Brain PET Imaging of Synaptic Density in Alzheimer’s Dementia

A new PET tracer may improve Alzheimer’s disease detection and progression

Ming-Kai Chen, M.D., Ph.D.

Yale University

Funded in September, 2015: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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A new PET tracer may improve Alzheimer’s disease detection and progression

Can a new PET imaging tracer outperform the currently used one in diagnosing Alzheimer’s disease (AD) and in monitoring its progression?

Diagnosing probable AD currently relies on three major measures. One is whether there is a decrease in glucose metabolism in major cognitive areas in the brain, suggesting lower brain activity. This assessment is made by PET imaging, using a tracer called FDG which measures glucose metabolism. A second measure is the amount of the protein called amyloid that builds up in the brain. Amyloid can be measured by PET using tracers such as PiB which binds to amyloid. The third measure is neurocognitive testing results. But results from the first of these measures, FDG-PET imaging, are confounded by several factors that are prevalent in the elderly population: medication use; high blood glucose levels associated with diabetes; and distractions in the clinical environment.    

A new PET imaging tracer, called [C-11]-UCB-J, may be able to eliminate those confounding factors and outperform FDG-PET in helping clinicians diagnose AD and monitor its progression. Instead of measuring glucose like FDG-PET does, this new tracer measures a glycoprotein called SV2A. This protein is found at all brain cell synapses, where one brain cell transmits an electrochemical message to another. The investigators hypothesize that this tracer can quantify the density of brain synapses and therefore identify synaptic loss in AD, and that this measure will be a more reliable indicator of AD diagnosis and its progression compared to FDG-PET.  

They will test this hypothesis in three ways. First, they will use their new PET tracer to compare synaptic density in ten AD patients and ten healthy volunteers; they expect to find less binding of the tracer in the AD patients compared to the volunteers, indicating that the patients have synaptic loss. Second, in the same 20 participants, the investigators will determine whether their PET tracer shows a greater magnitude of difference between the AD patients and healthy volunteers compared to that seen on FDG-PET imaging. Third, they will determine whether the severity of each AD patient’s cognitive functioning, as measured by cognitive testing, correlates better with the brain scan findings from their PET tracer compared to those from FDG-PET. 

Significance :   This study will provide preliminary evidence of whether this new PET imaging tracer, which measures synaptic loss, has the potential to become the new gold standard for diagnosing AD and assessing the disease’s progress.   

 

ABSTRACT

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Our goal is to explore the use of positron emission tomography (PET) with [11C]UCB-J, a novel tracer for synaptic vesicle 2A (SV2A), for measuring synaptic density loss in Alzheimer’s disease (AD). AD afflicts 6 million people in the USA, with an annual health care burden near $200 billion. The clinical dementia of AD is coupled to a distinct pathology, with plaques composed of Amyloid-ß (Aß), neurofibrillary tangles of hyper-phosphorylated Tau protein, and synaptic loss. Non-invasive in vivo diagnostic biomarker strategies including PET imaging with fluorodeoxyglucose (FDG) and Aβ ligands for early diagnostic purposes are well accepted. [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. Radioligands for new, specific molecular targets are required to provide a better diagnostic tool and surrogate for monitoring AD progression. SV2 receptors are localized in synaptic vesicles in presynaptic neuron terminals. SV2A isoform is ubiquitously expressed in all synapse and can be an ideal biomarker for synaptic density. We recently developed [11C]UCB-J as a promising radioligand for quantitative measurement of SV2A with PET. In our pilot first-in-human SV2A PET studies in healthy subjects, we found that [11C]UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain. In addition, this tracer has the potential to measure synaptic vesicle density in vivo. We hypothesize that [11C]UCB-J PET can be used as a biomarker to quantify synaptic density loss 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 marker of AD progression than FDG. In the first aim, we will explore the use of [11C]UCB-J PET for assessment of synaptic density loss in AD compared to sex and age-matched healthy controls (HC). In the second aim, we will compare the diagnostic value of [11C]UCB-J PET with [18F]FDG in differentiating AD and HC. These studies will be performed on the High Resolution Research Tomography (HRRT) with very high resolution of 2-3 mm and state-of-the-art methodology. In the third aim, we will determine whether [11C]UCB-J or [18F]FDG PET is better correlated with cognitive function and the severity of dementia in AD. This will be the first PET study using our newly developed SV2A tracer for imaging AD. We expect to see significant SV2A reduction in expected cerebral cortices in AD compared to HC. The direct comparison of [11C]UCB-J and [18F]FDG PET with further correlation with severity of dementia will determine the better tracer for clinical use. The success of this study could provide a promising noninvasive in vivo biomarker for early detection, monitoring AD progression, and evaluating the efficacy of intervention.

KEYWORDS


Anatomy: Amyloid
Conditions: Alzheimer's disease
Function: Cognition
Technology: MRI
PET