Fast online spectral-spatial pulse design for subject-specific fat saturation in cervical spine and foot imaging at 1.5 T.

OBJECTIVE: To compensate subject-specific field inhomogeneities and enhance fat pre-saturation with a fast online individual spectral-spatial (SPSP) single-channel pulse design. METHODS: The RF shape is calculated online using subject-specific field maps and a predefined excitation k-space trajectory. Calculation acceleration options are explored to increase clinical viability. Four optimization configurations are compared to a standard Gaussian spectral selective pre-saturation pulse and to a Dixon acquisition using phantom and volunteer (N = 5) data at 1.5 T with a turbo spin echo (TSE) sequence. Measurements and simulations are conducted across various body parts and image orientations. RESULTS: Phantom measurements demonstrate up to a 3.5-fold reduction in residual fat signal compared to Gaussian fat saturation. In vivo evaluations show improvements up to sixfold for dorsal subcutaneous fat in sagittal cervical spine acquisitions. The versatility of the tailored trajectory is confirmed through sagittal foot/ankle, coronal, and transversal cervical spine experiments. Additional measurements indicate that excitation field (B1) information can be disregarded at 1.5 T. Acceleration methods reduce computation time to a few seconds. DISCUSSION: An individual pulse design that primarily compensates for main field (B0) inhomogeneities in fat pre-saturation is successfully implemented within an online "push-button" workflow. Both fat saturation homogeneity and the level of suppression are improved.

Contrast-agent-based perfusion MRI code repository and testing framework: ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

PURPOSE: Software has a substantial impact on quantitative perfusion MRI values. The lack of generally accepted implementations, code sharing and transparent testing reduces reproducibility, hindering the use of perfusion MRI in clinical trials. To address these issues, the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI) aimed to establish a community-led, centralized repository for sharing open-source code for processing contrast-based perfusion imaging, incorporating an open-source testing framework. METHODS: A repository was established on the OSIPI GitHub website. Python was chosen as the target software language. Calls for code contributions were made to OSIPI members, the ISMRM Perfusion Study Group, and publicly via OSIPI websites. An automated unit-testing framework was implemented to evaluate the output of code contributions, including visual representation of the results. RESULTS: The repository hosts 86 implementations of perfusion processing steps contributed by 12 individuals or teams. These cover all core aspects of DCE- and DSC-MRI processing, including multiple implementations of the same functionality. Tests were developed for 52 implementations, covering five analysis steps. For T1 mapping, signal-to-concentration conversion and population AIF functions, different implementations resulted in near-identical output values. For the five pharmacokinetic models tested (Tofts, extended Tofts-Kety, Patlak, two-compartment exchange, and two-compartment uptake), differences in output parameters were observed between contributions. CONCLUSIONS: The OSIPI DCE-DSC code repository represents a novel community-led model for code sharing and testing. The repository facilitates the re-use of existing code and the benchmarking of new code, promoting enhanced reproducibility in quantitative perfusion imaging.

Investigation of perfusion impairment in degenerative cervical myelopathy beyond the site of cord compression.

