Early Mild Cognitive Impairment Patients Research Articles

Atrophy of the cholinergic regions advances from early to late mild cognitive impairment.

We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients' apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. Structural magnetic resonance imaging data were collected. Patients' demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients' neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R2 = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R2 = 0.095 and 0.042 for EMCI and LMCI, respectively) function. Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.

Edge‐centric functional network reveals new spatiotemporal biomarkers of early mild cognitive impairment

AbstractMost neuroimaging studies of the pathogenesis of early mild cognitive impairment (EMCI) rely on a node‐centric network model, which only calculates correlations between brain regions. Considering the interaction of low‐order correlations between pairs of brain regions, we use an edge‐centric network model to study high‐order functional network correlations. Here, we compute edge time series (eTS) to obtain overlapping communities and study the relationship between subnetworks and communities in space. Then, based on the overlapping communities, we calculate the normalized entropy to measure the diversity of each node. Next, we compute the high‐amplitude co‐fluctuation of the eTS to explore the pattern of brain activity with temporal precision. Our results show that the normal control and EMCI patients differ in brain regions, subnetworks, and the whole brain. In particular, entropy values show a gradual decrease, and brain network co‐fluctuation increases with disease progression. Our study is the first to investigate the pathogenesis of EMCI from the perspective of spatiotemporal flexibility and cognitive diversity based on high‐order edge connectivity, further characterizing brain dynamics and providing new insights into the search for biomarkers of EMCI.

A pairwise functional connectivity similarity measure method based on few-shot learning for early MCI detection.

Alzheimer's disease is an irreversible neurological disease, therefore prompt diagnosis during its early stage, i.e., early mild cognitive impairment (MCI), is crucial for effective treatment. In this paper, we propose an automatic diagnosis method, a few-shot learning-based pairwise functional connectivity (FC) similarity measure method, to detect early MCI. We first employ a sliding window strategy to generate a dynamic functional connectivity network (FCN) using each subject's rs-fMRI data. Then, normal controls (NCs) and early MCI patients are distinguished by measuring the similarity between the dynamic FC series of corresponding brain regions of interest (ROIs) pairs in different subjects. However, previous studies have shown that FC patterns in different ROI-pairs contribute differently to disease classification. To enable the FCs of different ROI-pairs to make corresponding contributions to disease classification, we adopt a self-attention mechanism to weight the FC features. We evaluated the suggested strategy using rs-fMRI data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and the results point to the viability of our approach for detecting MCI at an early stage.

BMNet: A New Region-Based Metric Learning Method for Early Alzheimer's Disease Identification With FDG-PET Images.

18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) reveals altered brain metabolism in individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Some biomarkers derived from FDG-PET by computer-aided-diagnosis (CAD) technologies have been proved that they can accurately diagnosis normal control (NC), MCI, and AD. However, existing FDG-PET-based researches are still insufficient for the identification of early MCI (EMCI) and late MCI (LMCI). Compared with methods based other modalities, current methods with FDG-PET are also inadequate in using the inter-region-based features for the diagnosis of early AD. Moreover, considering the variability in different individuals, some hard samples which are very similar with both two classes limit the classification performance. To tackle these problems, in this paper, we propose a novel bilinear pooling and metric learning network (BMNet), which can extract the inter-region representation features and distinguish hard samples by constructing the embedding space. To validate the proposed method, we collect 898 FDG-PET images from Alzheimer’s disease neuroimaging initiative (ADNI) including 263 normal control (NC) patients, 290 EMCI patients, 147 LMCI patients, and 198 AD patients. Following the common preprocessing steps, 90 features are extracted from each FDG-PET image according to the automatic anatomical landmark (AAL) template and then sent into the proposed network. Extensive fivefold cross-validation experiments are performed for multiple two-class classifications. Experiments show that most metrics are improved after adding the bilinear pooling module and metric losses to the Baseline model respectively. Specifically, in the classification task between EMCI and LMCI, the specificity improves 6.38% after adding the triple metric loss, and the negative predictive value (NPV) improves 3.45% after using the bilinear pooling module. In addition, the accuracy of classification between EMCI and LMCI achieves 79.64% using imbalanced FDG-PET images, which illustrates that the proposed method yields a state-of-the-art result of the classification accuracy between EMCI and LMCI based on PET images.

Data-Limited Deep Learning Methods for Mild Cognitive Impairment Classification in Alzheimer's Disease Patients.

