TY - JOUR
T1 - Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease
T2 - an in vivo11C-BU99008 PET study
AU - Wilson, Heather
AU - Dervenoulas, Georgios
AU - Pagano, Gennaro
AU - Tyacke, Robin J
AU - Polychronis , Sotirios
AU - Myers, Jim
AU - Gunn, Roger N.
AU - Rabiner, Eugenii
AU - Nutt, David
AU - Politis, Marios
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial a-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using
11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min
11C-BU99008 PET scan with volume of distribution (V
T) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased
11C-BU99008 V
T uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest
11C-BU99008 V
T increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of
11C-BU99008 V
T was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of
11C-BU99008 V
T in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of
11C-BU99008 V
T in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to a-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment.
AB - Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial a-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using
11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min
11C-BU99008 PET scan with volume of distribution (V
T) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased
11C-BU99008 V
T uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest
11C-BU99008 V
T increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of
11C-BU99008 V
T was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of
11C-BU99008 V
T in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of
11C-BU99008 V
T in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to a-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment.
KW - Astroglia
KW - Imidazoline 2 binding sites
KW - Neuroinflammation
KW - Parkinson's disease
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=85072718412&partnerID=8YFLogxK
U2 - 10.1093/brain/awz260
DO - 10.1093/brain/awz260
M3 - Article
C2 - 31504212
AN - SCOPUS:85072718412
SN - 0006-8950
VL - 142
SP - 3116
EP - 3128
JO - Brain
JF - Brain
IS - 10
ER -