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ObjectiveTo characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease.DesignCross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers.SettingAcademic medical center.ParticipantsA total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level.Main outcome measuresThe measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume.ResultsAlthough there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P = .60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P = .001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P < .05, determined by use of pairwise Fisher z tests).ConclusionsAlthough our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players. Method: In this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria. Result: Significantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C). Conclusion: Elevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology. [ABSTRACT FROM AUTHOR]

Background: We previously examined the impact of using a cerebellar, pons, or cerebral white matter (WM) reference region (RR) on the ability of each to distinguish cortical measures of fibrillar amyloid‐(Aβ) deposition with baseline data in unimpaired presenilin (PSEN1) E280A mutation carriers and non‐carriers (NC) from the Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (API ADAD) Colombia Trial (NCT01998841). In this study, we extend our findings by comparing these RRs on their ability to distinguish longitudinal changes in cortical measures of serial Aβ‐PET scans from the completed clinical trial. Method: We estimated template‐based (SPM12) cortical mean change using baseline, 2, and 5‐year florbetapir PET standard‐uptake value ratios (SUVRs) with three different RRs (whole cerebellum, pons, and WM) and compared carriers on placebo (placebo‐carriers, n = 82) with NC all on placebo (NC, n = 83). We calculated Cohen's D with [95% CI] and standard deviation of NC as effect‐sizes for 2 and 5‐year cortical changes. Additionally, we characterized cerebellar Aβ burden in carriers on crenezumab (treatment‐carriers, n = 81), placebo‐carriers, and NC, using our previously reported method targeting the whole cerebellum region‐of‐interest (ROI) with pons as RR to estimate cerebellar‐to‐pons‐SUVRs and compare using a mixed‐model repeated‐measures ANOVA adjusted for age but not multiple comparisons. Result: As expected, placebo‐carriers had significantly greater SUVR change compared with NC for all three RRs. However, the pons RR was best at detecting 2‐year changes (d = 1.75[1.39‐2.11]), and WM and pons were best at detecting 5‐year changes in cortical‐Aβ levels between placebo‐carriers and NC (pons d = 2.01[1.64‐2.39], WM d = 2.51[2.10‐2.92]). Additionally, treatment‐carriers had higher cerebellar‐to‐pons‐SUVRs compared with placebo‐carriers at baseline and 2‐years, but not 5‐years (p =.034, p =.027,& p =.06,respectively), both carrier groups had higher cerebellar‐to‐pons‐SUVRs compared to NC at each interval(p<.001). Cerebellar‐to‐pons‐SUVRs continued to increase within carrier groups at each interval(5‐year>2‐year>baseline,p<.05) and remained constant within the NC‐group(p>.05). Conclusion: Use of pons for 2‐year and WM or pons RRs for 5‐year changes may improve the power to track longitudinal increases and evaluate Aβ‐modifying treatments in 2 and 5‐year studies, in this ADAD population. A cerebellar RR may be confounded by early Aβ deposition in the cerebellum which can artificially reduce average cortical Aβ‐PET SUVRs even in preclinical stages of ADAD. [ABSTRACT FROM AUTHOR]

Background: We previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the inflated Type 1 error associated with voxel‐wise multiple comparisons (Stern et al, NEJM 2019). We now confirm this finding in a larger group of former NFL players, former college football players and asymptomatic controls without exposure to repetitive head impacts from the DIAGNOSE CTE Research Project. Method: Flortaucipir PET images were acquired in 106 former NFL players, 51 former college players, and 53 unexposed controls, 57.71+8.37 years of age. An automated algorithm (SPM12) and co‐registered MRIs were used to spatially normalize PET images into Montreal Neurological Institute template, and compute statistical brain maps of group differences in regional cerebral‐to‐cerebellar crus1 standard uptake value ratio (SUVR), controlling for the participants' age and race with P≤0.005, uncorrected for multiple comparisons. Our MCS was then applied with 1,000 iterations to test the hypothesis that there would be a greater number of cerebral voxels with SUVR elevations in each and combined player group versus control group, as well as between the NFL versus college player groups. Result: As predicted, the NFL, college player and aggregate player groups each had significantly more cerebral voxels with flortaucipir SUVR elevations than in the control group (postulated vs opposite directions: 53,879 vs 79, 79,552 vs 89 and 100,837 vs 86 voxels), respectively, MCS P<0.001, but not between former NFL and former college players (482 versus 306, p = 0.305). Conclusion: Using a voxel based MCS analysis, former NFL and college football players have a greater spatial extent of elevations in tau PET measurements than asymptomatic controls. Additional work is needed to clarify the biological nature of these small but spatially extensive elevations, the extent to which they are related to symptom severity, cognitive performance, repetitive head impact exposure, and other risk or resilience factors, and the extent to which they are associated with subsequent clinical decline. [ABSTRACT FROM AUTHOR]

