Microglial activation in regions related to cognitive function predicts disease onset in Huntington's disease: a multimodal imaging study

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5-year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, (11)C-PK11195 and (11)C-raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat-matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease-burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD.

Figure 1

Brain regions involved in motor symptoms of Huntington's disease. Decreases in volume (green), loss of D2/D3 receptors (blue) and increases in activated microglia (red) in the averaged 45‐CAG repeat premanifest HD, the averaged 45‐CAG repeat Symptomatic HD and Normal Brain. Decreases in RAC BP_ND, mm³ and increases in PK BP_ND in the premanifest and symptomatic Huntington's disease brain are expressed as percentage changes from the normal brain values. Dotted lines represent normality range defined as mean RAC BP_ND − SD, mean mm³ − SD, mean PK BP_ND + SD for D2/D3 receptors, volume and microglia activation, respectively. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Regions involved in cognitive symptoms of Huntington's disease. Decreases in volume (green), loss of D2/D3 receptors (blue) and increases in activated microglia (red) in the averaged 45‐CAG repeat premanifest HD, the averaged 45‐CAG repeat Symptomatic HD and Normal Brain. Decreases in RAC BP_ND, mm³ and increases in PK BP_ND in the premanifest and symptomatic Huntington's disease brain are expressed as percentage changes from the normal brain values. Dotted lines represent normality range defined as mean RAC BP_ND − SD, mean mm³ − SD, mean PK BP_ND + SD for D2/D3 receptors, volume and microglia activation, respectively. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

Regions involved in psychiatric symptoms of Huntington's disease. Decreases in volume (green), loss of D2/D3 receptors (blue) and increases in activated microglia (red) in the averaged 45‐CAG repeat premanifest HD, the averaged 45‐CAG repeat Symptomatic HD and Normal Brain. Decreases in RAC BP_ND, mm³ and increases in PK BP_ND in the premanifest and symptomatic Huntington's disease brain are expressed as percentage changes from the normal brain values. Dotted lines represent normality range defined as mean RAC BP_ND − SD, mean mm³ − SD, mean PK BP_ND + SD for D2/D3 receptors, volume and microglia activation, respectively. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

Correlation between AST 11C‐PK11195 BP_ND and the predicted 5‐year probability of symptomatic HD onset in the averaged 45‐CAG repeat premanifest HD brain (r = 0.8095, P = 0.0218).

Figure 5

Correlation between Cognitive Group of Regions 11C‐PK11195 BP_ND and the predicted 5‐year probability of symptomatic HD onset in the averaged 45‐CAG repeat premanifest HD brain (r = 0.8810, P = 0.0072).