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Principal Investigator  
Principal Investigator's Name: Jana Ivanidze
Institution: Weill Cornell Medicine
Department: Radiology
Country:
Proposed Analysis: Alzheimer Disease (AD) is the most common cause of cognitive impairment and dementia, accounting for 50-60% of cases and currently affecting over 5 million individuals in the US. Investigation of therapeutic options depends upon optimization of early diagnosis and treatment response monitoring. Accumulation of extracellular Amyloid-beta (Aβ) plaques and intracellular abnormally phosphorylated tau deposits (neurofibrillary tangles) represents the neuropathologic hallmark of AD, resulting in synaptic loss and neurodegeneration. Histopathologic analysis remains the gold standard for the diagnosis of AD, however brain biopsies are not practical and not commonly performed in this patient population. Clinical assessment and differential diagnosis is challenging given significant overlap in clinical presentation especially at the early stage, as well as confounding effects of certain comorbidities. In current clinical practice, assessment of region-specific patterns of cortical glucose metabolism with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (F-18-FDG) PET aids in the diagnostic workup of patients with clinically suspected AD. We have recently evaluated the diagnostic performance of pre-defined quantitative criteria applied to statistical parametric mapping (SPM) using different types of normalization techniques. In our preliminary work, SPM with pre-defined quantitative criteria outperformed qualitative clinical radiology reports, demonstrated by a higher rate of concordance with the final neurologic diagnosis. Limitations of this study included a heterogeneous clinical reference as the gold standard, which could be directly addressed using an imaging database of patients with AD, MCI, and normal subjects with documented standardized clinical exams, such as the Alzheimer Disease Neuroimaging Initiative (ADNI) database described below. An early rise in Aβ accumulation has been proposed to play a key role in the presymptomatic phase of AD. F-18-Florbetapir is a PET tracer binding to Aβ, allowing to image Aβ plaque burden in vivo with high sensitivity and specificity, and a promising surrogate biomarker of treatment efficacy in clinical trials. AV-1451 is a PET tracer targeting unsoluble forms of tau and allowing quantification of tau deposition. Tau PET imaging with AV-1451 has recently been demonstrated to correlate with atrophy as determined by structural MRI, as well as with CSF t-tau and p-tau levels in AD. Matrix metalloproteinases (MMPs) regulate the cleavage of extracellular matrix proteins. Our preliminary work has included the study of CSF MMP-9 levels in the context of neuroinflammation and blood-brain-barrier degradation in aneurysmal subarachnoid hemorrhage (ASAH). In AD, MMP-9 was found to be elevated in the serum as well as in postmortem brain tissue, and was found to be inducible by Aβ in vitro. The tau cleavage pattern of MMP-9 was found to facilitate neurofibrillary tangle aggregation, with increase in MMP-9 levels resulting in a proaggregatory influence on tau oligomer formation. However, the relationship between MMP-9 CSF levels and in vivo tau PET imaging in AD has to date not been explored. The Alzheimer Disease Neuroimaging Initiative (ADNI) has the central aim of validating biomarkers for, and informing the design of, therapeutic trials in AD. Data available in ADNI includes clinical, imaging, and serum and CSF biomarker data from over 1100 individuals, collected over the course of the past 14 years, including patients with clinically manifest AD, individuals with MCI, and cognitively normal control subjects. All data is public at University of South California (USC)/Laboratory of Neuroimaging (LONI)/ADNI, without embargo. Our objective is to leverage the ADNI database in order to evaluate the relationship between CSF MMP-9 levels and in vivo tau imaging using AV-1451 PET. Our central hypothesis is that increased CSF MMP-9 levels promote tau aggregation and will thus correlate to tau-, amyloid-, and FDG-PET abnormalities encountered in AD. We will pursue the following specific aims. Specific Aim 1: to validate our preliminary work on SPM in FDG PET as a differential diagnostic tool in dementia using the ADNI cohort, and to correlate quantitative FDG PET with CSF MMP-9 protein levels. Hypothesis 1A: Our quantitative FDG PET criteria developed in a retrospective, clinically heterogeneous cohort can be applied and validated in the clinically robust ADNI cohort including patients with clinically manifest AD and NC individuals. Hypothesis 1B: CSF MMP-9 protein levels correlate with quantitative FDG PET findings in patients with clinically manifest AD. Specific Aim 2: to compare tau PET, amyloid PET and CSF MMP-9 protein levels in AD patients and cognitively normal individuals utilizing the ADNI cohort. Hypothesis 2A: tau PET correlates significantly with CSF MMP-9 levels in patients with AD. Hypothesis 2B: Amyloid PET correlates significantly with CSF MMP-9 levels in patients with AD. Hypothesis 2C: Correlation between tau PET and CSF MMP-9 levels is stronger in amyloid PET positive individuals.
Additional Investigators  
Investigator's Name: Jeremy Ford
Proposed Analysis: Dr. Ford is going to participate in the project discussed above.
Investigator's Name: Myrto Skafida
Proposed Analysis: Dr. Skafida is going to participate in the project referenced above.
Investigator's Name: Natasha Smith
Proposed Analysis: Ms Smith is a medical student in my lab who is going to participate in the project referenced above.