Our Pilot Grant Awardee Winners!

This year we were fortunate to have an amazing pool of applicants for our Pilot Grant here at the Boston University ADRC! We would love to take this opportunity to thank everyone for applying and to congrats our two winners on winning the Pilot Grant Award!

Pilot 27-1  Aytan, Nurgul

Title: TDP-43 mis-spliced transcripts associated with repetitive head impacts and Alzheimer disease related disorders including chronic traumatic encephalopathy (CTE) and limbic TDP-43 proteinopathy.

PROJECT SUMMARY

Disruptions in RNA homeostasis contribute to neurodegeneration in dementia and related diseases. Changes in the cellular localization of the RNA binding protein TDP-43 are detected in affected brain regions in 97% of amyotrophic lateral sclerosis (ALS), ~50% of frontotemporal dementia(FTD),~30% of Alzheimer’s disease (AD), and, by definition, all limbic age-related TDP-43 encephalopathy (LATE) patients. Repetitive head impacts (RHI) are a form of traumatic brain injury that commonly occur with contact sports participation and military service and that are increasingly associated with a variety of Alzheimer disease related disorders (ADRD), including chronic traumatic encephalopathy (CTE), limbic TDP-43 inclusions. Despite recent progress, the pathogeneses of these disparate TDP-43 proteinopathies as well as risk factors, such as RHI, are still unclear, and therapies for LATE and CTE remain elusive. Hence, elucidating the functional consequences of TDP-43 pathology and the effect of RHI in LATE and CTE is critical to determine whether there are shared or distinct disease mechanisms among diverse degenerative diseases.

We hypothesize that TDP-43 pathology in CTE is associated with dysfunctional RNA processing of key transcripts that may contribute to neurodegeneration upon brain injury. Specifically, we expect that increased expression of cryptic STMN2 is present in selected brain regions in CTE. We will perform quantitative PCR for isoforms of TDP-43 related cryptic exons such as STMN2, UNC13A from post-mortem brain samples, representing a sensitive measure of TDP-43 activity in the CNS. Hence, we request knowing age of onset for neurological symptoms, disease duration, and sex of cases and age-matched controls as well as neuropathological features. Linear regression analyses will be performed between clinical and pathological features and TDP-43 related cryptic exon levels. This study is important because it may suggest that therapies in clinical development that target cryptic exon expression in neurodegenerative diseases may also be beneficial to those suffering from traumatic encephalopathy syndrome.

Pilot 27-2  Antreas, Charidimou

Title:  Improving cerebral amyloid angiopathy diagnosis for ARIA risk stratification

PROJECT SUMMARY

The recent approval of anti-amyloid immunotherapy for Alzheimer’s disease (AD) opens an exciting avenue for slowing cognitive. Nonetheless, success is tempered by a major adverse side-effect associated with infusion of anti-amyloid antibodies, termed Amyloid-Related Imaging Abnormalities (ARIA) and characterized by edema and/or hemorrhage in the brain. ARIA is strongly linked to pre-existing cerebral amyloid angiopathy (CAA)–a common small vessel disease characterized by amyloid deposition within the blood vessel wall. CAA contributes to ARIA by providing a direct target for antibody-mediated vessel damage leading to downstream inflammation and bleeding. We postulate that the risk of ARIA can be mitigated by accurate radiological assessment and detection of CAA. The Boston criteria, the standard for clinical-MRI diagnosis of CAA, are not tailored for AD patients, leading to potential underdiagnosis in the AD population. In fact, the diagnostic performance of these criteria in a memory clinic setting remains largely undefined, and is likely moderate at best. There is a critical need to refine and validate neuroimaging biomarkers to identify patients with CAA more accurately and, by extension, those at risk for ARIA. Our proposal addresses this critical need. In Aim 1, we will systematically investigate the prevalence of CAA diagnosis during life based on different versions of the MRI-based Boston criteria and explore additional yield of the latest criteria version, leveraging the well-characterized cohort of the BU ADRC population. In Aim 2 we will use the BU ADRC neuropathology core and the FHS brain donation program, including participants with both in vivo (antemortem) brain MRI and postmortem neuropathological evaluation for CAA. We will assess a range of MRI markers of small vessel disease and CAA using state of the art visual ratings. We will define the diagnostic accuracy of different versions of the Boston criteria against neuropathology and integrate novel MRI biomarkers to construct a more accurate CAA diagnostic framework in a tiered approach and based on diagnostic performance metrics. Through this work, we aspire to provide actionable data that will inform clinical decision-making and contribute to the safer deployment of emerging anti-amyloid treatments in AD.