Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI images, demographic information, global cortical amyloid-β burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. MRI images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage by sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage by sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage by sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all twelve regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxelwise analysis were similar to the ones obtained from regions of interest analysis. Our findings suggest that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer’s disease and uncovers a potential explanation underlying differential apolipoprotein E ε4-associated Alzheimer’s risk in males and females.

Purpose The objective of this study is to investigate the hippocampal neurodegeneration and its associated aberrant functions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients using simultaneous PET/MRI. Methods Forty-two cognitively normal controls (NC), 38 MCI, and 22 AD patients were enrolled in this study. All subjects underwent 18 F-FDG PET/functional MRI (fMRI) and high-resolution T1-weighted MRI scans on a hybrid GE Signa PET/ MRI scanner. Neurodegeneration in hippocampus and its subregions was quantified by regional gray matter volume and 18 F-FDG standardized uptake value ratio (SUVR) relative to cerebellum. An iterative reblurred Van Cittert iteration method was used for voxelwise partial volume correction on 18 F-FDG PET images. Regional gray matter volume was estimated from voxel-based morphometric analysis with MRI. fMRI data were analyzed after slice time correction and head motion correction using statistical parametric mapping (SPM12) with DPARSF toolbox. The regions of interest including hippocampus, cornu ammonis (CA1), CA2/3/dentate gyrus (DG), and subiculum were defined in the standard MNI space. Results Patient groups had reduced SUVR, gray matter volume, and functional connectivity compared to NC in CA1, CA2/3/ DG, and subiculum (AD < MCI < NC). There was a linear correlation between the left CA2/3DG gray matter volume and 18 F-FDG SUVR in AD patients (P < 0.001, r = 0.737). Significant correlation was also found between left CA2/3/DG-superior medial frontal gyrus functional connectivity and left CA2/3/DG hypometabolism in patients with AD. The functional connectivity of right CA1-precuneus in patients with MCI and right subiculum-superior frontal gyrus in patients with AD was positively correlated with mini mental status examination scores (P < 0.05). Conclusion Our findings demonstrate that the associations existed at subregional hippocampal level between the functional connectivity measured by fMRI and neurodegeneration measured by structural MRI and 18 F-FDG PET. Our results may provide a basis for precision neuroimaging of hippocampus in AD.

Background: Vascular factors contributing to cerebral hypoperfusion are implicated in the risk of developing Alzheimer's disease (AD). Purpose: To investigate the time-shift mapping created time-shift value of the brain by resting-state functional magnetic resonance imaging (rs-fMRI), and to determine the differences in time-shift value among AD, mild cognitive impairment (MCI), and normal control (NC) groups to better understand the disease. Study Type: Prospective. Subjects: Twenty-four AD, 24 MCI, and 24 age-matched NC participants. Field Strength/Sequence: T 2 *-weighted single-shot echo-planar imaging sequence was performed at 3T. In addition, a T 1 -weighted fast spoiled gradient-echo sequence was acquired for coregistration. Assessment: The brain time-shift value was determined from rs-fMRI-based blood oxygenation level-dependent (BOLD) signal in the three groups by time-shift mapping. The perfusion patterns were also investigated in the NC group. Statistical Tests: One-way analysis of variance and chi-squared tests were used to compare demographic information. The normalized time-shift maps were analyzed in a second-level test using SPM8. All analyses were evaluated with a significance level of P < 0.05 after false discovery rate (FDR) correction. Results: The time-shift maps obtained from rs-fMRI are consistent with the cerebral blood supply atlas. Compared with NC, both MCI and AD groups had less early perfusion arrival areas among the whole brain. In the delayed time-shift value for the AD group, the areas were located in the bilateral precuneus, the sensory-motor cortex in the left hemisphere, and the bilateral calcarine sulcus, which were different from the MCI group (both P < 0.05, FDR corrected). Data Conclusion: The time-shift mapping method could detect perfusion deficits in AD and MCI noninvasively. The perfusion deficits detected by rs-fMRI may provide new insight for understanding the mechanism of neurodegeneration. Level of Evidence: 2 Technical Efficacy: Stage 3

