bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging of amyloid, tau and synaptic dysfunction in the brains of type 2 diabetic rats ‐ a multitracer PET study
Authors: Kong Yanyan , Zuo Chuantao , Xie Fang , Xiao Jianfei , Huang Qi , Guan Yihui , Ni Ruiqing 
Published: January 2025

AbstractBackgroundType 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease (AD). Synaptic impairment and protein aggregates have been reported in the brains of T2DM rodent models. Here, we assessed the changes in synaptic vesicle 2A (SV2A), amyloid‐β, and tau that are featured pathologies in AD in T2DM rats in vivo.MethodPositron emission tomography (PET) using [18F]SynVesT‐1 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid‐β), [18F]APN‐1607 (tau), was carried out in 12‐month‐old diabetic Zucker diabetic fatty (ZDF) and Sprague‒Dawley (SD) rats. Immunofluorescence staining as well as proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats.ResultsReduced cortical [18F]SynVesT‐1 uptake were observed in 12‐month‐old ZDF rats compared to SD rats. No difference was observed in the [18F]florbetapir and [18F]APN‐1607 uptake in the brains of 12‐month‐old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S‐negative, phospho‐tau‐positive inclusions in the cortex and hypothalamus of ZDF rats, without amyloid‐beta deposits. Proteomic analysis further demonstrated downregulated synaptic‐related proteins pathways in the hippocampus of ZDF rats compared to SD rats.ConclusionThese findings provide in vivo evidence for synaptic impairment in the brains of aged T2DM ZDF rats.
Structural flexibility and heterogeneity of recombinant human glial fibrillary acidic protein
Authors: Gogishvili Dea 
Published: January 2025

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is a promising biomarker for brain and spinal cord disorders. Recent studies have highlighted the differences in the reliability of GFAP measurements in different biological matrices. The reason for these discrepancies is poorly understood as our knowledge of the protein's 3‐dimensional conformation, proteoforms, and aggregation remains limited.MethodHere, we investigate the structural properties of GFAP under different conditions. For this, we characterised recombinant GFAP proteins from various suppliers and applied hydrogen‐deuterium exchange mass spectrometry (HDX‐MS) to provide a snapshot of the conformational dynamics of GFAP in artificial cerebrospinal fluid (aCSF) compared to the phosphate buffer.ResultOur findings indicate that recombinant GFAP exists in various conformational species. Furthermore, we show that GFAP dimers remained intact under denaturing conditions. HDX‐MS experiments show an overall decrease in H‐bonding and an increase in solvent accessibility of GFAP in aCSF compared to the phosphate buffer, with clear indications of mixed EX2 and EX1 kinetics. To understand possible structural interface regions and the evolutionary conservation profiles, we combined HDX‐MS results with the predicted GFAP‐dimer structure by AlphaFold‐Multimer. We found that deprotected regions with high structural flexibility in aCSF overlap with predicted conserved dimeric 1B and 2B domain interfaces.ConclusionStructural property predictions combined with the HDX data show an overall deprotection of GFAP in aCSF and signatures of aggregation. We anticipate that the outcomes of this research will contribute to a deeper understanding of the structural flexibility of GFAP and ultimately shed light on its behaviour in different biological matrices.
Neurological and cognitive impairment in long‐term COVID‐19: clinical characterization in a longitudinal study and correlation with neuroimaging and biomarkers
Authors: Júnior José Wagner Leonel Tavares , Neto Manoel Alves Sobreira , Braga‐Neto Pedro 
Published: January 2025

