IMPORTANCEThe use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants. OBJECTIVE To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance.DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated.MAIN OUTCOMES AND MEASURES Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests. RESULTSThe mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F 1,162 = 8.63, P = .02), N-acetylaspartate (F 1,161 = 5.93, P = .03), GABA (F 1,163 = 6.38, P = .03), and glutathione (F 1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F 1,136 = 7.23, P = .05) and thalamus (F 1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F 1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01).CONCLUSIONS AND RELEVANCE Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis.

Huntington disease is a genetic neurodegenerative disorder that arises from an expanded polyglutamine region in the N terminus of the HD gene product, huntingtin. Protein inclusions comprised of N-terminal fragments of mutant huntingtin are a characteristic feature of disease, though are likely to play a protective role rather than a causative one in neurodegeneration. Soluble oligomeric assemblies of huntingtin formed early in the aggregation process are candidate toxic species in HD. In the present study, we established an in vitro system to generate recombinant huntingtin in mammalian cells. Using both denaturing and native gel analysis, we have identified novel oligomeric forms of mammalian-derived expanded huntingtin exon-1 N-terminal fragment. These species are transient and were not previously detected using bacterially expressed exon-1 protein. Importantly, these species are recognized by 3B5H10, an antibody that recognizes a two-stranded hairpin conformation of expanded polyglutamine believed to be associated with a toxic form of huntingtin. Interestingly, comparable oligomeric species were not observed for expanded huntingtin shortstop, a 117-amino acid fragment of huntingtin shown previously in mammalian cell lines and transgenic mice, and here in primary cortical neurons, to be non-toxic. Further, we demonstrate that expanded huntingtin shortstop has a reduced ability to form amyloid-like fibrils characteristic of the aggregation pathway for toxic expanded polyglutamine proteins. Taken together, these data provide a possible candidate toxic species in HD. In addition, these studies demonstrate the fundamental differences in early aggregation events between mutant huntingtin exon-1 and shortstop proteins that may underlie the differences in toxicity. Huntington disease (HD)3 is an inherited neurodegenerative disorder caused by an expanded polyglutamine (polyQ) region in the N terminus of the HD gene product, huntingtin (htt), a large protein over 3,000 amino acids in length (1-3). Individuals affected with HD have a polyQ region of 36 or more glutamine residues (4), and clinical studies have shown an inverse correlation between polyQ length and age of disease onset (5, 6). Recent work indicates that Htt may undergo proteolysis, generating several truncation products (7,8). One of the smallest products is an N-terminal fragment that corresponds to the first exon of the HD gene and is comprised of the first 90 amino acids of Htt (based on a polyQ region of 23 glutamine repeats (3)). Htt exon-1 is of particular interest, as it is believed to be a mediator of toxicity in animal models of HD and in HD patients.HD is characterized by the deposition of large intracellular protein aggregates, or inclusion bodies, comprised of N-terminal fragments of mutant Htt. In HD, there is a strong correlation between polyQ repeat length and the threshold for aggregation and disease (4). While inclusions are a pathological hallmark of disease, inclusion formation does not correlate well with pathogenesis in vivo (9 -12). ...

A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.