Random forest prediction of Alzheimer's disease using pairwise selection from time series data

Time-dependent data collected in studies of Alzheimer's disease usually has missing and irregularly sampled data points. For this reason time series methods which assume regular sampling cannot be applied directly to the data without a pre-processing step. In this paper we use a machine learning method to learn the relationship between pairs of data points at different time separations. The input vector comprises a summary of the time series history and includes both demographic and non-time varying variables such as genetic data. The dataset used is from the 2017 TADPOLE grand challenge which aims to predict the onset of Alzheimer's disease using including demographic, physical and cognitive data. The challenge is a three-fold diagnosis classification into AD, MCI and control groups, the prediction of ADAS-13 score and the normalised ventricle volume. While the competition proceeds, forecasting methods may be compared using a leaderboard dataset selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with standard metrics for measuring accuracy. For diagnosis, we find an mAUC of 0.82, and a classification accuracy of 0.73. The results show that the method is effective and comparable with other methods.Comment: 6 pages, 1 figure, 6 table

Multimodal MRI-based Imputation of the Aβ+ in Early Mild Cognitive Impairment.

ObjectiveTo identify brain atrophy from structural-MRI and cerebral blood flow(CBF) patterns from arterial spin labeling perfusion-MRI that are best predictors of the Aβ-burden, measured as composite 18F-AV45-PET uptake, in individuals with early mild cognitive impairment(MCI). Furthermore, to assess the relative importance of imaging modalities in classification of Aβ+/Aβ- early mild cognitive impairment.MethodsSixty-seven ADNI-GO/2 participants with early-MCI were included. Voxel-wise anatomical shape variation measures were computed by estimating the initial diffeomorphic mapping momenta from an unbiased control template. CBF measures normalized to average motor cortex CBF were mapped onto the template space. Using partial least squares regression, we identified the structural and CBF signatures of Aβ after accounting for normal cofounding effects of age, sex, and education.Results18F-AV45-positive early-MCIs could be identified with 83% classification accuracy, 87% positive predictive value, and 84% negative predictive value by multidisciplinary classifiers combining demographics data, ApoE ε4-genotype, and a multimodal MRI-based Aβ score.InterpretationMultimodal-MRI can be used to predict the amyloid status of early-MCI individuals. MRI is a very attractive candidate for the identification of inexpensive and non-invasive surrogate biomarkers of Aβ deposition. Our approach is expected to have value for the identification of individuals likely to be Aβ+ in circumstances where cost or logistical problems prevent Aβ detection using cerebrospinal fluid analysis or Aβ-PET. This can also be used in clinical settings and clinical trials, aiding subject recruitment and evaluation of treatment efficacy. Imputation of the Aβ-positivity status could also complement Aβ-PET by identifying individuals who would benefit the most from this assessment

Reduced [¹⁸F]flortaucipir retention in white matter hyperintensities compared to normal-appearing white matter

PURPOSE: Recent research has suggested the use of white matter (WM) reference regions for longitudinal tau-PET imaging. However, tau tracers display affinity for the β-sheet structure formed by myelin, and thus WM lesions might influence tracer retention. Here, we explored whether the tau-sensitive tracer [18F]flortaucipir shows reduced retention in WM hyperintensities (WMH) and how this retention changes over time. METHODS: We included 707 participants from the Alzheimer's Disease Neuroimaging Initiative with available [18F]flortaucipir-PET and structural and FLAIR MRI scans. WM segments and WMH were automatically delineated in the structural MRI and FLAIR scans, respectively. [18F]flortaucipir standardized uptake value ratios (SUVR) of WMH and normal-appearing WM (NAWM) were calculated using the inferior cerebellar grey matter as reference region, and a 3-mm erosion was applied to the combined NAWM and WMH masks to avoid partial volume effects. Longitudinal [18F]flortaucipir SUVR changes in NAWM and WMH were estimated using linear mixed models. The percent variance of WM-referenced cortical [18F]flortaucipir SUVRs explained by longitudinal changes in the WM reference region was estimated with the R2 coefficient. RESULTS: Compared to NAWM, WMH areas displayed significantly reduced [18F]flortaucipir SUVR, independent of cognitive impairment or Aβ status (mean difference = 0.14 SUVR, p < 0.001). Older age was associated with lower [18F]flortaucipir SUVR in both NAWM (- 0.002 SUVR/year, p = 0.005) and WMH (- 0.004 SUVR/year, p < 0.001). Longitudinally, [18F]flortaucipir SUVR decreased in NAWM (- 0.008 SUVR/year, p = 0.03) and even more so in WMH (- 0.02 SUVR/year, p < 0.001). Between 17% and 66% of the variance of longitudinal changes in cortical WM-referenced [18F]flortaucipir SUVRs were explained by longitudinal changes in the reference region. CONCLUSIONS: [18F]flortaucipir retention in the WM decreases over time and is influenced by the presence of WMH, supporting the hypothesis that [18F]flortaucipir retention in the WM is partially myelin-dependent. These findings have implications for the use of WM reference regions for [18F]flortaucipir-PET imaging