Background: Chronic 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. Method: The 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. Result: Entorhinal 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). Conclusion: While 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. [ABSTRACT FROM AUTHOR]

Background: Blood‐based biomarkers are a promising tool for early detection of Alzheimer's disease (AD). We recently showed that individuals with autosomal‐dominant AD due to the E280A mutation in the presenilin1 gene (PSEN1) showed elevated levels of plasma tau phosphorylated at threonine 217 (P‐tau217) and neurofilament light chain (NfL), as early as approximately 20 years before clinical onset. We examined sex differences in the age‐related trajectory of these blood‐based biomarkers, and whether they predicted cognitive performance in PSEN1 mutation carriers. Method: Cross‐sectional plasma P‐tau217 and NfL concentrations were measured using highly sensitive immunoassays from 622 participants, including 259 cognitively‐unimpaired mutation carriers (mean age: 31, range 24‐39; %male: 45.6), 106 cognitively‐impaired mutation carriers (mean age: 49, range 46‐52; %male: 45.3), and 257 age‐matched noncarriers (mean age: 34, range 25.5‐42; %male: 39.3). Bivariate local polynomial regressions (LOESS) were used to characterize relationships between log‐transformed P‐tau217 and NfL with age. Linear mixed effect models were used to estimate the fixed slope and intercept of female and male among carriers and noncarriers. Linear regressions examined the association between blood biomarkers and CERAD word list delayed recall in mutation carriers. Result: There were no sex differences in the association between age and plasma P‐tau217 among mutation carriers (Slope test, p=.055). Female carriers showed a steeper slope for the association between age and plasma NfL, compared to male carriers (Slope test, p=.001). There was a significant interaction between sex and plasma NfL in predicting verbal memory delayed recall (b=.020, p=.000) in mutation carriers. No sex differences were observed in the association between age and any blood biomarkers among noncarriers (Slope tests: NfL, p=.963; P‐tau271, p=.867). Conclusion: Our findings indicate that there are no sex differences in plasma tau pathology in PSEN1 carriers and noncarriers. However, female carriers showed greater levels of plasma NfL along their age‐related trajectory, compared to male carriers, suggesting that female carriers may be more susceptible to AD‐related neurodegeneration. Further research examining sex/gender differences in blood‐based biomarkers and its relation to cognitive trajectories is needed to understand mechanisms of resilience and susceptibility in AD. [ABSTRACT FROM AUTHOR]

Background: In contrast to late onset Alzheimer's disease (LOAD), the late clinical stages of autosomal dominant Alzheimer's disease (ADAD) are associated with greater neuropathological evidence of cerebellar amyloid plaque (Aß) deposition. In this study, we used PET measurements of fibrillar Aß burden to characterize the presence and age at onset of cerebellar Aß deposition in cognitively unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. Method: Florbetapir and PiB PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and the Colombia‐Boston (COLBOS) longitudinal biomarker study were included. Template‐based cerebellar standard uptake value ratios (SUVR), using a known‐to‐be‐spared pontine reference region, were used to 1) compare 290 cognitively unimpaired 28‐56 year‐old mutation carriers and non‐carriers; 2) characterize associations among cerebellar‐to‐pontine SUVR and age, mean cortical SUVRs, and episodic memory performance; and 3) estimate the age at which cerebellar‐to‐pontine SUVRs begins to differ significantly in the carrier and non‐carrier groups. Result: Compared to non‐carriers, cognitively unimpaired carriers had higher cerebellar‐to‐pontine florbetapir and PiB SUVRs (p<.0001). Mean cortical SUVRs were positively correlated with age and negatively correlated with episodic memory performance (p<.05). SUVRs began to distinguish carriers from non‐carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Conclusion: This PET study provides evidence of cerebellar Aß plaque deposition in cognitively unimpaired mutation carriers starting years before their clinical onset. Additional studies are needed to clarify the impact of using a cerebellar versus pontine reference region on the power to detect and track ADAD progression, even in preclinical stages of this disorder. [ABSTRACT FROM AUTHOR]

Introduction: Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers., Methods: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing., Results: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory., Discussion: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience., (© 2021 the Alzheimer's Association.)

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo., Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity., Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores., Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)