In-vivo neuronal dysfunction by Aß and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer's disease.

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aß) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aß- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aß and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aß-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aß and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aß and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aß-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.

Single-nucleus RNA velocity reveals critical synaptic and cell-cycle dysregulations in neuropathologically confirmed Alzheimer's disease.

Typical differential single-nucleus gene expression (snRNA-seq) analyses in Alzheimer's disease (AD) provide fixed snapshots of cellular alterations, making the accurate detection of temporal cell changes challenging. To characterize the dynamic cellular and transcriptomic differences in AD neuropathology, we apply the novel concept of RNA velocity to the study of single-nucleus RNA from the cortex of 60 subjects with varied levels of AD pathology. RNA velocity captures the rate of change of gene expression by comparing intronic and exonic sequence counts. We performed differential analyses to find the significant genes driving both cell type-specific RNA velocity and expression differences in AD, extensively compared these two transcriptomic metrics, and clarified their associations with multiple neuropathologic traits. The results were cross-validated in an independent dataset. Comparison of AD pathology-associated RNA velocity with parallel gene expression differences reveals sets of genes and molecular pathways that underlie the dynamic and static regimes of cell type-specific dysregulations underlying the disease. Differential RNA velocity and its linked progressive neuropathology point to significant dysregulations in synaptic organization and cell development across cell types. Notably, most of the genes underlying this synaptic dysregulation showed increased RNA velocity in AD subjects compared to controls. Accelerated cell changes were also observed in the AD subjects, suggesting that the precocious depletion of precursor cell pools might be associated with neurodegeneration. Overall, this study uncovers active molecular drivers of the spatiotemporal alterations in AD and offers novel insights towards gene- and cell-centric therapeutic strategies accounting for dynamic cell perturbations and synaptic disruptions.

Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions.

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types' contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.

Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.

Unified epigenomic, transcriptomic, proteomic, and metabolomic taxonomy of Alzheimer's disease progression and heterogeneity.

Alzheimer's disease (AD) is a heterogeneous disorder with abnormalities in multiple biological domains. In an advanced machine learning analysis of postmortem brain and in vivo blood multi-omics molecular data (N = 1863), we integrated epigenomic, transcriptomic, proteomic, and metabolomic profiles into a multilevel biological AD taxonomy. We obtained a personalized multilevel molecular index of AD dementia progression that predicts severity of neuropathologies, and identified three robust molecular-based subtypes that explain much of the pathologic and clinical heterogeneity of AD. These subtypes present distinct patterns of alteration in DNA methylation, RNA, proteins, and metabolites, identifiable in the brain and subsequently in blood. In addition, the genetic variations that predispose to the various AD subtypes in brain predict distinct spatial patterns of alteration in cell types, suggesting a unique influence of each putative AD variant on neuropathological mechanisms. These observations support that an individually tailored multi-omics molecular taxonomy of AD may represent distinct targets for preventive or treatment interventions.

Personalized brain models identify neurotransmitter receptor changes in Alzheimer's disease.

Alzheimer's disease involves many neurobiological alterations from molecular to macroscopic spatial scales, but we currently lack integrative, mechanistic brain models characterizing how factors across different biological scales interact to cause clinical deterioration in a way that is subject-specific or personalized. As important signalling molecules and mediators of many neurobiological interactions, neurotransmitter receptors are promising candidates for identifying molecular mechanisms and drug targets in Alzheimer's disease. We present a neurotransmitter receptor-enriched multifactorial brain model, which integrates spatial distribution patterns of 15 neurotransmitter receptors from post-mortem autoradiography with multiple in vivo neuroimaging modalities (tau, amyloid-ß and glucose PET, and structural, functional and arterial spin labelling MRI) in a personalized, generative, whole-brain formulation. In a heterogeneous aged population (n = 423, ADNI data), models with personalized receptor-neuroimaging interactions showed a significant improvement over neuroimaging-only models, explaining about 70% (±20%) of the variance in longitudinal changes to the six neuroimaging modalities. In Alzheimer's disease patients (n = 25, ADNI data), receptor-imaging interactions explained up to 39.7% (P < 0.003, family-wise error-rate-corrected) of inter-individual variability in cognitive deterioration, via an axis primarily affecting executive function. Notably, based on their contribution to the clinical severity in Alzheimer's disease, we found significant functional alterations to glutamatergic interactions affecting tau accumulation and neural activity dysfunction and GABAergic interactions concurrently affecting neural activity dysfunction, amyloid and tau distributions, as well as significant cholinergic receptor effects on tau accumulation. Overall, GABAergic alterations had the largest effect on cognitive impairment (particularly executive function) in our Alzheimer's disease cohort (n = 25). Furthermore, we demonstrate the clinical applicability of this approach by characterizing subjects based on individualized 'fingerprints' of receptor alterations. This study introduces the first robust, data-driven framework for integrating several neurotransmitter receptors, multimodal neuroimaging and clinical data in a flexible and interpretable brain model. It enables further understanding of the mechanistic neuropathological basis of neurodegenerative progression and heterogeneity, and constitutes a promising step towards implementing personalized, neurotransmitter-based treatments.

