JNNP: Plasma NfL level and longitudinal change rate of C9orf72 and GRN-related diseases: from customized reference to clinical application

GRN and C9orf72 gene mutations are the main genetic factors for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)
.

The GRN-related phenotype is mainly controlled by the behavioral variation of FTD (bvFTD).

GRN and C9orf72 gene mutations are the main genetic factors for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)

There is still a lack of conditions to transform the pNfL dose from research to trial and clinical
.

In particular, it is necessary to further understand the variability of NfL levels in healthy people in order to establish appropriate reference values ​​for neurodegenerative diseases

Therefore, this article first evaluated the physiological changes of pNfL and its longitudinal changes in healthy controls to propose reference values ​​for the life cycle of different age groups

This article assessed the variability of pNfL levels in 165 neurologically healthy controls under physiological conditions
.

65 patients underwent longitudinal pNfL assessment with an average interval of 3.

165 neurological health controls evaluated 101 C9orf72 and 86 GRN mutation carriers

In the patient group, the median age of onset (AAO) was 58.
0 years, and the duration of the disease at baseline was 3.
5 years (4.
9 years for C9orf72 and 2.
9 years for GRN carriers)
.

All GRN patients have FTD

PNfL level of the control group

The pNfL levels of 668 patients (352 baseline examination and 316 follow-up) patients, PS and control group were analyzed
.

The measurement is performed in the same facility, regardless of the clinical-genetic status, using single molecule array (SiMoA) technology for 13 runs

The course of GRN patients was fairly uniform, while the course of the C9orf72 group was even more uneven due to a small number of slowly progressing carriers
.

At the baseline examination, the sampling age of the control group was between 21.

Patient's baseline pNfL level

In C9orf72 patients, advanced AAO was associated with higher pNfL levels (r=0.
389, p=0.
004)
.

The median value is lower in early-onset patients (≤50 years old: 22.

A cut-off value is set to distinguish between patients and control groups
.
Determine the thresholds for C9orf72 and GRN patients respectively
.
The resulting threshold for separating C9orf72 patients from the control group was 19 pg/mL
.
The higher threshold of 27.
48 pg/mL distinguishes GRN patients from the control group, with a sensitivity of 94% and a specificity of 97%
.

The 85 PSs included 48 C9orf72 and 37 GRN carriers
.
The median sampling age (41.
2 years) of the two genotypes was similar
.
Their pNfL values ​​are comparable to those of the control group and significantly lower than those of the patients (p<0.
0001)
.
C9orf72 has a higher pNfL level (8.
48 pg/mL) than GRN carriers (7.
69 pg/mL, p=0.
004)
.
Like the control group, the PS level increased significantly with age at the time of sampling (p<0.
0001)
.
The correlation of C9orf72 (r=0.
651, p<0.
0001) is much stronger than that of GRN (r=0.
359, p=0.
029)
.
In summary, in the presymptomatic stage of C9orf72 disease, pNfLs is slightly higher and shows a more age-related trend
.

C9orf72 has a higher pNfL level (8.
48 pg/mL) than GRN carriers (7.
69 pg/mL, p=0.
004)
.
Like the control group, the PS level increased significantly with age at the time of sampling (p<0.
0001)
.
The correlation of C9orf72 (r=0.
651, p<0.
0001) is much stronger than that of GRN (r=0.
359, p=0.
029)
.

This study emphasizes the importance of gene-specific and age-specific references in clinical and therapeutic trials of hereditary FTD/ALS
.
Support repeat pNfL measurement and consider the clinical significance of ARC as a prognostic marker of disease progression
.

Saracino  D ,  Dorgham  K ,  Camuzat  A Saracino  DSaracino Dorgham  KDorgham Camuzat  ACamuzat, et alPlasma NfL levels and longitudinal change rates in  C9orf72  and  GRN -associated diseases: from tailored references to clinical applicationsC9orf72GRNJournal of Neurology, Neurosurgery & Psychiatry  Published Online First:  04 August 2021.
 Published Online First: doi:  10.
1136/jnnp-2021-326914doi:Leave a message here