Altered Neuronal Activity Patterns of the Prefrontal Cortex in Alzheimer's Disease After Transcranial Alternating Current Stimulation: A Resting-State fMRI Study.

Background: Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer's disease (AD). However, the effects of tACS on brain activity remain unclear. Objective: The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate the regional brain activity. Results: Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. Conclusions: The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients.

TRanscranial AlterNating current stimulation FOR patients with mild Alzheimer's Disease (TRANSFORM-AD): a randomized controlled clinical trial.

BACKGROUND: The mechanistic effects of gamma transcranial alternating current stimulation (tACS) on hippocampal gamma oscillation activity in Alzheimer's Disease (AD) remains unclear. This study aimed to clarify beneficial effects of gamma tACS on cognitive functioning in AD and to elucidate effects on hippocampal gamma oscillation activity. METHODS: This is a double-blind, randomized controlled single-center trial. Participants with mild AD were randomized to tACS group or sham group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 days. Cognitive functioning, structural magnetic resonance imaging (MRI), and simultaneous electroencephalography-functional MRI (EEG-fMRI) were evaluated at baseline, the end of the intervention and at 3-month follow-up from the randomization. RESULTS: A total of 46 patients were enrolled (23 in the tACS group, 23 in the sham group). There were no group differences in the change of the primary outcome, 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) score after intervention (group*time, p = 0.449). For secondary outcomes, compared to the control group, the intervention group showed significant improvement in MMSE (group*time, p = 0.041) and MoCA scores (non-parametric test, p = 0.025), which were not sustained at 3-month follow-up. We found an enhancement of theta-gamma coupling in the hippocampus, which was positively correlated with improvements of MMSE score and delayed recall. Additionally, fMRI revealed increase of the local neural activity in the hippocampus. CONCLUSION: Effects on the enhancement of theta-gamma coupling and neural activity within the hippocampus suggest mechanistic models for potential therapeutic mechanisms of tACS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03920826; Registration Date: 2019-04-19.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

Comparison of 18F-FDG PET and arterial spin labeling MRI in evaluating Alzheimer's disease and amnestic mild cognitive impairment using integrated PET/MR.

BACKGROUND: Developing biomarkers for early stage AD patients is crucial. Glucose metabolism measured by 18F-FDG PET is the most common biomarker for evaluating cellular energy metabolism to diagnose AD. Arterial spin labeling (ASL) MRI can potentially provide comparable diagnostic information to 18F-FDG PET in patients with neurodegenerative disorders. However, the conclusions about the diagnostic performance of AD are still controversial between 18F-FDG PET and ASL. This study aims to compare quantitative cerebral blood flow (CBF) and glucose metabolism measured by 18F-FDG PET diagnostic values in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) using integrated PET/MR. RESULTS: Analyses revealed overlapping between decreased regional rCBF and 18F-FDG PET SUVR in patients with AD compared with NC participants in the bilateral parietotemporal regions, frontal cortex, and cingulate cortex. Compared with NC participants, patients with aMCI exclusively demonstrated lower 18F-FDG PET SUVR in the bilateral temporal cortex, insula cortex, and inferior frontal cortex. Comparison of the rCBF in patients with aMCI and NC participants revealed no significant difference (P > 0.05). The ROC analysis of rCBF in the meta-ROI could diagnose patients with AD (AUC, 0.87) but not aMCI (AUC, 0.61). The specificity of diagnosing aMCI has been improved to 75.56% when combining rCBF and 18F-FDG PET SUVR. CONCLUSION: ASL could detect similar aberrant patterns of abnormalities compared to 18F-FDG PET in patients with AD compared with NC participants but not in aMCI. The diagnostic efficiency of 18F-FDG-PET for AD and aMCI patients remained higher to ASL. Our findings support that applying 18F-FDG PET may be preferable for diagnosing AD and aMCI.

Multiparametric hippocampal signatures for early diagnosis of Alzheimer's disease using 18F-FDG PET/MRI Radiomics.

