Human cortical transcriptome informs brain imaging
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58604 | GEO | 2015/11/18
SECONDARY ACCESSION(S): PRJNA253002
REPOSITORIES: GEO
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This model is described in the article:
Mathematical analysis of the
influence of brain metabolism on the BOLD signal in Alzheimer's
disease
Felix Winter1,2, Catrin
Bludszuweit-Philipp1 and Olaf Wolkenhauer2,3
Journal of Cerebral Blood Flow &
Metabolism
Abstract:
Blood oxygen level-dependent functional magnetic resonance
imaging (BOLD-fMRI) is a standard clinical tool for the
detection of brain activation. In Alzheimer’s disease
(AD), task-related and resting state fMRI have been used to
detect brain dysfunction. It has been shown that the shape of
the BOLD response is affected in early AD. To correctly
interpret these changes, the mechanisms responsible for the
observed behaviour need to be known. The parameters of the
canonical hemodynamic response function (HRF) commonly used in
the analysis of fMRI data have no direct biological
interpretation and cannot be used to answer this question. We
here present a model that allows relating AD-specific changes
in the BOLD shape to changes in the underlying energy
metabolism. According to our findings, the classic view that
differences in the BOLD shape are only attributed to changes in
strength and duration of the stimulus does not hold. Instead,
peak height, peak timing and full width at half maximum are
sensitive to changes in the reaction rate of several metabolic
reactions. Our systems-theoretic approach allows the use of
patient-specific clinical data to predict dementia- driven
changes in the HRF, which can be used to improve the results of
fMRI analyses in AD patients.
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Project description:The full complement of molecular pathways contributing to Parkinson’s disease (PD) pathogenesis remains unknown. Here, to address this issue, we began by using a high-resolution variant of functional magnetic resonance imaging (fMRI) to pinpoint brainstem regions differentially affected by, and resistant to, the disease. Then, relying on the imaging information as a guide, we profiled gene expression levels of postmortem brain samples and used a factorial statistical model to identify a disease related decrease in the expression of the polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a series of studies were performed to confirm the pathogenic relevance of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, while Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, we genotyped PD patients and controls and isolated a rare but novel variant in the SAT1 gene, although the functional significance of this genetic variant was not identified. Taken together, the results suggest that the polyamine pathway contributes to PD pathogenesis.
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