scholarly journals P.002 Exosomal miR-204-5 and miR-632 in CSF are candidate biomarkers for frontotemporal dementia: a GENFI study

2018 ◽  
Vol 45 (s2) ◽  
pp. S16-S16
Author(s):  
R Schneider ◽  
P McKeever ◽  
T Kim ◽  
C Graff ◽  
J van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Mutation Carrier ◽  
Mirna Expression ◽  
Pathogenic Mutation ◽  
Healthy Controls ◽  
Degree Relative ◽  
Sporadic Alzheimer’S Disease ◽  
Diagnostic Biomarkers ◽  
Mutation Carriers ◽  
Receiver Operator Characteristics

Background: To determine whether exosomal microRNAs (miRNAs) in CSF of patients with FTD can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic FTD Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation or at risk of carrying a mutation because a first-degree relative was a symptomatic mutation carrier. Exosomes were isolated from CSF of 23 -pre-symptomatic and 15 symptomatic mutation carriers, and 11 healthy non-mutation carriers. Expression of miRNAs was measured using qPCR arrays. MiRNAs differentially expressed in symptomatic compared to pre-symptomatic mutation carriers were evaluated in 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD), and 10 healthy controls (HCs). Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared to pre-symptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 [90% CI: 0.79-0.98] and 0.81 [90% CI: 0.68-0.93], and when combined an area of 0.93 [90% CI: 0.87-0.99]. In sporadic FTD, only miR-632 was significantly decreased compared to sporadic AD and HCs. Decrease of miR-632 revealed an area of 0.89 [90% CI: 0.80-0.98]. Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

scholarly journals Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

2018 ◽  
Vol 89 (8) ◽  
pp. 851-858 ◽  
Author(s):  
Raphael Schneider ◽  
Paul McKeever ◽  
TaeHyung Kim ◽  
Caroline Graff ◽  
John Cornelis van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Degree Relative ◽  
Sporadic Alzheimer’S Disease ◽  
Diagnostic Biomarkers ◽  
Reading Frame ◽  
Protein Tau ◽  
Mutation Carriers ◽  
Receiver Operator Characteristics

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

scholarly journals Cognitive Composites for Genetic Frontotemporal Dementia: GENFI-Cog

2021 ◽  
Author(s):  
Jackie M. Poos ◽  
Katrina M. Moore ◽  
Jennifer Nicholas ◽  
Lucy L. Russell ◽  
Georgia Peakman ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Sample Size ◽  
Frontotemporal Dementia ◽  
Treatment Effect ◽  
Mutation Carrier ◽  
Cognitive Tests ◽  
Event Analysis ◽  
Trial Duration ◽  
Mutation Carriers ◽  
Composite Scores

Abstract Background: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) and recommend on recruitment and duration in clinical trial design.Methods: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD≥0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier groups and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD=0.5 to ≥1 (and therefore how long a trial would need to be). Results: Results from the logistic regression analyses resulted in different composite scores for each mutation carrier group. The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after three years ~50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥1.DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.

scholarly journals Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

2020 ◽  
Vol 91 (9) ◽  
pp. 975-984 ◽  
Author(s):  
Tamara Paulo Tavares ◽  
Derek G V Mitchell ◽  
Kristy KL Coleman ◽  
Brenda L Coleman ◽  
Christen L Shoesmith ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neuropsychiatric Symptoms ◽  
Family Members ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Reading Frame ◽  
Memory Impairments ◽  
Mutation Carriers ◽  
Composite Indices ◽  
Initial Symptoms

ObjectivesThe clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.MethodsThe current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.ResultsThe most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.ConclusionPreclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

scholarly journals Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

2020 ◽  
Vol 91 (6) ◽  
pp. 612-621 ◽  
Author(s):  
Emma L van der Ende ◽  
Meifang Xiao ◽  
Desheng Xu ◽  
Jackie M Poos ◽  
Jessica L Panman ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Rating Scale ◽  
Pathogenic Mutation ◽  
Grey Matter Volume ◽  
Clinical Dementia Rating ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Parietal Lobes ◽  
Mutation Carriers ◽  
Neuronal Pentraxin

IntroductionSynapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD.MethodsWe included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses.ResultsSymptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p<0.001) and non-carriers (990 pg/mL (597–1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage.DiscussionWe conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.

