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Abstract Details

Regional Brain 3R/4R RT-QuIC Seeding Reflects Patterns of AD Pathology and Correlates with Histopathological Burden of Disease
Aging, Dementia, Cognitive, and Behavioral Neurology
P4 - Poster Session 4 (11:45 AM-12:45 PM)
9-001

Alzheimer’s Disease (AD) is pathologically marked by the accumulation of 3R/4R tau whereas Progressive Supranuclear Palsy (PSP) has accumulations of 4R tau species. Recently 3R/4R isoform selective RT-QuIC assays for brain homogenates have been developed but topographic differences in seeding activity and their correlations with histopathology remain unknown.

To explore spatial differences and specificity of brain 3R/4R tau seeding and its relationship with histopathological burden using real time quaking induced conversion (RT-QuIC) and digital histological immunohistochemistry in patients with tauopathies.

34 autopsy-validated subjects with AD (n=11), PSP (n=13), AD/PSP mixed pathologies (n=6), and control cases (n=4) were studied. Frozen samples from the hippocampus (HP) and mid frontal cortex (MF) were assayed using 3R/4R RT-QuIC, generating seeding doses needed to turn 50% of wells positive (SD50). Each section was immunostained with AD-specific tau inclusions (GT38) and total phosphorylated tau (PHF1).  We compared the relationship of HP and MF seeding activity with GT38 and PHF1 inclusion burden as measured by digital image analysis methods.

A range of Braak tau stages were represented (B0=2, B1=14, B2=2, B3=15, missing=1). GT38 signal in HP and MF and PHF1 signal in the HP increased over Braak stages (F=10.6-13.5, p>0.0007) while PHF1 signal in MF did not (p=0.2). GT38 and PHF1 signal was higher in the HP than MF (Z=3.98, 5.32, p<0.001). 3R/4R SD50 from HP and MF increased across Braak stages (F=12.2, 37.0, p=0.0004, <0.0001) and was higher in the HP than MF (z=5.9, p<0.0001). There were significant correlations of GT38 staining and 3R/4R seeding activity (HP: R2=0.47. MF: R2=0.48, P<0.001 for both).  PHF1 signal from MF and HP did not correlate with 3R/4R RT-QuIC seeding in PSP cases (p=0.4, 0.5).

3R/4R selective RT-QuIC seeding activity recapitulate spatial patterns expected in AD progression and correlate with global and regional histopathological burden of AD tau pathology.

Authors/Disclosures
Varun S. Rachakonda
PRESENTER
Mr. Rachakonda has nothing to disclose.
David G. Coughlin, MD (University of California San Diego) The institution of Dr. Coughlin has received research support from American Academy of Neurology. The institution of Dr. Coughlin has received research support from NIA. The institution of Dr. Coughlin has received research support from NINDS.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Douglas Galasko, MD (Dept. of Neurosciences, UCSD) Dr. Galasko has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Galasko has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for vTv Therapeutics. Dr. Galasko has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fujirebio. Dr. Galasko has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Esai. Dr. Galasko has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cognition Therapeutics. Dr. Galasko has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for BioMed Central.
No disclosure on file
Anne E. Hiniker, MD (University of California, San Francisco) No disclosure on file