Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Deep learning-based dynamic ventilatory threshold estimation from electrocardiograms.

BACKGROUND AND OBJECTIVE: The ventilatory threshold (VT) marks the transition from aerobic to anaerobic metabolism and is used to assess cardiorespiratory endurance. A conventional way to assess VT is cardiopulmonary exercise testing, which requires a gas analyzer. Another method for measuring VT involves calculating the heart rate variability (HRV) from an electrocardiogram (ECG) by computing the variability of heartbeats. However, the HRV method has some limitations. ECGs should be recorded for at least 5 minutes to calculate the HRV, and the result may depend on the utilized ECG preprocessing algorithms. METHODS: To overcome these problems, we developed a deep learning-based model consisting of long short-term memory (LSTM) and convolutional neural network (CNN) for a lead II ECG. Variables reflecting subjects' physical characteristics, as well as ECG signals, were input into the model to estimate VT. We applied joint optimization to the CNN layers to generate an informative latent space, which was fed to the LSTM layers. The model was trained and evaluated on two datasets, one from the Bruce protocol and the other from a protocol including multiple tasks (MT). RESULTS: Acceptable performances (mean and 95% CI) were obtained on the datasets from the Bruce protocol (-0.28[-1.91,1.34] ml/min/kg) and the MT protocol (0.07[-3.14,3.28] ml/min/kg) regarding the differences between the predictions and labels. The coefficient of determination, Pearson correlation coefficient, and root mean square error were 0.84, 0.93, and 0.868 for the Bruce protocol and 0.73, 0.97, and 3.373 for the MT protocol, respectively. CONCLUSIONS: The results indicated that it is possible for the proposed model to simultaneously assess VT with the inputs of successive ECGs. In addition, from ablation studies concerning the physical variables and the joint optimization process, it was demonstrated that their use could boost the VT assessment performance of the model. The proposed model enables dynamic VT estimation with ECGs, which could help with managing cardiorespiratory fitness in daily life and cardiovascular rehabilitation in patients.

Real-world prediction of preclinical Alzheimer's disease with a deep generative model.

Amyloid positivity is an early indicator of Alzheimer's disease and is necessary to determine the disease. In this study, a deep generative model is utilized to predict the amyloid positivity of cognitively normal individuals using proxy measures, such as structural MRI scans, demographic variables, and cognitive scores, instead of invasive direct measurements. Through its remarkable efficacy in handling imperfect datasets caused by missing data or labels, and imbalanced classes, the model outperforms previous studies and widely used machine learning approaches with an AUROC of 0.8609. Furthermore, this study illuminates the model's adaptability to diverse clinical scenarios, even when feature sets or diagnostic criteria differ from the training data. We identify the brain regions and variables that contribute most to classification, including the lateral occipital lobes, posterior temporal lobe, and APOE ϵ4 allele. Taking advantage of deep generative models, our approach can not only provide inexpensive, non-invasive, and accurate diagnostics for preclinical Alzheimer's disease, but also meet real-world requirements for clinical translation of a deep learning model, including transferability and interpretability.

Sex differences in the structural rich-club connectivity in patients with Alzheimer's disease.

Background and objectives: Alzheimer's disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD. Methods: In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis. Results: We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia. Conclusion: Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.

Differentiation between multiple sclerosis and neuromyelitis optica spectrum disorder using a deep learning model.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory disorders of the central nervous system (CNS) with similar characteristics. The differential diagnosis between MS and NMOSD is critical for initiating early effective therapy. In this study, we developed a deep learning model to differentiate between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) using brain magnetic resonance imaging (MRI) data. The model was based on a modified ResNet18 convolution neural network trained with 5-channel images created by selecting five 2D slices of 3D FLAIR images. The accuracy of the model was 76.1%, with a sensitivity of 77.3% and a specificity of 74.8%. Positive and negative predictive values were 76.9% and 78.6%, respectively, with an area under the curve of 0.85. Application of Grad-CAM to the model revealed that white matter lesions were the major classifier. This compact model may aid in the differential diagnosis of MS and NMOSD in clinical practice.

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

Local striatal volume and motor reserve in drug-naïve Parkinson's disease.

