Huntington's disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.

We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?

Huntington's disease (HD) is a fatal, neurodegenerative movement disorder that has no cure and few treatment options. In these preclinical studies, we tested the effects of chronic treatment of glatiramer acetate (GA; Copaxone®), an FDA-approved drug used as first-line therapy for MS, in two different HD mouse models, and explored potential mechanisms of action of drug efficacy. Groups of CAG140 knock-in and N171-82Q transgenic mice were treated with GA for up to 1year of age (CAG140 knock-in mice) or 20weeks (N171-82Q mice). Various behavioral assays were measured over the course of drug treatment whereby GA treatment delayed the onset and reduced the severity of HD behavioral symptoms in both mouse models. The beneficial actions of GA were associated with elevated levels of promoter I- and IV-driven brain-derived neurotrophic factor (Bdnf) expression and reduced levels of cytokines, in particular, interleukins IL4 and IL12, in the brains of HD mice. In addition, the GA-induced effects on BDNF, IL4 and IL12 levels were detected in plasma from drug-treated mice and rats, suggesting utility as a peripheral biomarker of treatment effectiveness. These preclinical studies support the use of GA as a relevant clinical therapy for HD patients.