AbstractBackgroundCOVID‐19 can course with persistent symptoms after infection in a condition called long Covid (NATH, 2020). In this context, cognitive complaints, sleep disorders, headache, smell disorders, in addition to anxiety and depression are common (DELGADO‐ALONSO et al, 2022; ISMAEL et al, 2021.). The present study aims to describe the cognitive manifestations in patients who had a previous COVID‐19 infection and is justified by the need to better explain the pathophysiological mechanisms behind these manifestations.MethodThis is a cross‐sectional view of a prospective longitudinal study carried out on an outpatient basis. Patients have been evaluated on an outpatient basis since March 2023. Patients were evaluated by a neurologist and sleep specialist, with the application of MMSE, GDS/BECK, Pittsburgh, Epworth, Pfeffer and CDR. In addition, a blood sample is collected to analyze APOE and markers of neurodegenerative and inflammatory processes (NfL, AB42, AB40, p‐tau, t‐tau, GFAP, alpha‐synuclein and clusterin). In addition, all patients will undergo cranial MRI, polysomnography and neuropsychological evaluation. The project is approved by the local CEP, all patients have signed an informed consent form.ResultSo far, 93 patients have been evaluated, with 79% female. 1.1% had <4 years of schooling, 4.5% between 4‐8 years and 94.3% > 8 years of schooling. The average duration of symptoms was about 2 years. The average age was 42.8 years. During the illness, only 13.9% were hospitalized, and 10.7% in the ICU. As for the applied batteries, 4.3% of the patients presented alterations in the Pfeffer, and 3.2% presented alterations in MMSE for education. As for post‐Covid symptoms, 96.7% had cognitive complaints, 73.1% sleep disorders, 63.4% anxiety, 35.4% headache, 32.2% depression and 24.7% smell disorders. Results of neuropsychological assessment, biomarkers, cranial MRI and PSNG are pending.ConclusionIn our study, cognitive manifestations and sleep disturbances were common in the Long Covid phase, even in a population with x months after the acute infection. In addition, cognitive complaints were common even in a sample with a mean age < 50 years, after a mild case of Covid‐19 and with a high level of education.
Harmonization of diffusion MRI measures is crucial for white matter tract normative assessment in ADNI
Authors: Descoteaux Maxime , Girard Gabriel , Edde Manon , Dumais Félix , Dumont Matthieu , Houde Jean‐Christophe , Jodoin Pierre‐Marc , Belanger Jean‐Rene 
Published: January 2025

AbstractBackgroundDiffusion MRI (dMRI) measures are variable across sites and MRI vendors, which leads to a site bias in the reported quantitative white matter metrics (Figure 1). ComBat is currently the go‐to method for harmonizing MRI data. However, to our knowledge, the harmonization power of ComBat has not been convincingly demonstrated on the ADNI cohort and was never tested in the context of normative assessment for Alzheimer’s disease (AD) patients.MethodsWe select 21 sites in the ADNI cohort with at least 10 healthy controls (HC) datapoints per site. Instead of harmonizing all patients from every site onto an average template, as done in ComBat, we identified a reference site containing a large number of HC of all ages and gender. We use the Cam‐CAN dataset, with 441 subjects aged 18‐87. Moreover, instead of computing the harmonization function from every subject (HC and AD), only HC are used. The harmonization function of each site is thus computed in a pairwise fashion between each ADNI site and the Cam‐CAN site. Finally, once the harmonization function of each site is computed, all subjects of every site are harmonized towards the Cam‐CAN site. All results are shown for the Mean Diffusivity and Apparent Fiber Density dMRI measures in the left arcuate fasciculus.ResultsThe left panel of Figure 1 shows how dMRI measures vary across sites/vendors. The most striking bias is between Philips sites/scanners and the rest. The right panel of Figure 1 shows the successful harmonization effect of ComBat. In Figure 2, the Cam‐CAN reference is shown in gray with different percentile distributions across ages and AD patients from the GE ADNI site #127 before and after harmonization. Harmonization clearly moves HC and AD datapoints in the correct measurement “space” and preserves disease stage (HC vs AD).ConclusionsWe showed that harmonization is crucial in white matter dMRI in ADNI. Harmonization methods can correct site biases and are robust to pathology, as HC and AD patients are successfully harmonized across sites. Harmonization is thus crucial for data pooling and quantitative comparison in large multi‐site datasets such as ADNI.
Melatonin to treat sleep disturbances in patients with Alzheimer’s disease
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich 
Published: January 2025

