Introduction We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. Methods Ten patients with mild cognitive impairment due to underlying AD received 1‐hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Results Gamma flicker was safe, tolerable, and adherable. Participants’ neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. Discussion These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

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Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N=8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R=−0.86, p<0.01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.

We explore the association between three Alzheimer’s disease-related and ten inflammation-related CSF markers and freezing of gait (FOG) in patients with Parkinson’s disease (PD). The study population includes PD patients with FOG (PD-FOG, N = 12), without FOG (PD-NoFOG, N = 19), and healthy controls (HC, N = 12). Age and PD duration are not significantly different between groups. After adjusting for covariates and multiple comparisons, the anti-inflammatory marker, fractalkine, is significantly decreased in the PD groups compared to HC (P = 0.002), and further decreased in PD-FOG compared to PD-NoFOG (P = 0.007). The Alzheimer’s disease-related protein, Aβ42, is increased in PD-FOG compared to PD-NoFOG and HC (P = 0.001). Group differences obtained in individual biomarker analyses are confirmed with multivariate discriminant partial least squares regression (P < 0.001). High levels of Aβ42 in PD-FOG patients supports an increase over time from early to advanced state. Low levels of fractalkine might suggest anti-inflammatory effect. These findings warrant replication.

breast cancer (TNBC), which lacks hormone receptor and excess HER2 protein expression, is the most aggressive type of breast cancer, with higher rates of metastasis and shorter overall survival. [3] Immunotherapies have emerged as one of the most promising tools in the fight against breast cancer. However, response rates in the clinic are disappointingly low-only ≈16% of patients respond to immune checkpoint blockade (ICB) therapy, [4] and no vaccine therapies have been approved for breast cancer, despite successes in melanoma and prostate cancer. [5,6] These poor outcomes reflect an unmet need in understanding the differences in patient responses and tools to develop new and better immunotherapeutic strategies for patients who are less likely to respond to immunotherapies.Substantial efforts in the immune oncology field are currently dedicated to unraveling the determinants of the anti-cancer immune response, given its role in disease progression and response to immunotherapy. Immunologically "hot" tumors generally have more immune infiltration, while "cold" tumors harbor fewer immune cells. [7] Additionally, other stratifications have been identified, with the potential to influence immunotherapy responses-among immune-infiltrated (hot) tumors, macrophages, and CD8 T cells have been shown to have opposite impacts on patient survival, and in turn on Immunotherapy has emerged as one of the most powerful anti-cancer therapies but is stymied by the limits of existing preclinical models with respect to disease latency and reproducibility. Additionally, the influence of differing immune microenvironments within tumors observed clinically and associated with immunotherapeutic resistance cannot be tuned to facilitate drug testing workflows without changing model system or laborious genetic approaches. To address this testing platform gap in the immune oncology drug development pipeline, the authors deploy engineered biomaterials as scaffolds to increase tumor formation rate, decrease disease latency, and diminish variability of immune infiltrates into tumors formed from murine mammary carcinoma cell lines implanted into syngeneic mice. By altering synthetic gel formulations that reshape infiltrating immune cells within the tumor, responsiveness of the same tumor model to varying classes of cancer immunotherapies, including in situ vaccination with a molecular adjuvant and immune checkpoint blockade, diverge. These results demonstrate the significant role the local immune microenvironment plays in immunotherapeutic response. These engineered tumor immune microenvironments therefore improve upon the limitations of current breast tumor models used for immune oncology drug screening to enable immunotherapeutic testing relevant to the variability in tumor immune microenvironments underlying immunotherapeutic resistance seen in human patients.

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BackgroundOur understanding of the impact of astrocytes in Alzheimer’s disease (AD) is hindered by the lack of astrocyte-specific omics data from patients diagnosed with dementia due to AD. Studies aiming to profile human AD astrocytes—including single-nucleus RNA sequencing—were limited by the low number of differentially expressed genes detected, and by the small size of cohorts. We improved on prior studies with a novel systems-biology-based approach.Methods Human astrocytic and neuronal gene clusters were generated from RNA sequencing data from isolated healthy human brain cells using a cell-type enrichment score and clustering. The cell-specific gene clusters were localized in 766 subjects from three AD whole-brain transcriptomes generated by the Mount Sinai Hospital, the Mayo Clinic, and the Religious Order Study/Memory and Aging Project (ROSMAP), which also contains subjects with mild cognitive impairment (MCI). Gene clusters were organized into functional categories and subcategories using manual curation. Functional changes among subject groups were determined by gene set variation analysis (GSVA) and principal component analysis (PCA).Results Hierarchical clustering of transcriptomic data revealed molecular heterogeneity in individuals with the same clinical diagnosis. Particularly in the Mayo Clinic and ROSMAP cohorts, over 50% of Controls presented massive down-regulation of genes encoding for synaptic proteins, as widely documented in AD, suggesting that these subjects might have been at a preclinical stage at the time of death. Conversely, approximately 30% of AD patients showed preservation of neuronal genes as if they were non demented subjects, suggesting that they were resilient to AD pathology (present, according to CERAD and Braak scoring), but developed dementia due to comorbidities. The astrocytic gene profiles in AD patients presenting down-regulation of neuronal genes were termed ‘AD astrocytes’. According to GSVA and PCA, AD astrocytes showed down-regulation of genes encoding for mitochondrial and endolysosomal proteins, and up-regulation of genes related to perisynaptic astrocytic processes (PAP), and survival and stress responses.Discussion Astrocytes undergo a profound transcriptional change in a remarkable percentage of Control, MCI and AD subjects, affecting organelles and astrocyte-neuron interactions. We argue that therapies preventing organelle dysfunction in astrocytes may protect neural circuits in preclinical and clinical AD.

INTRODUCTIONOur understanding of the impact of astrocytes in Alzheimer’s disease (AD) is hindered by limited astrocyte-specific data from AD and mild cognitive impairment (MCI).METHODSAn astrocytic gene cluster was generated from RNAseq data of isolated healthy human brain cells using a cell-type enrichment score and clustering. The astrocytic cluster was localized in whole-brain transcriptomes from three independent cohorts totaling 766 individuals with MCI or AD, and controls. Changes in astrocytic gene expression were analyzed by gene set and principal component analyses.RESULTSIndividuals with the same clinical diagnosis, including controls, were molecularly heterogeneous. Astrocytes in MCI and AD showed downregulation of ‘mitochondria’ and ‘endomembrane system’, and upregulation of ‘stress responses’, ‘plasticity’, and ‘perisynaptic astrocyte processes’/’gliotransmission’.DISCUSSIONAstrocytes undergo a profound transcriptional change in MCI and AD, affecting organelles and astrocyte-neuron interactions. We posit that therapies preventing organelle dysfunction in astrocytes may protect neural circuits in AD.