The objective of this study was to assess the association of sex and the apolipoprotein E (APOE) ε4 allele with brain tau deposition and atrophy in older adults with Alzheimer's disease (AD) using quantitative 18 F-AV-1451 positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: Preprocessed 18 F-AV-1451 tau PET, raw T1-weighted structural MR images, demographic information, cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 57 elderly individuals with AD were downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. An iteratively reblurred Van Cittert partial volume correction (PVC) method was applied to all preprocessed PET images. MRI images were used for PET spatial normalization and gray matter volume calculation. 18 F-AV-1451 PET standardized uptake value ratio (SUVR) was calculated relative to the cerebellum gray matter. The effect of sex and APOE ε4 status on SUVR and gray matter volume were assessed at both region of interest (ROI) and voxelwise levels. Results: Female APOE ε4 carriers (FACs) had significant higher 18 F-AV-1451 SUVRs in the lateral temporal, parietal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions, and exhibited smaller gray matter volumes in the posterior cingulate, medial temporal, inferior temporal and amygdala regions, as compared to the non-FACs (NFACs) comprised of female APOE ε4 non-carriers, male APOE ε4 carriers and male APOE ε4 non-carriers. Voxelwise analysis revealed forebrain and limbic clusters with greater 18 F-AV-1451 SUVRs and lower gray matter volume between FACs compared to the NFACs. Negative correlations between ROI 18 F-AV-1451 SUVRs and gray matter volumes were significant after adjusting for age and years of education. Conclusions: Among elderly individuals with AD, sex modified the effects of the APOE ε4 allele on region-specific tau deposition and gray matter volume. FACs had elevated brain region-specific tau PET SUVR and decreased gray matter volume in comparison to NFACs. The study provides a basis for the use of precision medicine in the diagnosis of AD and evaluation of therapeutics using 18 F-AV-1451 PET and structural MRI.

Purpose: To investigate the characteristics of cervicocephalic spotty calcium (SC) and coronary atherosclerosis in patients with acute ischemic stroke (AIS) and to assess the predictive value of SC for coronary atherosclerosis using combined coronary and cervicocephalic CTA.Materials and Methods: Patients with AIS (n = 70) confirmed by brain MRI or CT and patients with asymptomatic carotid atherosclerosis (n = 58) confirmed by carotid ultrasonography were enrolled in our study. Subjects in both groups underwent combined coronary and cervicocephalic CTA. SC was used to evaluate cervicocephalic atherosclerosis. Coronary artery stenosis (CAS) ≥ 50% by segment and coronary artery calcium score (CACS) were used to evaluate coronary atherosclerosis. The SC frequency and the difference in coronary atherosclerosis between the two groups were compared, and the correlation between SC and coronary atherosclerosis was analyzed. Independent factors for CAS ≥ 50% were assessed via logistic regression analysis. Receiver operating characteristic curve analysis was performed to evaluate the added value of SC for predicting CAS ≥ 50%.Results: Both SC and the CACS were significantly higher in the Stroke group than in the Control group (total SC count: 6.83 ± 4.34 vs. 2.98 ± 2.87, P &lt; 0.05; CACS: 477.04 ± 798.01 vs. 136.31 ± 205.65, P &lt; 0.05). There were significant differences in the presence of CAS ≥ 50% (61.4 vs. 27.6%, P &lt; 0.001). SC and coronary atherosclerosis were significantly correlated for both the CACS and CAS ≥ 50% (r = 0.746 and 0.715, respectively; P &lt; 0.001). SC was an independent predictor for CAS ≥ 50%.Conclusion: SC correlates significantly with the CACS and could serve as an independent predictor of CAS ≥ 50% in patients with AIS, which suggests that combined cerebrovascular and cardiovascular assessments are of importance for such patients.

