Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

Abstract

Frontotemporal dementia is a clinically, genetically and pathologically heterogeneous neurodegenerative disorder, enclosing a wide range of different pathological entities, associated with the accumulation of proteins such as tau and TPD-43. Characterized by a high hereditability, mutations in three main genes, MAPT, GRN and C9orf72, can drive the neurodegenerative process. The connection between different genes and proteinopathies through specific mechanisms has shed light on the pathophysiology of the disease, leading to the identification of potential pharmacological targets. New experimental strategies are emerging, in both preclinical and clinical settings, which focus on small molecules rather than gene therapy. In this review, we provide an insight into the aberrant mechanisms leading to FTLD-related proteinopathies and discuss recent therapies with the potential to ameliorate neurodegeneration and disease progression.

Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration—Insights into disease mechanisms and current therapeutic approaches

“…In addition to therapeutics targeting the neurotransmitter systems, emerging therapeutic options directly targeting the fundamental molecular mechanisms of the disease such as those related to the C9-HRE or other genetic alterations by antisense oligonucleotides, micro-RNAs or small molecules have been reported [ 126 – 129 ]. These have been discussed in several recent reviews and will therefore not be considered here.…”

Differences and similarities between familial and sporadic frontotemporal dementia: An Italian single‐center cohort study

“…Conversely, different rates of progression between groups have fundamental implications when considering potential generalizability in future pharmacological and non‐pharmacological clinical trials. In view of recent advances in disease‐modifying therapies that target specific pathogenic routes, 48 f‐FTD and s‐FTD should be considered separately to measure the effects of treatment interventions, given the different disease trajectories.…”

Generalidades sobre los parkinsonismos atípicos

“…Ya que algunos fenotipos presentan herencia familiar, se han logrado identificar genes específicos afectados, por lo que a futuro podría desarrollarse terapia génica y molecular personalizada. Las mutaciones más importantes son en los genes MAPT, GRN y C9orf72 (16). Actualmente, el tratamiento es sintomático.…”

“…Farmacológicamente, se pueden utilizar inhibidores de la recaptura de serotonina para reducir síntomas como agresividad, depresión, impulsividad y trastornos de la conducta alimentaria. Para la agitación o impulsividad también se han utilizado antipsicóticos atípicos; sin embargo, estos podrían aumentar la mortalidad, por lo que deben utilizarse con precaución para prevenir eventos cardiacos o caídas (16,17).…”