Publications by authors named "M Calhoun"

180 Publications

Altered Blood Flow in the Ophthalmic and Internal Carotid Arteries in Patients with Age-Related Macular Degeneration Measured Using Noncontrast MR Angiography at 7T.

AJNR Am J Neuroradiol 2021 Jul 1. Epub 2021 Jul 1.

Athinoula A. Martinos Center for Biomedical Imaging (M.L.H., Y.I.C., N. O., J.R.P.), Massachusetts General Hospital, Charlestown, Massachusetts

Background And Purpose: Age-related macular degeneration is associated with reduced perfusion of the eye; however, the role of altered blood flow in the upstream ophthalmic or internal carotid arteries is unclear. We used ultra-high-field MR imaging to investigate whether the diameter of and blood flow in the ophthalmic artery and/or the ICA are altered in age-related macular degeneration and whether any blood flow changes are associated with disease progression.

Materials And Methods: Twenty-four patients with age-related macular degeneration and 13 similarly-aged healthy controls participated. TOF and high-resolution dynamic 2D phase-contrast MRA (0.26 × 0.26 × 2mm, 100-ms effective sampling rate) was acquired at 7T. Vessel diameters were calculated from cross-sectional areas in phase-contrast acquisitions. Blood flow time-series were measured across the cardiac cycle.

Results: The ophthalmic artery vessel diameter was found to be significantly smaller in patients with age-related macular degeneration than in controls. Volumetric flow through the ophthalmic artery was significantly lower in patients with late age-related macular degeneration, with a significant trend of decreasing volumetric ophthalmic artery flow rates with increasing disease severity. The resistance index was significantly greater in patients with age-related macular degeneration than in controls in the ophthalmic artery. Flow velocity through the ophthalmic artery and ICA was significantly higher in patients with age-related macular degeneration. Ophthalmic artery blood flow as a percentage of ipsilateral ICA blood flow was nearly double in controls than in patients with age-related macular degeneration.

Conclusions: These findings support the hypothesis that vascular changes upstream to the eye are associated with the severity of age-related macular degeneration. Additional investigation into the potential causality of this relationship and whether treatments that improve ocular circulation slow disease progression is warranted.
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July 2021

Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo.

J Med Chem 2021 05 4;64(9):6358-6380. Epub 2021 May 4.

Department of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.

Structural analysis of the known NIK inhibitor bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by (cell IC: 571 nM). Systematic optimization of this series of analogs led to the discovery of , a potent (cell IC: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat K: 0.32) for in vivo proof of pharmacology studies. The ability of to inhibit tau phosphorylation at the disease-relevant Ser 422 epitope was demonstrated in both a mouse hypothermia and a rat developmental model and provided evidence that modulation of this target may be relevant in the treatment of Alzheimer's disease and other tauopathies.
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May 2021

Radiomics in the evaluation of lung nodules: Intrapatient concordance between full-dose and ultra-low-dose chest computed tomography.

Diagn Interv Imaging 2021 Apr 11;102(4):233-239. Epub 2021 Feb 11.

Department of Diagnostic Imaging (Radio B), Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; IMAGeS Team, ICube Laboratory, 67412 Illkirch Graffenstaden, France.

Purpose: The purpose of this study was to retrospectively evaluate the quantitative and qualitative intrapatient concordance of pulmonary nodule risk assessment by commercially available radiomics software between full-dose (FD) chest-CT and ultra-low-dose (ULD) chest CT.

Materials And Methods: Between July 2013 and September 2015, 68 patients (52 men and16 women; mean age, 65.5±10.6 [SD] years; range: 35-87 years) with lung nodules≥5mm and<30mm who underwent the same day FD chest CT (helical acquisition; 120kV; automated tube current modulation) and ULD chest CT (helical acquisition; 135kV; 10mA fixed) were retrospectively included. Each nodule on each acquisition was assessed by a commercial radiomics software providing a similarity malignancy index (mSI), classifying it as "benign-like" (mSI<0.1); "malignant-like" (mSI>0.9) or "undetermined" (0.1≤mSI≤0.9). Intrapatient qualitative agreement was evaluated with weighted Cohen-Kappa test and quantitative agreement with intraclass correlation coefficient (ICC).

