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Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

© 2017 American Medical Association. All rights reserved. IMPORTANCE: There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts. OBJECTIVE: To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts. MAIN OUTCOMES AND MEASURES: Participants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]). RESULTS: The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ-N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ-N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ-N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ-N+ and Aβ+N+ cases. CONCLUSIONS AND RELEVANCE: In MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ-N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

INTRODUCTION: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users. METHODS: Brain glucose metabolism in rest was assessed using 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography ((18)FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. (18)FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test. RESULTS: As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex. CONCLUSIONS: Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.