Digital biomarkers and sex impacts in Alzheimer’s disease management — potential utility for innovative 3P medicine approach

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer’s, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida’s digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida’s application, achieved a 75% ROC-AUC (receiver operating characteristic — area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline.RLH and IT were supported by Altoida Inc. JM was supported in this work by the Charles University Grant Agency (GA UK) project no. 436119 at Charles University, Second Faculty of Medicine, Prague, Czech Republic.Peer Reviewed"Article signat per 16 autors/es: Robbert L. Harms, Alberto Ferrari, Irene B. Meier, Julie Martinkova, Enrico Santus, Nicola Marino, Davide Cirillo, Simona Mellino, Silvina Catuara Solarz, Ioannis Tarnanas, Cassandra Szoeke, Jakub Hort, Alfonso Valencia, Maria Teresa Ferretti, Azizi Seixas & Antonella Santuccione Chadha "Postprint (published version

Compressed Sensing Diffusion Spectrum Imaging for Accelerated Diffusion Microstructure MRI in Long-Term Population Imaging

Mapping non-invasively the complex microstructural architecture of the living human brain, diffusion magnetic resonance imaging (dMRI) is one of the core imaging modalities in current population studies. For the application in longitudinal population imaging, the dMRI protocol should deliver reliable data with maximum potential for future analysis. With the recent introduction of novel MRI hardware, advanced dMRI acquisition strategies can be applied within reasonable scan time. In this work we conducted a pilot study based on the requirements for high resolution dMRI in a long-term and high throughput population study. The key question was: can diffusion spectrum imaging accelerated by compressed sensing theory (CS-DSI) be used as an advanced imaging protocol for microstructure dMRI in a long-term population imaging study? As a minimum requirement we expected a high level of agreement of several diffusion metrics derived from both CS-DSI and a 3-shell high angular resolution diffusion imaging (HARDI) acquisition, an established imaging strategy used in other population studies. A wide spectrum of state-of-the-art diffusion processing and analysis techniques was applied to the pilot study data including quantitative diffusion and microstructural parameter mapping, fiber orientation estimation and white matter fiber tracking. When considering diffusion weighted images up to the same maximum diffusion weighting for both protocols, group analysis across 20 subjects indicates that CS-DSI performs comparable to 3-shell HARDI in the estimation of diffusion and microstructural parameters. Further, both protocols provide similar results in the estimation of fiber orientations and for local fiber tracking. CS-DSI provides high radial resolution while maintaining high angular resolution and it is well-suited for analysis strategies that require high b-value acquisitions, such as CHARMED modeling and biomarkers from the diffusion propagator

Robust and Fast Markov Chain Monte Carlo Sampling of Diffusion MRI Microstructure Models

In diffusion MRI analysis, advances in biophysical multi-compartment modeling have gained popularity over the conventional Diffusion Tensor Imaging (DTI), because they can obtain a greater specificity in relating the dMRI signal to underlying cellular microstructure. Biophysical multi-compartment models require a parameter estimation, typically performed using either the Maximum Likelihood Estimation (MLE) or the Markov Chain Monte Carlo (MCMC) sampling. Whereas, the MLE provides only a point estimate of the fitted model parameters, the MCMC recovers the entire posterior distribution of the model parameters given in the data, providing additional information such as parameter uncertainty and correlations. MCMC sampling is currently not routinely applied in dMRI microstructure modeling, as it requires adjustment and tuning, specific to each model, particularly in the choice of proposal distributions, burn-in length, thinning, and the number of samples to store. In addition, sampling often takes at least an order of magnitude, more time than non-linear optimization. Here we investigate the performance of the MCMC algorithm variations over multiple popular diffusion microstructure models, to examine whether a single, well performing variation could be applied efficiently and robustly to many models. Using an efficient GPU-based implementation, we showed that run times can be removed as a prohibitive constraint for the sampling of diffusion multi-compartment models. Using this implementation, we investigated the effectiveness of different adaptive MCMC algorithms, burn-in, initialization, and thinning. Finally we applied the theory of the Effective Sample Size, to the diffusion multi-compartment models, as a way of determining a relatively general target for the number of samples needed to characterize parameter distributions for different models and data sets. We conclude that adaptive Metropolis methods increase MCMC performance and select the Adaptive Metropolis-Within-Gibbs (AMWG) algorithm as the primary method. We furthermore advise to initialize the sampling with an MLE point estimate, in which case 100 to 200 samples are sufficient as a burn-in. Finally, we advise against thinning in most use-cases and as a relatively general target for the number of samples, we recommend a multivariate Effective Sample Size of 2,200