Motor reserve (MR) may explain why individuals with similar pathological changes show marked differences in motor deficits in Parkinson's disease (PD). In this study, we investigated whether estimated individual MR was linked to local striatal volume (LSV) in PD. We analyzed data obtained from 333 patients with drug naïve PD who underwent dopamine transporter scans and high-resolution 3-tesla T1-weighted structural magnetic resonance images. Using a residual model, we estimated individual MRs on the basis of initial UPDRS-III score and striatal dopamine depletion. We performed a correlation analysis between MR estimates and LSV. Furthermore, we assessed the effect of LSV, which is correlated with MR estimates, on the longitudinal increase in the levodopa-equivalent dose (LED) during the 4-year follow-up period using a linear mixed model. After controlling for intracranial volume, there was a significant positive correlation between LSV and MR estimates in the bilateral caudate, anterior putamen, and ventro-posterior putamen. The linear mixed model showed that the large local volume of anterior and ventro-posterior putamen was associated with the low requirement of LED initially and accelerated LED increment thereafter. The present study demonstrated that LSV is crucial to MR in early-stage PD, suggesting LSV as a neural correlate of MR in PD.

Unified framework for brain connectivity-based biomarkers in neurodegenerative disorders.

Background: Brain connectivity is useful for deciphering complex brain dynamics controlling interregional communication. Identifying specific brain phenomena based on brain connectivity and quantifying their levels can help explain or diagnose neurodegenerative disorders. Objective: This study aimed to establish a unified framework to identify brain connectivity-based biomarkers associated with disease progression and summarize them into a single numerical value, with consideration for connectivity-specific structural attributes. Methods: This study established a framework that unifies the processes of identifying a brain connectivity-based biomarker and mapping its abnormality level into a single numerical value, called a biomarker abnormality summarized from the identified connectivity (BASIC) score. A connectivity-based biomarker was extracted in the form of a connected component associated with disease progression. BASIC scores were constructed to maximize Kendall's rank correlation with the disease, considering the spatial autocorrelation between adjacent edges. Using functional connectivity networks, we validated the BASIC scores in various scenarios. Results: Our proposed framework was successfully applied to construct connectivity-based biomarker scores associated with disease progression, characterized by two, three, and five stages of Alzheimer's disease, and reflected the continuity of brain alterations as the diseases advanced. The BASIC scores were not only sensitive to disease progression, but also specific to the trajectory of a particular disease. Moreover, this framework can be utilized when disease stages are measured on continuous scales, resulting in a notable prediction performance when applied to the prediction of the disease. Conclusion: Our unified framework provides a method to identify brain connectivity-based biomarkers and continuity-reflecting BASIC scores that are sensitive and specific to disease progression.

White matter tract-specific microstructural disruption is associated with depressive symptoms in isolated RBD.

OBJECTIVE: White matter (WM) tract-specific changes may precede gray matter loss in isolated rapid eye movement sleep behavior disorder (iRBD). We aimed to evaluate tract-specific WM changes using tract-specific statistical analysis (TSSA) and their correlation with clinical variables in iRBD patients. METHODS: This was a cross-sectional single-center study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used TSSA to identify tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in fourteen major fiber tracts and analyzed between-group differences in these values. Correlations between FA or MD values and clinical variables, including RBD symptom severity, depression and cognition, were evaluated. RESULTS: Patients with iRBD showed lower FA in the right anterior thalamic radiation (ATR) and higher MD in the bilateral ATR and right inferior fronto-occipital fasciculus (IF-OF) than controls after adjusting for age, sex, and years of education. MD values in the IF-OF positively correlated with scores on the Korean version of the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong (RBDQ-KR, p = 0.042) and the Korean version of the geriatric depression scale (GDS-K, p = 0.002) in iRBD patients. Only GDS-K scores independently correlated with IF-OF MD values after adjusting for RBDQ-KR scores (adjusted p = 0.026). CONCLUSION: This study suggests WM microstructural disruption in the bilateral ATR and right IF-OF in patients with iRBD and that alterations in the IF-OF may contribute to depressive symptoms.

Dynamic network model reveals distinct tau spreading patterns in early- and late-onset Alzheimer disease.

