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The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of non-neurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.

Spatial and temporal brain transcriptomics has recently emerged as an invaluable data source for molecular neuroscience. The complexity of such data poses considerable challenges for analysis and visualization. We present BrainScope: a web portal for fast, interactive visual exploration of the Allen Atlases of the adult and developing human brain transcriptome. Through a novel methodology to explore high-dimensional data (dual t-SNE), BrainScope enables the linked, all-in-one visualization of genes and samples across the whole brain and genome, and across developmental stages. We show that densities in t-SNE scatter plots of the spatial samples coincide with anatomical regions, and that densities in t-SNE scatter plots of the genes represent gene co-expression modules that are significantly enriched for biological functions. We also show that the topography of the gene t-SNE maps reflect brain region-specific gene functions, enabling hypothesis and data driven research. We demonstrate the discovery potential of BrainScope through three examples: (i) analysis of cell type specific gene sets, (ii) analysis of a set of stable gene co-expression modules across the adult human donors and (iii) analysis of the evolution of co-expression of oligodendrocyte specific genes over developmental stages. BrainScope is publicly accessible at www.brainscope.nl., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The immense complexity of the mammalian brain is largely reflected in the underlying molecular signatures of its billions of cells. Brain transcriptome atlases provide valuable insights into gene expression patterns across different brain areas throughout the course of development. Such atlases allow researchers to probe the molecular mechanisms which define neuronal identities, neuroanatomy, and patterns of connectivity. Despite the immense effort put into generating such atlases, to answer fundamental questions in neuroscience, an even greater effort is needed to develop methods to probe the resulting high-dimensional multivariate data. We provide a comprehensive overview of the various computational methods used to analyze brain transcriptome atlases.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.