The aim of this study was to determine tissue-specific blood perfusion impairment of the cervical cord above the compression site in patients with degenerative cervical myelopathy (DCM) using intravoxel incoherent motion (IVIM) imaging. A quantitative MRI protocol, including structural and IVIM imaging, was conducted in healthy controls and patients. In patients, T2-weighted scans were acquired to quantify intramedullary signal changes, the maximal canal compromise, and the maximal cord compression. T2*-weighted MRI and IVIM were applied in all participants in the cervical cord (covering C1-C3 levels) to determine white matter (WM) and grey matter (GM) cross-sectional areas (as a marker of atrophy), and tissue-specific perfusion indices, respectively. IVIM imaging resulted in microvascular volume fraction ([Formula: see text]), blood velocity ([Formula: see text]), and blood flow ([Formula: see text]) indices. DCM patients additionally underwent a standard neurological clinical assessment. Regression analysis assessed associations between perfusion parameters, clinical outcome measures, and remote spinal cord atrophy. Twenty-nine DCM patients and 30 healthy controls were enrolled in the study. At the level of stenosis, 11 patients showed focal radiological evidence of cervical myelopathy. Above the stenosis level, cord atrophy was observed in the WM (- 9.3%; p = 0.005) and GM (- 6.3%; p = 0.008) in patients compared to healthy controls. Blood velocity (BV) and blood flow (BF) indices were decreased in the ventral horns of the GM (BV: - 20.1%, p = 0.0009; BF: - 28.2%, p = 0.0008), in the ventral funiculi (BV: - 18.2%, p = 0.01; BF: - 21.5%, p = 0.04) and lateral funiculi (BV: - 8.5%, p = 0.03; BF: - 16.5%, p = 0.03) of the WM, across C1-C3 levels. A decrease in microvascular volume fraction was associated with GM atrophy (R = 0.46, p = 0.02). This study demonstrates tissue-specific cervical perfusion impairment rostral to the compression site in DCM patients. IVIM indices are sensitive to remote perfusion changes in the cervical cord in DCM and may serve as neuroimaging biomarkers of hemodynamic impairment in future studies. The association between perfusion impairment and cervical cord atrophy indicates that changes in hemodynamics caused by compression may contribute to the neurodegenerative processes in DCM.

Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration.

INTRODUCTION: While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration. METHODS: Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense-mediated mRNA decay (NMD), a key RNA quality-control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau-induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau-induced deficits in RNA quality control are druggable. DISCUSSION: Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.

Exploration and analysis of R-loop mapping data with RLBase.

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. In 2012, Ginno et al. introduced the first R-loop mapping method. Since that time, dozens of R-loop mapping studies have been conducted, yielding hundreds of publicly available datasets. Current R-loop databases provide only limited access to these data. Moreover, no web tools for analyzing user-supplied R-loop datasets have yet been described. In our recent work, we reprocessed 810 R-loop mapping samples, building the largest R-loop data resource to date. We also defined R-loop consensus regions and developed a framework for R-loop data analysis. Now, we introduce RLBase, a user-friendly database that provides the capability to (i) explore hundreds of public R-loop mapping datasets, (ii) explore R-loop consensus regions, (iii) analyze user-supplied data and (iv) download standardized and reprocessed datasets. RLBase is directly accessible via the following URL: https://gccri.bishop-lab.uthscsa.edu/shiny/rlbase/.

Pulmonary Dysfunction after Pediatric COVID-19.

Background Long COVID occurs at a lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field-strength MRI may help identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma at low-field-strength MRI in children and adolescents with post-COVID-19 condition compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional clinical trial using low-field-strength MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes at MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive reverse transcriptase-polymerase chain reaction test result, and serologic parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants, and those with long COVID. Results A total of 54 participants after COVID-19 infection (mean age, 11 years ± 3 [SD]; 30 boys [56%]) and nine healthy controls (mean age, 10 years ± 3; seven boys [78%]) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (ventilation-perfusion [V/Q] match) was higher in healthy controls (81% ± 6.1) compared with the recovered group (62% ± 19; P = .006) and the group with long COVID (60% ± 20; P = .003). V/Q match was lower in patients with time from COVID-19 infection to study participation of less than 180 days (63% ± 20; P = .03), 180-360 days (63% ± 18; P = .03), and 360 days (41% ± 12; P < .001) as compared with the never-infected healthy controls (81% ± 6.1). Conclusion Low-field-strength MRI showed persistent pulmonary dysfunction in children and adolescents who recovered from COVID-19 and those with long COVID. Clinical trial registration no. NCT04990531 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Clinically compatible subject-specific dynamic parallel transmit pulse design for homogeneous fat saturation and water-excitation at 7T: Proof-of-concept for CEST MRI of the brain.