AbstractBackgroundAlzheimer’s disease can cause sleep disturbances in humans, which can worsen other symptoms of the disease.MethodIn our study, we examined the sleep patterns of 23 patients with Alzheimer’s disease, aged 65‐74 years (20 women and 3 men), over 4 months. All patients reported experiencing poor sleep, including difficulty sleeping in the ward, frequent awakenings during the night, early morning awakenings, and daytime sleepiness. To assess their sleep, we conducted a polysomnographic study in a specialized ward with continuous monitoring of indicators, video, and audio control. This was done both before the patients were included in the study and after a month of melatonin administration. During the diagnostic night, a nurse was present to continuously observe the polysomnography process. Based on the results of the polysomnography, we constructed a hypnogram, which is a curve that depicts the quality of sleep, the number and duration of sleep stages, and their structure. The patients were given a dose of 1.5 mg of melatonin (half a tablet) 30 minutes before bedtime for 4 weeks, with gradual withdrawal.ResultIn the initial polysomnographic study, all patients showed shortened phases of rapid eye movement (REM) and slow eye movement (SEM), with a rapid transition between them during sleep. They also experienced long periods before falling asleep and 3 to 4 nocturnal awakenings. However, after a month of melatonin administration, the majority of patients showed a normalization of REM and SEM phases, in line with their age norms, and an improvement in the duration of sleep. The number of nocturnal awakenings also decreased to 1‐2, mostly between 4 and 6 hours. Additionally, patients were able to fall back asleep after awakening, and the time it took for them to fall asleep decreased. However, even after a month of melatonin supplementation, some patients still experienced early morning awakenings and daytime sleepiness and reported feeling unrefreshed after a night’s sleep.ConclusionIn conclusion, our study suggests that melatonin is effective in treating sleep disorders in patients with Alzheimer’s disease, and can help normalize the duration and frequency of REM and SEM phases during sleep.
Correlation between alterations in resting‐state functional alterations of brain and cerebrospinal fluid pathological markers in patients with Alzheimer's disease
Authors: Zhao Hui , Gong Cheng Bing 
Published: January 2025

AbstractBackgroundThe aim of this study was to explore the correlation between brain functional alterations and cerebrospinal fluid (CSF) pathological biomarkers in Alzheimer's disease (AD) patients.MethodA total of 39 individuals were recruited, including 23 AD patients and 16 control subjects. All subjects underwent a battery of neuropsychological examinations, CSF measurement and multimodal magnetic resonance imaging scans. Independent component analysis was used to investigate the variations of functional connectivity (FC) between the two groups by utilizing the resting‐sate functional MRI (RS‐fMRI) data. Differences in ALFF and ReHo between the two groups were also calculated. Then correlation analyses were used to estimate the possible association between functional alterations and CSF β‐amyloid (Aβ1‐42.) and tau.ResultMultiple inter‐ and intra‐network functional connections were altered in AD patients compared to the Non ADCI group. In the AD group, ALFF decreased in the right Superior Frontal Gyrus, Middle Frontal Gyrus, left superior temporal gyrus. and increased in the right cerebellum anterior lobe, and caudate nucleus as compared to Non‐AD CI group (p < 0.001). In addition, ReHo decreased in the right insula and left middle temporal gyrus (p < 0.001). Dynamic fluctuations of CSF Tau were observed to be associated with changes in FC between VN and PCC, FC of SMN, as well as the altered ReHo in the right insula and left middle temporal gyrus. Compared the AD group with the non‐AD CI group, the aforementioned altered functional brain connectivity, with the exception of FC in the PCC and VN, was significantly associated with a decrease in CSF Aβ1‐42.ConclusionAD patients have exhibited functional changes in more than one brain region. These changes are linked to the variations of Tau protein and Aβ1‐42 in CSF, with Aβ1‐42 having a particularly large impact on brain network function. From an imaging standpoint, this study validated the impact of pathological changes on brain function in AD.
Inter‐ and intra‐subject variability of quantitative EEG biosignatures and their effect on interpretation of normalized effect size
Authors: Meghdadi Amir H. , Berka Chris , Malek‐Ahmadi Michael H. 
Published: January 2025

