Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

Abstract

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.

Trial registration information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

Classification of evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Figure 1. Baseline Plasma NfL Chain Concentrations by Clinical Phenotype

(A) Original (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects [LEFFTDS]/Advancing Research and Treatment in Frontotemporal Lobar Degeneration [ARTFL]) cohort. (B) Validation (Genetic Frontotemporal Dementia Initiative [GENFI]) cohort. Phenotypes are based on clinical diagnosis and did not rely on severity scales. Only the original cohort included clinically diagnosed prodromal disease (mild behavioral impairment [MBI] or mild cognitive impairment [MCI]). Horizontal bars represent median values. Upper and lower quartiles are delimitated by the boxes. Lowest and highest values are indicated by whiskers. bvFTD = behavioral variant frontotemporal dementia; CBS = corticobasal syndrome; FTD/ALS = frontotemporal dementia with amyotrophic lateral sclerosis; NfL = neurofilament light chain; PPA = primary progressive aphasia (nonfluent or semantic). *Compared to normal. **Compared to normal and MCI, p < 0.05.

Figure 2. Baseline Plasma NfL Concentrations by Disease Severity and Diagnostic Performance

(A–C) Original (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects [LEFFTDS]/Advancing Research and Treatment in Frontotemporal Lobar Degeneration [ARTFL]) cohort. (D–F) Validation (Genetic Frontotemporal Dementia Initiative [GENFI]) cohort. Severity was determined by the CDR Dementia Staging Instrument plus Behavior and Language domains from the National Alzheimer's Disease Coordinating Center Frontotemporal Lobar Degeneration module (CDR+NACC-FTLD). (A and D) Boxplots show plasma neurofilament light chain (NfL) concentrations in asymptomatic carriers (i.e., CDR+NACC-FTLD score 0), those with mild behavioral or cognitive impairment (mild behavioral impairment/mild cognitive impairment [MBI/MCI], CDR+NACC-FTLD score 0.5), and patients with full phenotypes (CDR+NACC-FTLD score ≥1). Horizontal bars represent median values. Upper and lower quartiles are delimitated by the boxes. Lowest and highest values are indicated by whiskers. (B and E) Receiver operating characteristic (ROC) curves show that plasma NfL was a good discriminator between individuals with full phenotype and those either asymptomatic or with MBI/MCI. (C and F) Proportion of patients with low or high plasma NfL concentrations, determined by the ROC curve, is presented for each disease severity. AUC = area under the curve.

Figure 3. Plasma NfL Concentrations by Disease Severity in Each Genotype Group

(A–C) Original cohort. (D–F) Validation cohort. MBI/MCI = mild behavioral or cognitive impairment (CDR Dementia Staging Instrument plus Behavior and Language domains from the National Alzheimer's Disease Coordinating Center Frontotemporal Lobar Degeneration module score 0.5); C90rf72 = chromosome 9 open reading frame 72; GRN = progranulin; MAPT = microtubule-associated protein tau; NC = noncarrier; NfL = neurofilament light chain.

Figure 4. Baseline Plasma NfL Concentrations According to Conversion Status by Follow-Up

Severity was determined with the CDR Dementia Staging Instrument plus Behavior and Language domains from the National Alzheimer's Disease Coordinating Center Frontotemporal Lobar Degeneration module (CDR+NACC-FTLD). (A–C) Original (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects [LEFFTDS]/Advancing Research and Treatment in Frontotemporal Lobar Degeneration [ARTFL]) cohort. (D–F) Validation (Genetic Frontotemporal Dementia Initiative [GENFI]) cohort. (A and D) Median baseline neurofilament light chain (NfL) concentrations were higher in asymptomatic mutation carriers (CDR+NACC-FTLD score 0) who progressed to either mild behavioral or cognitive impairment (MBI/MCI; CDR+NACC-FTLD score 0.5) or full phenotype (CDR+NACC-FTLD score ≥1) on follow-up. (B and E) A similar trend was observed in individuals who had MBI/MCI at baseline and when all participants (asymptomatic mutation carriers and those with MBI/MCI) were combined (C and F). Horizontal bars represent median values. Upper and lower quartiles are delimitated by the boxes. Lowest and highest values are indicated by whiskers. Circles = asymptomatic; triangles = MBI/MCI; blue = chromosome 9 open reading frame 72(C9orf72) mutation carriers; red = microtubule-associated protein tau (MAPT) mutation carriers; yellow = progranulin (GRN) mutation carriers;.

Figure 5. Prediction of Clinical Progression by Plasma NfL in Familial Frontotemporal Lobar Degeneration

(A–C) Original (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects [LEFFTDS]/Advancing Research and Treatment in Frontotemporal Lobar Degeneration [ARTFL) cohort. (D–F) Validation (Genetic Frontotemporal Dementia Initiative [GENFI]) cohort. Figure shows the results of models using data from all genotypes in each severity group. In the original cohort, patients with high (red; ≥13.6 pg/mL) baseline plasma neurofilament light chain (NfL) showed worse clinical scores at 2 years compared to patients with low (blue; <13.6 pg/mL) NfL, which was supported by NfL level–by–time interaction. This differential predictive effect by NfL level was observed regardless of disease severity, including asymptomatic carriers. Similar results were observed in the validation cohort with a cut point value of 19.8 pg/mL. CDR+NACC-FTLDsb = CDR Dementia Staging Instrument plus Behavior and Language domains from the National Alzheimer's Disease Coordinating Center Frontotemporal Lobar Degeneration module sum of boxes score. *Between-group contrast at that time point, p < 0.05.