The differential diagnosis of neurodegenerative diseases, characterized by overlapping symptoms, may be challenging. Brain imaging coupled with artificial intelligence has been previously proposed for diagnostic support, but most of these methods have been trained to discriminate only isolated diseases from controls. Here, we develop a novel machine learning framework, named lifespan tree of brain anatomy, dedicated to the differential diagnosis between multiple diseases simultaneously. It integrates the modeling of volume changes for 124 brain structures during the lifespan with non-linear dimensionality reduction and synthetic sampling techniques to create easily interpretable representations of brain anatomy over the course of disease progression. As clinically relevant proof-of-concept applications, we constructed a cognitive lifespan tree of brain anatomy for the differential diagnosis of six causes of neurodegenerative dementia and a motor lifespan tree of brain anatomy for the differential diagnosis of four causes of parkinsonism using 37594 MRI as a training dataset. This original approach enhanced significantly the efficiency of differential diagnosis in the external valid
Identifying preclinical biomarkers of neurodegenerative diseases remains a major challenge in aging research. In this study, we demonstrate that frequent "Don't know/can't remember" (DK) responses, often treated as missing data in touchscreen questionnaires, serve as a novel digital behavioral biomarker of early cognitive vulnerability and neurodegenerative disease risk. Using data from 502,234 UK Biobank participants, we stratified individuals based on DK response frequency (0-1, 2-4, 5-7, >7) and observed a robust, dose-dependent association with an increased risk of Alzheimer's disease (HR = 1.64, 95% CI: 1.26-2.14) and vascular dementia (HR = 1.93, 95% CI: 1.37-2.72), independent of established risk factors. As DK response frequency increased, participants exhibited higher BMI, reduced physical activity, higher smoking rates, and a higher prevalence of chronic diseases, particularly hypertension, diabetes, and depression. Further analysis revealed a dose-dependent relationship between DK response frequency and the risk of Alzheimer's disease and vascular dementia, with high DK responders showing early neurodegenerative changes, marked by elevated levels of Abeta40, Abeta42,
Parkinson's disease ranks as the second most prevalent neurodegenerative disorder globally. This research aims to develop a system leveraging Mixed Reality capabilities for tracking and assessing eye movements. In this paper, we present a medical scenario and outline the development of an application designed to capture eye-tracking signals through Mixed Reality technology for the evaluation of neurodegenerative diseases. Additionally, we introduce a pipeline for extracting clinically relevant features from eye-gaze analysis, describing the capabilities of the proposed system from a medical perspective. The study involved a cohort of healthy control individuals and patients suffering from Parkinson's disease, showcasing the feasibility and potential of the proposed technology for non-intrusive monitoring of eye movement patterns for the diagnosis of neurodegenerative diseases. Clinical relevance - Developing a non-invasive biomarker for Parkinson's disease is urgently needed to accurately detect the disease's onset. This would allow for the timely introduction of neuroprotective treatment at the earliest stage and enable the continuous monitoring of intervention outcomes. The abili
A central challenge in modeling neurodegenerative diseases is connecting cellular-level mechanisms to tissue-level pathology, in particular to determine whether pathology is driven primarily by cell-autonomous triggers or by propagation from cells that are already in a pathological, runaway aggregation state. To bridge this gap, we here develop a bottom-up physical model that explicitly incorporates these two fundamental cell-level drivers of protein aggregation dynamics. We show that our model naturally explains the characteristic long, slow development of pathology followed by a rapid acceleration, a hallmark of many neurodegenerative diseases. Furthermore, the model reveals the existence of a critical switch point at which the system's dynamics transition from being dominated by slow, spontaneous formation of diseased cells to being driven by fast propagation. This framework provides a robust physical foundation for interpreting pathological data and offers a method to predict which class of therapeutic strategies is best matched to the underlying drivers of a specific disease.