BACKGROUND: The clinical features of Alzheimer's disease (AD) vary substantially depending on whether the onset of cognitive deficits is early or late. The amount and distribution patterns of tau pathology are thought to play a key role in the clinical characteristics of AD, which spreads throughout the large-scale brain network. Here, we describe the differences between tau-spreading processes in early- and late-onset symptomatic individuals on the AD spectrum. METHODS: We divided 74 cognitively unimpaired (CU) and 68 cognitively impaired (CI) patients receiving 18F-flortaucipir positron emission tomography scans into two groups by age and age at onset. Members of each group were arranged in a pseudo-longitudinal order based on baseline tau pathology severity, and potential interregional tau-spreading pathways were defined following the order using longitudinal tau uptake. We detected a multilayer community structure through consecutive tau-spreading networks to identify spatio-temporal changes in the propagation hubs. RESULTS: In each group, ordered tau-spreading networks revealed the stage-dependent dynamics of tau propagation, supporting distinct tau accumulation patterns. In the young CU/early-onset CI group, tau appears to spread through a combination of three independent communities with partially overlapped territories, whose specific driving regions were the basal temporal regions, left medial and lateral temporal regions, and left parietal regions. For the old CU/late-onset CI group, however, continuation of major communities occurs in line with the appearance of hub regions in the order of bilateral entorhinal cortices, parahippocampal and fusiform gyri, and lateral temporal regions. CONCLUSION: Longitudinal tau propagation depicts distinct spreading pathways of the early- and late-onset AD spectrum characterized by the specific location and appearance period of several hub regions that dominantly provide tau.

On the reliability of deep learning-based classification for Alzheimer's disease: Multi-cohorts, multi-vendors, multi-protocols, and head-to-head validation.

Structural changes in the brain due to Alzheimer's disease dementia (ADD) can be observed through brain T1-weighted magnetic resonance imaging (MRI) images. Many ADD diagnostic studies using brain MRI images have been conducted with machine-learning and deep-learning models. Although reliability is a key in clinical application and applicability of low-resolution MRI (LRMRI) is a key to broad clinical application, both are not sufficiently studied in the deep-learning area. In this study, we developed a 2-dimensional convolutional neural network-based classification model by adopting several methods, such as using instance normalization layer, Mixup, and sharpness aware minimization. To train the model, MRI images from 2,765 cognitively normal individuals and 1,192 patients with ADD from the Samsung medical center cohort were exploited. To assess the reliability of our classification model, we designed external validation in multiple scenarios: (1) multi-cohort validation using four additional cohort datasets including more than 30 different centers in multiple countries, (2) multi-vendor validation using three different MRI vendor subgroups, (3) LRMRI image validation, and finally, (4) head-to-head validation using ten pairs of MRI images from ten individual subjects scanned in two different centers. For multi-cohort validation, we used the MRI images from 739 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, 125 subjects from the Dementia Platform of Korea cohort, 234 subjects from the Premier cohort, and 139 subjects from the Gachon University Gil Medical Center. We further assessed classification performance across different vendors and protocols for each dataset. We achieved a mean AUC and classification accuracy of 0.9868 and 0.9482 in 5-fold cross-validation. In external validation, we obtained a comparable AUC of 0.9396 and classification accuracy of 0.8757 to other cross-validation studies in the ADNI cohorts. Furthermore, we observed the possibility of broad clinical application through LRMRI image validation by achieving a mean AUC and classification accuracy of 0.9404 and 0.8765 at cross-validation and AUC and classification accuracy of 0.8749 and 0.8281 at the ADNI cohort external validation.

Machine learning-based automatic estimation of cortical atrophy using brain computed tomography images.

Cortical atrophy is measured clinically according to established visual rating scales based on magnetic resonance imaging (MRI). Although brain MRI is the primary imaging marker for neurodegeneration, computed tomography (CT) is also widely used for the early detection and diagnosis of dementia. However, they are seldom investigated. Therefore, we developed a machine learning algorithm for the automatic estimation of cortical atrophy on brain CT. Brain CT images (259 Alzheimer's dementia and 55 cognitively normal subjects) were visually rated by three neurologists and used for training. We constructed an algorithm by combining the convolutional neural network and regularized logistic regression (RLR). Model performance was then compared with that of neurologists, and feature importance was measured. RLR provided fast and reliable automatic estimations of frontal atrophy (75.2% accuracy, 93.6% sensitivity, 67.2% specificity, and 0.87 area under the curve [AUC]), posterior atrophy (79.6% accuracy, 87.2% sensitivity, 75.9% specificity, and 0.88 AUC), right medial temporal atrophy (81.2% accuracy, 84.7% sensitivity, 79.6% specificity, and 0.88 AUC), and left medial temporal atrophy (77.7% accuracy, 91.1% sensitivity, 72.3% specificity, and 0.90 AUC). We concluded that RLR-based automatic estimation of brain CT provided a comprehensive rating of atrophy that can potentially support physicians in real clinical settings.