PURPOSE: This study aimed to explore the utility of hippocampal radiomics using multiparametric simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) for early diagnosis of Alzheimer's disease (AD). METHODS: A total of 53 healthy control (HC) participants, 55 patients with amnestic mild cognitive impairment (aMCI), and 51 patients with AD were included in this study. All participants accepted simultaneous PET/MRI scans, including 18F-fluorodeoxyglucose (18F-FDG) PET, 3D arterial spin labeling (ASL), and high-resolution T1-weighted imaging (3D T1WI). Radiomics features were extracted from the hippocampus region on those three modal images. Logistic regression models were trained to classify AD and HC, AD and aMCI, aMCI and HC respectively. The diagnostic performance and radiomics score (Rad-Score) of logistic regression models were evaluated from 5-fold cross-validation. RESULTS: The hippocampal radiomics features demonstrated favorable diagnostic performance, with the multimodal classifier outperforming the single-modal classifier in the binary classification of HC, aMCI, and AD. Using the multimodal classifier, we achieved an area under the receiver operating characteristic curve (AUC) of 0.98 and accuracy of 96.7% for classifying AD from HC, and an AUC of 0.86 and accuracy of 80.6% for classifying aMCI from HC. The value of Rad-Score differed significantly between the AD and HC (p < 0.001), aMCI and HC (p < 0.001) groups. Decision curve analysis showed superior clinical benefits of multimodal classifiers compared to neuropsychological tests. CONCLUSION: Multiparametric hippocampal radiomics using PET/MRI aids in the identification of early AD, and may provide a potential biomarker for clinical applications.

Cerebral hypometabolism mediates the effect of stroke volume on cognitive impairment in heart failure patients.

AIMS: The present study aimed to phenotype the cerebral structural and glucose metabolic alterations in patients with heart failure (HF) using simultaneous positron emission tomography (PET)/magnetic resonance (MR) and to investigate their relationship to cardiac biomarkers and cognitive performance. METHODS AND RESULTS: Forty-two HF patients caused by ischaemic heart disease (mean age 67.2 ± 10.4, 32 males) and 32 age- and sex-matched healthy volunteers (mean age 61.3 ± 4.8, 18 males) were included in this study. Participants underwent simultaneous cerebral fluorine-18 (18 F) fluorodeoxyglucose PET/MR followed by cardiac MR scan, and neuropsychological scores were obtained to assess cognitive performance. The grey matter volume (GMV) and standardized uptake value ratio (SUVR) were calculated to examine cerebral structural and metabolic alterations. Cardiac biomarkers included cardiac MR parameters and cardiac serum laboratory tests. Mediation analysis was performed to explore the associations among cerebral alterations, cardiac biomarkers, and cognitive performance. HF patients demonstrated notable cognitive impairment compared with normal controls (P < 0.001). Furthermore, HF patients exhibited regional brain hypometabolism in the bilateral calcarine cortex, caudate nucleus, thalamus, hippocampus, precuneus, posterior cingulate cortex, lingual and olfactory cortex, and GMV reduction in bilateral thalamus and hippocampus (cluster level at P < 0.05, Gaussian random field correction). The SUVR of the hypometabolic brain regions was correlated with the Montreal Cognitive Assessment (MoCA) scores (r = 0.55, P = 0.038) and cardiac stroke volume (r = 0.49, P = 0.002). Cerebral hypometabolism played a key role in the relationship between the decreased stroke volume and MoCA scores, with a mediation effect of 33.2%. CONCLUSIONS: HF patients suffered cerebral metabolic and structural alterations in regions associated with cognition. The observed correlation between cardiac stroke volume and cognitive impairment underscored the potential influence of cerebral hypometabolism, suggesting that cerebral hypometabolism due to chronic systemic hypoperfusion may significantly contribute to cognitive impairment in HF patients.

Impact of brain segmentation methods on regional metabolism quantification in 18F-FDG PET/MR analysis.

BACKGROUND: Accurate analysis of quantitative PET data plays a crucial role in studying small, specific brain structures. The integration of PET and MRI through an integrated PET/MR system presents an opportunity to leverage the benefits of precisely aligned structural MRI and molecular PET images in both spatial and temporal dimensions. However, in many clinical workflows, PET studies are often performed without the aid of individually matched structural MRI scans, primarily for the sake of convenience in the data collection and brain segmentation possesses. Currently, two commonly employed segmentation strategies for brain PET analysis are distinguished: methods with or without MRI registration and methods employing either atlas-based or individual-based algorithms. Moreover, the development of artificial intelligence (AI)-assisted methods for predicting brain segmentation holds promise but requires further validation of their efficiency and accuracy for clinical applications. This study aims to compare and evaluate the correlations, consistencies, and differences among the above-mentioned brain segmentation strategies in quantification of brain metabolism in 18F-FDG PET/MR analysis. RESULTS: Strong correlations were observed among all methods (r = 0.932 to 0.999, P < 0.001). The variances attributable to subject and brain region were higher than those caused by segmentation methods (P < 0.001). However, intraclass correlation coefficient (ICC)s between methods with or without MRI registration ranged from 0.924 to 0.975, while ICCs between methods with atlas- or individual-based algorithms ranged from 0.741 to 0.879. Brain regions exhibiting significant standardized uptake values (SUV) differences due to segmentation methods were the basal ganglia nuclei (maximum to 11.50 ± 4.67%), and various cerebral cortexes in temporal and occipital regions (maximum to 18.03 ± 5.52%). The AI-based method demonstrated high correlation (r = 0.998 and 0.999, P < 0.001) and ICC (0.998 and 0.997) with FreeSurfer, substantially reducing the time from 8.13 h to 57 s on per subject. CONCLUSIONS: Different segmentation methods may have impact on the calculation of brain metabolism in basal ganglia nuclei and specific cerebral cortexes. The AI-based approach offers improved efficiency and is recommended for its enhanced performance.

