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1. Ensemble Machine Learning for Alzheimer’s disease Classification from Retinal Vasculature

   Lin, Hely; Fang, Ruogu (October 2021, Biomedical Engineering Society Annual Meeting)

   null (Ed.)

   Introduction: Alzheimer’s disease (AD) causes progressive irreversible cognitive decline and is the leading cause of dementia. Therefore, a timely diagnosis is imperative to maximize neurological preservation. However, current treatments are either too costly or limited in availability. In this project, we explored using retinal vasculature as a potential biomarker for early AD diagnosis. This project focuses on stage 3 of a three-stage modular machine learning pipeline which consisted of image quality selection, vessel map generation, and classification [1]. The previous model only used support vector machine (SVM) to classify AD labels which limited its accuracy to 82%. In this project, random forest and gradient boosting were added and, along with SVM, combined into an ensemble classifier, raising the classification accuracy to 89%. Materials and Methods: Subjects classified as AD were those who were diagnosed with dementia in “Dementia Outcome: Alzheimer’s disease” from the UK Biobank Electronic Health Records. Five control groups were chosen with a 5:1 ratio of control to AD patients where the control patients had the same age, gender, and eye side image as the AD patient. In total, 122 vessel images from each group (AD and control) were used. The vessel maps were then segmented from fundus images through U-net. A t-test feature selection was first done on the training folds and the selected features was fed into the classifiers with a p-value threshold of 0.01. Next, 20 repetitions of 5-fold cross validation were performed where the hyperparameters were solely tuned on the training data. An ensemble classifier consisting of SVM, gradient boosting tree, and random forests was built and the final prediction was made through majority voting and evaluated on the test set. Results and Discussion: Through ensemble classification, accuracy increased by 4-12% relative to the individual classifiers, precision by 9-15%, sensitivity by 2-9%, specificity by at least 9-16%, and F1 score by 712%. Conclusions: Overall, a relatively high classification accuracy was achieved using machine learning ensemble classification with SVM, random forest, and gradient boosting. Although the results are very promising, a limitation of this study is that the requirement of needing images of sufficient quality decreased the amount of control parameters that can be implemented. However, through retinal vasculature analysis, this project shows machine learning’s high potential to be an efficient, more cost-effective alternative to diagnosing Alzheimer’s disease. Clinical Application: Using machine learning for AD diagnosis through retinal images will make screening available for a broader population by being more accessible and cost-efficient. Mobile device based screening can also be enabled at primary screening in resource-deprived regions. It can provide a pathway for future understanding of the association between biomarkers in the eye and brain. 

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2. Dynamic fluctuations of intrinsic brain activity are associated with consistent topological patterns in puberty and are biomarkers of neural maturation

   https://doi.org/10.1162/netn_a_00452  

   Lim, Jethro; Cooper, Kaitlynn; Stamoulis, Catherine (June 2025, Network Neuroscience)

   Abstract Intrinsic brain dynamics play a fundamental role in cognitive function, but their development is incompletely understood. We investigated pubertal changes in temporal fluctuations of intrinsic network topologies (focusing on the strongest connections and coordination patterns) and signals, in an early longitudinal sample from the Adolescent Brain Cognitive Development (ABCD) study, with resting-state fMRI (n = 4,099 at baseline; n = 3,376 at follow-up [median age = 10.0 (1.1) and 12.0 (1.1) years; n = 2,116 with both assessments]). Reproducible, inverse associations between low-frequency signal and topological fluctuations were estimated (p < 0.05, β = −0.20 to −0.02, 95% confidence interval (CI) = [−0.23, −0.001]). Signal (but not topological) fluctuations increased in somatomotor and prefrontal areas with pubertal stage (p < 0.03, β = 0.06–0.07, 95% CI = [0.03, 0.11]), but decreased in orbitofrontal, insular, and cingulate cortices, as well as cerebellum, hippocampus, amygdala, and thalamus (p < 0.05, β = −0.09 to −0.03, 95% CI = [−0.15, −0.001]). Higher temporal signal and topological variability in spatially distributed regions were estimated in girls. In racial/ethnic minorities, several associations between signal and topological fluctuations were in the opposite direction of those in the entire sample, suggesting potential racial differences. Our findings indicate that during puberty, intrinsic signal dynamics change significantly in developed and developing brain regions, but their strongest coordination patterns may already be sufficiently developed and remain temporally consistent. 

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3. Precise and rapid whole-head segmentation from magnetic resonance images of older adults using deep learning

   https://doi.org/10.1162/imag_a_00090  

   Stolte, Skylar E; Indahlastari, Aprinda; Chen, Jason; Albizu, Alejandro; Dunn, Ayden; Pedersen, Samantha; See, Kyle B; Woods, Adam J; Fang, Ruogu (February 2024, Imaging Neuroscience)

   Abstract Whole-head segmentation from Magnetic Resonance Images (MRI) establishes the foundation for individualized computational models using finite element method (FEM). This foundation paves the path for computer-aided solutions in fields such as non-invasive brain stimulation. Most current automatic head segmentation tools are developed using healthy young adults. Thus, they may neglect the older population that is more prone to age-related structural decline such as brain atrophy. In this work, we present a new deep learning method called GRACE, which stands for General, Rapid, And Comprehensive whole-hEad tissue segmentation. GRACE is trained and validated on a novel dataset that consists of 177 manually corrected MR-derived reference segmentations that have undergone meticulous manual review. Each T1-weighted MRI volume is segmented into 11 tissue types, including white matter, grey matter, eyes, cerebrospinal fluid, air, blood vessel, cancellous bone, cortical bone, skin, fat, and muscle. To the best of our knowledge, this work contains the largest manually corrected dataset to date in terms of number of MRIs and segmented tissues. GRACE outperforms five freely available software tools and a traditional 3D U-Net on a five-tissue segmentation task. On this task, GRACE achieves an average Hausdorff Distance of 0.21, which exceeds the runner-up at an average Hausdorff Distance of 0.36. GRACE can segment a whole-head MRI in about 3 seconds, while the fastest software tool takes about 3 minutes. In summary, GRACE segments a spectrum of tissue types from older adults’ T1-MRI scans at favorable accuracy and speed. The trained GRACE model is optimized on older adult heads to enable high-precision modeling in age-related brain disorders. To support open science, the GRACE code and trained weights are made available online and open to the research community at https://github.com/lab-smile/GRACE. 

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4. Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment

   https://doi.org/10.1073/pnas.2214634120  

   Yin, Chenzhong; Imms, Phoebe; Cheng, Mingxi; Amgalan, Anar; Chowdhury, Nahian F.; Massett, Roy J.; Chaudhari, Nikhil N.; Chen, Xinghe; Thompson, Paul M.; Bogdan, Paul; et al (January 2023, Proceedings of the National Academy of Sciences)

   The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk. 

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5. Classifying Non-Dementia and Alzheimer’s Disease/Vascular Dementia Patients Using Kinematic, Time-Based, and Visuospatial Parameters: The Digital Clock Drawing Test

   https://doi.org/10.3233/JAD-201129  

   Davoudi, Anis; Dion, Catherine; Amini, Shawna; Tighe, Patrick J.; Price, Catherine C.; Libon, David J.; Rashidi, Parisa (June 2021, Journal of Alzheimer's Disease)

   Bondi, Mark (Ed.)

   Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination. Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer’s disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer’s disease (AD) versus vascular dementia (VaD). Methods: Healthy, community-dwelling control participants (n = 175), patients diagnosed clinically with Alzheimer’s disease (n = 29), and vascular dementia (n = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were extracted and used with Random Forest classification models. Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features. Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes. 

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