bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finding a novel method to understand the role of salivary exosome in progression of cognitive impairment to Alzheimer's disease
Authors: Rastogi Simran , Rani Komal , Nikolajeff Fredrik , Kumar Saroj 
Published: December 2020

AbstractBackgroundCognitive impairment is an prominent aspect of aging and a common accomplice of dementia. Majority of dementia cases are dictated by Alzheimer’s disease (AD) pathology. There are many neuroimaging and molecular biomarkers to differentiate between cognitive impairment and dementia however, these are either invasive or expensive; also, for a patient without any cognitive complain, it is impractical to use these as an early diagnostic tool. Currently, extra‐cellular vesicles like exosomes are widely researched as they carry signals of disease pathology in there protein cargos. Its release and uptake in case of Parkinson’s and AD is already explored. In this study, we have demonstrated a novel method: nanoparticle tracking analysis to investigate how salivary exosomes concentration can elucidate the correlation between CI and AD and that could open a new way for early and cost‐effective screening of this disease.MethodThe exosomes were isolated from saliva using chemical precipitation. Total salivary exosomes concentration was measured by nanoparticle tracking analysis followed by exosomal cargo protein validation through automated western blot system using amyloid‐beta (Aβ) oligomer, monomer, phospho‐tau antibody.ResultThe exosome were validated using electron microscopy and exosomal surface marker CD63 [Figure 1 A & B] and its neuronal origin through, CD171 antibody [Figure 1 C]. We observed a significant difference in salivary exosomal concentration in cognitively impaired and AD patients (p=0.0001) [Figure 1 D] compared to age matched healthy control using NTA. We further validated and correlated our NTA findings by observing the protein expression level of oligomer Aβ, p‐tau. The Aβ oligomer/fibril abundance (p=0.0291) [Figure 2 A, B, C], p‐tau (p=0.0325) [Figure 2 D, E] and Aβ protein abundance (p=0.0198) [Figure 2 F, G] was significantly high in AD and CI patients in comparison to healthy control.ConclusionWe demonstrated for the first time that the salivary exosome concentration as well as the expression level of hallmark proteins is higher in cognitively impaired and AD patient than healthy control as well is in accordance with the disease severity staging. This study has a potential to be developed as an early, cost‐effective screening method for detection of disease severity stage.
Metabolomics biomarker discovery in cerebrospinal fluid for cerebral amyloid angiopathy
Authors: van den Berg Emma , Kuiperij H. Bea , Van Nostrand William E. , Peters Tessa M.A. , Coene Karlien L.M. , Engelke Udo F.H. , de Boer Siebolt , Verbeek Marcel M. 
Published: December 2020

AbstractBackgroundCerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhages and contributes to cognitive decline. Probable diagnosis is currently determined using the modified Boston criteria. However, these in vivo imaging correlates only represent late‐stage disease manifestations, are unable to set definitive CAA diagnosis, and do not reflect disease progression or track severity. Thus there is an unmet need for an early‐stage CAA biomarker to bypass these limitations. Next to vascular amyloid‐ß accumulation and increased neuroinflammation, metabolite levels may also be altered due to changes induced by amyloid‐ß deposits.MethodIn the Cerebral Amyloid Angiopathy Fluid Biomarker Evaluation (CAFE) study, we aim to discover and validate new CAA‐specific biofluid markers. By using a transgenic rat model for small‐vessel CAA, the rTg‐DI model, we are able to study a genetically homogenous group, housed in an environment equal to wild‐type rats. An unbiased combined liquid chromatography‐mass spectrometry protocol to analyze cerebrospinal fluid (CSF) from these rats will be generated and optimized. With the obtained distinct metabolite profiles, we aim to identify novel CAA‐associated metabolite biomarkers.ResultNext‐generation metabolic screening (NGMS) is our newly developed methodology to study the metabolome, using high‐resolution liquid chromatography quadrupole time‐of‐flight mass spectrometry. This high‐throughput unbiased NGMS approach enables us to detect >10,000 different features in one plasma sample, defined by their unique combination of accurate mass, specific retention time and intensity. In human CSF, 206 metabolites were annotated using the Human Metabolome Database. Application to rodent models requires only 25µL of CSF for analysis. Currently, we are analyzing CSF from 6‐months old rTg‐DI rats compared to age‐matched wild‐type rats (each n=10); the results will be presented during the conference.ConclusionWe expect that our powerful innovative technology for untargeted and simultaneous analysis of a large number of metabolites in body fluids will be promising in discovering novel potential biomarkers for CAA. Using a robust animal model allows us to study biomarkers along the trajectory of disease progression. Furthermore, it will gain more insight in underlying processes and metabolic pathways that are involved in the pathophysiology of CAA. After the initial discovery phase, candidate markers will be validated in patient cohorts.
Microglial activation: A process potentially related to Alzheimer's disease and late‐life major depression
Authors: Heslegrave Amanda J. , Foiani Martha S , Bruno Davide , Reichert Chelsea , Zlokovic Berislav V. , Huang Yadong , Zetterberg Henrik , Blennow Kaj , Pomara Nunzio 
Published: December 2020