Mild Cognitive Impairment (MCI) is the stage between the declining of normal brain function and the more serious decline of dementia. Alzheimer's disease (AD) is one of the leading forms of dementia. Although MCI does not always lead to AD, an early diagnosis of MCI may be helpful in finding those with early signs of AD. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has utilized magnetic resonance imaging (MRI) for the diagnosis of MCI and AD. MCI can be separated into two types: Early MCI (EMCI) and Late MCI (LMCI). Furthermore, MRI results can be separated into three views of axial, coronal and sagittal planes. In this work, we perform binary classifications between healthy people and the two types of MCI based on limited MRI images using deep learning approaches. Specifically, we implement and compare two various convolutional neural network (CNN) architectures. The MRIs of 516 patients were used in this study: 172 control normal (CN), 172 EMCI patients and 172 LMCI patients. For this data set, 50% of the images were used for training, 20% for validation, and the remaining 30% for testing. The results showed that the best classification for one model was between CN and LMCI for the coronal view with an accuracy of 79.67%. In addition, we achieved 67.85% accuracy for the second proposed model for the same classification group.

The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

Brain controllability distinctiveness between depression and cognitive impairment

Alzheimer's disease (AD) is a progressive form of dementia marked by cognitive and memory deficits, estimated to affect ∼5.7 million Americans and account for ∼$277 billion in medical costs in 2018. Depression is one of the most common neuropsychiatric disorders that accompanies AD, appearing in up to 50% of patients. AD and Depression commonly occur together with overlapped symptoms (depressed mood, anxiety, apathy, and cognitive deficits.) and pose diagnostic challenges early in the clinical presentation. Understanding their relationship is critical for advancing treatment strategies, but the interaction remains poorly studied and thus often leads to a rapid decline in functioning. Modern systems and control theory offer a wealth of novel methods and concepts to assess the important property of a complex control system, such as the brain. In particular, the brain controllability analysis captures the ability to guide the brain behavior from an initial state (healthy or diseased) to a desired state in finite time, with suitable choice of inputs such as external or internal stimuli. The controllability property of the brain's dynamic processes will advance our understanding of the emergence and progression of brain diseases and thus helpful in the early diagnosis and novel treatment approaches. This study aims to assess the brain controllability differences between mild cognitive impairment (MCI), as prodromal AD, and Depression. This study used diffusion tensor imaging (DTI) data from 60 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 15 cognitively normal subjects and 45 patients with MCI, including 15 early MCI (EMCI) patients without depression, 15 EMCI patients with mild depression (EMCID), and 15 late MCI (LMCI) patients without depression. The structural brain network was firstly constructed and the brain controllability was characterized for each participant. The controllability of default mode network (DMN) and its sub-regions were then compared across groups in a structural basis. Results indicated that the brain average controllability of DMN in EMCI, LMCI, and EMCID were significantly decreased compared to healthy subjects (P < 0.05). The EMCI and LMCI groups also showed significantly greater average controllability of DMN versus the EMCID group. Furthermore, compared to healthy subjects, the regional controllability of the left/right superior prefrontal cortex and the left/right cingulate gyrus in the EMCID group showed a significant decrease (P < 0.01). Among these regions, the left superior prefrontal region's controllability was significantly decreased (P < 0.05) in the EMCID group compared with EMCI and LMCI groups. Our results provide a new perspective in understanding depressive symptoms in MCI patients and provide potential biomarkers for diagnosing depression from MCI and AD.

Identifying and characterizing different stages toward Alzheimer's disease using ordered core features and machine learning

Based on the joint HCPMMP parcellation method we developed before, which divides the cortical brain into 360 regions, the concept of ordered core features (OCF) is first proposed to reveal the functional brain connectivity relationship among different cohorts of Alzheimer's disease (AD), late mild cognitive impairment (LMCI), early mild cognitive impairment (EMCI) and healthy controls (HC). A set of core network features that change significantly under the specifically progressive relationship were extracted and used as supervised machine learning classifiers. The network nodes in this set mainly locate in the frontal lobe and insular, forming a narrow band, which are responsible for cognitive impairment as suggested by previous finding. By using these features, the accuracy ranged from 86.0% to 95.5% in binary classification between any pair of cohorts, higher than 70.1%–91.0% when using all network features. In multi-group classification, the average accuracy was 75% or 78% for HC, EMCI, LMCI or EMCI, LMCI, AD against baseline of 33%, and 53.3% for HC, EMCI, LMCI and AD against baseline of 25%. In addition, the recognition rate was lower when combining EMCI and LMCI patients into one group of mild cognitive impairment (MCI) for classification, suggesting that there exists a big difference between early and late MCI patients. This finding supports the EMCI/LMCI inclusion criteria introduced by ADNI based on neuropsychological assessments.

