Jeffrey Helgager

Bio: Jeffrey Helgager is an academic researcher from Brigham and Women's Hospital. The author has contributed to research in topics: Medicine & Glioma. The author has an hindex of 6, co-authored 10 publications receiving 201 citations.

Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease

Abstract: The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.

Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma

Abstract: Introduction We describe the imaging findings encountered in GBM patients receiving immune checkpoint blockade and assess the potential of quantitative MRI biomarkers to differentiate patients who derive therapeutic benefit from those who do not.

Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab.

Abstract: Importance:Powassan virus is a rare but increasingly recognized cause of severe neurological disease. Objective:To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. Design, Setting, and Participants:Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. Exposure:Infection with Powassan virus. Main Outcomes and Measures:Results of individual assays compared retrospectively. Results:In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. Conclusions and Relevance:Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

A novel GIT2-BRAF fusion in pilocytic astrocytoma.

Abstract: KIAA1549-BRAF fusion is the most common genetic event in pilocytic astrocytoma (PA), and leads to activation of the mitogen activated protein kinase (MAPK) signaling pathway. Fusions of BRAF with other partner genes, as well as other genetic alterations not involving BRAF but also leading to MAPK pathway activation have been described rarely. We present a new fusion partner in the low-grade glioma of a 10-year-old male, who presented with headaches and recent episodes of seizures. Magnetic resonance imaging (MRI) demonstrated a right temporal lobe tumor. Histological and immunohistochemical evaluation, and a next generation sequencing assay (Oncopanel, Illumina, 500 genes) including breaKmer analysis for chromosomal rearrangements were performed. Histology was remarkable for a low-grade glioma composed of mildly atypical astrocytes with piloid processes, in a focally microcystic background. Mitoses were not seen; unequivocal Rosenthal fibers or eosinophilic granular bodies were absent. The tumor was positive for OLIG2 and GFAP and negative for BRAF V600E and IDH1 R132H mutant protein immunostains. Oncopanel showed low SOX2 (3q26.33) copy number gain, and no gains at 7q34. There were no significant single nucleotide variants. BreaKmer detected a GIT2-BRAF fusion with loss of BRAF exons 1–8. The integrated diagnosis was low-grade glioma with piloid features, most consistent with pilocytic astrocytoma, WHO grade I. GIT2-BRAF fusion has not been reported in the literature in any tumor. Given that the BRAF sequence deleted is identical to that seen in other fusion events in PA, it most likely acts as tumor driver by activation of the MAPK pathway.

A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain

Abstract: Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.

Abstract: Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges.

Abstract: Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents-originally developed to starve tumors-could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.

The Amyloid-β Pathway in Alzheimer's Disease.

Abstract: Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.

The multiplex model of the genetics of Alzheimer’s disease

Abstract: Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.