AbstractBackgroundSince genetic findings have implicated microglia and TREM2 in the aetiology of neurodegenerative diseases, particularly Alzheimer's disease (AD), there have been numerous studies indicating changes in the levels of sTREM2 in cerebrospinal fluid (CSF) in sporadic and familial disease. Inflammation has also been implicated in depression and associated with an increased risk for AD. This prompted us to investigate levels of sTREM2 in late life major depression (LLMD).MethodCSF was obtained from 47 older subjects with intact cognition having an MMSE score of at least 28 and no gross MRI abnormalities other than white matter hyperintensities (22 LLMD, 19 controls). Severity of depression was determined at baseline and screening visits using the HAM‐D. CSF sTREM2 was determined using an electrochemiluminescence immunoassay. We also determined AD biomarker levels and indices of blood brain barrier (BBB) dysfunction.ResultsTREM2 levels were significantly lower in the CSF of LLMD subjects compared to controls (3476±525.1 pg/mL, 5178±2787 pg/mL p = 0.00351). Levels of sTREM2 were positively correlated with Aβ40 (r = 0.495, p = <0.001), Aβ42 (r = 0.461, p = 0.001) tTau (r = 0.417, p = 0.003) pTau181(r = 0.413, p = 0.004) and IL8 (r = 0.338, p = 0.022), this was driven by controls only. Markers of BBB integrity, the albumin quotient (AQ), cyclophilin A and soluble platelet derived growth factor beta (sPDGFβ) all show a positive correlation with sTREM2 (r = 0.503, p = 0.028; r = 0.479, p = 0.024; r = 0.455, p = 0.017 respectively) but this correlation is only seen in LLMD subjects, apart from sPDGFRβ, where a positive correlation was also seen in the whole cohort (r = 0.0337, p = 0.022).ConclusionThe correlation of sTREM2 with indices of BBB dysfunction suggests that in LLMD the sTREM2 measured could be peripheral, and that there is a decrease or suppression of microglial activation. It is possible then, that LLMD leads to a higher risk of AD due to an inability of microglia to react appropriately and further studies should focus on investigating this in more detail.
PET imaging of net availability in humans using [11C]MRB: Age, gender and ethnicity effects
Authors: Ding Yu‐Shin , Wang Jiacheng , Chen Jingyun , Babb James , Rusinek Henry ,   Ding Group
Published: December 2020