PURPOSE: To evaluate the benefits and challenges of dynamic parallel transmit (pTx) pulses for fat saturation (FS) and water-excitation (WE), in the context of CEST MRI. METHODS: "Universal" kT -points (for FS) and spiral non-selective (for WE) trajectories were optimized offline for flip angle (FA) homogeneity. Routines to optimize the pulse shape online, based on the subject's fields maps, were implemented (target FA of 110°/0° for FS, 0°/5° for WE at fat/water frequencies). The pulses were inserted in a CEST sequence with a pTx readout. The different fat suppression schemes and their effects on CEST contrasts were compared in 12 volunteers at 7T. RESULTS: With a 25%-shorter pulse duration, pTx FS largely improved the FA homogeneity (root-mean-square-error (RMSE) = 12.3° vs. 53.4° with circularly-polarized mode, at the fat frequency). However, the spectral selectivity was degraded mainly in the cerebellum and close to the sinuses (RMSE = 5.8° vs. 0.2° at the water frequency). Similarly, pTx WE showed a trade-off between FA homogeneity and spectral selectivity compared to pTx non-selective pulses (RMSE = 0.9° and 1.1° at the fat and water frequencies, vs. 4.6° and 0.5°). In the brain, CEST metrics were reduced by up to 31.9% at -3.3 ppm with pTx FS, suggesting a mitigated lipid-induced bias. CONCLUSION: This clinically compatible implementation of dynamic pTx pulses improved the fat suppression homogeneity at 7T taking into account the subject-specific B0 heterogeneities online. This study highlights the lipid-induced biases on the CEST z-spectrum. The results are promising for body applications where B0 heterogeneities and fat are more substantial.

TauLUM, an in vivo Drosophila sensor of tau multimerization, identifies neuroprotective interventions in tauopathy.

Tau protein aggregates are a defining neuropathological feature of "tauopathies," a group of neurodegenerative disorders that include Alzheimer's disease. In the current study, we develop a Drosophila split-luciferase-based sensor of tau-tau interaction. This model, which we term "tauLUM," allows investigators to quantify tau multimerization at individual time points or longitudinally in adult, living animals housed in a 96-well plate. TauLUM causes cell death in the adult Drosophila brain and responds to both pharmacological and genetic interventions. We find that transgenic expression of an anti-tau intrabody or pharmacological inhibition of HSP90 reduces tau multimerization and cell death in tauLUM flies, establishing the suitability of this system for future drug and genetic modifier screening. Overall, our studies position tauLUM as a powerful in vivo discovery platform that leverages the advantages of the Drosophila model organism to better understand tau multimerization.

Quality-controlled R-loop meta-analysis reveals the characteristics of R-loop consensus regions.

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. While the pathological consequences of R-loops have been well-studied to date, the locations, classes, and dynamics of physiological R-loops remain poorly understood. R-loop mapping studies provide insight into R-loop dynamics, but their findings are challenging to generalize. This is due to the narrow biological scope of individual studies, the limitations of each mapping modality, and, in some cases, poor data quality. In this study, we reprocessed 810 R-loop mapping datasets from a wide array of biological conditions and mapping modalities. From this data resource, we developed an accurate R-loop data quality control method, and we reveal the extent of poor-quality data within previously published studies. We then identified a set of high-confidence R-loop mapping samples and used them to define consensus R-loop sites called 'R-loop regions' (RL regions). In the process, we identified a stark divergence between RL regions detected by S9.6 and dRNH-based mapping methods, particularly with respect to R-loop size, location, and colocalization with RNA binding factors. Taken together, this work provides a much-needed method to assess R-loop data quality and offers novel context regarding the differences between dRNH- and S9.6-based R-loop mapping approaches.

Free-Breathing Low-Field MRI of the Lungs Detects Functional Alterations Associated With Persistent Symptoms After COVID-19 Infection.