Contracted thalamic shape is associated with early development of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson's disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Harmonization of Multicenter Cortical Thickness Data by Linear Mixed Effect Model.

Objective: Analyzing neuroimages being useful method in the field of neuroscience and neurology and solving the incompatibilities across protocols and vendors have become a major problem. We referred to this incompatibility as "center effects," and in this study, we attempted to correct such center effects of cortical feature obtained from multicenter magnetic resonance images (MRIs). Methods: For MRI of a total of 4,321 multicenter subjects, the harmonized w-score was calculated by correcting biological covariates such as age, sex, years of education, and intercranial volume (ICV) as fixed effects and center information as a random effect. Afterward, we performed classification tasks using principal component analysis (PCA) and linear discriminant analysis (LDA) to check whether the center effect was successfully corrected from the harmonized w-score. Results: First, an experiment was conducted to predict the dataset origin of a random subject sampled from two different datasets, and it was confirmed that the prediction accuracy of linear mixed effect (LME) model-based w-score was significantly closer to the baseline than that of raw cortical thickness. As a second experiment, we classified the data of the normal and patient groups of each dataset, and LME model-based w-score, which is biological-feature-corrected values, showed higher classification accuracy than the raw cortical thickness data. Afterward, to verify the compatibility of the dataset used for LME model training and the dataset that is not, intraobject comparison and w-score RMSE calculation process were performed. Conclusion: Through comparison between the LME model-based w-score and existing methods and several classification tasks, we showed that the LME model-based w-score sufficiently corrects the center effects while preserving the disease effects from the dataset. We also showed that the preserved disease effects have a match with well-known disease atrophy patterns such as Alzheimer's disease or Parkinson's disease. Finally, through intrasubject comparison, we found that the difference between centers decreases in the LME model-based w-score compared with the raw cortical thickness and thus showed that our model well-harmonizes the data that are not used for the model training.

Regional Aß-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading.

Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

Anti-PD-L1 peptide-conjugated prodrug nanoparticles for targeted cancer immunotherapy combining PD-L1 blockade with immunogenic cell death.

Rationale: Cancer immunotherapy combining immune checkpoint blockade (ICB) with chemotherapeutic drugs has provided significant clinical advances. However, such combination therapeutic regimen has suffered from severe toxicity of both drugs and low response rate of patients. In this study, we propose anti-PD-L1 peptide-conjugated prodrug nanoparticles (PD-NPs) to overcome these obstacles of current cancer immunotherapy. Methods: The functional peptide, consisted of anti-PD-L1 peptide and cathepsin B-specific cleavable peptide, is conjugated to a doxorubicin (DOX), resulting in prodrug nanoparticles of PD-NPs via intermolecular interactions. The antitumor efficacy and immune responses with minimal side effects by PD-NPs combining PD-L1 blockade and ICD are evaluated in breast tumor models. Results: The PD-NPs are taken up by PD-L1 receptor-mediated endocytosis and then induce ICD in cancer cells by DOX release. Concurrently, PD-L1 blockade by PD-NPs disrupt the immune-suppressing pathway of cancer cells, resulting in proliferation and reinvigoration of T lymphocytes. In tumor models, PD-NPs accumulate within tumor tissues via enhanced permeability and retention (EPR) effect and induce immune-responsive tumors by recruiting a large amount of immune cells. Conclusions: Collectively, targeted tumor delivery of anti-PD-L1 peptide and DOX via PD-NPs efficiently inhibit tumor progression with minimal side effects.

Association of subcortical structural shapes with fatigue in neuromyelitis optica spectrum disorder.

