Neuronal gene expression correlates of Parkinson's disease with dementia

Abstract

Dementia is a common disabling complication in patients with Parkinson's disease (PD). The underlying molecular causes of Parkinson's disease with dementia (PDD) are poorly understood. To identify candidate genes and molecular pathways involved in PDD, we have performed whole genome expression profiling of susceptible cortical neuronal populations. Results show significant differences in expression of 162 genes (P < 0.01) between PD patients who are cognitively normal (PD-CogNL) and controls. In contrast, there were 556 genes (P < 0.01) significantly altered in PDD compared to either healthy controls or to PD-CogNL cases. These results are consistent with increased cortical pathology in PDD relative to PD-CogNL and identify underlying molecular changes associated with the increased pathology of PDD. Lastly, we have identified expression differences in 69 genes in PD cortical neurons that occur before the onset of dementia and that are exacerbated upon the development of dementia, suggesting that they may be relevant presymptomatic contributors to the onset of dementia in PD. These results provide new insights into the cortical molecular changes associated with PDD and provide a highly useful reference database for researchers interested in PDD.

FIG. 1

A unique set of dysregulated genes in cortical neurons are associated with Parkinson's disease. Shown are heat maps representing the expression levels of each gene (horizontal rows) in all control, PD-CogNL, and PDD samples (vertical columns). Red indicates significant gene induction associated with PD and blue indicates significant repression. Heat maps were generated using GeneCluster version 2.1.7. Text columns represent (from left to right) the Affymetrix Probe ID, Gene Symbol, fold change and P-value for PD-CogNL vs control, fold change and P-value for PDD vs PD-CogNL, and fold change and P-value for PDD vs control. Only genes with at least a 2-fold increase or decrease are shown. Genes are ordered based on their fold change in the PD-CogNL vs control.

FIG. 2

A unique set of cortical neuronal genes are dysregulated in Parkinson's disease with dementia. Shown are heat maps representing the expression levels of each gene (horizontal rows) in all control, PD-CogNL, and PDD samples (vertical columns). Red indicates significant gene induction associated with PD and blue indicates significant repression. Heat maps were generated using GeneCluster version 2.1.7. Text columns represent (from left to right) the Affymetrix Probe ID, Gene Symbol, fold change and P-value for PD-CogNL vs control, fold change and P-value for PDD vs PD-CogNL, and fold change and P-value for PDD vs control. Only genes with at least a 2-fold increase or decrease are shown and are ordered based on their fold change in the PDD vs PD-CogNL comparison.

FIG. 3

A subset of genes may underlie the onset or progression of dementia in PD. Shown are all genes with altered expression occurring before the onset of dementia and that are further altered following the development of dementia associated with PD. All column labels are as for figures 2 and 3. Genes were ordered based on their fold change in PD-CogNL vs controls.

FIG. 4

qRT-PCR experiments confirm significant gene dysregulation in PDD and PD-CogNL cortical neurons. Shown in (A) are results for the genes indicated on the X-axis. The relevant comparisons are indicated across the top of the graph. A single asterix indicates significance at the P < 0.05 level. Double asterices indicate significance at the P < 0.01 level. Specific fold changes are reported in the text. Shown in (B) are results for the indicated genes and comparisons. Asterices have the same significance as in A and specific fold changes are reported in the text.