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.

Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

“…[9][10][11] Changes in extrastriatal [ 11 C]raclopride binding have also been associated with brain pathologic assesment, such as Parkinson's, Huntington's, and Alzheimer's diseases. [12][13][14] Moreover, a recent study using diffusion-weighted magnetic resonance imaging and PET found that connectivity-based subdivision of human striatum improved the evaluation of regional differences in DA transmission, supporting an association between striatal DA release and cortical connectivity. 35 36,37 In the current study, cortical VAR and ICC values were good to moderate, ranging from 6.1%, 0.79 (temporal cortex) to 13.1%, 0.67 (superior frontal gyrus).…”

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

“…Interest in the contribution of inflammation to HD pathology has fostered the study of microglia and their receptors [13,70,71]. Thus, microglial activation may predict an onset of symptoms, but similar to aggregates, the question is unresolved as to whether microglial activation is destructive or protective [72,73]. To date, expression of polyQ-htt directed specifically to, or deleted from, microglia has not been studied.…”

The Ventral Striatopallidum and Extended Amygdala in Huntington Disease

“…Cross section analysis of the amygdala has shown a reduced area (Mann et al, 1993) and amygdaloid volume atrophy was detected by MRI studies, which may occur at a very early stage of the disease (Van den Bogaard et al, 2011;Rosas et al, 2003). It should be noted that the reduction of D2/D3 receptor binding and a microglia activation has been observed in the bed nucleus of the stria terminalis, the ventral striatum and the amygdala of premanifest and symptomatic HD gene carriers (Politis et al, 2011). In contrast, Enkephalin, Neuropeptid Y and Neurotensin immunohistochemistry in the central nucleus of the amygdala showed no obvious changes (Zech et al, 1986).…”