Su, Yi‐Chang

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.MethodThe graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.ResultEntorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).ConclusionWhile there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.

AbstractBackgroundAPOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and CSF measurements of amyloid‐β (Aβ) pathophysiology in APOE4 gene dose. Here, we characterize the core AD CSF biomarkers (Aβ42/40, pTau181, tTau), the neurodegeneration marker neurofilament light chain (NfL) and the glial biomarkers soluble TREM2 (sTREM2), and glial fibrillary acidic protein (GFAP) measurements in age‐matched 48‐70 year‐old cognitively unimpaired (CU) APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs) from the Arizona cohort.MethodCSF biomarker measurements were performed at the University of Gothenburg using Lumipulse and ELISA immunoassays. CSF biomarker measurements were characterized and compared using linear‐tend ANOVAs in 12 HMs, 17 HTs, and 20 NCs who were CU, 48‐70 years old and did not differ significantly in their age, sex, or educational level.ResultAs expected, CSF Aβ42/40 ratios were inversely associated with APOE4 gene dose (linear trend, HM<HT<NC, p<0.05), and tTau/Aβ42 and pTau181/Aβ42 ratios were directly associated with APOE4 gene dose (HM>HT>NC p<0.05). Non‐significant trends suggested that CSF sTREM2 and sTREM2/pTau181 measurements were inversely associated with APOE4 gene dose (HM<HT≤NC, (0.05<p≤0.06). We failed to detect significant differences or linear trends in CSF pTau181, tTau, GFAP, or NfL measurements among these small subject groups.ConclusionAPOE4 gene dose is associated with measures of CSF Aβ42/40 and Aβ‐related tau pathophysiology, reflecting higher Aβ plaque burden in CU subjects close to their estimated ages at clinical onset. Additional studies are needed to clarify relationships between different Aβ, tau, neurodegenerative, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose in larger subject groups and at other ages.