A Novel Joint Brain Network Analysis Using Longitudinal Alzheimer's Disease Data.

There is well-documented evidence of brain network differences between individuals with Alzheimer's disease (AD) and healthy controls (HC). To date, imaging studies investigating brain networks in these populations have typically been cross-sectional, and the reproducibility of such findings is somewhat unclear. In a novel study, we use the longitudinal ADNI data on the whole brain to jointly compute the brain network at baseline and one-year using a state of the art approach that pools information across both time points to yield distinct visit-specific networks for the AD and HC cohorts, resulting in more accurate inferences. We perform a multiscale comparison of the AD and HC networks in terms of global network metrics as well as at the more granular level of resting state networks defined under a whole brain parcellation. Our analysis illustrates a decrease in small-worldedness in the AD group at both the time points and also identifies more local network features and hub nodes that are disrupted due to the progression of AD. We also obtain high reproducibility of the HC network across visits. On the other hand, a separate estimation of the networks at each visit using standard graphical approaches reveals fewer meaningful differences and lower reproducibility

The Relationship Between Anxiety and Incident Agitation in Alzheimer's Disease

Background: Agitation in Alzheimer’s disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown. Objective: We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up. Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between baseline and incident anxiety with incident agitation. Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation. Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions

Predicting Short-term MCI-to-AD Progression Using Imaging, CSF, Genetic Factors, Cognitive Resilience, and Demographics.

In the Alzheimer’s disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate highdimensional data (multimodal neuroimaging and cerebrospinal fuid biomarkers, genetic factors, and measures of cognitive resilience) for identifcation of MCI individuals who progress to AD within 3 years. Our main fndings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments

Quantifying uncertainty in brain-predicted age using scalar-on-image quantile regression

Prediction of subject age from brain anatomical MRI has the potential to provide a sensitive summary of brain changes, indicative of different neurodegenerative diseases. However, existing studies typically neglect the uncertainty of these predictions. In this work we take into account this uncertainty by applying methods of functional data analysis. We propose a penalised func16 tional quantile regression model of age on brain structure with cognitively normal (CN) subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and use it to predict brain age in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD) subjects. Unlike the machine learning approaches available in the literature of brain age prediction, which provide only point predictions, the outcome of our model is a prediction interval for each subject

Atlas selection strategy in multi-atlas segmentation propagation with locally weighted voting using diversity-based MMR re-ranking

In multi-atlas based image segmentation, multiple atlases with label maps are propagated to the query image, and fused into the segmentation result. Voting rule is commonly used classifier fusion method to produce the consensus map. Local weighted voting (LWV) is another method which combines the propagated atlases weighted by local image similarity. When LWV is used, we found that the segmentation accuracy converges slower comparing to simple voting rule. We therefore propose to introduce diversity in addition to image similarity by using Maximal Marginal Relevance (MMR) criteria as a more efficient way to rank and select atlases. We test the MMR re-ranking on a hippocampal atlas set of 138 normal control (NC) subjects and another set of 99 Alzheimer's disease patients provided by ADNI. The result shows that MMR re-ranking performed better than similarity based atlas selection when same number of atlases were selected