Integrating molecular, histopathological, neuroimaging and clinical neuroscience data with NeuroPM-box.

Understanding and treating heterogeneous brain disorders requires specialized techniques spanning genetics, proteomics, and neuroimaging. Designed to meet this need, NeuroPM-box is a user-friendly, open-access, multi-tool cross-platform software capable of characterizing multiscale and multifactorial neuropathological mechanisms. Using advanced analytical modeling for molecular, histopathological, brain-imaging and/or clinical evaluations, this framework has multiple applications, validated here with synthetic (N > 2900), in-vivo (N = 911) and post-mortem (N = 736) neurodegenerative data, and including the ability to characterize: (i) the series of sequential states (genetic, histopathological, imaging or clinical alterations) covering decades of disease progression, (ii) concurrent intra-brain spreading of pathological factors (e.g., amyloid, tau and alpha-synuclein proteins), (iii) synergistic interactions between multiple biological factors (e.g., toxic tau effects on brain atrophy), and (iv) biologically-defined patient stratification based on disease heterogeneity and/or therapeutic needs. This freely available toolbox ( neuropm-lab.com/neuropm-box.html ) could contribute significantly to a better understanding of complex brain processes and accelerating the implementation of Precision Medicine in Neurology.

Integrated transcriptomic and neuroimaging brain model decodes biological mechanisms in aging and Alzheimer's disease.

Both healthy aging and Alzheimer's disease (AD) are characterized by concurrent alterations in several biological factors. However, generative brain models of aging and AD are limited in incorporating the measures of these biological factors at different spatial resolutions. Here, we propose a personalized bottom-up spatiotemporal brain model that accounts for the direct interplay between hundreds of RNA transcripts and multiple macroscopic neuroimaging modalities (PET, MRI). In normal elderly and AD participants, the model identifies top genes modulating tau and amyloid-ß burdens, vascular flow, glucose metabolism, functional activity, and atrophy to drive cognitive decline. The results also revealed that AD and healthy aging share specific biological mechanisms, even though AD is a separate entity with considerably more altered pathways. Overall, this personalized model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying effective genetic targets for extending healthy aging and treating AD progression.

Blood and brain gene expression trajectories mirror neuropathology and clinical deterioration in neurodegeneration.

Most prevalent neurodegenerative disorders take decades to develop and their early detection is challenged by confounding non-pathological ageing processes. For all neurodegenerative conditions, we continue to lack longitudinal gene expression data covering their large temporal evolution, which hinders the understanding of the underlying dynamic molecular mechanisms. Here, we overcome this key limitation by introducing a novel gene expression contrastive trajectory inference (GE-cTI) method that reveals enriched temporal patterns in a diseased population. Evaluated on 1969 subjects in the spectrum of late-onset Alzheimer's and Huntington's diseases (from ROSMAP, HBTRC and ADNI datasets), this unsupervised machine learning algorithm strongly predicts neuropathological severity (e.g. Braak, amyloid and Vonsattel stages). Furthermore, when applied to in vivo blood samples at baseline (ADNI), it significantly predicts clinical deterioration and conversion to advanced disease stages, supporting the identification of a minimally invasive (blood-based) tool for early clinical screening. This technique also allows the discovery of genes and molecular pathways, in both peripheral and brain tissues, that are highly predictive of disease evolution. Eighty-five to ninety per cent of the most predictive molecular pathways identified in the brain are also top predictors in the blood. These pathways support the importance of studying the peripheral-brain axis, providing further evidence for a key role of vascular structure/functioning and immune system response. The GE-cTI is a promising tool for revealing complex neuropathological mechanisms, with direct implications for implementing personalized dynamic treatments in neurology.