AbstractBackgroundQuantitative EEG measures can be used as biosignatures of disease conditions. As such, the effect of interventions/treatments can be studied by longitudinal analysis of changes in these measures. The consistency of these measures can be assessed by test‐retest reliability scores such as intra‐class correlation coefficient (ICC) that depends on intra‐ and inter‐subject variability. The magnitude of an effect can be described by a normalized effect size (i.e. normalizing the effect with respect to the sample variability). However, the inherent variability of EEG and its effect on interpretation of effect size is less explored. The aim of this work is to investigate inter‐ and intra‐subject variability of PSD‐based resting‐state EEG measures and their effect on analysis of change scores.MethodsWe collected 20‐channel longitudinal EEG data (initial visit and 1‐year follow‐up) from healthy volunteers (n=61, ages 40‐82). After artifact decontamination, we computed power spectral density (PSD) at 1‐40 Hz frequency bins. At each frequency, we computed inter‐ and intra‐subject variability of PSD as well as ICC. We simulated a hypothetical effect by adding a constant value to the 2nd visit’s data equivalent to half the standard deviation of the sample. We computed the normalized effect size (Cohen’s d) using both the pooled variance as well the variability in the change score. We compared these effect sizes for different frequencies.ResultsOverall, absolute PSD exhibited high test‐retest reliability in the frequencies 2‐20 Hz (ICC>0.7) with 7‐9 Hz having the highest ICC (ICC>0.94). Inter‐subject variability was highest at 8Hz, and intra‐subject variability was lowest at 13‐15 Hz frequencies. For frequencies between 5 – 10 Hz (fast‐Theta/slow‐Alpha bands), the difference between the two types of normalized effect size ranged between 0.3 to 0.6.ConclusionsInter‐ and intra‐subject variability of PSD‐based EEG measures depend on frequency. As such, changes in PSD due to potential interventions should be interpreted with respect to the inherent variability of PSDs. In longitudinal analysis of paired data, normalized effect size should be reported using both population variability (inter‐subject) and change‐score variability (intra‐subject).
Nasal tissues from Alzheimer’s disease patients induces the formation of aggregates in a cellular model of tau propagation
Authors: Yanagisawa Daijiro , Arrozi Aslina Pahrudin , Kato Tomoko , Mizukami Tamio , Akatsu Hiroyasu , Yoshio Hashizume , Kaneda Daita , Tooyama Ikuo 
Published: January 2025

AbstractBackgroundAbnormal protein depositions of amyloid β and tau are present in the nasal cavity in patients with Alzheimer’s disease. This finding raises an idea that nasal tissues would be a promising source of diagnostic biomarkers for Alzheimer’s disease. However, the amounts of amyloid β and tau are extremely small, making it difficult to quantify the levels using conventional methods such as ELISA, and thus it is challenging to utilize them for the diagnostic biomarkers. In the present study, we tested the nasal tissues as the source of diagnostic biomarkers using a cellular model of tau propagation.MethodThis study was approved by the institutional Ethics Committees. Postmortem nasal mucosa and brain tissues from patients with AD (n = 10) and normal subjects (n = 10) were collected with patient consent at the Fukushimura Brain Bank. Nasal and brain tissue homogenates were added to HEK293 cells expressing tau 3‐repeat domain with the L266V and V337M mutations (3RD∗VM) or 4‐repeat domain with the P301L and V337M mutations (4RD∗LM), which was fused with GFP at the C‐terminus.ResultGFP fluorescence was detected uniformly within the cell bodies of HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP. There were no changes in the fluorescence after the additions of the brain homogenates from normal subjects. In contrast, a large number of fluorescent puncta was detected both in HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP at 4 days after the additions of the brain homogenates from patients with AD. Furthermore, the nasal tissue homogenates from patients with AD also induce the formation of fluorescent aggregates in HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP. Quantitative analysis revealed that the nasal tissue homogenates from AD patients significantly induced the aggregate formation, compared with normal subjects.ConclusionThese results suggest that the nasal tissues from AD patients contain tau seeds with prion activity, similar to the brain. A cellular bioassay using nasal tissues would be great potential as an AD biomarker because of the usefulness of nasal tissue biopsy, and would provide an important contribution to the development of ex vivo diagnosis method for AD using the nasal extracts.
Quantitative‐ and visual read‐based flortaucipir PET T+ criteria for the pathophysiological assessment of Alzheimer’s Disease
Authors: Tunali Ilke , Kotari Vikas , Kennedy Ian A. , Burnham Samantha C. , Shcherbinin Sergey 
Published: January 2025

