Author Correction: FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease (Nature Communications, (2020), 11, 1, (411), 10.1038/s41467-019-13962-0)

In the original version of the manuscript, the image shown in Figure 4g, bottom row (Aβ1–42 + rAggregatin), under “6h” was incorrect. This image incorrectly showed the same sample as shown in the original Figure 4g, top row (Aβ1–42), under “0.5h”. The correct version of figure 4g is as follows: (Figure presented.) which replaces the previous incorrect version: (Figure presented.)

Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P 18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification

EVMS Self-Surveillance of Remote Handled Low Level Waste (RHLLW) Project

DOE G 413.3-10A, Section 3.a states: “The Contractor has primary responsibility for implementing and maintaining a surveillance program to ensure continued compliance of the system with ANSI/EIA-748B. DOE O 413.3B requires the FPD to ensure the contractor conducts a Self-Surveillance annually. This annual Self-Surveillance,…should cover all 32 guidelines of the ANSI/EIA748B. Documentation of the Self-Surveillance is sent to the CO and the PMSO (copy to OECM) confirming the continued compliance of their EVMS ANSI/EIA748B...” This review, and the associated report, is deemed to satisfy this requirement

FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD

FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD

Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease

Objective: To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD). / Methods: Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis. / Results: The TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed. / Conclusions: The blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD. / Classification of evidence: The study is rated Class III because of the case control design and the risk of spectrum bias