Due to the aging of the world population and westernization of lifestyles, the prevalence of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is rapidly rising and is expected to put a strong socioeconomic burden on health systems worldwide. Due to the limited success of clinical trials of therapies against neurodegenerative diseases, research has extended its scope to a systems medicine point of view, with a particular focus on the gastrointestinal-brain axis as a potential main actor in disease development and progression. Microbiome as well as metabolome studies along the gastrointestinal-brain axis have already revealed important insights into disease pathomechanisms. Both the microbiome and metabolome can be easily manipulated by dietary and lifestyle interventions, and might thus offer novel, readily available therapeutic options to prevent the onset as well as the progression of PD and AD. This review summarizes our current knowledge on the association between microbiota, metabolites, and neurodegeneration in light of the gastrointestinal-brain axis. In this context, we also illustrate state-of-the art methods of microbiome and metabol
Mechanistic models of progressive neurodegeneration offer great potential utility for clinical use and novel treatment development. Toward this end, several connectome-informed models of neuroimaging biomarkers have been proposed. However, these models typically do not scale well beyond a small number of biomarkers due to heterogeneity in individual disease trajectories and a large number of parameters. To address this, we introduce the Connectome-based Monotonic Inference of Neurodegenerative Dynamics (COMIND). The model combines concepts from diffusion and logistic models with structural brain connectivity. This guarantees monotonic disease trajectories while maintaining a limited number of parameters to improve scalability. We evaluate our model on simulated data as well as on the Parkinson's Progressive Markers Initiative (PPMI) data. Our model generalizes to anatomical imaging representations from a standard brain atlas without the need to reduce biomarker number.
Recent advances in Artificial Intelligence (AI) and the exploration of noninvasive, objective biomarkers, such as speech signals, have encouraged the development of algorithms to support the early diagnosis of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Voice changes in subjects suffering from ALS typically manifest as progressive dysarthria, which is a prominent neurodegenerative symptom because it affects patients as the disease progresses. Since voice signals are complex data, the development and use of advanced AI techniques are fundamental to extracting distinctive patterns from them. Validating AI algorithms for ALS diagnosis and monitoring using voice signals is challenging, particularly due to the lack of annotated reference datasets. In this work, we present the outcome of a collaboration between a multidisciplinary team of clinicians and Machine Learning experts to create both a clinically annotated validation dataset and the "Speech Analysis for Neurodegenerative Diseases" (SAND) challenge based on it. Specifically, by analyzing voice disorders, the SAND challenge provides an opportunity to develop, test, and evaluate AI models for the auto
High Frequency Oscillations (HFOs), rapid bursts of brain activity above 80 Hz, have emerged as a highly specific biomarker for epileptogenic tissue. Recent evidence suggests that HFOs are also present in Alzheimer's Disease (AD), reflecting underlying network hyperexcitability and offering a promising, noninvasive tool for early diagnosis and disease tracking. This synoptic review provides a comprehensive analysis of publicly available electroencephalography (EEG) datasets relevant to HFO research in neurodegenerative disorders. We conducted a bibliometric analysis of 1,222 articles, revealing a significant and growing research interest in HFOs, particularly within the last ten years. We then systematically profile and compare key public datasets, evaluating their participant cohorts, data acquisition parameters, and accessibility, with a specific focus on their technical suitability for HFO analysis. Our comparative synthesis highlights critical methodological heterogeneity across datasets, particularly in sampling frequency and recording paradigms, which poses challenges for cross-study validation, but also offers opportunities for robustness testing. By consolidating disparate
Progressive neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), exhibit complex, nonlinear trajectories that challenge deterministic modeling. Traditional time-domain analyses of multiomic and neuroimaging data often fail to capture hidden oscillatory patterns, limiting predictive accuracy. We propose a theoretical mathematical framework that transforms time-series data into frequency or s-domain using Fourier and Laplace transforms, models neuronal dynamics via Hamiltonian formulations, and employs quantum-classical hybrid computing with variational quantum eigensolvers (VQE) for enhanced pattern detection. This theoretical construct serves as a foundation for future empirical works in quantum-enhanced analysis of neurodegenerative diseases. We extend this to quaternionic representations with three imaginary axes ($i, j, k$) to model multistate Hamiltonians in multifaceted disorders, drawing from quantum neuromorphic computing to capture entangled neural dynamics \citep{Pehle2020, Emani2019}. This approach leverages quantum advantages in handling high-dimensional amplitude-phase
Rankings of scholarly journals based on citation data are often met with skepticism by the scientific community. Part of the skepticism is due to disparity between the common perception of journals' prestige and their ranking based on citation counts. A more serious concern is the inappropriate use of journal rankings to evaluate the scientific influence of authors. This paper focuses on analysis of the table of cross-citations among a selection of Statistics journals. Data are collected from the Web of Science database published by Thomson Reuters. Our results suggest that modelling the exchange of citations between journals is useful to highlight the most prestigious journals, but also that journal citation data are characterized by considerable heterogeneity, which needs to be properly summarized. Inferential conclusions require care in order to avoid potential over-interpretation of insignificant differences between journal ratings. Comparison with published ratings of institutions from the UK's Research Assessment Exercise shows strong correlation at aggregate level between assessed research quality and journal citation `export scores' within the discipline of Statistics.