Automatic prediction of hepatic arterial infusion chemotherapy response in advanced hepatocellular carcinoma with deep learning radiomic nomogram.

OBJECTIVES: Hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen (oxaliplatin plus fluorouracil and leucovorin) is a promising option for advanced hepatocellular carcinoma (Ad-HCC). As identifying patients with Ad-HCC who would obtain objective response (OR) to HAIC preoperatively remains a challenge, we aimed to develop an automatic and non-invasive model for predicting HAIC response. METHODS: A total of 458 patients with Ad-HCC who underwent HAIC were retrospectively included from three hospitals (310 for training, 77 for internal validation, and 71 for external validation). The deep learning and radiomic features were extracted from the automatically segmented liver region on contrast-enhanced computed tomography images. Then, a deep learning radiomic nomogram (DLRN) was constructed by integrating deep learning scores, radiomic scores, and significant clinical variables with multivariate logistic regression. Model performance was assessed by AUC and Kaplan-Meier estimator. RESULTS: After automatic segmentation, only a few modifications were needed (less than 30 min for 458 patients). The DLRN achieved an AUC of 0.988 in the training cohort, 0.915 in the internal validation cohort, and 0.896 in the external validation cohort, respectively, outperforming other models in HAIC response prediction. Moreover, survival risk stratification was also successfully performed by the DLRN. The overall survival (OS) of the predictive OR group was significantly longer than that of the predictive non-OR group (median OS: 26.0 vs. 12.3 months, p < 0.001). CONCLUSIONS: The DLRN provided a satisfactory performance for predicting HAIC response, which is essential to identify Ad-HCC patients for HAIC and may potentially benefit personalized pre-treatment decision-making. CLINICAL RELEVANCE STATEMENT: This study presents an accurate and automatic method for predicting response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma, and therefore help in defining the best candidates for this treatment. KEY POINTS: • Deep learning radiomic nomogram (DLRN) based on automatic segmentation of CECT can accurately predict hepatic arterial infusion chemotherapy (HAIC) response of advanced HCC patients. • The proposed prediction model can perform survival risk stratification and is an easy-to-use tool for personalized pre-treatment decision-making for advanced HCC patients.

The effects of noninvasive brain stimulation on cognitive function in patients with mild cognitive impairment and Alzheimer's disease using resting-state functional magnetic resonance imaging: A systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the efficacy of noninvasive brain stimulation (NIBS) on cognition using functional magnetic resonance imaging (fMRI) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), thus providing the neuroimaging mechanism of cognitive intervention. METHODS: English articles published up to April 30, 2023 were searched in the PubMed, Web of Science, Embase, and Cochrane Library databases. We included randomized controlled trials where resting-state fMRI was used to observe the effect of NIBS in patients with MCI or AD. RevMan software was used to analyze the continuous variables, and SDM-PSI software was used to perform an fMRI data analysis. RESULTS: A total of 17 studies comprising 258 patients in the treatment group and 256 in the control group were included. After NIBS, MCI patients in the treatment group showed hyperactivation in the right precuneus and decreased activity in the left cuneus and right supplementary motor area. In contrast, patients in the control group showed decreased activity in the right middle frontal gyrus and no hyperactivation. The clinical cognitive scores in MCI patients were significantly improved by NIBS, while not in AD. Some evidence regarding the modulation of NIBS in resting-state brain activity and functional brain networks in patients with AD was found. CONCLUSIONS: NIBS could improve cognitive function in patients with MCI and AD. fMRI evaluations could be added to evaluate the contribution of specific NIBS treatment therapeutic effectiveness.