Results: Ninety-nine lung nodules with a mean size of 9.14±4.3 (SD) mm (range: 5-25mm) in 68 patients (mean 1.46 nodule per patient; range: 1-5) were assessed; mean mSI was 0.429±0.331 (SD) (range: 0.001-1) with FD chest CT (22/99 [22%] "benign-like", 67/99 [68%] "undetermined" and 10/99 [10%] "malignant-like") and mean mSI was 0.487±0.344 (SD) (range: 0.002-1) with ULD chest CT (20/99 [20%] "benign-like", 59/99 [60%] "undetermined" and 20/99 [20%] "malignant-like"). Qualitative and quantitative agreement of FD chest CT with ULD chest CT were "good" with Kappa value of 0.60 (95% CI: 0.46-0.74) and ICC of 0.82 (95% CI: 0.73-0.87), respectively.

Conclusion: A good agreement in malignancy similarity index can be obtained between ULD chest CT and FD chest CT using radiomics software. However, further studies must be done with more case material to confirm our results and elucidate the diagnostic capabilities of radiomics software using ULD chest CT for lung nodule characterization by comparison with FD chest CT.
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April 2021

Temporal Progression of Excitotoxic Calcium Following Distal Middle Cerebral Artery Occlusion in Freely Moving Mice.

Front Cell Neurosci 2020 3;14:566789. Epub 2020 Dec 3.

Biogen, Cambridge, MA, United States.

Ischemic stroke is recognized as one of the leading causes of adult disability, morbidity, and death worldwide. Following stroke, acute neuronal excitotoxicity can lead to many deleterious consequences, one of which is the dysregulation of intracellular calcium ultimately culminating in cell death. However, to develop neuroprotective treatments that target neuronal excitotoxicity, it is essential to know the therapeutic time window for intervention following an ischemic event. To address this question, the current study aimed to characterize the magnitude and temporal progression of neuronal intracellular calcium observed following distal middle cerebral artery occlusion (dMCAO) in mice. Using the calcium fluorescence indicator, GCaMP, we tracked neuronal population response in freely moving animals immediately following dMCAO in both the core infarct and peri-infarct regions. Our results demonstrate that calcium excitotoxicity following artery occlusion can be generally characterized by two phases: a transient increase in activity that lasts tens of minutes, followed by a long, slow sustained increase in fluorescence signal. The first phase is primarily thought to represent neuronal hyperexcitability, defining our therapeutic window, while the second may represent gradual cell death. Importantly, we show that the level of intracellular calcium following artery occlusion correlated with the infarct size at 24 h demonstrating a direct connection between excitotoxicity and cell death in our stroke model. In addition, we show that administration of the NMDA antagonist MK-801 resulted in both a decrease in calcium signal and a subsequent reduction in the infarct size. Altogether, this study represents the first demonstration in freely moving animals characterizing the temporal progression of toxic calcium signaling following artery occlusion. In addition, these results define a critical time window for neuroprotective therapeutic intervention in mice.
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December 2020

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells.

J Neuroinflammation 2020 Jun 20;17(1):197. Epub 2020 Jun 20.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).

Methods: To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs with synthetic IL-4 mRNA to transiently express IL-4. These IL-4 expressing MSCs (IL-4 MSCs) were characterized for expression and functionality and then delivered in a modified mouse TBI model of closed head injury. Groups were assessed for functional deficits and MR imaging. Brain tissue was analyzed through flow cytometry, multi-plex ELISA, qPCR, histology, and RNA sequencing.

Results: We observed that IL-4 MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression after TBI. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes, or improvements in WMI on MR imaging. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists despite acute enrichment of M2-like macrophages in the brain.

Conclusion: The results demonstrate that MSCs can be engineered to induce a stronger M2-like macrophage response in vivo. However, they also suggest that acute enrichment of only M2-like macrophages after diffuse TBI cannot orchestrate neurogenesis, axonal regeneration, or improve WMI. Here, we also discuss our modified TBI model and methods to assess severity, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.
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June 2020