Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia

Abstract

Objective: We aimed to understand the impact of dopamine receptor D₄ (DRD₄) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD₄dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD₄ is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.

Methods: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD₄ genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.

Results: DRD₄ dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.

Conclusions: We conclude that DRD₄ polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.

Keywords: Anterior cingulate cortex; Apathy; DRD(4); Frontotemporal dementia; Insula; Salience network.

Fig. 1

Global atrophy patterns between dementia patients and age-matched controls. VBM analyses controlling for age, sex, scanner type, and total intracranial volume confirmed the AD and FTD diagnostic groups exhibited atrophy patterns that were consistent with their clinical syndromes. Statistical parametric maps were corrected at p_FWE-corr < 0.05. N = 337. Results are displayed on a coronal MNI slice-labeled average template brain.

Fig. 2

Regions where DRD₄ dampened function is associated with greater atrophy in FTD with results nested in FTD versus control atrophy maps. Interaction effect by group and genotype showed significant clusters of decreased gray matter intensity in FTD patients predicted by DRD₄ dampened-variants. VBM analyses controlled for age, sex, scanner type, total intracranial volume, and disease severity (CDR sum-of-boxes). Corrected statistical parametric maps are displayed at p_FWE-corr < 0.05. Significant results are displayed with the orange/red heat map and embedded in larger regional atrophy maps from FTD compared to controls, which is displayed with the blue/green color map. Slices are labeled with MNI coordinates. Results are overlaid on an MNI average template brain. Interaction effects by genotype and group in AD and controls were not significant predictors of gray matter intensity change. Table 3 lists the MNI coordinates of significant voxels/clusters in FTD predicted by interaction effects with DRD₄ dampened-variants.

Fig. 3

Regional atrophy in FTD correlated with worsened apathy and repetitive motor behavior which covaried with decreased gray matter signal predicted by DRD₄ dampened function. Statistical parametric maps of significantly decreased gray matter intensities which were predicted by interaction effect between FTD group and NPI apathy and repetitive motor sub-scores. Results were masked by regions of atrophy related to DRD₄ dampened function. Results are displayed at p_FWE-corr < 0.05 with red/purple heat maps embedded in blue maps which denote regions of significant atrophy related to worsened apathy and repetitive motor behavior in all patients with FTD. Results are overlaid on an MNI average template brain. Coronal slices are labeled with MNI coordinates.

Fig. 4

Syndrome-specific atrophy in FTD related to DRD₄ dampened function. 50 patients with bvFTD (yellow/orange heat maps) and 26 with svPPA (green/blue maps) showed intensified atrophy associated with DRD₄ polymorphisms. Corrected maps are displayed at p_FWE-corr < 0.05. Results are overlaid on an MNI average template brain. Slices are labeled with MNI coordinates. Table 4 displays the MNI coordinates to attain significance by interaction effect between FTD-syndromic diagnosis and DRD₄ dampened function.