Involvement of specific striatal subregion contributes to executive deficits in Alzheimer disease.

BACKGROUND: There is growing evidence that the striatum plays a central role in cognitive dysfunction. However, it remains unclear whether and how the striatum contributes specifically to executive deficits in Alzheimer disease (AD). We sought to elucidate aberrations in the striatal subregion associated with executive function and its metabolic connectivity with the cortical regions to investigate its role in the pathogenesis of executive deficits in patients with AD. METHODS: Patients with AD and healthy controls underwent a neuropsychological assessment battery, including assessment of executive function, and a hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) scan. We performed voxel-wise analyses of cerebral metabolism between patients and controls, focusing on the executive subregion of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. We assessed the correlation between the [18F]-fluorodeoxyglucose standardized uptake value ratio of the striatal executive subregion and clinical variables, and we analyzed seed-based metabolic connectivity of the striatal executive subregion with the dorsolateral prefrontal cortex (DLPFC) using [18F]-fluorodeoxyglucose PET. RESULTS: We included 50 patients with AD and 33 controls in our analyses. The patterns of striatal hypometabolism in patients with AD were specific to executive and caudal motor subregions. Metabolic activity in the executive subregion of the striatum correlated negatively with the severity of executive dysfunction, as measured with the Trial-Making Test (TMT) part B and the difference score TMT B-A, and correlated positively with Digit Span (backward) and Verbal Fluency Test scales, particularly on the left side. Compared with controls, patients with AD showed reduced metabolic connectivity between striatal executive subregions and the dorsolateral prefrontal cortex (DLPFC). LIMITATIONS: Our study was limited by small sample sizes and cross-sectional findings. CONCLUSION: Our findings show that patients with AD have impairments in the executive subregion of the striatum, and these deficits may be associated with a disconnection between the executive striatum and DLPFC, providing valuable insight into the pathogenesis of this disease.

Effect of APOE ε4 genotype on amyloid-ß, glucose metabolism, and gray matter volume in cognitively normal individuals and amnestic mild cognitive impairment.

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-ß (Aß) 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, 18 F-florbetapir positron emission tomography (PET), and 18 F-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 Aß 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 18 F-FDG PET standardized uptake value ratio and GM volume. Region of interest-based analysis showed statistically significant greater Aß 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 Aß deposition than APOE ε4 noncarriers in both diagnostic groups. CONCLUSIONS: Our findings suggest a differential effect of APOE ε4 on Aß 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.

Reliability and Validity of Power Spectrum Slope (PSS): A Metric for Measuring Resting-State Functional Magnetic Resonance Imaging Activity of Single Voxels.

Methods that capture the features of single voxels of resting-state fMRI (RS-fMRI) could precisely localize the abnormal spontaneous activity and hence guide precise brain stimulation. As one of these metrics, the amplitude of low-frequency fluctuation (ALFF) has been used in numerous studies, however, it is frequency-dependent and the division of frequency bands is still controversial. Based on the well-accepted power law of time series, this study proposed an approach, namely, power spectrum slope (PSS), to characterize the RS-fMRI time series of single voxels. Two metrics, i.e., linear coefficient b and power-law slope b' were used and compared with ALFF. The reliability and validity of the PSS approach were evaluated on public RS-fMRI datasets (n = 145 in total) of eyes closed (EC) and eyes open (EO) conditions after image preprocessing, with 21 subjects scanned two times for test-retest reliability analyses. Specifically, we used the paired t-test between EC and EO conditions to assess the validity and intra-class correlation (ICC) to assess the reliability. The results included the following: (1) PSS detected similar spatial patterns of validity (i.e., EC-EO differences) and less test-retest reliability with those of ALFF; (2) PSS linear coefficient b showed better validity and reliability than power-law slope b'; (3) While the PPS showed less validity in most regions, PSS linear coefficient b showed exclusive EC-EO difference in the medial temporal lobe which did not show in ALFF. The power spectrum plot in the parahippocampus showed a "cross-over" of power magnitudes between EC and EO conditions in the higher frequency bands (>0.1 Hz). These results demonstrated that PSS (linear coefficient b) is complementary to ALFF for detecting the local spontaneous activity.

Modulation effect of substantia nigra iron deposition and functional connectivity on putamen glucose metabolism in Parkinson's disease.

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 [18 F]-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.

Tracer-specific reference tissues selection improves detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes in Alzheimer's disease.

