ORIGINAL ARTICLE Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation A. Alberici • S. Archetti • A. Pilotto • E. Premi • M. Cosseddu • A. Bianchetti • F. Semeraro • M. Salvetti • M. L. Muiesan • A. Padovani • B. Borroni Received: 1 December 2013 / Accepted: 11 February 2014 Ó Springer-Verlag Italia 2014 Abstract Frontotemporal dementia (FTD) is one of the most important neurodegenerative conditions and Granulin (GRN) is one of the major genes associated to the disease. FTD-GRN patients are still orphan for any evidence-based target-therapy approach. Interestingly, it has been recently found that alkalizing agents rescued haploinsufficiency in cellular models expressing FTD-GRN mutations. We set up a pilot phase II clinical trial in five FTD patients with GRN Thr272s(g.1977_1980delCACT) mutation, to determine if amiodarone (200 mg/day) may (1) reverse progranulin deficiency and (2) delay disease progression. Each patient was scheduled for 7 study visits over 12 months period. We assessed GRN levels at baseline and after amiodarone administration during the treatment course. Somatic and neurologic examinations, along with cognitive and behav- ioral assessment were recorded as well. No significant effect on peripheral GRN levels was observed. In treated FTD, disease course did not differ when compared with a group of untreated FTD-GRN patients. This is the first trial targeting progranulin rescue in FTD-GRN patients using amiodarone. Despite the negative findings, it may be interesting to extend this attempt to a larger sample of subjects and to other alkalizing agents to restore granulin haploinsufficiency. Keywords Frontotemporal dementia Á Progranulin Á Granulin Á Amiodarone Á Treatment Introduction Frontotemporal dementia (FTD) is a common cause of dementia in presenium, also recognized affecting aged population. Presenting features are characterized by social misconduct, language and executive deficits, or motor impairment, therefore encompassing different clinical syndromes: the behavioral variant FTD (bv-FTD), the agrammatic (avPPA) and semantic (svPPA) variant of primary progressive aphasia [1–3]. The broad clinical spectrum is the result of the predominant atrophy of frontal and temporal lobes, in which at autopsy examination the distinctive hallmarks are mainly represented by microtu- bule-associated protein tau (MAPT) depositions, TAR DNA-binding protein 43 (TDP-43) inclusions, or fused in sarcoma (FUS) [4]. The strong genetic background, with almost 40 % of patients showing a positive family history, prompted the identification of a number of genes respon- sible for the disease. In particular, mutations in granulin (GRN), MAPT, and more recently in the hexanucleotide repeat expansion in C9orf72, are considered the most fre- quent causes of genetic FTD [4]. A. Alberici (&) Á A. Pilotto Á E. Premi Á M. Cosseddu Á A. Padovani Á B. Borroni Department of Medical Sciences, Clinic of Neurology, Spedali Civili, University of Brescia, Piazzale Spedali Civili 1, 25100 Brescia, Italy e-mail: antoalberici@yahoo.it S. Archetti Third Laoratory, Spedali Civili, Piazzale Spedali Civili 1, 25100 Brescia, Italy A. Bianchetti Medicine Unit, Sant’Anna Hospital, 25100 Brescia, Italy F. Semeraro Oftalmology Unit, Spedali Civili, University of Brescia, Piazzale Spedali Civili 1, 25100 Brescia, Italy M. Salvetti Á M. L. Muiesan Department of Internal Medicine, Spedali Civili, University of Brescia, Piazzale Spedali Civili 1, 25100 Brescia, Italy 123 Neurol Sci DOI 10.1007/s10072-014-1683-y