scholarly journals Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

2021 ◽  
pp. jnnp-2020-323541
Author(s):  
Jessica L Panman ◽  
Vikram Venkatraghavan ◽  
Emma L van der Ende ◽  
Rebecca M E Steketee ◽  
Lize C Jiskoot ◽  
...  
Keyword(s):  
White Matter ◽  
Frontotemporal Dementia ◽  
Disease Severity ◽  
Grey Matter ◽  
Clinical Stage ◽  
Data Driven ◽  
Grey Matter Volume ◽  
Matter Volume ◽  
Mutation Carriers ◽  
Individual Disease

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.

scholarly journals The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hannah D. Franklin ◽  
Lucy L. Russell ◽  
Georgia Peakman ◽  
Caroline V. Greaves ◽  
Martina Bocchetta ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Medial Temporal Lobe ◽  
Social Cognitive ◽  
Early Stage ◽  
Self Monitoring ◽  
Self Presentation ◽  
Genetic Groups ◽  
Mutation Carriers ◽  
Large Patient ◽  
Weighted Magnetic Resonance Imaging

Abstract Background Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. Methods We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. Results The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. Conclusions The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.

scholarly journals Multiple Sclerosis and Diabetes Mellitus: Further Evidence of a Relationship

1982 ◽  
Vol 9 (4) ◽  
pp. 415-419 ◽  
Author(s):  
Sharon A. Warren ◽  
K.G. Warren
Keyword(s):  
Diabetes Mellitus ◽  
Multiple Sclerosis ◽  
Healthy Controls ◽  
Degree Relative ◽  
Significant Difference ◽  
The Difference ◽  
The Relationship ◽  
Prevalence Of Diabetes Mellitus ◽  
Second Degree

SUMMARY:One hundred multiple sclerosis (MS) patients were compared to healthy controls to determine the prevalence of diabetes mellitus in their families. Significantly, more MS patients than controls were diabetic or reported at least one first degree relative (parent, sibling, child) with diabetes. The relationship between MS and diabetes persisted when second degree relatives (grandparents, aunts and uncles) were taken into consideration.A greater percentage of MS patients with another MS relative were diabetic or reported a first degree relative with diabetes mellitus than MS patients without an MS relative. However the difference was not statistically significant. Nor was there a significant difference when percentages reporting either a first or a second degree relative with diabetes were compared.

scholarly journals Combination of Urine Exosomal mRNAs and lncRNAs as Novel Diagnostic Biomarkers for Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Haiming Huang ◽  
Jialin Du ◽  
Bo Jin ◽  
Lu Pang ◽  
Nan Duan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Progression ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Healthy Controls ◽  
Direct Products ◽  
Diagnostic Biomarkers ◽  
Diagnostic Potential ◽  
Urine Exosomes

BackgroundThe recent discovery of miRNAs and lncRNAs in urine exosomes has emerged as promising diagnostic biomarkers for bladder cancer (BCa). However, mRNAs as the direct products of transcription has not been well evaluated in exosomes as biomarkers for BCa diagnosis. The purpose of this study was to identify tumor progression-related mRNAs and lncRNAs in urine exosomes that could be used for detection of BCa.MethodsRNA-sequencing was performed to identify tumor progression-related biomarkers in three matched superficial tumor and deep infiltrating tumor regions of muscle-invasive bladder cancer (MIBC) specimens, differently expressed mRNAs and lncRNAs were validated in TCGA dataset (n = 391) in the discovery stage. Then candidate RNAs were chosen for evaluation in urine exosomes of a training cohort (10 BCa and 10 healthy controls) and a validation cohort (80 BCa and 80 healthy controls) using RT-qPCR. The diagnostic potential of the candidates were evaluated by receiver operating characteristic (ROC) curves.ResultsRNA sequencing revealed 8 mRNAs and 32 lncRNAs that were significantly upregulated in deep infiltrating tumor region. After validation in TCGA database, 10 markedly dysregulated RNAs were selected for further investigation in urine exosomes, of which five (mRNAs: KLHDC7B, CASP14, and PRSS1; lncRNAs: MIR205HG and GAS5) were verified to be significantly dysregulated. The combination of the five RNAs had the highest AUC to disguising the BCa (0.924, 95% CI, 0.875–0.974) or early stage BCa patients (0.910, 95% CI, 0.850 to 0.971) from HCs. The expression levels of these five RNAs were correlated with tumor stage, grade, and hematuria degrees.ConclusionsThese findings highlight the potential of urine exosomal mRNAs and lncRNAs profiling in the early diagnosis and provide new insights into the molecular mechanisms involved in BCa.

