Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.

BackgroundMutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition.MethodsPlasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS.ResultsLevels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment.ConclusionThese results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.

ObjectiveTo evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adult phenylketonuria patients.MethodsIn this prospective cross-sectional study, early-treated phenylketonuria patients older than 30 years and age and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were in addition evaluated in a subset of 10 patients.ResultsNineteen phenylketonuria patients (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures and atrophy in putamen and right thalamus compared to controls. In CSF, Phenylketonuria patients exhibited higher Aβ1-42 (p = 0.003), T-Tau (p < 0.001) and P-Tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001) motor evoked potential latency (r = 0.48, p = 0.030) and parietal lobe atrophy.ConclusionsOur study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical and imaging alterations in adult phenylketonuria patients.