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Background: Establishing the short-term prognosis in Frontotemporal Lobar Degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. No reliable neuropsychological assessment balancing all FTLD aspects is available yet, thus no clear-cut follow-up study has been performed. Objective: To evaluate the rate of progression and the predictors of worsening in FTLD patients. Methods: One-hundred twenty-seven FTLD patients entered the study and were re-evaluated at 1-year follow-up. A statistical driven approach on wide neuropsychological, behavioral, and functional data was applied to identify homogeneous groups both at baseline and at follow-up within FTLD. Three set of predictors on disease progression were considered: (i) the demographic characteristics, (ii) the genetic background, i.e. Apolipoprotein E (APOE) genotype, Tau haplotype, and functional polymorphisms affecting serotonin and dopamine pathways, and (iii) the clinical phenotype. Results: Among FTLD, two groups of patients were recognized on the basis of the overall assessment, thus termed for different disease severity as "good performers" and "bad performers". At 1-year follow-up, almost 30% of FTLD patients progressed from "good" to "bad" performances, whilst 70% maintained stable "good" performances. APOE ε4 allele, Tau H2 haplotype and behavioral variant FTD phenotype were associated with worse prognosis over time. Conclusions: This preliminary study proposed genetic and clinical predictors in FTLD progression. The identification of disease-modifying predictors of prognosis opens a new avenue in studying FTLD, and may contribute to define outcomes and to monitor pharmacological targets. © 2008 Elsevier Inc. All rights reserved.