TY - JOUR
T1 - Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration
AU - Asken, Breton M.
AU - Ljubenkov, Peter A.
AU - Staffaroni, Adam M.
AU - Casaletto, Kaitlin B.
AU - Vandevrede, Lawren
AU - Cobigo, Yann
AU - Rojas-Rodriguez, Julio C.
AU - Rankin, Katherine P.
AU - Kornak, John
AU - Heuer, Hilary
AU - Shigenaga, Judy
AU - Appleby, Brian S.
AU - Bozoki, Andrea C.
AU - Domoto-Reilly, Kimiko
AU - Ghoshal, Nupur
AU - Huey, Edward
AU - Litvan, Irene
AU - Masdeu, Joseph C.
AU - Mendez, Mario F.
AU - Pascual, Belen
AU - Pressman, Peter
AU - Tartaglia, Maria Carmela
AU - Kremers, Walter
AU - Forsberg, Leah K.
AU - Boeve, Brad F.
AU - Boxer, Adam L.
AU - Rosen, Howie J.
AU - Kramer, Joel H.
N1 - Publisher 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.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - 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 (ΔR
2=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.
AB - 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 (ΔR
2=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.
KW - CLINICAL NEUROLOGY
KW - FRONTOTEMPORAL DEMENTIA
KW - C9orf72 Protein/genetics
KW - tau Proteins/genetics
KW - Frontotemporal Dementia/diagnosis
KW - Humans
KW - Frontotemporal Lobar Degeneration/diagnosis
KW - Inflammation
KW - Mutation
KW - Tumor Necrosis Factor-alpha
KW - Disease Progression
KW - Interleukin-6
UR - http://www.scopus.com/inward/record.url?scp=85152647126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152647126&partnerID=8YFLogxK
U2 - 10.1136/jnnp-2022-330866
DO - 10.1136/jnnp-2022-330866
M3 - Article
C2 - 36977552
AN - SCOPUS:85152647126
SN - 0022-3050
VL - 94
SP - 541
EP - 549
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 7
ER -