Neurodegenerative diseases are characterized as the progressive loss of neural cells, e.g. neurons, glial cells. Ageing, monogenic variations, viral infections, and many other factors are determined and speculated as causes for them. While many individual genes, such as APP for Alzheimer disease and HTT for Huntington disease, and biological pathways are studied for neurodegenerative diseases, system-wide pathogenesis studies are limited. In this study, we carried out a meta-analysis of RNA-Seq studies for three neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS) to minimize the batch effect derived differences and identify the similarly altered factors among studies. Our main assumption is that these three diseases share some pathological pathway pattern. For this purpose, we downloaded publicly available Alzheimer's disease (84 patients + 33 controls = 117 individuals), Parkinson's disease (28 patients + 43 controls = 71 individuals) and ALS (2 studies: 46 patients + 25 control = 71 individuals) RNA-Seq data from Sequence Read Archive (SRA) database. The significantly differentially expressed genes common to these st
This work presents a structure-preserving, high-order, unconditionally stable numerical method for approximating the solution to the Fisher-Kolmogorov equation on polytopic meshes, with a particular focus on its application in simulating misfolded protein spreading in neurodegenerative diseases. The model problem is reformulated using an entropy variable to guarantee solution positivity, boundedness, and satisfaction of a discrete entropy-stability inequality at the numerical level. The scheme combines a local discontinuous Galerkin method on polytopal meshes for the space discretization with a $ν$-step backward differentiation formula for the time integration. Implementation details are discussed, including a detailed derivation of the linear systems arising from Newton's iteration. The accuracy and robustness of the proposed method are demonstrated through extensive numerical tests. Finally, the method's practical performance is demonstrated through simulations of $α$-synuclein propagation in a two-dimensional brain geometry segmented from MRI data, providing a relevant computational framework for modeling synucleopathies (such as Parkinson's disease) and, more generally, neurode
Voice biomarkers--human-generated acoustic signals such as speech, coughing, and breathing--are promising tools for scalable, non-invasive detection and monitoring of mental health and neurodegenerative diseases. Yet, their clinical adoption remains constrained by inconsistent quality and limited usability of publicly available datasets. To address this gap, we present the first systematic FAIR (Findable, Accessible, Interoperable, Reusable) evaluation of 27 publicly available voice biomarker datasets focused on these disease areas. Using the FAIR Data Maturity Model and a structured, priority-weighted scoring method, we assessed FAIRness at subprinciple, principle, and composite levels. Our analysis revealed consistently high Findability but substantial variability and weaknesses in Accessibility, Interoperability, and Reusability. Mental health datasets exhibited greater variability in FAIR scores, while neurodegenerative datasets were slightly more consistent. Repository choice also significantly influenced FAIRness scores. To enhance dataset quality and clinical utility, we recommend adopting structured, domain-specific metadata standards, prioritizing FAIR-compliant repositori
Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent and incurable neurodegenerative diseases (NDs) worldwide, for which early diagnosis is critical to delay their progression. However, the high dimensionality of multi-metric data with diverse structural forms, the heterogeneity of neuroimaging and phenotypic data, and class imbalance collectively pose significant challenges to early ND diagnosis. To address these challenges, we propose a dynamically weighted dual graph attention network (DW-DGAT) that integrates: (1) a general-purpose data fusion strategy to merge three structural forms of multi-metric data; (2) a dual graph attention architecture based on brain regions and inter-sample relationships to extract both micro- and macro-level features; and (3) a class weight generation mechanism combined with two stable and effective loss functions to mitigate class imbalance. Rigorous experiments, based on the Parkinson Progression Marker Initiative (PPMI) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies, demonstrate the state-of-the-art performance of our approach.
Neurodegenerative diseases are associated with the assembly of specific proteins into oligomers and fibrillar aggregates. At the brain scale, these protein assemblies can diffuse through the brain and seed other regions, creating an autocatalytic protein progression. The growth and transport of these assemblies depend on various mechanisms that can be targeted therapeutically. Here, we use spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain to study the effect of different drugs on whole-brain Alzheimer's disease progression.