Random forest model for feature-based Alzheimer's disease conversion prediction from early mild cognitive impairment subjects.

Alzheimer's Disease (AD) conversion prediction from the mild cognitive impairment (MCI) stage has been a difficult challenge. This study focuses on providing an individualized MCI to AD conversion prediction using a balanced random forest model that leverages clinical data. In order to do this, 383 Early Mild Cognitive Impairment (EMCI) patients were gathered from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Of these patients, 49 would eventually convert to AD (EMCI_C), whereas the remaining 334 did not convert (EMCI_NC). All of these patients were split randomly into training and testing data sets with 95 patients reserved for testing. Nine clinical features were selected, comprised of a mix of demographic, brain volume, and cognitive testing variables. Oversampling was then performed in order to balance the initially imbalanced classes prior to training the model with 1000 estimators. Our results showed that a random forest model was effective (93.6% accuracy) at predicting the conversion of EMCI patients to AD based on these clinical features. Additionally, we focus on explainability by assessing the importance of each clinical feature. Our model could impact the clinical environment as a tool to predict the conversion to AD from a prodromal stage or to identify ideal candidates for clinical trials.

A Transfer Learning Approach for Early Diagnosis of Alzheimer’s Disease on MRI Images

Mild cognitive impairment (MCI) detection using magnetic resonance image (MRI), plays a crucial role in the treatment of dementia disease at an early stage. Deep learning architecture produces impressive results in such research. Algorithms require a large number of annotated datasets for training the model. In this study, we overcome this issue by using layer-wise transfer learning as well as tissue segmentation of brain images to diagnose the early stage of Alzheimer’s disease (AD). In layer-wise transfer learning, we used the VGG architecture family with pre-trained weights. The proposed model segregates between normal control (NC), the early mild cognitive impairment (EMCI), the late mild cognitive impairment (LMCI), and the AD. In this paper, 85 NC patients, 70 EMCI, 70 LMCI, and 75 AD patients access form the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Tissue segmentation was applied on each subject to extract the gray matter (GM) tissue. In order to check the validity, the proposed method is tested on preprocessing data and achieved the highest rates of the classification accuracy on AD vs NC is 98.73%, also distinguish between EMCI vs LMCI patients testing accuracy 83.72%, whereas remaining classes accuracy is more than 80%. Finally, we provide a comparative analysis with other studies which shows that the proposed model outperformed the state-of-the-art models in terms of testing accuracy.

Deep Learning and Risk Score Classification of Mild Cognitive Impairment and Alzheimer's Disease.

Many neurocognitive and neuropsychological tests are used to classify early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer's disease (AD) from cognitive normal (CN). This can make it challenging for clinicians to make efficient and objective clinical diagnoses. It is possible to reduce the number of variables needed to make a reasonably accurate classification using machine learning. The goal of this study was to develop a deep learning algorithm to identify a few significant neurocognitive tests that can accurately classify these four groups. We also derived a simplified risk-stratification score model for diagnosis. Over 100 variables that included neuropsychological/neurocognitive tests, demographics, genetic factors, and blood biomarkers were collected from 383 EMCI, 644 LMCI, 394 AD patients, and 516 cognitive normal from the Alzheimer's Disease Neuroimaging Initiative database. A neural network algorithm was trained on data split 90% for training and 10% testing using 10-fold cross-validation. Prediction performance used area under the curve (AUC) of the receiver operating characteristic analysis. We also evaluated five different feature selection methods. The five feature selection methods consistently yielded the top classifiers to be the Clinical Dementia Rating Scale - Sum of Boxes, Delayed total recall, Modified Preclinical Alzheimer Cognitive Composite with Trails test, Modified Preclinical Alzheimer Cognitive Composite with Digit test, and Mini-Mental State Examination. The best classification model yielded an AUC of 0.984, and the simplified risk-stratification score yielded an AUC of 0.963 on the test dataset. The deep-learning algorithm and simplified risk score accurately classifies EMCI, LMCI, AD and CN patients using a few common neurocognitive tests.

ALTEA: A Software Tool for the Evaluation of New Biomarkers for Alzheimer's Disease by Means of Textures Analysis on Magnetic Resonance Images.

