Citations

C9orf72 encodes a protein that is important for both typical neurodevelopment and homeostatic processes across the lifespan. Pathogenic C9orf72 repeat expansions constitute the most common genetic cause of frontotemporal lobar degeneration (FTLD). Collectively, preclinical models and clinical neuroimaging studies have observed smaller thalamic volumes in C9orf72-associated FTLD, including in asymptomatic young adult C9orf72 repeat expansion carriers across 18 to 30 years old, supportive of potential neurodevelopmental origins. However, it is unknown whether asymptomatic young adult C9orf72 expansion carriers demonstrate volume differences in specific thalamic nuclei, as reported in older asymptomatic carriers and symptomatic patients; if so, normative transcriptomic patterns could reveal relevant neurodevelopmental and/or FTLD-related neurodegenerative processes. This study investigated volumetric MRI differences of the thalamic nuclei in asymptomatic young adult C9orf72 expansion carriers compared to non-carriers, and examined spatial associations with normative thalamic transcriptomics from 8 weeks post-conception through middle age. Young adult C9orf72 expansion carriers (n=72) and non-carriers (n=48) were enrolled in the Frontotemporal Dementia Prevention Initiative across Europe, Canada, and the USA (ages: 18-30 years; sex: 57% female). Spatial associations between young adult thalamic nuclei volumes and normative transcriptomics from the Allen Human Brain Atlas were examined using complementary data-driven and hypothesis-driven approaches. Spatial expression patterns of transcripts of interest were characterized across prenatal and postnatal neurodevelopment using BrainSpan data. Smaller volumes of the pulvinar, mediodorsal, and lateral nuclei were observed in young adult C9orf72 expansion carriers compared to non-carriers. These nuclei showed higher normative expression of transcripts involved concurrently in neurodevelopmental and C9orf72-associated FTLD neurodegenerative processes (including lysosomal, autophagic, and small GTPase functions), and lower normative expression of CALB1, a marker of prenatal human thalamic development. Normative expression of CALB2 (another human thalamic development marker) yielded positive correlations with C9orf72 across prenatal development to adulthood. These findings identify candidate transcripts that may provide insight into the molecular architecture leading to smaller thalamic nuclei volumes in C9orf72-associated FTLD.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28‐day, double‐blind, placebo‐controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000‐000)