Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging

A. Benussi, S. Gazzina, E. Premi, M. Cosseddu, S. Archetti, V. Dell'Era, V. Cantoni, M.S. Cotelli, A. Alberici, A. Micheli, L. Benussi, R. Ghidoni, A. Padovani, B. Borroni

Research output: Contribution to journalArticlepeer-review


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. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how 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. © 2019 Elsevier Inc.
Original languageEnglish
Pages (from-to)133-140
Number of pages8
JournalNeurobiol. Aging
Publication statusPublished - 2019


  • Biomarkers
  • C9orf72
  • Frontotemporal dementia
  • GRN
  • Transcranial magnetic stimulation
  • adult
  • Article
  • brain atrophy
  • brain tissue
  • C9orf72 gene
  • cognitive defect
  • female
  • follow up
  • frontotemporal dementia
  • gene
  • gene mutation
  • GRN gene
  • heterozygote
  • human
  • major clinical study
  • male
  • middle aged
  • neurotransmission
  • priority journal
  • tissue structure
  • white matter lesion
  • aged
  • atrophy
  • brain
  • genetics
  • mutation
  • pathology
  • pathophysiology
  • psychology
  • transcranial magnetic stimulation
  • biological marker
  • C9orf72 protein, human
  • fungichromin
  • GRN protein, human
  • guanine nucleotide exchange C9orf72
  • macrolide
  • polyene
  • Adult
  • Aged
  • Atrophy
  • Brain
  • C9orf72 Protein
  • Female
  • Frontotemporal Dementia
  • Heterozygote
  • Humans
  • Macrolides
  • Male
  • Middle Aged
  • Mutation
  • Polyenes
  • Progranulins
  • Transcranial Magnetic Stimulation


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