Sex-Specific Heterogeneity of Mild Cognitive Impairment Identified Based on Multi-Modal Data Analysis.

BACKGROUND: Mild cognitive impairment (MCI), a prodromal phase of Alzheimer's disease (AD), is heterogeneous with different rates and risks of progression to AD. There are significant gender disparities in the susceptibility, prognosis, and outcomes in patients with MCI, with female being disproportionately negatively impacted. OBJECTIVE: The aim of this study was to identify sex-specific heterogeneity of MCI using multi-modality data and examine the differences in the respective MCI subtypes with different prognostic outcomes or different risks for MCI to AD conversion. METHODS: A total of 325 MCI subjects (146 women, 179 men) and 30 relevant features were considered. Mixed-data clustering was applied to women and men separately to discover gender-specific MCI subtypes. Gender differences were compared in the respective subtypes of MCI by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. RESULTS: We identified three MCI subtypes: poor-, good-, and best-prognosis for women and for men, separately. The subtype-wise comparison (for example, poor-prognosis subtype in women versus poor-prognosis subtype in men) showed significantly different means for brain volumetric, cognitive test-related, also for the proportion of comorbidities. Also, there were substantial gender differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. CONCLUSION: Analyzing sex-specific heterogeneity of MCI offers the opportunity to advance the understanding of the pathophysiology of both MCI and AD, allows stratification of risk in clinical trials of interventions, and suggests gender-based early intervention with targeted treatment for patients at risk of developing AD.

Comorbidity-driven multi-modal subtype analysis in mild cognitive impairment of Alzheimer's disease.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition with high individual variabilities in clinical outcomes driven by patient demographics, genetics, brain structure features, blood biomarkers, and comorbidities. Multi-modality data-driven approaches have been used to discover MCI subtypes; however, disease comorbidities have not been included as a modality though multiple diseases including hypertension are well-known risk factors for Alzheimer's disease (AD). The aim of this study was to examine MCI heterogeneity in the context of AD-related comorbidities along with other AD-relevant features and biomarkers. METHODS: A total of 325 MCI subjects with 32 AD-relevant comorbidities and features were considered. Mixed-data clustering is applied to discover and compare MCI subtypes with and without including AD-related comorbidities. Finally, the relevance of each comorbidity-driven subtype was determined by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. RESULTS: We identified four (five) MCI subtypes: poor-, average-, good-, and best-AD prognosis by including comorbidities (without including comorbidities). We demonstrated that comorbidity-driven MCI subtypes differed from those identified without comorbidity information. We further demonstrated the clinical relevance of comorbidity-driven MCI subtypes. Among the four comorbidity-driven MCI subtypes there were substantial differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. The groups showed different behaviors, having significantly different MCI to AD prognosis, significantly different means for cognitive test-related and plasma features, and by the proportion of comorbidities. CONCLUSIONS: Our study indicates that AD comorbidities should be considered along with other diverse AD-relevant characteristics to better understand MCI heterogeneity.

Predict Alzheimer's disease using hippocampus MRI data: a lightweight 3D deep convolutional network model with visual and global shape representations.

BACKGROUND: Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Hippocampus is one of the involved regions and its atrophy is a widely used biomarker for AD diagnosis. We have recently developed DenseCNN, a lightweight 3D deep convolutional network model, for AD classification based on hippocampus magnetic resonance imaging (MRI) segments. In addition to the visual features of the hippocampus segments, the global shape representations of the hippocampus are also important for AD diagnosis. In this study, we propose DenseCNN2, a deep convolutional network model for AD classification by incorporating global shape representations along with hippocampus segmentations. METHODS: The data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and was T1-weighted structural MRI from initial screening or baseline, including ADNI 1,2/GO and 3. DenseCNN2 was trained and evaluated with 326 AD subjects and 607 CN hippocampus MRI using 5-fold cross-validation strategy. DenseCNN2 was compared with other state-of-the-art machine learning approaches for the task of AD classification. RESULTS: We showed that DenseCNN2 with combined visual and global shape features performed better than deep learning models with visual or global shape features alone. DenseCNN2 achieved an average accuracy of 0.925, sensitivity of 0.882, specificity of 0.949, and area under curve (AUC) of 0.978, which are better than or comparable to the state-of-the-art methods in AD classification. Data visualization analysis through 2D embedding of UMAP confirmed that global shape features improved class discrimination between AD and normal. CONCLUSION: DenseCNN2, a lightweight 3D deep convolutional network model based on combined hippocampus segmentations and global shape features, achieved high performance and has potential as an efficient diagnostic tool for AD classification.