Compressed Sensing Diffusion Spectrum Imaging for Accelerated Diffusion Microstructure MRI in Long-Term Population Imaging

Mapping non-invasively the complex microstructural architecture of the living human brain, diffusion magnetic resonance imaging (dMRI) is one of the core imaging modalities in current population studies. For the application in longitudinal population imaging, the dMRI protocol should deliver reliable data with maximum potential for future analysis. With the recent introduction of novel MRI hardware, advanced dMRI acquisition strategies can be applied within reasonable scan time. In this work we conducted a pilot study based on the requirements for high resolution dMRI in a long-term and high throughput population study. The key question was: can diffusion spectrum imaging accelerated by compressed sensing theory (CS-DSI) be used as an advanced imaging protocol for microstructure dMRI in a long-term population imaging study? As a minimum requirement we expected a high level of agreement of several diffusion metrics derived from both CS-DSI and a 3-shell high angular resolution diffusion imaging (HARDI) acquisition, an established imaging strategy used in other population studies. A wide spectrum of state-of-the-art diffusion processing and analysis techniques was applied to the pilot study data including quantitative diffusion and microstructural parameter mapping, fiber orientation estimation and white matter fiber tracking. When considering diffusion weighted images up to the same maximum diffusion weighting for both protocols, group analysis across 20 subjects indicates that CS-DSI performs comparable to 3-shell HARDI in the estimation of diffusion and microstructural parameters. Further, both protocols provide similar results in the estimation of fiber orientations and for local fiber tracking. CS-DSI provides high radial resolution while maintaining high angular resolution and it is well-suited for analysis strategies that require high b-value acquisitions, such as CHARMED modeling and biomarkers from the diffusion propagator.</p

Associations of digital neuro-signatures with molecular and neuroimaging measures of brain resilience: The altoida large cohort study

BackgroundMixed results in the predictive ability of traditional biomarkers to determine cognitive functioning and changes in older adults have led to misdiagnosis and inappropriate treatment plans to address mild cognitive impairment and dementia among older adults. To address this critical gap, the primary goal of the current study is to investigate whether a digital neuro signature (DNS-br) biomarker predicted global cognitive functioning and change over time relative among cognitively impaired and cognitive healthy older adults. The secondary goal is to compare the effect size of the DNS-br biomarker on global cognitive functioning compared to traditional imaging and genomic biomarkers. The tertiary goal is to investigate which demographic and clinical factors predicted DNS-br in cognitively impaired and cognitively healthy older adults. MethodsWe conducted two experiments (Study A and Study B) to assess DNS for brain resilience (DNS-br) against the established FDG-PET brain imaging signature for brain resilience, based on a 10 min digital cognitive assessment tool. Study A was a semi-naturalistic observational study that included 29 participants, age 65+, with mild to moderate mild cognitive impairment and AD diagnosis. Study B was also a semi-naturalistic observational multicenter study which included 496 participants (213 mild cognitive impairment (MCI) and 283 cognitively healthy controls (HC), a total of 525 participants-cognitively healthy (n = 283) or diagnosed with MCI (n = 213) or AD (n = 29). ResultsDNS-br total score and majority of the 11 DNS-br neurocognitive subdomain scores were significantly associated with FDG-PET resilience signature, PIB ratio, cerebral gray matter and white matter volume after adjusting for multiple testing. DNS-br total score predicts cognitive impairment for the 80+ individuals in the Altoida large cohort study. We identified a significant interaction between the DNS-br total score and time, indicating that participants with higher DNS-br total score or FDG-PET in the resilience signature would show less cognitive decline over time. ConclusionOur findings highlight that a digital biomarker predicted cognitive functioning and change, which established biomarkers are unable to reliably do. Our findings also offer possible etiologies of MCI and AD, where education did not protect against cognitive decline

Augmented reality versus standard tests to assess cognition and function in early Alzheimer’s disease

Abstract Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer’s disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUCclinic_visit = 0.84 [0.75–0.93], AUCat_home = 0.77 [0.61–0.93]) was as good as the cognitive score (AUC = 0.85 [0.78–0.93]), while for classifying the preAD group, the digital score (AUCclinic_visit = 0.66 [0.53–0.78], AUCat_home = 0.76 [0.61–0.91]) was superior to the cognitive score (AUC = 0.55 [0.42–0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p < 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p < 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aβ-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests

Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients

Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients

Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients