Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

Abstract

BACKGROUND:

Measuring 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).

METHODS:

We 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).

RESULTS:

We 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).

CONCLUSIONS:

Systemic 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.

• Authors: Breton M Asken, Peter A Ljubenkov, Adam M Staffaroni, Kaitlin B Casaletto, Lawren Vandevrede, Yann Cobigo, Julio C Rojas-Rodriguez, Katherine P Rankin, John Kornak, Hilary Heuer, Judy Shigenaga, Brian S Appleby, Andrea C Bozoki, Kimiko Domoto-Reilly, Nupur Ghoshal, Edward Huey, Irene Litvan, Joseph C Masdeu, Mario F Mendez, Belen Pascual, Peter Pressman, Maria Carmela Tartaglia, Walter Kremers, Leah K Forsberg, Brad F Boeve, Adam L Boxer, Howie J Rosen, Joel H Kramer, ALLFTD Consortium Investigators
• Journal: Journal of neurology, neurosurgery, and psychiatry (J Neurol Neurosurg Psychiatry) Vol. 94 Issue 7 Pg. 541-549 (07 2023) ISSN: 1468-330X [Electronic] England
• PMID: 36977552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• C9orf72 Protein
• Interleukin-6
• tau Proteins
• Tumor Necrosis Factor-alpha

Topics

• Humans
• C9orf72 Protein (genetics)
• Disease Progression
• Frontotemporal Dementia (diagnosis)
• Frontotemporal Lobar Degeneration (diagnosis, genetics, pathology)
• Inflammation
• Interleukin-6
• Mutation
• tau Proteins (genetics)
• Tumor Necrosis Factor-alpha