Neurodegeneration of the substantia nigra affects putamen activity in Parkinson's disease (PD), yet in vivo evidence of how the substantia nigra modulates putamen glucose metabolism in humans is missing. We aimed to investigate how substantia nigra modulates the putamen glucose metabolism using a cross‐sectional design. Resting‐state fMRI, susceptibility‐weighted imaging, and [18F]‐fluorodeoxyglucose‐PET (FDG‐PET) data were acquired. Forty‐two PD patients and 25 healthy controls (HCs) were recruited for simultaneous PET/MRI scanning. The main measurements of the current study were R2* images representing iron deposition (28 PD and 25 HCs), standardized uptake value ratio (SUVr) images representing FDG‐uptake (33 PD and 25 HCs), and resting state functional connectivity maps from resting state fMRI (34 PD and 25 HCs). An interaction term based on the general linear model was used to investigate the joint modulation effect of nigral iron deposition and nigral‐putamen functional connectivity on putamen FDG‐uptake. Compared with HCs, we found increased iron deposition in the substantia nigra (p = .007), increased FDG‐uptake in the putamen (left: PFWE < 0.001; right: PFWE < 0.001), and decreased functional connectivity between the substantia nigra and the anterior putamen (left PFWE < 0.001, right: PFWE = 0.007). We then identified significant interaction effect of nigral iron deposition and nigral‐putamen connectivity on FDG‐uptake in the putamen (p = .004). The current study demonstrated joint modulation effect of the substantia nigra iron deposition and nigral‐putamen functional connectivity on putamen glucose metabolic distribution, thereby revealing in vivo pathological mechanism of nigrostriatal neurodegeneration of PD.

This study aims to investigate the association between long‐term donepezil treatment and brain neuropathological burden and cognitive function in mild cognitive impairment (MCI) patients. Preprocessed 18F‐AV‐45 amyloid and 18F‐AV‐1451 tau positron emission tomography (PET) images, magnetic resonance imaging images (MRIs), demographic information, and donepezil use status were downloaded from 255 MCI participants enrolled in the Alzheimer's Disease Neuroimaging Initiative database. Partial volume correction was applied to all PET images. Structural MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to the cerebellum were computed. Multiple linear regression with the least absolute shrinkage selector operator was performed to analyze the effect of long‐term donepezil treatment on (a) the SUVR of each 18F‐AV‐45 or 18F‐AV‐1451 brain PET ROI after adjusting for age, sex, education, ApoE ε4 status, and AD‐associated disease risk factors; and (b) cognitive performance after adjusting for age, sex education, ApoE ε4 status, AD‐associated disease risk factors, and regional amyloid or tau burden. In adjusted models, long‐term donepezil treatment was associated with greater amyloid load in the orbital frontal, superior frontal, parietal, posterior precuneus, posterior cingulate, lateral temporal, inferior temporal and fusiform regions, and tau burden in the posterior cingulate, entorhinal and parahippocampal gyrus. Long‐term donepezil treatment was also associated with worse performance on the 13‐item Alzheimer's Disease Assessment Scale‐Cognitive subscale after adjusting for AD‐related risk factors and regional brain amyloid or tau load. These results indicate that long‐term donepezil treatment is associated with increased regional amyloid and tau burden and worse cognitive performance among individuals with MCI. Our study highlights the importance of using noninvasive and quantitative 18F‐AV‐45 and 18F‐AV‐1451 PET to elucidate the consequences of drug administration in AD studies.

Background and purpose The presence of apolipoprotein E ε4 (APOE ε4) is associated with an increased risk of developing Alzheimer disease (AD). The aim of this study was to assess the effects of APOE ε4 on amyloid‐β (Aβ) pathology, glucose metabolism, and gray matter (GM) volume and their longitudinal changes in healthy control (HC) and amnestic mild cognitive impairment (aMCI). Methods We included 50 HCs and 109 aMCI patients from the Alzheimer's Disease Neuroimaging Initiative phase 2/GO based on availability of baseline T1‐weighted magnetic resonance imaging, 18F‐florbetapir positron emission tomography (PET), and 18F‐fluorodeoxyglucose (FDG) PET. Of these, 35 HCs and 67 aMCI patients who underwent 24‐month scans were included for follow‐up study. Results Voxelwise analysis revealed that APOE ε4 carriers exhibited greater baseline Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. However, there was no significant difference between APOE ε4 noncarriers and APOE ε4 carriers in terms of 18F‐FDG PET standardized uptake value ratio and GM volume. Region of interest‐based analysis showed statistically significant greater Aβ deposition in APOE ε4 carriers than APOE ε4 noncarriers only in aMCI patients. Furthermore, APOE ε4 carriers generally exhibited a greater magnitude and spatial extent of longitudinal changes in Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. Conclusions Our findings suggest a differential effect of APOE ε4 on Aβ pathology, glucose metabolism, and GM volume. Studying APOE ε4‐related brain changes with neuroimaging biomarkers in preclinical AD offers an opportunity to further our understanding of the pathophysiology of AD at an early stage.