Although fatigue is a major symptom in patients with neuromyelitis optica spectrum disorder (NMOSD), the underlying mechanism remains unclear. We explored the relationship between subcortical structures and fatigue severity to identify neural substrates of fatigue in NMOSD. Clinical characteristics with brain magnetic resonance imaging were evaluated in forty patients with NMOSD. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) questionnaire (a higher score indicates less fatigue). We assessed the correlation between subcortical structures and fatigue severity using surface-based shape analysis. Most of the enrolled patients showed fatigue (72.5%; mean FACIT-fatigue score, 34.8 ± 10.8). The FACIT-fatigue score was negatively correlated with Expanded Disability Status Scale and Beck Depression Inventory scores (r = - 0.382, p = 0.016; r = - 0.578, p < 0.001). We observed that the right thalamus was the only extracted region for various threshold experiments. Further, patients with lower FACIT-fatigue scores (more fatigue) had decreased local shape volume in the right thalamus. Fatigue is common in patients with NMOSD, and atrophy in the right thalamus is strongly correlated with fatigue severity. The local shape volume of the right thalamus might serve as a biomarker of fatigue in NMOSD.

Distinctive Mediating Effects of Subcortical Structure Changes on the Relationships Between Amyloid or Vascular Changes and Cognitive Decline.

Objective: We investigated the mediation effects of subcortical volume change in the relationship of amyloid beta (Aß) and lacune with cognitive function in patients with mild cognitive impairment (MCI). Methods: We prospectively recruited 101 patients with MCI who were followed up with neuropsychological tests, MRI, or Pittsburgh compound B (PiB) PET for 3 years. The mediation effect of subcortical structure on the association of PiB or lacunes with cognitive function was analyzed using mixed effects models. Results: Volume changes in the amygdala and hippocampus partially mediated the effect of PiB changes on memory function (direct effect = -0.168/-0.175, indirect effect = -0.081/-0.077 for amygdala/hippocampus) and completely mediated the effect of PiB changes on clinical dementia rating scale sum of the box (CDR-SOB) (indirect effect = 0.082/0.116 for amygdala/hippocampus). Volume changes in the thalamus completely mediated the effect of lacune on memory, frontal executive functions, and CDR-SOB (indirect effect = -0.037, -0.056, and 0.047, respectively). Conclusions: Our findings provide a better understanding of the distinct role of subcortical structures in the mediation of the relationships of amyloid or vascular changes with a decline in specific cognitive domains.

Effect of education on functional network edge efficiency in Alzheimer's disease.

We investigated the effect of education on the edge efficiency in resting state functional networks (RSFNs) in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). We collected the data of 57 early aMCI, 141 late aMCI, 173 mild ADD, and 39 moderate-to-severe ADD patients. We used years of education as a proxy for cognitive reserve. We measured edge efficiency for each edge in RSFNs, and performed simple slope analyses to discover their associations with education level among the four groups. In the late aMCI, a sub-network that had hub nodes in the right middle frontal gyrus and the right posterior cingulate gyrus, showed a positive association between RSFN edge efficiency and education (threshold = 2.5, p = 0.0478). There was no negative effect of education on the RSFN edge efficiency. In the early aMCI, mild ADD, and moderate-to-severe ADD, there were no sub-networks showing positive or negative correlation between education and RSFN edge efficiency. There was a positive effect of higher education on RSFN edge efficiency in the late aMCI, but not in the early aMCI or ADD. This indicates that in late aMCI, those who have higher education level have greater ability to resist collapsed functional network.

White matter tract-specific alterations in patients with primary restless legs syndrome.

Prior diffusion tensor imaging (DTI) studies have investigated white matter (WM) changes in patients with primary restless legs syndrome (RLS), but the results were inconsistent. Here, we proposed using tract-specific statistical analysis (TSSA) to find alterations in specific WM tracts to clarify the pathophysiological mechanisms of RLS. We enrolled 30 patients with RLS and 31 age- and sex- matched controls who underwent brain magnetic resonance imaging, neuropsychological tests, and polysomnography. Fractional anisotropy (FA) maps obtained from whole-brain diffusion tensor imaging and TSSA were used to localize WM changes in patients with RLS. Subsequently, a comparison of FA values for each tract between patients and controls was performed. The associations between FA values and clinical, polysomnographic, and neuropsychological parameters in RLS patients were assessed. RLS patients demonstrated decreased FA values in the left corticospinal tract (CST) and cingulum, and in the right anterior thalamic radiation (ATR) and inferior fronto-occipital fasciculus (IFO). Patients' attention/executive function and visual memory scores positively correlated with FA values in the right ATR, and anxiety levels negatively correlated with FA values in the right IFO. Additionally, the number of periodic leg movements and movement arousal index were negatively correlated with FA values in the left CST. The TSSA method identified previously unknown tract-specific alterations in patients with RLS and significant associations with distinct clinical manifestations of RLS.