Brain PET Imaging of Synaptic Density in Alzheimer’s Disease (PI) Ming-Kai Chen, MD, PhD
We will explore the use of brain positron emission tomography (PET) scanner with our newly developed C-11 radioisotope labeled drug [11C]UCB-J, a novel imaging probe for synaptic vesicle glycoprotein 2A (SV2A), as a potential imaging tool of measuring synaptic loss in Alzheimer’s disease (AD).
[18F]FDG PET for glucose metabolism has been widely used for diagnosis and tracking disease progression in AD. However, brain FDG uptake is affected by environmental neurostimulation, a long list of medications, and blood glucose levels. Inadequate patient fasting before the scan can result in a false positive of AD. New imaging probes for specific molecular targets are required to provide a better diagnostic tool and surrogate for monitoring AD progression. Synaptic vesicles in presynaptic terminals secrete neurotransmitters by fusing with the terminal membrane. One essential vesicle membrane protein is the SV2, with one of its subtypes, SV2A, ubiquitously expressed in virtually all presynaptic terminals. We recently developed [11C]UCB-J as a promising imaging probe for quantitative measurement of SV2A with PET. We hypothesize that [11C]UCB-J PET can be used as an imaging probe to quantify loss of synaptic density in AD. As a direct measure of synaptic morphology, [11C]UCB-J has the potential to be more reliable and diagnostically useful and thus a better imaging probe of AD progression than FDG. We will perform consecutive [11C]UCB-J and FDG PET scans in the same AD subjects and sex and age-matched healthy controls (HC) for direct comparison . These studies will be performed on the dedicated brain scanner with very high resolution and state-of-the-art methodology. The success of this study could provide a promising noninvasive imaging probe for early detection, monitoring AD progression, and evaluating effects of multiple new treatments.
The role of neuroinflammation in the pathogenesis of Alzheimer’s disease (PI) Janghoo Lim, PhD
Our long-term research goals are to determine the cellular and molecular mechanisms that are responsible for neuron degeneration in Alzheimer’s disease (AD) and ultimately to translate the findings into the development of therapeutics. The objective here is to reveal the relevance of neuroinflammation to the pathogenesis of AD. Neuroinflammation is an immune response to damaged nervous tissue and is one of the most common disease features observed in AD and other neurodegenerative diseases. In the central nervous system, microglia are the resident innate immune cells that are activated in response to diverse types of brain damage, including neuron degeneration. Signals released by injured neurons and active microglia also activate astrocytes, a type of glial cell abundant in the brain. Many studies using human patient tissues and mouse models suggest that neuroinflammation strongly occurs in numerous brain regions associated with AD. However, the precise role of neuroinflammation and the function of microglia and astrocytes in AD still remain unclear. Here, we hypothesize that the disease-causing oligomeric A (Ao) directly or indirectly regulates the activation of microglia and/or astrocytes in the brain, and this chronic neuroinflammation significantly contributes to AD neuropathology. In this proposal, we will first determine the temporal and spatial relationships between AD and neuroinflammation in AD mouse models. Second, we will also determine the in vivo relevance of neuroinflammation to the pathology of AD by testing whether the decreased levels of neuroinflammation is able to modulate neurodegeneration phenotypes in AD. We believe that this study will not only fundamentally advance our understanding of AD-induced neuroinflammation, but also provide a new target for the development of effective therapeutics to treat AD.