Using the Scopus dataset (1996-2007) a grand matrix of aggregated journal-journal citations was constructed. This matrix can be compared in terms of the network structures with the matrix contained in the Journal Citation Reports (JCR) of the Institute of Scientific Information (ISI). Since the Scopus database contains a larger number of journals and covers also the humanities, one would expect richer maps. However, the matrix is in this case sparser than in the case of the ISI data. This is due to (i) the larger number of journals covered by Scopus and (ii) the historical record of citations older than ten years contained in the ISI database. When the data is highly structured, as in the case of large journals, the maps are comparable, although one may have to vary a threshold (because of the differences in densities). In the case of interdisciplinary journals and journals in the social sciences and humanities, the new database does not add a lot to what is possible with the ISI databases.
Protein aggregates in the brain play a central role in cognitive decline and structural damage associated with neurodegenerative diseases. For instance, in Alzheimer's disease the formation of Amyloid-beta plaques and tau proteins neurofibrillary tangles follows from the accumulation of different proteins into large aggregates through specific mechanisms such as nucleation and elongation. These mechanisms have been studied in vitro where total protein mass is conserved. However, in vivo, clearance mechanisms may play an important role in limiting the formation of aggregates. Here, we generalise classical models of protein aggregation to take into account both production of monomers and the clearance of protein aggregates. Depending on the clearance model, we show that there may be a critical clearance value above which aggregation does not take place. Our result offers further evidence in support of the hypotheses that clearance mechanisms play a potentially crucial role in neurodegenerative disease initiation and progression; and as such, are a possible therapeutic target.
Progressive cognitive decline spanning across decades is characteristic of Alzheimer's disease (AD). Various predictive models have been designed to realize its early onset and study the long-term trajectories of cognitive test scores across populations of interest. Research efforts have been geared towards superimposing patients' cognitive test scores with the long-term trajectory denoting gradual cognitive decline, while considering the heterogeneity of AD. Multiple trajectories representing cognitive assessment for the long-term have been developed based on various parameters, highlighting the importance of classifying several groups based on disease progression patterns. In this study, a novel method capable of self-organized prediction, classification, and the overlay of long-term cognitive trajectories based on short-term individual data was developed, based on statistical and differential equation modeling. We validated the predictive accuracy of the proposed method for the long-term trajectory of cognitive test score results on two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and the Japanese ADNI study. We also presented two practical illustrations
Neurodegenerative diseases are closely associated with the amplification and invasion of toxic proteins. In particular Alzheimer's disease is characterized by the systematic progression of amyloid-$β$ and $τ$-proteins in the brain. These two protein families are coupled and it is believed that their joint presence greatly enhances the resulting damage. Here, we examine a class of coupled chemical kinetics models of healthy and toxic proteins in two spatial dimensions. The anisotropic diffusion expected to take place within the brain along axonal pathways is factored in the models and produces a filamentary, predominantly one-dimensional transmission. Nevertheless, the potential of the anisotropic models towards generating interactions taking advantage of the two-dimensional landscape is showcased. Finally, a reduction of the models into a simpler family of generalized Fisher-Kolmogorov-Petrovskii-Piskunov (FKPP) type systems is examined. It is seen that the latter captures well the qualitative propagation features, although it may somewhat underestimate the concentrations of the toxic proteins.
We introduce Disease Knowledge Transfer (DKT), a novel technique for transferring biomarker information between related neurodegenerative diseases. DKT infers robust multimodal biomarker trajectories in rare neurodegenerative diseases even when only limited, unimodal data is available, by transferring information from larger multimodal datasets from common neurodegenerative diseases. DKT is a joint-disease generative model of biomarker progressions, which exploits biomarker relationships that are shared across diseases. Our proposed method allows, for the first time, the estimation of plausible, multimodal biomarker trajectories in Posterior Cortical Atrophy (PCA), a rare neurodegenerative disease where only unimodal MRI data is available. For this we train DKT on a combined dataset containing subjects with two distinct diseases and sizes of data available: 1) a larger, multimodal typical AD (tAD) dataset from the TADPOLE Challenge, and 2) a smaller unimodal Posterior Cortical Atrophy (PCA) dataset from the Dementia Research Centre (DRC), for which only a limited number of Magnetic Resonance Imaging (MRI) scans are available. Although validation is challenging due to lack of data i