Therapeutic evaluation of low‐dose IL‐2‐based immunomodulatory approach in patients with early AD.

Background: Chronic innate neuroinflammation mediated by microglia and astrocytes in response to Aβ and pathological Tau species is a cardinal feature of AD that contributes to disease pathogenesis. Accumulating evidence now also highlight an instrumental role of T cells and peripheral‐central immune crosstalk in the pathophysiology of AD. Both preclinical and clinical reports suggest the potential therapeutic interest of peripheral immunomodulatory approaches aimed at amplifying regulatory T cells (Tregs), e.

Imagine, Discover, Inspire: Proceedings of the 4th International Conference of the Trisomy 21 Research Society.

Down syndrome (DS) or trisomy 21 (T21) is present in a significant number of children and adults around the world and is associated with cognitive and medical challenges. Through research, the T21 Research Society (T21RS), established in 2014, unites a worldwide community dedicated to understanding the impact of T21 on biological systems and improving the quality of life of people with DS across the lifespan. T21RS hosts an international conference every two years to support collaboration, dissemination, and information sharing for this goal.

The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer's disease.

The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer's disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD.

Automated deep learning segmentation of neuritic plaques and neurofibrillary tangles in Alzheimer disease brain sections using a proprietary software.

Neuropathological diagnosis of Alzheimer disease (AD) relies on semiquantitative analysis of phosphorylated tau-positive neurofibrillary tangles (NFTs) and neuritic plaques (NPs), without consideration of lesion heterogeneity in individual cases. We developed a deep learning workflow for automated annotation and segmentation of NPs and NFTs from AT8-immunostained whole slide images (WSIs) of AD brain sections. Fifteen WSIs of frontal cortex from 4 biobanks with varying tissue quality, staining intensity, and scanning formats were analyzed.

An integrated precision medicine approach in major depressive disorder: a study protocol to create a new algorithm for the prediction of treatment response.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures.

EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model.

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A.

Increased plasma DYRK1A with aging may protect against neurodegenerative diseases.

Early markers are needed for more effective prevention of Alzheimer's disease. We previously showed that individuals with Alzheimer's disease have decreased plasma DYRK1A levels compared to controls. We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer's disease (AD), tauopathies or Down syndrome (DS), and in lymphoblastoids from individuals with DS.

Modifications of the endosomal compartment in fibroblasts from sporadic Alzheimer's disease patients are associated with cognitive impairment.

Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD.

Multi-omics data integration methods and their applications in psychiatric disorders.

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently.

Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology.

The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer's disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology.

Pharmacological Signature and Target Specificity of Inhibitory Circuits Formed by Martinotti Cells in the Mouse Barrel Cortex.

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions.

Ts66Yah, a mouse model of Down syndrome with improved construct and face validity.

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype-phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features.

Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.

Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS.

Theta Band-Power Shapes Amyloid-Driven Longitudinal EEG Changes in Elderly Subjective Memory Complainers At-Risk for Alzheimer's Disease.

Background: Alzheimer's disease (AD) includes progressive symptoms spread along a continuum of preclinical and clinical stages. Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks in elderly cognitively-healthy memory complainers at risk of AD for carrying pathophysiological biomarkers (amyloidopathy and tauopathy).

Objective: We analyzed resting-state electroencephalography (EEG) of 318 cognitively-healthy subjective memory complainers from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24).

Conserved meningeal lymphatic drainage circuits in mice and humans.

Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies.

Association of -Independent Alzheimer Disease Polygenic Risk Score With Brain Amyloid Deposition in Asymptomatic Older Adults.

Background And Objectives: Brain amyloid deposition, a major risk factor for Alzheimer disease (AD), is currently estimated by measuring CSF or plasma amyloid peptide levels or by PET imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on , a major AD genetic risk factor.

Alterations of Neuronal Lysosomes in Alzheimer's Disease and in APPxPS1-KI Mice.

Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer's disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42) intracellularly.

Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology.