Alzheimer & Parkinson

The introduction of anti-amyloid therapies for Alzheimer's disease challenged current care models, particularly for older adults with frailty. The potential low efficacy of anti-amyloid drugs in these patients may be attributed to chronic inflammation, impaired repair mechanisms, and multisystem dysregulation. Neuropathological studies suggested that the accumulation of common brain pathologies may contribute to progressive physical frailty in older age. At present, there is no certified...

CONCLUSIONS: While classical cell lines remain essential for initial mechanistic screening, establishing disease-level relevance requires validation through orthogonal readouts and high-fidelity human models, such as multicellular organoids or blood-brain barrier systems.

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases represent a growing global health crisis. Despite significant research efforts, disease-modifying therapies remain elusive. Immunotherapy, particularly vaccination, offers a promising avenue by leveraging the body's immune system to clear pathological protein aggregates central to these disorders. This review critically analyzes the historical trajectory, current advancements, and...

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by severe cognitive dysfunctions and brain disorders. The emergence of deep learning methods provides a feasible way to develop effective representations for clinical diagnosis of brain diseases. In this study, we proposed a deep manifold representation learning network to characterize the alteration of functional brain connectivity for AD detection. The proposed framework used a convolutional autoencoder (CAE) to infer...

Freezing of gait (FOG) is a disabling motor symptom in Parkinson's disease (PD), linked to impaired motor automaticity and cognitive control. Cognitive strategies like motor imagery (gait imagination, GI) and action observation (gait observation, GO) are used in rehabilitation, but their neural mechanisms are not well understood. This study used EEG to examine midfrontal oscillations during GI and GO in healthy controls (HC, n = 21), PD without FOG (PDFOG-, n = 16), and PD with FOG (PDFOG+, n =...

Alzheimer's disease and related dementias are typically described at two levels: the accumulation of molecular pathology and the emergence of cognitive impairment. Understanding the relationship between pathology, often studied in animal models, and human cognition will require measurements spanning intermediate scales, including single neurons, neuronal populations, and distributed networks. Here we combine longitudinal measurements of behavior and neuronal population activity with fluid and...

CONCLUSIONS: Emergency diagnosis is common and associated with worse clinical outcomes in a wide range of conditions with diverse aetiology. Further research and investment to reduce the number of emergency diagnoses is needed, particularly for diseases where diagnosis in community settings should be expected (e.g., rheumatoid arthritis and COPD), and conditions such as coeliac disease, IBD, and MS, where emergency diagnosis is associated with particularly poor outcomes.

Alzheimer's disease is triggered by amyloid-β, with symptoms linked to synapse loss. Oligomeric amyloid-β, rather than monomeric or fibrillar amyloid-β, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. To define the biologically relevant species, we isolated a receptor-bound amyloid-β pool from Alzheimer's disease brain by release with a receptor antagonist and purification to homogeneity. This discrete receptor-bound...

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain")....

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This systematic review investigates the mediating factors in the relationship between ambient air pollution exposure and cognitive aging. We identified 16 studies examining 72 unique exposure-mediator-outcome associations for six pollutants (PM2.5, PM10, NO2, NOX, black carbon, and PM1 components). The most studied pollutant was PM2.5 (65% of analyses). Cognitive outcomes included memory, cognitive processing speed, and clinically diagnosed conditions such as dementia incidence. Potential...

Parkinson's disease (PD) motor symptoms are linked to excessive beta band (13-35 Hz) oscillations and basal ganglia-cortical (BGC) synchrony, yet their dynamic inter-relation remains unclear. Based on computational modeling, we hypothesize that transient high-beta (20-35 Hz) BGC coupling induces subcortical low-beta (13-20 Hz) amplification. We recorded intraoperative neural signals from the globus pallidus internus and externus (GPi and GPe, respectively) and motor cortex (M1) in 23 PD patients...

Neuroinflammation is a major secondary driver of Alzheimer's disease (AD). In this issue of Cell Chemical Biology, Carnevale et al.¹ demonstrate that S-nitrosylation of the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway sustains pathological neuroinflammation in AD, identifying a promising therapeutic target for this devastating disease.

Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted...

Alzheimer's disease is now defined by underlying pathology, with elevated amyloid-beta (Aβ) sufficient for diagnosis in the absence of cognitive symptoms. We combined longitudinal magnetic resonance imaging and Aβ positron emission tomography data from three cognitively healthy cohorts to examine cortical thickness trajectories in individuals who later converted to Aβ-positive status, using magnetic resonance images acquired years before conversion. Individuals who subsequently developed...

Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome^(1,2). It can be mitigated by mapping to multiple haplotypes represented in a pangenome^(3-5). Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent-offspring trio data. Using Emblask, we assembled 698...

Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to...

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Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, primarily due to the lack of reliable tools for its early and non-invasive diagnosis. Exosomes, nanosized extracellular vesicles secreted by neural and peripheral cells, have emerged as promising biomarkers reflecting the molecular alterations associated with AD pathogenesis. Fourier Transform Infrared (FTIR) spectroscopy, with its capacity to capture unique biochemical fingerprints of biomolecules,...

Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493...