Late-onset Tay-Sachs disease

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of β-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease

A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets

OBJECTIVE: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature. METHODS: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review. RESULTS: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging. CONCLUSIONS: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning

In vivo detection of activated platelets allows characterizing rupture of atherosclerotic plaques with molecular magnetic resonance imaging in mice

BACKGROUND: Early and non-invasive detection of platelets on micro atherothrombosis provides a means to identify unstable plaque and thereby allowing prophylactic treatment towards prevention of stroke or myocardial infarction. Molecular magnetic resonance imaging (mMRI) of activated platelets as early markers of plaque rupture using targeted contrast agents is a promising strategy. In this study, we aim to specifically image activated platelets in murine atherothrombosis by in vivo mMRI, using a dedicated animal model of plaque rupture. METHODS: An antibody targeting ligand-induced binding sites (LIBS) on the glycoprotein IIb/IIIa-receptor of activated platelets was conjugated to microparticles of iron oxide (MPIO) to form the LIBS-MPIO contrast agent causing a signal-extinction in T2*-weighted MRI. ApoE(-/-) mice (60 weeks-old) were fed a high fat diet for 5 weeks. Using a small needle, the surface of their carotid plaques was scratched under blood flow to induce atherothrombosis. In vivo 9.4 Tesla MRI was performed before and repetitively after intravenous injection of either LIBS-MPIO versus non-targeted-MPIO. RESULTS: LIBS-MPIO injected animals showed a significant signal extinction (p/= 2% of the vascular lumen. Histology further confirmed significant binding of LIBS-MPIO compared to control-MPIO on the thrombus developing on the surface of ruptured plaques (p<0.01). CONCLUSION: in vivo mMRI detected activated platelets on mechanically ruptured atherosclerotic plaques in ApoE(-/-) mice with a high sensititvity. This imaging technology represents a unique opportunity for noninvasive detection of atherothrombosis and the identification of unstable atherosclerotic plaques with the ultimate promise to prevent strokes and myocardial infarctions

Activated Platelets in Carotid Artery Thrombosis in Mice Can Be Selectively Targeted with a Radiolabeled Single-Chain Antibody

BACKGROUND: Activated platelets can be found on the surface of inflamed, rupture-prone and ruptured plaques as well as in intravascular thrombosis. They are key players in thrombosis and atherosclerosis. In this study we describe the construction of a radiolabeled single-chain antibody targeting the LIBS-epitope of activated platelets to selectively depict platelet activation and wall-adherent non-occlusive thrombosis in a mouse model with nuclear imaging using in vitro and ex vivo autoradiography as well as small animal SPECT-CT for in vivo analysis. METHODOLOGY/PRINCIPAL FINDINGS: LIBS as well as an unspecific control single-chain antibody were labeled with (111)Indium ((111)In) via bifunctional DTPA ( = (111)In-LIBS/(111)In-control). Autoradiography after incubation with (111)In-LIBS on activated platelets in vitro (mean 3866 ± 28 DLU/mm(2), 4010 ± 630 DLU/mm(2) and 4520 ± 293 DLU/mm(2)) produced a significantly higher ligand uptake compared to (111)In-control (2101 ± 76 DLU/mm(2), 1181 ± 96 DLU/mm(2) and 1866 ± 246 DLU/mm(2)) indicating a specific binding to activated platelets; P<0.05. Applying these findings to an ex vivo mouse model of carotid artery thrombosis revealed a significant increase in ligand uptake after injection of (111)In-LIBS in the presence of small thrombi compared to the non-injured side, as confirmed by histology (49630 ± 10650 DLU/mm(2) vs. 17390 ± 7470 DLU/mm(2); P<0.05). These findings could also be reproduced in vivo. SPECT-CT analysis of the injured carotid artery with (111)In-LIBS resulted in a significant increase of the target-to-background ratio compared to (111)In-control (1.99 ± 0.36 vs. 1.1 ± 0.24; P < 0.01). CONCLUSIONS/SIGNIFICANCE: Nuclear imaging with (111)In-LIBS allows the detection of platelet activation in vitro and ex vivo with high sensitivity. Using SPECT-CT, wall-adherent activated platelets in carotid arteries could be depicted in vivo. These results encourage further studies elucidating the role of activated platelets in plaque pathology and atherosclerosis and might be of interest for further developments towards clinical application

Fluorescence-Quenched Substrates for Live Cell Imaging of Human Glucocerebrosidase Activity

Deficiency of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) leads to abnormal accumulation of glucosyl ceramide in lysosomes and the development of the lysosomal storage disease known as Gaucher’s disease. More recently, mutations in the&nbsp;GBA1&nbsp;gene that encodes GCase have been uncovered as a major genetic risk factor for Parkinson’s disease (PD). Current therapeutic strategies to increase GCase activity in lysosomes involve enzyme replacement therapy (ERT) and molecular chaperone therapy. One challenge associated with developing and optimizing these therapies is the difficulty in determining levels of GCase activity present within the lysosomes of live cells. Indeed, visualizing the activity of endogenous levels of any glycoside hydrolases, including GCase, has proven problematic within live mammalian cells. Here we describe the successful modular design and synthesis of fluorescence-quenched substrates for GCase. The selection of a suitable fluorophore and quencher pair permits the generation of substrates that allow convenient time-dependent monitoring of endogenous GCase activity within cells as well as localization of activity within lysosomes. These efficiently quenched (∼99.9%) fluorescent substrates also permit assessment of GCase inhibition in live cells by either confocal microscopy or high content imaging. Such substrates should enable improved understanding of GCase in situ as well the optimization of small-molecule chaperones for this enzyme. These findings also suggest routes to generate fluorescence-quenched substrates for other mammalian glycoside hydrolases for use in live cell imaging

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049