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir, respectively. Positron emission tomography (PET) and T1-weighted images of participants were collected from the Alzheimer's disease Neuroimaging Initiative database, followed by partial volume correction. The standardized uptake value ratios (SUVRs) calculated from the cerebellum gray matter, centrum semiovale, and pons were evaluated at both region of interest (ROI) and voxelwise levels. The statistical power of reference tissues in detecting longitudinal SUVR changes was assessed via paired t-test. In cross-sectional analysis, the impact of reference tissue-based SUVR differences between cognitively normal and cognitively impaired groups was evaluated by effect sizes Cohen's d and two sample t-test adjusted by age, sex, and education levels. The average ROI t values of pons were 86.62 and 38.40% higher than that of centrum semiovale and cerebellum gray matter in detecting glucose metabolism decreases, while the centrum semiovale reference tissue-based SUVR provided higher t values for the detection of amyloid and tau deposition increases. The three reference tissues generated comparable d images for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir and comparable t maps for 18 F-florbetapir and 18 F-flortaucipir, but pons-based t map showed superior performance in 18 F-FDG. In conclusion, the tracer-specific reference tissue improved the detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes, which helps the early diagnosis, monitoring of disease progression, and therapeutic response in Alzheimer's disease.

Multimodal Classification of Alzheimer's Disease and Amnestic Mild Cognitive Impairment: Integrated 18F-FDG PET and DTI Study.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory impairment. Amnestic mild cognitive impairment (aMCI) is the intermediate stage between normal cognitive aging and early dementia caused by AD. It can be challenging to differentiate aMCI patients from healthy controls (HC) and mild AD patients. OBJECTIVE: To validate whether the combination of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and diffusion tensor imaging (DTI) will improve classification performance compared with that based on a single modality. METHODS: A total of thirty patients with AD, sixty patients with aMCI, and fifty healthy controls were included. AD was diagnosed according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable. aMCI diagnosis was based on Petersen's criteria. The 18F-FDG PET and DTI measures were each used separately or in combination to evaluate sensitivity, specificity, and accuracy for differentiating HC, aMCI, and AD using receiver operating characteristic analysis together with binary logistic regression. The rate of accuracy was based on the area under the curve (AUC). RESULTS: For classifying AD from HC, we achieve an AUC of 0.96 when combining two modalities of biomarkers and 0.93 when using 18F-FDG PET individually. For classifying aMCI from HC, we achieve an AUC of 0.79 and 0.76 using the best individual modality of biomarkers. CONCLUSION: Our results show that the combination of two modalities improves classification performance, compared with that using any individual modality.

Association between long-term donepezil treatment and brain regional amyloid and tau burden among individuals with mild cognitive impairment assessed using 18 F-AV-45 and 18 F-AV-1451 PET.

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 18 F-AV-45 amyloid and 18 F-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 18 F-AV-45 or 18 F-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 18 F-AV-45 and 18 F-AV-1451 PET to elucidate the consequences of drug administration in AD studies.

Cervicocephalic Spotty Calcium for the Prediction of Coronary Atherosclerosis in Patients With Acute Ischemic Stroke.

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 < 0.05; CACS: 477.04 ± 798.01 vs. 136.31 ± 205.65, P < 0.05). There were significant differences in the presence of CAS ≥ 50% (61.4 vs. 27.6%, P < 0.001). SC and coronary atherosclerosis were significantly correlated for both the CACS and CAS ≥ 50% (r = 0.746 and 0.715, respectively; P < 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.

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals.

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, demographic information, global cortical amyloid-ß 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. Magnetic resonance 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 × 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 × 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 × sex interaction effect on tau deposition after adjusting for global cortical amyloid-ß (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 12 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 voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate 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 APOE ε4-associated Alzheimer's risk in males and females.

Association of sex and APOE ε4 with brain tau deposition and atrophy in older adults with Alzheimer's disease.

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 18F-AV-1451 positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: Preprocessed 18F-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. 18F-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 18F-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 18F-AV-1451 SUVRs and lower gray matter volume between FACs compared to the NFACs. Negative correlations between ROI 18F-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 18F-AV-1451 PET and structural MRI.

Multiparametric imaging hippocampal neurodegeneration and functional connectivity with simultaneous PET/MRI in Alzheimer's disease.

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 18F-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 18F-FDG standardized uptake value ratio (SUVR) relative to cerebellum. An iterative reblurred Van Cittert iteration method was used for voxelwise partial volume correction on 18F-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 18F-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 18F-FDG PET. Our results may provide a basis for precision neuroimaging of hippocampus in AD.