AbstractBackgroundThe revised NIA‐AA biological Alzheimer’s disease (AD) staging scheme considers various tau positivity (T+) rules based on global and regional neocortical tau PET uptakes. In AD clinical trials, various tau PET criteria (e.g., visual+quantitative [TauVQ], Mintun et al., 2021) have been employed to select eligible patients. In this study, we compared six T+ criteria in terms of their potential usefulness for biological staging and clinical trial eligibility.MethodsN=296 symptomatic (189/107 MCI/AD‐dementia) subjects from AV‐1451‐A05 (NCT02016560) were included. Six different tau‐PET stratifications (T+/T‐) were employed: Two quantitative global neocortical uptake measures (CenTauR‐Universal, Villemagne et al., 2023, and AD‐signature weighted neocortical, Devous et al., 2018); two quantitative temporal‐based uptake measures (CenTauR‐Meta‐temporal, Villemagne et al., 2023 and Early Tau VOI, Kotari et al., 2023), a visual read‐based method (Fleisher et al., 2021) and TauVQ method. A dataset of young cognitively normal subjects (N=16) was utilized to determine T+ thresholds for quantitative measures (mean+2.5xSD SUVr). The tau stratifications were evaluated for their agreement with amyloid‐PET positivity and for AD‐related prognostic utility using signal‐to‐noise ratios (SNRs) of T+ for (1) Annualized change in AD Assessment Scale‐Cognitive (ADAS‐Cog11) and (2) 18‐month change in CenTauR‐Meta‐temporal SUVr.ResultsCenTauR‐Universal and CenTauR‐Meta‐Temporal derived T+ groups showed comparable SNRs (Figure 1A‐B) and agreement with amyloid positivity (Figure 2). The TauVQ‐ and the visual read‐derived T+ groups also performed similarly. The regional early tau VOI‐based T+ group, compared to the global AD‐signature neocortical‐based T+ group, showed a higher SNR for 18‐month change in CenTauR‐Meta‐temporal SUVr. However, a lower SNR for annualized ADAS‐Cog11 change and a lesser agreement with amyloid positivity were observed. Comparisons using PET‐to‐autopsy cohort will be presented.ConclusionsOur analyses suggest using CenTauR‐Meta‐temporal and visual read‐based regional T+ criteria may identify a larger subgroup of symptomatic patients exhibiting similar amyloid positivity prevalence and clinical decline compared to those determined by corresponding global T+ criteria. Among examined methods, the early tau VOI‐based T+ criterion possibly captures the earliest pathologic stage. Lastly, CenTauR‐based T+ groups showed lower SNRs for tau and clinical progression, suggesting flortaucipir‐specific criteria might be more sensitive for prognostic evaluations. Further validations using different datasets and cut points are warranted.
Learning from Real‐World Data Platforms: Insights into Care and Representation in Research Through ALZ‐NET and New IDEAS
Authors: Windon Charles , Dilworth‐Anderson Peggye , Wilkins Consuelo H. , Carrillo Maria C. , Apgar Charles , Edelmayer Rebecca M. , Gatsonis Constantine , Hanna Lucy , Hillner Bruce E , March Andrew , O'Bryant Sid E. , Rafii Michael , Rissman Robert A , Siegel Barry A. , Snyder Heather M , Whitmer Rachel A. , Rabinovici Gil D. 
Published: January 2025

AbstractReal‐World data platforms for Alzheimer’s Disease (AD) offer a unique opportunity to improve health equity through better understanding of health disparities and inclusivity in research, which is critical to translatability of research findings. AD research in the US and globally remains largely inaccessible to many individuals due to individual‐level, study‐level, investigator‐level and larger systemic barriers. ALZ‐NET, a US‐based registry to evaluate longitudinal outcomes of patients being evaluated for or treated with novel FDA‐approved AD therapy, and New IDEAS, an observational US‐based longitudinal study of amyloid PET clinical utility, both offer opportunities for examining care, inclusivity, and disparities.ALZ‐NET (Alzheimer’s Network for Treatment and Diagnostics) is a national, provider‐enrolled, patient registry collecting longitudinal regulatory grade clinical data. It also features a diagnostic imaging and biospecimen repository. Providers at clinical sites across the US enroll and longitudinally follow patients being considered for Food and Drug Administration (FDA)‐approved AD therapies according to local site practice standards. Clinical practice sites across the US are eligible for ALZ‐NET participation, allowing a greater diversity of participating patients. Registry data is maintained using centralized, secure electronic data capture and management systems that will allow for co‐enrollment of participants into affiliated clinical trials, merging of data with existing databases, and data sharing to facilitate additional research studies.NEW IDEAS (Imaging Dementia ‐ Evidence for Amyloid Scanning) has enrolled cognitively impaired Medicare beneficiaries at memory clinics across the US since 2020. New IDEAS features a dedicated recruitment and engagement strategy that leverages community partnerships and liaisons in 9 targeted, highly diverse US metro areas to specifically address barriers to participation in traditional research. New IDEAS has identified and developed novel methodology that can inform future studies in successfully increasing representation in AD research on a large scale, with >40% of the current patient population consisting of individuals historically not included in research. New IDEAS also offers insights into rates of amyloid pathology by in vivo biomarkers among diverse populations.Real world data platforms like ALZ‐NET and New IDEAS serve an important role in fostering greater understanding of health disparities and inclusivity in research to improve care.