OBJECTIVES: With the COVID-19 pandemic, repetitive lung examinations have become necessary to follow-up symptoms and associated alterations. Low-field MRI, benefiting from reduced susceptibility effects, is a promising alternative for lung imaging to limit radiations absorbed by patients during CT examinations, which also have limited capability to assess functional alterations. The aim of this investigative study was to explore the functional abnormalities that free-breathing 0.55 T MRI in combination with the phase-resolved functional lung (PREFUL) analysis could identify in patients with persistent symptoms after COVID-19 infection. MATERIALS AND METHODS: Seventy-four COVID-19 patients and 8 healthy volunteers were prospectively scanned in free-breathing with a balanced steady-state free-precession sequence optimized at 0.55 T, 5 months postinfection on average. Normalized perfusion (Q), fractional ventilation (FV), and flow-volume loop correlation (FVLc) maps were extracted with the PREFUL technique. Q, FV, and FVLc defects as well as defect overlaps between these metrics were quantified. Morphological turbo-spin-echo images were also acquired, and the extent of abnormalities was scored by a board-certified radiologist. To investigate the functional correlates of persistent symptoms, a recursive feature elimination algorithm was applied to find the most informative variables to detect the presence of persistent symptoms with a logistic regression model and a cross-validation strategy. All MRI metrics, sex, age, body mass index, and the presence of preexisting lung conditions were included. RESULTS: The most informative variables to detect persistent symptoms were the percentage of concurrent Q and FVLc defects and of areas free of those defects. A detection accuracy of 71.4% was obtained with these 2 variables when fitting the model on the entire dataset. Although none of the single variables differed between patients with and without persistent symptoms ( P > 0.05), the combined score of these 2 variables did ( P < 0.02). This score also showed a consistent increase from healthy volunteers (7.7) to patients without persistent symptoms (8.2) and with persistent symptoms (8.6). The morphological abnormality score showed poor correlation with the functional parameters. CONCLUSIONS: Functional pulmonary examinations using free-breathing 0.55 T MRI with PREFUL analysis revealed potential quantitative markers of impaired lung function in patients with persistent symptoms after COVID-19 infection, potentially complementing morphologic imaging. Future work is needed to explore the translational relevance and clinical implication of these findings.

[Imaging of the lung using low-field magnetic resonance imaging]. / Lungenbildgebung in der Niederfeld-Magnetresonanztomographie.

BACKGROUND: Lung magnetic resonance imaging (MRI) examinations are challenging and have not become established in the routine clinical setting. Recent developments in low-field MRI, combined with computer-assisted algorithms for acquisition and evaluation, promise new perspectives for imaging of pulmonary diseases. OBJECTIVES: This review aims to inform about the physical advantages of low-field MRI for imaging the lungs, provide a review of the sparse literature, and present first results from a new low-field MRI scanner. MATERIALS AND METHODS: This article provides information on the physical principles, an review of the literature, and our first experiences in lung imaging on a modern 0.55 T MRI. CONCLUSION: Low-field MRI (< 1 T) may have technical and economic advantages over higher field strength MRI in lung imaging. The physical preconditions of low-field MRI are advantageous for imaging the lungs due to reduced susceptibility effects, increased transversal relaxation times, and lower specific absorption rates. The lower investment and operating costs may enable increased availability and sustainability. Combining modern sequences and computer-based image processing may expand beyond morphological imaging by providing spatially and temporally resolved functional examinations of the lung parenchyma without ionizing radiation. In critical scenarios, like screening and short-term follow-up examinations, and patients at risk, low-field MRI may bridge the gap. These indications may include acute and chronic pulmonary diseases in pediatric patients and suspected pulmonary embolisms in pregnant women.

Biomechanical comparison of spinal cord compression types occurring in Degenerative Cervical Myelopathy.

