Publications by authors named "Keith L Black"

Article Synopsis
  • Pathological tau isoforms, particularly hyperphosphorylated tau at serine 396, and tau oligomers were found in the retinas of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), indicating a potential link between tauopathy and retinal changes.
  • The study analyzed retinal cross-sections from 25 patients with MCI or AD and 16 cognitively normal controls, revealing a significant reduction in retinal ganglion cells (RGCs) and increased signs of cell distress in MCI and AD patients compared to controls.
  • Findings showed that higher amounts of pS396-tau in RGCs were strongly correlated with decreased RGC integrity and related to severity in cognitive decline, suggesting that retinal
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Objective: The escalating healthcare expenditures in the United States, particularly in neurosurgery, necessitate effective tools for predicting patient outcomes and optimizing resource allocation. This study explores the utility of combining frailty and comorbidity indices, specifically the Johns Hopkins Adjusted Clinical Groups (JHACG) frailty index and the Elixhauser Comorbidity Index (ECI), in predicting hospital length of stay (LOS), non-routine discharge, and one-year readmission in patients undergoing craniotomy for benign and malignant primary brain tumors.

Methods: Leveraging the Nationwide Readmissions Database (NRD) for 2016-2019, we analyzed data from 645 patients with benign and 30,991 with malignant tumors.

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Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models.

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Article Synopsis
  • * Researchers analyzed retinal samples from AD patients (both mild cognitive impairment and dementia) and matched controls, finding significant increases in various tau isoforms, particularly in advanced AD cases.
  • * Strong correlations were identified between specific retinal tau isoforms and brain pathology, indicating that changes in the retina could reflect the severity of cognitive decline and neurodegeneration in AD patients.
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Article Synopsis
  • The study explores the connection between amyloidosis in retinal blood vessels and cognitive impairment, especially in Alzheimer's disease (AD), utilizing a new image processing method for analyzing retinal amyloid plaque distribution in individuals with varying cognitive abilities.
  • Results showed higher levels of amyloid plaques near retinal arteries compared to veins, with increased plaque counts linked to cognitive decline and neuroimaging metrics in cognitively impaired individuals.
  • The findings suggest that retinal imaging could serve as a predictive tool for cognitive decline and AD progression, highlighting the need for larger studies to better understand the relationship between retinal amyloid deposition and cognitive health over time.
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Article Synopsis
  • The retina is being studied as a promising, noninvasive way to diagnose and track Alzheimer's disease (AD) because it shows similar pathological features to those found in the brain, like amyloid and tau protein abnormalities.
  • Research has found that structural and functional issues in the retina, including reduced blood flow and inflammation, correlate with the severity of AD symptoms in patients.
  • Advanced imaging technologies are now capable of detecting AD-related changes in the retina, which could help in early diagnosis and monitoring of the disease, but more studies are needed with larger, diverse groups to confirm these findings and improve screening methods.
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Introduction: The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition.

Methods: Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects.

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Article Synopsis
  • - This study investigates the presence of various pathological tau proteins in the retinas of individuals with early and advanced Alzheimer's disease (AD) and their connection to the severity of the disease.
  • - Researchers analyzed retinal and brain samples from 75 donors with conditions ranging from normal cognition to mild cognitive impairment (MCI) and AD, using advanced histopathology and digital profiling methods.
  • - The results showed significant increases in multiple tau isoforms in the retinas of AD and MCI patients compared to normal controls, suggesting a correlation between retinal changes and cognitive decline.
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Article Synopsis
  • The study investigates how T cell abnormalities, specifically CD8 T cells, may play a crucial role in the early stages of Alzheimer's disease (AD) by influencing neurodegeneration before the formation of Aβ plaques and pTau tangles.
  • Researchers found that antigen-specific memory CD8 T cells induce changes associated with AD, such as plaque and tangle-like deposition, and are associated with gene expression alterations leading to neurodegeneration when activated by specific proteins (Perforin and IFNγ).
  • The findings suggest that monitoring these T cells in human AD patients could be more indicative of disease progression than traditional biomarkers like plasma pTau-217, thus offering new insights for early diagnosis and treatment strategies.
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Background: Meningiomas are the most common primary intracranial tumor with increasing incidence. Stereotactic Radiosurgery Gamma Knife (SRS-GK) is a commonly used modality for neoadjuvant and adjuvant treatment of these tumors and is often necessary for long-term disease control, particularly for the World Health Organization grade II/III meningiomas. While there is strong evidence to support the use of SRS-GK for meningioma, there exists a risk of secondary malignancy that is not well understood.

