JNNP: Model study of cascading changes in GRN-related temporal lobe dementia biomarkers

Mutations in the pre-granule protein (GRN) gene on chromosome 17q21 are a major cause of normal chromosomal pregenital frontal lobe dementia (FTD).
most mutant carriers develop behavioral variants of the FTD (bvFTD) estype, and the proportion of patients with non-fluent variant primary aphdilephpathy (nfvPPA) is also high.
GRN mutation carriers had symptoms between the ages of 35 and 90 and were not significantly related to the family age of onset.
changes in patients with FTD-GRN can develop symmetrically in the left or right hemisphere.
most biomarker studies in FTD-GRN have studied a biomarker, i.e. liquid, neuroimaging, or cognition, the time relationship and sequence of these biomarkers is unknown.
these time relationships may provide new insights into the progress mechanisms of disease in people with GRN mutations.
addition, due to rapid progress in pathophysiological changes, it is important to identify the earliest abnormal biomarkers.
recently, new data-driven methods of modeling disease progression have emerged, focusing on cascades of biomarker changes.
event-based model is a class of disease progression models used to estimate cascades of biomarker changes from cross-sectional data.
this was done without strong a priori assumptions about the relationship between different biomarkers.
promising new method for estimating the cascading of biomarker changes is event-based judgment model (DEBM).
model is robust for disease esopolyte heterogeneity in the queue and can handle missing data.
study, DEBM was used to assess the time cascade of changes in biomarkers before and during symptomatic FTD-GRN mutation carriers, distinguishing between early and late biomarkers.
addition, the ideopaedic differences in biomarker variation patterns in nfvPPA and bvFTD were measured to further understand their unique disease progression mechanisms.
subjects came from three European centres with hereditary frontal lobe dementia (GENFI): Rotterdam (Netherlands), Brescia (Italy) and Barcelona (Spain).
collected cognitive and clinical data, MRI and serum samples from 126 participants.
includes 35 cases of symptomatic GRN mutation carriers (Rotterdam: n=11, Brescia: n=22, Barcelona: n=2), 56 cases of pre-symptom GRN mutation carriers (Rotterdam: n) Brescia: n=17, Barcelona: n=6) and 35 cases of cognitive health non-carriers (Rotterdam: n=34, Brescia: n=0, Barcelona: n=1).
the local clinical genetics department conducted DNA genotypes to confirm the presence of GRN mutations.
non-carriers are first-class family members of GRN patients with no mutations.
persons with symptomatic mutations are diagnosed according to established clinical standards for bvFTD16 (n=17), nfvPPA17 (n=16), or cortical substrate syndrome 18 (n=2).
that the carrier of the mutation is defined as a symptom before it meets clinical standards, i.e. no behavioral or cognitive symptoms.
19 clinical questionnaires were distributed to caregivers, spouses, or family members, namely, the FTD-CDR-SOB, the Neuropsychiast Scale (NPI), and the Frontal Lobe Dementia Assessment Scale (FRS).
the study was carried out in accordance with the Helsinki Declaration and approved by the local Medical Ethics Committee at each location, with written informed consent from all participants.
the selection of biomarkers, a literature search was conducted using Pubmed.
studies include: (1) studies on carriers of GRN mutations before symptoms, and (2) studies on biomarkers in blood or cerebrospinal fluid (CSF), neuroimaging student markers, and cognition.
selected serum NfL, 9 simple mental state examination (MMSE), cognitive areas of attention and processing speed, executive function, language and social cognition;
serum samples are obtained through intravenous puncture and analyzed using single-molecule analysis techniques.
10 samples were measured in a single laboratory, in two copies, with an analysis of a coefficient of variation of less than 5%.
difference between batches was less than 8%.
NfL concentration is expressed as pg/mL.
3D T1-weighted and dispersed spread imaging of three parts using a 3TMRI scanner.
all selected biomarkers were tested for normality and converted in the case of biased distributions.
For each biomarker, it first uses the Gauss mixing model (GMM) to estimate the distribution of normal and pathological (or abnormal) values and uses these to calculate the probability of biomarker anomalies for each subject.
for imaging biomarkers, the GMM steps in DEBM have been modified to make them more suitable for the FTD-GRN population because of their asymmetrical atrophy patterns.
than early biomarkers, the outliers of biomarkers, which usually become abnormal in the later stages of the disease, are generally underperforming in a particular patient population.
results show an estimated average cascade of biomarker changes and uncertainties within non-imaging and multi-pattern biomarker models.
language is the earliest biomarker of abnormality, followed by NfL.
left frontal thychal radiation, left island leaves and two-sided hook bundles are the earliest image student markers.
also observed that imaging biomarkers in the left hemisphere were abnormal earlier than imaging biomarkers in the right hemisphere.
the severity of the disease distinguishes the subjects with symptoms from the subjects before the symptoms.
the use of non-imaging biomarkers, the sensitivity and specificity of this depiction are 1.0 and 0.982, respectively, and when using multi-mode biomarkers, the sensitivity and specificity of this depiction are 1.0 and 0.961, respectively.
the estimated severity of the disease in subjects with nfvPPA and bvFTD was associated with the number of years after the on-the-on-symptom and FTD-CDR-SB.
in nfvPPA patients, the estimated severity of the disease was closely related to the number of years after the on-on-the-look symptoms (R=0.95, p=0.0003) and FTD-CDR-SB (R=0.84, p=0.0189).
, however, in patients with bvFTD, the estimated severity of the disease was less relevant to the number of years after the on-on-the-appearance of symptoms (R=0.22, p=0.6331) and FTD-CDR-SB (R=0.28, p=0.5866).
nfvPPA patients were first shown to have language and NfL abnormalities, followed by other cognitive areas.
left hemisphere imaging biomarkers become abnormal before imaging biomarkers in the right hemisphere, starting with no bundles (white matter integrity), island leaves, and temporal lobes (gray matter volume).
only the upper left beam is considered a late biomarker, even later than the upper right beam.
bvFTD patients, biomarker sequencing also indicates that language and NfL are the earliest abnormal biomarkers.
the upper left beam (white matter integrity) is considered to be the first abnormal image biomarker of bvFTD compared to nfvPPA.
, however, the sequence of biomarkers in bvFTD is characterized by the great uncertainty of biomarker positioning in the disease timeline, and there is almost no observable difference between early and late biomarkers.
debM study in the FTD-GRN spectrum can prove that language function and NfL level are the earliest abnormal biomarkers.
, however, bvFTD exhibits more heterogeneity and uncertainty in disease progression, indicating that biomarkers are more mutant than nfvPPA.
analysis shows that axis mutation and language network damage are the earliest biomarkers of GRN mutation carriers and may serve as the end point of clinical trials for disease treatment.
future work should be to use longitudinal data to confirm and validate these findings.
Panman JL, Venkatraghavan V, van der Ende EL, et al Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia Journal of Neurology, Neurosurgery and Psysin Published Online First: 15 January 2021. doi:10.1136/jnnp-2020-323541MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Met Medical" or "Source: MedSci Original" are owned by Mets Medicine and are not authorized and may not be reproduced by any media, website or individual. "Source: Metz Medicine" shall be indicated at the time of authorization for reprint.
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