RESUMEN
Pre-symptomatic frontotemporal dementia (FTD) mutation carriers and first-degree family members that are 50% at-risk for FTD may experience symptoms of anxiety and depression as a result of the ambiguity of when or if symptoms of the disease will manifest. We conducted a pilot study to investigate the use of an online mindfulness-based stress reduction (MBSR) course to reduce symptoms of anxiety and depression in presymptomatic frontotemporal dementia (FTD) mutation carriers and individuals 50% at-risk. Seven known mutation carriers and six individuals 50% at-risk completed a standardized 8-week MBSR course, and filled out pre- and post and two-month follow-up questionnaires. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS). Measures of psychological distress (SCL-90-R), coping style (UCL), quality of life (SF-36) and mindfulness skills (FFMQ) were administered as secondary outcome. Group effects were analyzed with repeated measures ANOVA or Friedman's test, and the individual reliability change index (RCI) was calculated per participant for each outcome measure. Semi-quantitative data included an evaluation and process measure post-intervention. Significant decline was found on the HADS-A post-intervention and after 2 months (p = 0.01), with 54% and 62% of participants demonstrating a clinically significant RCI, respectively. On the HADS-D, significant decline was found 2 months post-intervention (p = 0.04), which was driven by 23% of participants whom had a clinically significant RCI. Additional changes were found between baseline and post-intervention on the seeking distraction and reassuring thoughts subscales of the UCL, the depression and interpersonal sensitivity subscales of the SCL, the observe subscale of the FFMQ, and on physical role limitations of the SF-36 (all p < 0.05). The process evaluation form indicated that the course was found beneficial by participants, and that they applied it in a wide range of everyday situations. This exploratory pilot study indicates the feasibility of MBSR in reducing anxiety and depression in presymptomatic FTD mutation carriers and 50% at-risk individuals. A randomized controlled trial is necessary to replicate these results.
RESUMEN
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.