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Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control.

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Delivery of therapeutic substances into the brain poses a significant challenge in the treatment of neurological disorders. This is primarily due to the blood-brain barrier (BBB), which restricts access, alongside the limited stability and distribution of these agents within the brain tissue. Here we demonstrate an efficient delivery of microRNA (miRNA) and antisense RNA preferentially to neurons compared to astroglia in the brain of healthy and Alzheimer's disease mice, via disulfide-linked conjugation with poly(ß-L-malic acid-trileucine)-copolymer a biodegradable, amphiphilic, and multivalent platform.

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This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque.

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Article Synopsis
  • - Osteopontin (OPN) is a vital cytokine in bone marrow-derived macrophages (BMMΦ) that influences immune responses by promoting either an anti-inflammatory or pro-inflammatory state depending on its levels; glatiramer acetate (GA) boosts OPN expression to support healing.
  • - Using mass spectrometry for global proteome profiling, researchers found 631 differentially expressed proteins (DEPs) in macrophages with either OPN knockout or GA-induced OPN, many of which are linked to immune functions and include notable proteins such as UCHL1 and HMOX-1.
  • - The study revealed that UCHL1, tied to anti-inflammatory responses, is regulated by OPN in
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Introduction: Vascular amyloid beta (Aβ) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that the retinal vascular tight junctions (TJs) were compromised and linked to disease status.

Methods: TJ components and Aβ expression in capillaries and larger blood vessels were determined in post mortem retinas from 34 MCI or AD patients and 27 cognitively normal controls and correlated with neuropathology.

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The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients.

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Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors.

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Naïve T cells become effector T cells following stimulation by antigen-loaded dendritic cells (DCs) and sequential cytokine activation. We aimed to develop procedures to efficiently activate T cells with tumor-associated antigens (TAAs) to glioblastoma (GBM) stem cells. To remove antigen presentation outside of the immunosuppressive tumor milieu, three different glioma stem cell (GSC) specific antigen sources to load DCs were compared in their ability to stimulate lymphocytes.

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Major advances have been made in our understanding of CNS tumors, especially glioma, however, the survival of patients with malignant glioma remains poor. While radiation and chemotherapy have increased overall survival, glioblastoma multiforme (GBM) still has one of the worst 5-year survival rates of all human cancers. Here, in this chapter, the authors review the abrogation of the immune system in the tumor setting, revealing many plausible targets for therapy and the current immunotherapy treatment strategies employed.

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Article Synopsis
  • Alzheimer's disease (AD) poses a significant risk to older adults, characterized by the abnormal buildup of amyloid β-protein (Aβ) and phosphorylated tau (pTau) in the retinas of affected patients, including those with early signs of cognitive decline.
  • The accumulation of Aβ, particularly the 42-residue form, is an early indicator of AD, and its identification, along with tau pathology, is crucial for diagnosing the disease.
  • Researchers have developed a new, label-free hyperspectral imaging technique that uses deep learning to detect Aβ and pTau in retinal cross-sections, overcoming the challenges associated with traditional imaging methods involving contrast agents.
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Objective: Glioblastoma has been known to be resistant to chemotherapy and radiation, whereas the underlying mechanisms of resistance have not been fully elucidated. The authors studied the role of the transcription factor ZEB1 (zinc finger E-box-binding homeobox 1 protein), which is associated with epithelial-mesenchymal transition (EMT) and is central to the stemness of glioblastoma, to determine its role in therapeutic resistance to radiation and chemotherapy. The authors previously demonstrated that ZEB1 is deleted in a majority of glioblastomas.

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Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina.

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The ability to cross the blood-brain barrier (BBB) is critical for targeted therapy of the central nerve system (CNS). Six peptide vectors were covalently attached to a 50 kDa poly(β-l-malic acid)-trileucine polymer forming P/LLL(40%)/vector conjugates. The vectors were Angiopep-2 (AP2), B6, Miniap-4 (M4), and d-configurated peptides D1, D3, and ACI-89, with specificity for transcytosis receptors low-density lipoprotein receptor-related protein-1 (LRP-1), transferrin receptor (TfR), bee venom-derived ion channel, and Aβ/LRP-1 related transcytosis complex, respectively.

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Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate-GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients.

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