longitudinal ePVS changes.ConclusionAgeing is a major contributor to the volumetric expansion of ePVS over time. WMH and ePVS growth are associated, suggesting shared underlying pathological mechanisms.
Association of AD risk factors with plasma GFAP levels in a memory clinic population
Authors: Marizzoni Moira , Chevalier Claire , Paquis Arthur , Zetterberg Henrik , Blennow Kaj , Lathuiliere Aurelien , Ribaldi Federica , Wyss‐Dominguez Carine , Blouin Jean‐Louis , Abramowicz Marc , Pievani Michela , Garibotto Valentina , Frisoni Giovanni B 
Published: December 2023

AbstractBackgroundPlasma glial fibrillary acidic protein (GFAP) is an emerging AD biomarker. We aimed to study how plasma GFAP correlated with age, clinical stage, sex, and the APOE4 status and whether amyloid pathology may mediate these associations.MethodsCohort of 330 individuals ranging from cognitively unimpaired to dementia due to AD from the Geneva Memory Center. Plasma GFAP was measured using Single molecule array (Simoa) technology. The effect of the variables of interest on plasma GFAP levels was assessed using linear regression models and partial eta squared (eta2
p). In a subset of 169 subject with amyloid PET, mediation analysis was performed to test the mediating effect of amyloid levels on the association between variable of interest and plasma GFAP.ResultsAge had the strongest effect on plasma GFAP levels (eta2
p = 0.39, p< 0.0001), followed by clinical stage (eta2
p = 0.10, p< 0.0001), sex (eta2
p = 0.06, p< 0.0001), and APOE4 (eta2
p = 0.02, p = 0.007). The effect of APOE4 status on plasma GFAP was fully mediated via the cortical amyloid uptake. The bootstrapped indirect effect was 0.09 (p< 0.0001) and the proportion of the effect of APOE4 status on GFAP that goes through the cortical amyloid uptake was 69%. No mediating effect by amyloid was found for age and sex.ConclusionThese results show that in a memory clinic population, i) AD risk factors and severity affected plasma GFAP levels and, ii) the effect of APOE4 on GFAP is amyloid‐dependent whereas that of age and sex is amyloid‐independent. GFAP cut‐offs for the early diagnosis of AD should take age and sex into account.
Profiling amyloid‐β peptides as diagnostic biomarkers for cerebral amyloid angiopathy
Authors: van den Berg Emma , de Kort Anna M. , Kersten Iris , Brinkmalm Gunnar , Johansson Kjell , Marques Tainá M. , Jäkel Lieke , Gobom Johan , Stoops Erik , Portelius Erik , Gkanatsiou Eleni , Abdo Wilson F. , Rasing Ingeborg , Voigt Sabine , Koemans Emma A. , Kaushik Kanishk , Warren Andrew D. , Greenberg Steven M. , Terwindt Gisela M. , Wermer Marieke J.H. , Klijn Catharina J.M. , Schreuder Floris H.B.M. , Zetterberg Henrik , Blennow Kaj , Kuiperij H. Bea , Verbeek Marcel M. 
Published: December 2023

AbstractBackgroundAmyloid‐β (Aβ) deposits are the main pathological hallmark of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD). Vascular deposits in CAA mainly consist of Aβ40, whereas Aβ42 is the predominant peptide in parenchymal plaques in AD. The diagnostic accuracy of other Aβ species in CAA remains understudied. We aimed to investigate the biomarker potential of various Aβ peptides for the differentiation of sporadic (sCAA) and hereditary Dutch‐type CAA (D‐CAA) from AD and controls.MethodCerebrospinal fluid (CSF) Aβ38, Aβ40, Aβ42, and Aβ43 levels were quantified by immunoassays in discovery (26 sCAA patients, 40 controls) and validation cohorts (40 sCAA patients, 40 AD patients, 37 controls), and D‐CAA patients (10 presymptomatic, 26 controls; 12 symptomatic, 28 controls). In a subset of samples (25 sCAA, 50 AD, 23 controls), we confirmed results using an extended panel of Aβ peptides (including Aβ34, Aβ37, and Aβ39, but not Aβ43) quantified by liquid chromatography mass spectrometry (LC‐MS). Area‐under‐the‐curve (AUC) was calculated using receiver operating characteristic curve to assess diagnostic accuracies.ResultWe found decreased levels of all Aβ peptides (quantified by immunoassays) in sCAA and D‐CAA compared with controls (Figures 1 and 2). All Aβ peptides, except Aβ43, were also decreased in sCAA compared with AD (Figure 1). LC‐MS verified the lower CSF levels of six Aβ peptides in sCAA compared with controls (Figure 3). All peptides, except Aβ42, were also decreased in sCAA compared with AD. Single peptide levels (using either method) differentiated sCAA from AD (immunoassays AUC 0.68‐0.88; LC‐MS AUC 0.51‐0.75) and controls (immunoassays AUC 0.61‐0.95; LC‐MS AUC 0.69‐0.85). Combinations of all Aβ peptides differentiated sCAA from AD patients (immunoassays AUC 0.93; LC‐MS AUC 0.84) and controls (immunoassays AUC 0.89‐0.98; LC‐MS AUC 0.91) with high accuracy.ConclusionCAA and AD each show a distinct disease‐specific profile of CSF Aβ peptides. All peptides shorter than Aβ42 were consistently decreased in sCAA, but not in AD, compared with controls. A panel of CSF Aβ peptides may diagnose CAA with high accuracy, and could have the potential to exclude patients with high load of CAA from anti‐Aβ therapies to avoid adverse events associated with CAA.
Can physical activity moderate the relation between systemic inflammation and cognitive performance in an elderly community dwelling population?
Authors: Fink Anne , Reinke Constantin , Aretz Benjamin , Doblhammer Gabriele 
Published: December 2023