The current criteria for diagnosing Alzheimer’s disease (AD) require the presence of relevant cognitive deficits, so the underlying neuropathological damage is important by the time the diagnosis is made. Therefore, the evaluation of new biomarkers to detect AD in its early stages has become one of the main research focuses. The purpose of the present study was to evaluate a set of texture parameters as potential biomarkers of the disease. To this end, the ALTEA (ALzheimer TExture Analyzer) software tool was created to perform 2D and 3D texture analysis on magnetic resonance images. This intuitive tool was used to analyze textures of circular and spherical regions situated in the right and left hippocampi of a cohort of 105 patients: 35 AD patients, 35 patients with early mild cognitive impairment (EMCI) and 35 cognitively normal (CN) subjects. A total of 25 statistical texture parameters derived from the histogram, the Gray-Level Co-occurrence Matrix and the Gray-Level Run-Length Matrix, were extracted from each region and analyzed statistically to study their predictive capacity. Several textural parameters were statistically significant (p < 0.05) when differentiating AD subjects from CN and EMCI patients, which indicates that texture analysis could help to identify the presence of AD.

Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials?

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients’ macrophages in the brain’s clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Morphological and Microstructural Changes of the Hippocampus in Early MCI: A Study Utilizing the Alzheimer's Disease Neuroimaging Initiative Database.

Background and PurposeWith the aim of facilitating the early detection of Alzheimer's disease, the Alzheimer's Disease Neuroimaging Initiative proposed two stages based on the memory performance: early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI). The current study was designed to investigate structural differences in terms of surface atrophy and microstructural changes of the hippocampus in EMCI and LMCI.MethodsHippocampal shape modeling based on progressive template surface deformation was performed on T1-weighted MRI images obtained from 20 cognitive normal (CN) subjects, 17 EMCI patients, and 20 LMCI patients. A template surface in CN was used as a region of interest for diffusion-tensor imaging (DTI) voxel-based morphometry (VBM) analysis. Cluster-wise group comparison was performed based on DTI indices within the hippocampus. Linear regression was performed to identify correlations between DTI metrics and clinical scores.ResultsThe hippocampal surface analysis showed significant atrophies in bilateral CA1 regions and the right ventral subiculum in EMCI, in contrast to widespread atrophy in LMCI. DTI VBM analysis showed increased diffusivity in the CA2–CA4 regions in EMCI and additionally in the subiculum region in LMCI. Hippocampal diffusivity was significantly correlated with scores both for the Mini Mental State Examination and on the Modified Alzheimer Disease Assessment Scale cognitive subscale. However, the hippocampal diffusivity did not vary significantly with the fractional anisotropy.ConclusionsEMCI showed hippocampal surface changes mainly in the CA1 region and ventral subiculum. Diffusivity increased mainly in the CA2–CA4 regions in EMCI, while it decreased throughout the hippocampus in LMCI. Although axial diffusivity showed prominent changes in the right hippocampus in EMCI, future studies need to confirm the presence of this laterality difference. In addition, diffusivity is strongly correlated with the cognitive performance, indicating the possibility of using diffusivity as a biomarker for disease progression.

Altered Amplitude of Low-frequency Fluctuations in Early and Late Mild Cognitive Impairment and Alzheimer's Disease

Previous studies have shown that the strength of the low frequency fluctuation in the medial-line brain areas are abnormally reduced in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. The purpose of this study was to explore the functional brain changes in early MCI (EMCI) and late MCI (LMCI) patients by measuring the amplitude of the blood oxygenation level dependent (BOLD) functional MRI (fMRI) signals at rest. 35 elderly normal controls (NC), 24 EMCI, 29 LMCI, and 14 AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI2) were included in this study. Resting state fMRI and 3D structural MRI data were acquired. The spatial patterns of spontaneous brain activity were measured by examining the amplitude of low-frequency fluctuations (ALFF) of BOLD signal during rest. A one-way analysis of variance (ANOVA) was then performed on ALFF maps, with age, sex and regional atrophy as covariates. There were widespread ALFF differences among the four groups. As compared with controls, AD, LMCI and EMCI patients showed decreased ALFF mainly in the posterior cingulate cortex, precuneus, right lingual gyrus and thalamus (with a linear trend: NC>EMCI>LMCI>AD), while there was increased activity in the right parahippocampal gyrus (with a linear trend: NC<EMCI<LMCI<AD). Additionally, we also showed that many regions with ALFF changes had significant correlations with the cognitive performance as measured by mini-mental state examination scores (MMSE) and the emotion states as measured by Geriatric Depression Scale (GD scale) for EMCI, LMCI and AD patients, but not for controls. Our results indicated that the significantly altered ALFF activities can be detected at EMCI stage, independent of age, sex and regional atrophy. The present study thus suggests ALFF abnormalities as a potential biomarker for the early diagnosis of AD and further provides insights into biological mechanisms of the diseases.

The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)

Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.