Plasma Neurofilament Light and Alzheimer's Disease Biomarkers in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI).

BACKGROUND: Adults with Down syndrome (DS) are at very high risk for Alzheimer's disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. OBJECTIVE: To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. METHODS: We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. RESULTS: We found significant correlations between NF-L plasma concentrations and amyloid pathology (r = 0.73, p = 0.007, pa = 0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r = -0.55, p = 0.067, pa = 0.067), Posterior cingulate r = -0.90, p < 0.001, pa < 0.001), Lateral Temporal (r = -0.78, p = 0.004, pa = 0.012), Frontal cortex (r = -0.90, p < 0.001, p pa < 0.001), Parietal cortex (r = -0.82, p = 0.002, pa = 0.008), Precuneus (r = -0.73, pa = 0.010, pa = 0.020), and with hippocampal volume (r = -0.52, p = 0.084, pa = 0.084); and an inverse correlation with direct measures of cognition: CAMCOG (r = -0.66 p = 0.022, pa = 0.066) and positive correlation with CANTAB Paired Associates Learning (PAL) error rate (r = 0.68, p = 0.015, pa = 0.060). Finally, we found inverse relationships with informant-based functional measures (r = -0.57, p = 0.059, pa = 0.084) and OMQ-PF (r = -0.74, p = 0.008, pa = 0.041). CONCLUSION: Plasma NF-L is associated with progressive neurodegeneration as well as with declines in cognitive and functional measures in adults with DS.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.

BACKGROUND: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. OBJECTIVE: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. RESULTS: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. CONCLUSION: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.