AbstractBackgroundElevated levels of systemic inflammation have been shown to be associated with poorer outcomes in cognitive performance. However, regular vigorous physical activity is associated with improved cognitive performance. This study analyzes if regular physical activity may moderate the effect of systemic inflammation on cognition.MethodWe used the first two waves of the Dutch Lifelines cohort study (2006‐2015) of 19,985 individuals, who were 50 years or older at baseline. Cognitive performance was measured as psychomotor speed in wave 2 using the Cogstate Brief Battery, with higher scores corresponding to lower cognitive performance. As a biomarker of systemic inflammation, we used leukocyte count within the normal range of 4 to 10×109 cells per liter in EDTA blood samples at baseline. First, we performed linear regression models to examine the effect of inflammation and vigorous physical activity on cognition, adjusting for cognitive task accuracy, age, sex, education, and various comorbidities associated with cognitive impairment. Second, an interaction effect was used to analyze the potential moderation of physical activity.ResultAfter adjusting for cognitive task accuracy, age, sex, and education, higher levels in leukocyte count were significantly associated with worse cognitive outcome (b = 0.020,p = 0.036). This effect attenuated when controlling for physical activity and comorbidities (b = 0.011,p = 0.257). Vigorous physical activity was highly significantly associated with better cognitive performance (b = ‐0.126,p<0.001). Analysis of the interaction between leukocyte count and physical activity showed a borderline significant slope for physically active subjects (b = 0.029,p = 0.093) and no effect for physically inactive subjects (b = 0.003,p = 0.782). When comparing predicted psychomotor speed scores for physically active and inactive individuals, we found significantly better cognitive outcomes for active individuals with leukocyte counts between 4 and 7×109 cells per liter, while individuals with leukocyte counts between 7 and 10×109 cells per liter did not differ significantly by physical activity.ConclusionIn individuals with leukocyte levels up to 7×109 cells per liter, indicating low levels of inflammation, we found a protective effect of physical activity on cognition. Because physical activity had no effect in individuals with higher leukocyte levels (albeit within the normal range), physical activity appears to have preventive rather than intervening effects on cognitive performance.
Metabolic cross‐talk between astrocytes and neurons: implications for Alzheimer’s disease
Authors: Magi Simona , Preziuso Alessandra , Piccirillo Silvia , Cerqueni Giorgia , Serfilippi Tiziano , Lariccia Vincenzo , Amoroso Salvatore 
Published: December 2023

AbstractBackgroundConverging evidence indicates that declining brain energetics contributes to the initiation and progression of neurodegenerative disorders, including Alzheimer’s disease (AD). Upstream events often characterizing AD include hypometabolism of glucose and oxygen in the brain, which may cause mitochondrial dysfunction, energetic failure, and oxidative stress (Moreira et al., 2010). Astrocytes, which have a main role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. By modulating the release of gliotransmitters (e.g. glutamate), they provide a fine control of neuronal metabolism and cell‐to‐cell communication, both of them involved in AD (Monterey et al., 2021). Impaired astrocytes metabolism may incite an inflammatory response that, in turn, negatively impacts neuronal viability.MethodPrimary rat cortical astrocytes were isolated from the cortex of Wistar rat pups. A metabolic stress was induced by using glyceraldehyde (GA) (Magi et al., 2021). We evaluated cell viability, the release of tumor necrosis factor alpha (TNFα) and the involvement of the nuclear factor‐kappa B (NF‐kB) pathway. In order to check the glutamate turnover, we analyzed the expression of GLAST and GLT1 and we evaluated the ATP content after glutamate exposure under physiological conditions. We also explored whether damaged astrocytes could elicit neuronal death in a co‐culture setting.ResultExposure to increasing concentrations of GA caused a concentration‐dependent cell injury in rat cortical astrocytes. GA (1mM) started to induce a significant cell damage after 24 h. After 48 h, GA exposure activated the NF‐kB pathway and the release of TNFα. GA treatment significantly increased GLAST and GLT1 levels after 48h. When injured astrocytes were co‐cultured with cortical neurons, neurons viability significantly decreased. Under physiological condition, glutamate significantly improved intracellular ATP levels after 4 and 8 hours of treatment, paving the way to the evaluation of its action in metabolic‐impaired setting, as induced by GA treatment.ConclusionOur results suggest that metabolically impaired astrocytes may damage neighboring neurons, suggesting astrocytes involvement in the pathophysiological development and progression of AD. Therefore, astrocytes can be considered a key therapeutic and neuroprotective target for future studies.