AbstractBackgroundUnderstanding the underlying pathological mechanisms of AD is urgently needed to enable the development of effective treatments. Tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our preliminary data using [11C]MRB have documented an age‐related decline in NE transporters (NET) starting in middle age, suggesting in vivo NET availability is a sensitive biomarker for aging and preclinical stages of AD. This report investigated the age, gender and ethnicity effects on NET availabilityMethodCoregistration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual to generate regional time‐activity curves (TAC) using Firevoxel. Binding potential (BPND) were determined using MRTM2 (t2* 20 min and k2’ 0.021 min‐1 with occipital as the reference region). Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 × (em
– 1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.ResultFor all HC (N=31), with both genders and all races included, the NET availability decline can be observed; e.g., ‐0.4%/yr for BS & ROfac. However, in gender‐separated group analysis [(19M, age 36.2±9.9) vs. (12F, age 36.6±9.0)], there was a significant gender effect for APC (P <0.01) with decline rates faster for M (e.g., ‐0.8%/yr for LTH), starting from mid 30 (p<0.001). Interestingly, out of 16 ROIs, while AA (N=14, age 34±7) had consistently higher regional BPND than white subjects (N=12, age 35±8)(P<0.000), the decline rate was much higher for AA (P<0.00001); e.g., ‐3%/yr in LTH for AA‐M.ConclusionIn addition to our previously determined age effect on MRB‐NET binding, this report further reveals, for the first time, the role of gender and ethnicity effects on NET availability, in the context of the aging brain. A bigger sample size is warranted to investigate these effects on the NET availability.
Microinfarcts in the deep gray matter on 7 Tesla MRI: Risk factors, MRI correlates and relation to cognitive functioning — the SMART‐MR study
Authors: Ghaznawi Rashid , Zwartbol Maarten H. T. , de Bresser Jeroen , Kuijf Hugo J. , Hendrikse Jeroen , Geerlings Mirjam I. 
Published: December 2020

AbstractBackgroundHistopathological studies suggest that microinfarcts in the deep gray matter are associated with ante‐mortem cognitive impairment, however in vivo data on subcortical microinfarcts are lacking. We examined the association of microinfarcts in the deep gray matter on 7T MRI with vascular risk factors, MRI markers of cerebrovascular disease and cognitive functioning in patients with a history of arterial disease.MethodWithin the SMART‐MR study, 213 patients (68 ± 8 years) had risk factor assessment, a 7T and 1.5T brain MRI, and cognitive examination. Microinfarcts in the deep gray matter on 7T MRI were defined as lesions ≤4 mm. Regression models were used to examine the age‐adjusted associations between risk factors, MRI markers and presence of microinfarcts in the deep gray matter. Cognitive function was summarized as composite and domain‐specific z‐scores.ResultA total of 47 microinfarcts were found in 28 patients (13%). Older age, history of stroke, hypertension and intima‐media thickness were significantly associated with microinfarcts. On 1.5T MRI, cerebellar infarcts (RR = 2.75, 95% CI: 1.42 ‐ 5.33), lacunes in the white (RR = 3.28, 95% CI: 3.28 ‐ 6.04) and deep gray matter (RR = 3.06, 95% CI: 1.75 ‐ 5.35) were associated with microinfarcts, and on 7T MRI cortical microinfarcts (RR = 2.33, 95% CI: 1.32 ‐ 4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in global z‐score between patients with multiple microinfarcts vs. none = ‐0.97, 95% CI: ‐1.66 to ‐0.28, p = 0.006) and across all cognitive domains, independent of age, education level and number of infarcts ≥5 mm in the deep gray matter.ConclusionMicroinfarcts in the deep gray matter on 7T MRI were associated with MRI markers of small and large vessel disease and worse cognitive functioning. These findings suggest that microinfarcts in the deep gray matter represent a novel imaging marker of vascular brain injury.
Neuropsychiatric symptoms in subjective cognitive complaints (SCC) and mild cognitive impairment (MCI): Detecting changes over time with the Mild Behavioral Impairment Checklist (MBI‐C)
Authors: Mallo Sabela C. , Pereiro Arturo X. , Campos‐Magdaleno Maria , Nieto‐Vieites Ana , Lojo‐Seoane Cristina , Facal David , Ismail Zahinoor , Juncos‐Rabadán Onésimo 
Published: December 2020

