JNNP: C9orf72 is associated with pre-onset and plasma microRNA characteristics of frontal lobe dementia and amyotrophic lateral sclerosis

Temporal lobe dementia (FTD) refers to dementia syndrome in middle-aged and elderly patients with slow personality changes, speech disorders, and abnormal behavior.
neuroimaging showed a contraction of the frontal temporal lobe.
is the more common cause of neurodegenerative dementia, accounting for about a quarter of all dementia patients.
about 1/4 of patients with frontal temporal lobe dementia have Pick small bodies that can be diagnosed with Pick disease.
frontal lobe dementia actually includes Pick disease and similar clinical manifestations of Pick syndrome, with a peak of 60 years of age and more women.
amyotrophy lateral sclerosis (ALS), also known as motor neurone disease (MND), is commonly used in the UK, Charcot in France and Lou Gehrig in the US.
It is damaged by upper and lower motor neurons, resulting in gradual weakness and atrophy of muscles including the ball (so-called ball, which refers to the part of the muscle dominated by the myelin), limbs, torso, chest abdomen.
FTD and ALS may be genetically related in the same patient (FTD-ALS).
they have common pathophysiological mechanisms and genetic causes.
most common genetic causes of familyal FTD and ALS is the repeated amplification of a hetenucleotide (GGGGCC) in the C9orf72 gene of chromosome 9.
this normal chromosomal explicit mutation may lead to neurodegenerative degenerative changes through the loss of C9orf72 function, the accumulation of mutant RNA in the nucleation of the cell, and ultimately the pathological encapsulation of TDP-43.
so far, there is no effective treatment for C9orf72 disease, and it is important to identify biomarkers of preclinical progression in FTD and ALS, which can be used to initiate and monitor potential disease treatment before any irreversible brain injury occurs.
microRNA (miRNA) expressions in body fluids, such as plasma/serum or cerebrospinal fluid (CSF), are associated with the diagnosis and progression of many neurodegenerative diseases.
TDP-43 promotes the biological production of miRNA, the TDP-43 activity disorder associated with FTD and ALS morbidity may affect the level of miRNA expression.
it is important to note that miRNAs of neurons and glial cells are released through extracellular vesicles, especially extracellular small bodies, and can be measured in different body fluids, including cerebrospinal fluids and plasma.
, abnormal expressions of miRNAs can be detected non-invasively and can be used as biomarkers.
study aims to study the expression levels of plasma miRNAs in C9orf72 mutant carriers, including pre-symptom and clinical stages, to identify potential non-invasive biomarkers of C9orf72-related FTD and ALS preclinical and clinical progression.
111 subjects were surveyed under the same programme at four university hospitals in France (Paris, Limogic, Lille and Rouen).
participants received 21 written informed consent forms.
the queue included 22 patients in 64 families with C9orf72 gene amplification (15 FTDs, 4 FTDs/ALS and 3 ALS) and 89 asymptomatic first-degree relatives in patients with C9orf72 (who were 50 percent at risk of carrying mutations).
46 of these cases showed pathogenic dilation, known as the "pre-symptom group."
control group consisted of 43 asymptomatic and non-expansional individuals.
clinical follow-up of participants from 2017 to 2020.
4 out of 45 pre-C9orf72 carriers experienced subtle pre-frontal changes and/or motor signs/symptoms during this time, but did not meet the diagnostic criteria for FTD or ALS, indicating that they were in the transition "pre-symptoms" phase at or after the time they were included in the study.
miRNASY serum/plasma kit (Qiagen) is used for MiRNA extraction according to the manufacturer's instructions.
three separate batches of MiRNA sequencing were performed on the Illumina NovaSeq 6000.
designed an experiment to evaluate the predicted performance of pre-symptom carriers in clinical conversion to FTD/ALS.
logistic regression classifiers matched the expression levels of miRNAs expressed differently from the control group and patients.
use regular 5x cross-validation to determine the optimal super parameter (L2 regularization factor).
then tested the model with the level of expression of four known pre-symptom carriers who were in the transition to clinical disease.
each subject was rated from 0 to 1, indicating a level of expression close to that of the control group (nearly 0) or the patient (close to 1).
four miRNAs were calculated as differential expressions between health control groups and patients: miR-34a-5p and miR-345-5p overexploitation, while miR-200c-3p and miR-10a-3p were low expressions in patients with symptoms.
interestingly, miR-34a-5p was also significantly expressed in pre-symptom mutant carriers compared to the healthy control group, suggesting that miR-34a-5p expression was associated with C9orf72 mutation status.
the level of miR-34a-5p expression between the control group and the C9orf72 amplification vector (pre-symptom and symptomatic).
addition, three other identified miRNAs distinguished mutation carriers at different pathological stages: miR-345-5p increased expression in patients, while miR-200c-3p and miR-10a-3p decreased expression.
the expression levels of miRNAs (miR-34a-5p, miR-345-5p, miR-200c-3p, and miR-10a-3p) expressed in four different expressions to establish a logistic regression model.
0.90 (90% CI is 0.83-0.95) and 0.90 (90% CI) in the health control group and in patients with pre-symptom mutation carriers 90% CI is 0.82-0.97) and the ROC AUC that distinguishes between pre-symptom carriers and patients is 0.80 (90% CI is 0.67-0.90).
the performance of predicting the transition period of FTD/ALS disease was evaluated by training the logistic regression classifier, which used the expression levels of patients and control groups and tested the expression levels of individuals before symptoms.
four subjects scored above 0.50 in the transition period, with greater similarities with patients: 0.54, 0.75, 0.80, and 0.82.
study aims to identify fluid biomarkers by analyzing plasma miRNAs levels in a large number of healthy control, pre-symptom and symptomatic C9orf72 carriers.
found that four miR-34a-5p, miR-345-5p, miR-200c-3p and miR-10a-3p were expressed differently under different clinical conditions.
the expression of miR-34a-5p in mutant carriers increased significantly compared to the healthy control group, indicating that the expression of miR-34a-5p was deregated in cases of C9orf72 mutation.
current studies show significant differences in miRNA expression levels in plasma compared to healthy control groups, pre-symptomatic and symptomatic C9orf72 mutation carriers.
highlights the potential of miR-34a-5p, miR-345-5p, miR-200c-3p and miR-10a-3p expression levels in plasma as biomarkers of C9orf72-related FTD and ALS preclinical progression.
results encourage the use of plasma miRNAs, in combination with other markers, to improve clinical trial design for neurodegenerative diseases.
Kmetzsch V, Anquetil V, Saracino D, et al Plasma microRNA signature in presymptomatic and symptom subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis Journal of Neurology, Neurosurgery and Psimology Published Online First: 25 November 2020. doi: 10.1136/jnnp-2020-324647MedSci Original Source: MedSci Original Copyright Notice: All on this website state "Source: Met Medical" or " Source: MedSci Originals" text, images and audio and video materials, copyrighted by Metz Medical, are not authorized to be reproduced by any media, website or individual, and must be reproduced with the words "Source: Mets Medicine".
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