BACKGROUND: Degenerative Cervical Myelopathy results from spine degenerations narrowing the spinal canal and inducing cord compressions. Prognosis is challenging. This study aimed at simulating typical spinal cord compressions observed in patients with a realistic model to better understand pathogenesis for later prediction of patients' evolution. METHODS: A 30% reduction in cord cross-sectional area at C5-C6 was defined as myelopathy threshold based on Degenerative Cervical Myelopathy features from literature and MRI measurements in 20 patients. Four main compression types were extracted from MRIs and simulated with a comprehensive three-dimensional finite element spine model. Median diffuse, median focal and lateral types were modelled as disk herniation while circumferential type additionally involved ligamentum flavum hypertrophy. All stresses were quantified along inferior-superior axis, compression development and across atlas-defined spinal cord regions. FINDINGS: Anterior gray and white matter globally received the highest stress while lateral pathways were the least affected. Median diffuse compression induced the highest stresses. Circumferential type focused stresses in posterior gray matter. Along inferior-superior axis, those two types showed a peak of constraints at compression site while median focal and lateral types showed lower values but extending further. INTERPRETATION: Median diffuse type would be the most detrimental based on stress amplitude. Anterior regions would be the most at risk, except for circumferential type where posterior regions would be equally affected. In addition to applying constraints, ischemia could be a significant component explaining the early demyelination reported in lateral pathways. Moving towards patient-specific simulations, biomechanical models could become strong predictors for degenerative changes.

Feasibility of human spinal cord perfusion mapping using dynamic susceptibility contrast imaging at 7T: Preliminary results and identified guidelines.

PURPOSE: To explore the feasibility of dynamic susceptibility contrast MRI at 7 Tesla for human spinal cord perfusion mapping and fill the gap between brain and spinal cord perfusion mapping techniques. METHODS: Acquisition protocols for high-resolution single shot EPI in the spinal cord were optimized for both spin-echo and gradient-echo preparations, including cardiac gating, acquisition times and breathing cycle recording. Breathing-induced MRI signal fluctuations were investigated in healthy volunteers. A specific image- and signal-processing pipeline was implemented to address them. Dynamic susceptibility contrast was then evaluated in 3 healthy volunteers and 5 patients. Bolus depiction on slice-wise signal within cord was investigated, and maps of relative perfusion indices were computed. RESULTS: Signal fluctuations were increased by 1.9 and 2.3 in free-breathing compared to apnea with spin-echo and gradient-echo, respectively. The ratio between signal fluctuations and bolus peak in healthy volunteers was 5.0% for spin-echo and 3.8% for gradient-echo, allowing clear depiction of the bolus on every slice and yielding relative blood flow and volume maps exhibiting the expected higher perfusion of gray matter. However, signal fluctuations in patients were increased by 4 in average (using spin-echo), compromising the depiction of the bolus in slice-wise signal. Moreover, 3 of 18 slices had to be discarded because of fat-aliasing artifacts. CONCLUSION: Dynamic susceptibility contrast MRI at 7 Tesla showed great potential for spinal cord perfusion mapping with a reliability never achieved thus far for single subject and single slice measurements. Signal stability needs to be improved in acquisition conditions associated with patients; guidelines to achieve that have been identified and shared.

Robustness Through Simplicity: A Minimalist Gateway to Neurorobotic Flight.

In attempting to build neurorobotic systems based on flying animals, engineers have come to rely on existing firmware and simulation tools designed for miniature aerial vehicles (MAVs). Although they provide a valuable platform for the collection of data for Deep Learning and related AI approaches, such tools are deliberately designed to be general (supporting air, ground, and water vehicles) and feature-rich. The sheer amount of code required to support such broad capabilities can make it a daunting task to adapt these tools to building neurorobotic systems for flight. In this paper we present a complementary pair of simple, object-oriented software tools (multirotor flight-control firmware and simulation platform), each consisting of a core of a few thousand lines of C++ code, that we offer as a candidate solution to this challenge. By providing a minimalist application programming interface (API) for sensors and PID controllers, our software tools make it relatively painless for engineers to prototype neuromorphic approaches to MAV sensing and navigation. We conclude our discussion by presenting a simple PID controller we built using the popular Nengo neural simulator in conjunction with our flight-simulation platform.