AbstractBackgroundNeurobehavioral Symptoms (NPS) have been usually measured with the Neuropsychiatric‐Inventory (NPI‐Q) (Kaufer et al., 2000) in pre‐dementia individuals. However, this instrument was designed to dementia states. The Mild Behavioral Impairment Checklist (MBI‐C) (Ismail et al., 2017) is an instrument developed to evaluate NPS in pre‐dementia states, including Mild cognitive impairment (MCI) and people with Subjective Cognitive Complaints (SCC). Evidence of longitudinal behavioral change obtained with the MBI‐C is still scarce. Our objective was to compare NPS scores, measured with the NPI‐Q and the MBI‐C, in MCI and SCC participants, at follow‐up.MethodTwo hundred forty participants from the Compostela Ageing Study recruited from primary care health centers, were classified into two groups, MCI (84) and SCC (166). Socio‐demographic, neuropsychological and NPS measures, including MBI‐C and NPI‐Q total scores on severity, were collected at baseline and at follow‐up (mean interval, 24 months) (Table 1). Instrument (NPI‐Q and MBI‐C) total score differences as a function of measurement Time (baseline vs follow‐up) were analyzed using repeated measure ANOVAs including Group (SCC vs MCI) as inter‐subject factor.ResultsSignificant main effects of Time, F(1, 251)=7.68, p = .006, ηp
2=.030, observed power=.789, and Group, F(1, 251)=9.88, p = .002, ηp
2=.038, observed power=.879, were observed for the NPI‐Q total scores (Figure 1). Time*Group interaction was not found. Mixed ANOVA for the MBI‐C total score showed significant main effect of Group, F(1, 248)=13.93, p < .001, ηp
2=.053, observed power=.961, and Time*Group interaction, F(1, 248)=4.89, p = .028, ηp
2=.020, observed power=.596. Post hoc Bonferroni tests for the MBI‐C total score showed (Figure 2) significantly higher behavioral impairment in MCI than in SCC group in both time measurements (baseline and follow‐up).ConclusionsTime main effect in NPI‐Q total scores showed decreases in severity of behavioral symptoms in the follow‐up measurement in spite of the Group (SCC vs MCI). On the contrary, MBI‐C scores pointed‐out slight increases in the follow‐up measurement and, considering the descriptive trends, particularly in MCI group. Only the MBI‐C was able to detect significant differences between MCI and SCC groups both in baseline and follow‐up measurements.
Cerebroprotective effects of D. triquetrum on sodium nitrite‐induced hypoxia and ethanol‐induced neurodegeneration in animal models relevant to dementia
Authors: Joshi Hanumanthachar , Sandhya P. , Charan C.S. 
Published: December 2020

AbstractBackgroundCognitive impairment is a multidimensional and complicated concept that subsumes the attention, concentration, learning, memory, problem‐solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency and manual dexterity.ObjectiveTo study the effects of aqueous extracts of roots of Desmodium triquetrum on cognitive deficit mice.MethodsAqueous extracts of Desmodium triquetrum (DTE) were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models such as rotarod, Passive shock avoidance paradigm, special water bottle case model, elevated plus maze and Morris water maze. DTE (5, 2.5 and 1.25 mg/kg p.o.) were administered to the mice. Acquisition, retention, Transfer latency (TLT), Time spent in target quadrant (TSTQ), Step down latency (SDL) and Escape latency (ELT) and biochemical parameters such as AChE, MAOA, TBARS, epinephrine, 5 HT were determined. DNA fragmentation studies were conducted which were compared with Donepezil.ResultsDTE (5, 2.5 and 1.25 mg kg(‐1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. DTE improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transfer Latency Time (TLT), escape latency time, TSTQ and increased the Step Down Latency (SDL. DTE inhibited Acetylcholinestrase (p < 0.01) activity, increased GSH, decreased TBARS and inhibited MAOA activity. Reduced the metabolism of epinephrine, 5‐HT. DTE (5 mg kg‐1) protected the DNA fragmentation of frontotemporal cortex from hypoxic effects.ConclusionDesmodium triquetrum are beneficial in the management of Neurodegenerative disorders particularly for Alzheimer’s disease.
A fully automated cognitive screening tool based on assessment of speech and language
Authors: O'Malley Ronan , Walker Traci , Mirheidari Bahman , Christensen Heidi , Reuber Markus , Blackburn Daniel J. , Venneri Annalena 
Published: December 2020

