Abstract
11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
Highlights
Astrocyte reactivity is a prominent feature of the neuropathology of Alzheimer’s disease (AD), but the extent to which it is a consequence or a contributing factor for the formation of amyloid (Aβ) and tau aggregation remains uncertain [1]
Metabolism of 11C-BU99008 was MATERIALS AND METHODS Subjects Eleven subjects with cognitively impaired (CI) who were clinically diagnosed as having probable AD dementia or mild cognitive impairment (MCI) due to AD [25, 26] (5 MCI, 6 AD; Mini-Mental State Examination score (MMSE) mean ± SD = 22.6 ± 4.1) and met the additional criteria below and 9 approximately age-matched healthy controls (HC) without a history of brain disease or contraindications to magnetic resonance imaging (MRI; MMSE mean ± SD = 29.1 ± 1.27) were included in the study (Table 1)
Ishiki et al [51] found that whilst CSF glial fibrillary acid protein (GFAP) was significantly higher in AD patients compared with controls, CSF GFAP findings were similar with other types of dementia such as. In this proof-of-principle study using the novel positron emission tomography (PET) tracer 11CBU99008, we demonstrated an increase in 11C-BU99008 uptake in dementia with Lewy Bodies and frontotemporal lobar degeneration
Summary
Astrocyte reactivity is a prominent feature of the neuropathology of Alzheimer’s disease (AD), but the extent to which it is a consequence or a contributing factor for the formation of amyloid (Aβ) and tau aggregation remains uncertain [1]. Whilst some methodologies exist to measure astrocyte reactivity in living AD patients, such as CSF [6, 7], blood [8] and positron emission tomography (PET) [9]. Non- or minimally invasive methods for monitoring astrocyte reactivity in patients with late-life cognitive impairment would provide a powerful tool for testing their contributions to disease progression. The only available PET tracer which can measure astrocyte reactivity in vivo is 11C-deuterium-Ldeprenyl (11C-DED) [10, 11]. This tracer binds to monoamine oxidase-B, which is not exclusively expressed in astrocytes and is not elevated in late disease stages when Aβ load is high [12]. Additional radioligands are needed to confidently image astrocyte reactivity and its relations to Aβ load and clinical symptoms
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