Association Between False Memories and Delusions in Alzheimer Disease

IMPORTANCE: Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that delusions arise as a consequence of false memories. OBJECTIVE: To investigate whether delusions in AD are associated with false recognition, and whether higher rates of false recognition and the presence of delusions are associated with lower regional brain volumes in the same brain regions. DESIGN, SETTING, AND PARTICIPANTS: Since the Alzheimer's Disease Neuroimaging Initiative (ADNI) launched in 2004, it has amassed an archive of longitudinal behavioral and biomarker data. This cross-sectional study used data downloaded in 2020 from ADNI participants with an AD diagnosis at baseline or follow-up. Data analysis was performed between June 24, 2020, and September 21, 2021. EXPOSURE: Enrollment in the ADNI. MAIN OUTCOMES AND MEASURES: The main outcomes included false recognition, measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Rey Auditory Verbal Learning Test (RAVLT) and volume of brain regions corrected for total intracranial volume. Behavioral data were compared for individuals with delusions in AD and those without using independent-samples t tests or Mann-Whitney nonparametric tests. Significant findings were further explored using binary logistic regression modeling. For neuroimaging data region of interest analyses using t tests, Poisson regression modeling or binary logistic regression modeling and further exploratory, whole-brain voxel-based morphometry analyses were carried out to explore the association between regional brain volume and false recognition or presence of delusions. RESULTS: Of the 2248 individuals in the ADNI database, 728 met the inclusion criteria and were included in this study. There were 317 (43.5%) women and 411 (56.5%) men. Their mean (SD) age was 74.8 (7.4) years. The 42 participants with delusions at baseline had higher rates of false recognition on the ADAS-Cog 13 (median score, 3; IQR, 1 to 6) compared with the 549 control participants (median score, 2; IQR, 0 to 4; U = 9398.5; P = .04). False recognition was not associated with the presence of delusions when confounding variables were included in binary logistic regression models. An ADAS-Cog 13 false recognition score was inversely associated with left hippocampal volume (odds ratio [OR], 0.91 [95% CI, 0.88-0.94], P < .001), right hippocampal volume (0.94 [0.92-0.97], P < .001), left entorhinal cortex volume (0.94 [0.91-0.97], P < .001), left parahippocampal gyrus volume (0.93 [0.91-0.96], P < .001), and left fusiform gyrus volume (0.97 [0.96-0.99], P < .001). There was no overlap between locations associated with false recognition and those associated with delusions. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, false memories were not associated with the presence of delusions after accounting for confounding variables, and no indication for overlap of neural networks for false memories and delusions was observed on volumetric neuroimaging. These findings suggest that delusions in AD do not arise as a direct consequence of misremembering, lending weight to ongoing attempts to delineate specific therapeutic targets for treatment of psychosis

Levels of Cortisol in CSF Are Associated With SNAP-25 and Tau Pathology but Not Amyloid-β

Objective: Preclinical studies have found both hyperactivity of hypothalamic- pituitary- adrenal (HPA) axis and synaptic degeneration are involved in the pathogenesis of Alzheimer’s disease (AD). However, the data on the relationship of activity of HPA axis and synaptic degeneration in humans are limited.Methods: We compared CSF cortisol levels in 310 subjects, including 92 cognitively normal older people, 149 patients with mild cognitive impairment (MCI), and 69 patients with mild AD. Several linear and logistic regression models were conducted to investigate associations between CSF cortisol and synaptosomal-associated protein 25 (SNAP-25, reflecting synaptic degeneration) and other AD-related biomarkers.Results: We found that levels of cortisol in CSF were associated with SNAP-25 levels and tau pathologies but not amyloid-β protein. However, there were no significant differences in CSF cortisol levels among the three diagnostic groups.Conclusion: The HPA axis may play a crucial role in synaptic degeneration in AD pathogenesis