Dataset Information

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.

SUBMITTER: Rojas JC

PROVIDER: S-EPMC8166434 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

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

Rojas Julio C JC Wang Ping P Staffaroni Adam M AM Heller Carolin C Cobigo Yann Y Wolf Amy A Goh Sheng-Yang M SM Ljubenkov Peter A PA Heuer Hilary W HW Fong Jamie C JC Taylor Joanne B JB Veras Eliseo E Song Linan L Jeromin Andreas A Hanlon David D Yu Lili L Khinikar Arvind A Sivasankaran Rajeev R Kieloch Agnieszka A Valentin Marie-Anne MA Karydas Anna M AM Mitic Laura L LL Pearlman Rodney R Kornak John J Kramer Joel H JH Miller Bruce L BL Kantarci Kejal K Knopman David S DS Graff-Radford Neill N Petrucelli Leonard L Rademakers Rosa R Irwin David J DJ Grossman Murray M Ramos Eliana Marisa EM Coppola Giovanni G Mendez Mario F MF Bordelon Yvette Y Dickerson Bradford C BC Ghoshal Nupur N Huey Edward D ED Mackenzie Ian R IR Appleby Brian S BS Domoto-Reilly Kimiko K Hsiung Ging-Yuek R GR Toga Arthur W AW Weintraub Sandra S Kaufer Daniel I DI Kerwin Diana D Litvan Irene I Onyike Chiadikaobi U CU Pantelyat Alexander A Roberson Erik D ED Tartaglia Maria C MC Foroud Tatiana T Chen Weiping W Czerkowicz Julie J Graham Danielle L DL van Swieten John C JC Borroni Barbara B Sanchez-Valle Raquel R Moreno Fermin F Laforce Robert R Graff Caroline C Synofzik Matthis M Galimberti Daniela D Rowe James B JB Masellis Mario M Finger Elizabeth E Vandenberghe Rik R de Mendonça Alexandre A Tagliavini Fabrizio F Santana Isabel I Ducharme Simon S Butler Chris R CR Gerhard Alexander A Levin Johannes J Danek Adrian A Otto Markus M Sorbi Sandro S Cash David M DM Convery Rhian S RS Bocchetta Martina M Foiani Martha M Greaves Caroline V CV Peakman Georgia G Russell Lucy L Swift Imogen I Todd Emily E Rohrer Jonathan D JD Boeve Bradley F BF Rosen Howard J HJ Boxer Adam L AL

Neurology 20210407 18

<h4>Objective</h4>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.<h4>Methods</h4>Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. <i>C9orf72</i>, <i>GRN</i>, and <i>MAPT</i> mutation carriers and noncarriers from the same families were classified by disease se ...[more]

PMID: 33827960

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Project description:ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, setting, and participantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main outcomes and measuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, -22.7 to -4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, -52.2 to -8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, -43.4 to -7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and relevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

Project description:BackgroundMeasuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).MethodsWe measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).ResultsWe studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).ConclusionsSystemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Dataset Information

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

Objective

Methods

Results

Conclusions

Trial registration information

Classification of evidence

Publications

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

Similar Datasets

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