AbstractBackgroundThe dramatic recent rise in referrals to specialist memory clinics has been associated with an increased proportion of patients referred with Functional Memory Disorder (FMD), i.e. non‐progressive cognitive complaints. These referrals have exerted time and financial pressures on secondary care services, impairing their ability to deliver high‐quality care for patients with neurodegenerative cognitive disorders. We have developed a fully automated system, “CognoSpeak”, which enables risk stratification at the primary‐secondary care interface and ongoing monitoring of patients with memory concerns.MethodWe recruited 15 participants to each of four groups: Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), FMD and healthy controls. Participants responded to 12 questions posed by a computer‐presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification.ResultCognoSpeak could distinguish between participants in the AD or MCI groups and those in the FMD or healthy control groups with a sensitivity of 86.7%. Patients with MCI were identified with a sensitivity of 80%.ConclusionOur fully automated system achieved levels of accuracy comparable to currently available, manually administered assessments. Greater accuracy should be achievable through further system training with a greater number of users, the inclusion of verbal fluency tasks and mood assessments. The current data supports CognoSpeak’s promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.
Show, don't tell: Brain visualisations for neuroimaging studies
Authors: Marinescu Razvan V , Young Alexandra L 
Published: December 2020

AbstractBackgroundEfficient visualisation of brain structure, function and pathology is crucial for understanding the mechanisms underlying neurodegenerative diseases such as Alzheimer’s disease (AD). However, visualisation of dynamic brain processes such as pathology spread in AD is difficult due to the slow progression of pathological cascades at multiple scales and over extended periods of time. Current visualisation software (e.g. Freesurfer or SPM) are excellent for interactive visualisation of single brain scans, but for a study population, do not enable easy generation of coloured brain templates or movies showing the temporal progression of pathology.MethodWe present BrainPainter (Fig 1), a recently released brain visualisation software that has two key advantages: (1) it can generate brain templates or movies showing dynamic processes in the brain, e.g. propagation of amyloid or tau pathology and (2) it does not require the input data to be in a specialised format, allowing it to be used in conjunction with any neuroimaging analysis software (e.g. Freesurfer, SPM).ResultWe highlight two use cases of BrainPainter for existing neuroimaging studies: (i) Fig. 2 – visualisation of the progression of pathology in Alzheimer’s disease and (ii) Fig. 3 – visualisation of pathology in subcortical regions in Huntington’s disease. We further present two novel functionalities of BrainPainter: (iii) generation of movies showing progression of atrophy in Alzheimer’s disease (e.g. https://brainpainter.csail.mit.edu/#examples ) and (iv) Fig. 4 – visualisation of individual regions‐of‐interest based on three supported atlases (Desikan‐Killiany, Destrieux and Trourville).ConclusionBrainPainter is customisable, easy to use, and runs straight from the web browser: https://brainpainter.csail.mit.edu. It can generate visualisations of imaging data from any modality, which can easily be included as images or videos into neuroimaging studies. Through the design of BrainPainter, we further demonstrate the possibility of turning Blender, the powerful 3D rendering engine, into a useful tool for the neuroscience community.
Occupational burnout‐like syndrome in early‐onset Alzheimer’s disease
Authors: Olivieri Pauline , Lagarde Julien , Hamelin Lorraine , Niel Philippe , Bottlaender Michel , Kas Aurélie , Habert Marie‐Odile , Sarazin Marie 
Published: December 2020

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to non‐amnesic cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients.MethodsWe retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years.ResultsEleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative.ConclusionWe describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis.