Background: Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objective: To assess biomarker changes in presymptomatic and symptomatic patients with monogenic frontotemporal dementia. Methods: Clinical, functional and neurophysiological measures were evaluated in 113 GRN or C9orf72 carriers, and in 73 noncarrier first-degree relatives. For 75 patients follow-up longitudinal data was available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. Results: We observed that biological changes and glutamatergic transmission abnormalities significantly antecede the emergence of clinical symptoms of at least three decades. These are followed by GABAergic transmission deficits, detected approximately two decades before expected symptom onset, then followed by an increase of white matter lesions, structural brain atrophy and cognitive impairment. Conclusion: Several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms.
Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia
Benussi A.;Gazzina S.;Premi E.;Cosseddu M.;Dell'Era V.;Cantoni V.;Cotelli M. S.;Alberici A.;Ghidoni R.;Padovani A.;Borroni B.
2019-01-01
Abstract
Background: Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objective: To assess biomarker changes in presymptomatic and symptomatic patients with monogenic frontotemporal dementia. Methods: Clinical, functional and neurophysiological measures were evaluated in 113 GRN or C9orf72 carriers, and in 73 noncarrier first-degree relatives. For 75 patients follow-up longitudinal data was available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. Results: We observed that biological changes and glutamatergic transmission abnormalities significantly antecede the emergence of clinical symptoms of at least three decades. These are followed by GABAergic transmission deficits, detected approximately two decades before expected symptom onset, then followed by an increase of white matter lesions, structural brain atrophy and cognitive impairment. Conclusion: Several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