scholarly journals Low-grade albuminuria in pulmonary arterial hypertension

2019 ◽  
Vol 9 (2) ◽  
pp. 204589401882456 ◽  
Author(s):  
Nils P. Nickel ◽  
Vinicio A. de Jesus Perez ◽  
Roham T. Zamanian ◽  
Joshua P. Fessel ◽  
Joy D. Cogan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Dysfunction ◽  
Urinary Albumin ◽  
Low Grade ◽  
Healthy Controls ◽  
Creatinine Ratio ◽  
Poor Outcome ◽  
Mutation Carriers ◽  
Pulmonary Arterial

Low-grade albuminuria, determined by the urinary albumin to creatinine ratio, has been linked to systemic vascular dysfunction and is associated with cardiovascular mortality. Pulmonary arterial hypertension is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and is increasingly recognized as a systemic disease. In a total of 283 patients (two independent cohorts) diagnosed with pulmonary arterial hypertension, 18 unaffected BMPR2 mutation carriers and 68 healthy controls, spot urinary albumin to creatinine ratio and its relationship to demographic, functional, hemodynamic and outcome data were analyzed. Pulmonary arterial hypertension patients and unaffected BMPR2 mutation carriers had significantly elevated urinary albumin to creatinine ratios compared with healthy controls ( P < 0.01; P = 0.04). In pulmonary arterial hypertension patients, the urinary albumin to creatinine ratio was associated with older age, lower six-minute walking distance, elevated levels of C-reactive protein and hemoglobin A1c, but there was no correlation between the urinary albumin to creatinine ratio and hemodynamic variables. Pulmonary arterial hypertension patients with a urinary albumin to creatinine ratio above 10 µg/mg had significantly higher rates of poor outcome ( P < 0.001). This study shows that low-grade albuminuria is prevalent in pulmonary arterial hypertension patients and is associated with poor outcome. This study shows that albuminuria in pulmonary arterial hypertension is associated with systemic inflammation and insulin resistance.

THUR 037 Identification of biofluid markers of TDP-43 pathology

2018 ◽  
Vol 89 (10) ◽  
pp. A5.4-A6
Author(s):  
Shafei Rachelle ◽  
Foiani Martha ◽  
Heller Carolin ◽  
Heslegrave Amanda ◽  
Woollacott Ione ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Frontotemporal Dementia ◽  
Observational Studies ◽  
Healthy Controls ◽  
The Novel ◽  
Healthy Individuals ◽  
University College ◽  
University College London ◽  
The Mean ◽  
The University

IntroductionFrontotemporal dementia (FTD) is usually caused pathologically by either tau or TDP-43. Previous biofluid assays of TDP-43 have not so far proved to be sensitive or specific for identifying those cases with TDP-43 pathology.Material and methodsWe set out to investigate the novel TDP-43 Simoa assay (Quanterix) assay in both plasma and CSF in a cohort of patients recruited from the University College London FTD observational studies with known or likely TDP-43 pathology (17), non-TDP-43 pathology (13), and healthy controls (10).ResultsThe mean [standard deviation] plasma TDP-43 concentration was higher in those with likely TDP-43 pathology (155.1 [223.4] pg/ml) than those with non-TDP pathology (112.39 [252.9] pg/ml), and healthy controls (50.0 [23.1] pg/ml), but the differences between groups was non-significant, with substantial overlap in concentrations between all three groups. The mean CSF TDP-43 concentration was 2.9 [0.3] pg/ml in those with likely TDP-43 pathology, 2.8 [0.4] pg/ml in those with non-TDP pathology, and 3.1 [0.5] pg/ml in healthy controls. DiscussionThe assay tested in this study does not accurately distinguish between those with likely TDP-43 pathology and either disease controls or healthy individuals. There remains an urgent need to develop a better biofluid assay for pathological TDP-43.

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