Intravoxel Incoherent Motion at 7 Tesla to quantify human spinal cord perfusion: limitations and promises.

PURPOSE: To develop a noninvasive technique to map human spinal cord (SC) perfusion in vivo. More specifically, to implement an intravoxel incoherent motion (IVIM) protocol at ultrahigh field for the human SC and assess parameters estimation errors. METHODS: Monte-Carlo simulations were conducted to assess estimation errors of 2 standard IVIM fitting approaches (two-step versus one-step fit) over the range of IVIM values reported for the human brain and for typical SC diffusivities. Required signal-to-noise ratio (SNR) was inferred for estimation of the parameters product, fIVIM D* (microvascular fraction times pseudo-diffusion coefficient), within 10% error margins. In-vivo IVIM imaging of the SC was performed at 7T in 6 volunteers. An image processing pipeline is proposed to generate IVIM maps and register them for an atlas-based region-wise analysis. RESULTS: Required b = 0 SNRs for 10% error estimation on fIVIM D* with the one-step fit were 159 and 185 for diffusion-encoding perpendicular and parallel to the SC axis, respectively. Average in vivo b = 0 SNR within cord was 141 ± 79, corresponding to estimation errors of 12.7% and 14.7% according to numerical simulations. Slice- and group-averaging reduced noise in IVIM maps, highlighting the difference in perfusion between gray and white matter. Mean ± standard deviation fIVIM and D* values across subjects within gray (respectively white) matter were 16.0 ± 1.7 (15.0 ± 1.6)% and 11.4 ± 2.9 (11.5 ± 2.4) × 10-3 mm2 /s. CONCLUSION: Single-subject data SNR at 7T was insufficient for reliable perfusion estimation. However, atlas-averaged IVIM maps highlighted the higher microvascular fraction of gray matter compared to white matter, providing first results of healthy human SC perfusion mapping with MRI.

Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts.

This study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson's disease (PD). Using live cell imaging with a pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown of mitochondria, mitophagy rates were found to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from healthy subject (HS) controls. The mutant LRRK2 increased kinase activity was reduced by pharmacological inhibition and targeted antisense oligonucleotide treatment, which normalized mitophagy rates in the G2019S cells and also increased mitophagy levels in HS cells. Detailed mechanistic analysis showed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition. These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation. The current results are relevant for cell phenotypic diagnostic approaches and potentially for stratification of PD patients for targeted therapy.

Neurite Collapse and Altered ER Ca2+ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation.

The Parkinson disease (PD) genetic LRRK2 gain-of-function mutations may relate to the ER pathological changes seen in PD patients at postmortem. Human induced pluripotent stem cell (iPSC)-derived neurons with the PD pathogenic LRRK2 G2019S mutation exhibited neurite collapse when challenged with the ER Ca2+ influx sarco/ER Ca2+-ATPase inhibitor thapsigargin (THP). Baseline ER Ca2+ levels measured with the ER Ca2+ indicator CEPIA-ER were lower in LRRK2 G2019S human neurons, including in differentiated midbrain dopamine neurons in vitro. After THP challenge, PD patient-derived neurons displayed increased Ca2+ influx and decreased intracellular Ca2+ buffering upon membrane depolarization. These effects were reversed following LRRK2 mutation correction by antisense oligonucleotides and gene editing. Gene expression analysis in LRRK2 G2019S neurons identified modified levels of key store-operated Ca2+ entry regulators, with no alterations in ER Ca2+ efflux. These results demonstrate PD gene mutation LRRK2 G2019S ER calcium-dependent pathogenic effects in human neurons.

Tau-induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila.

The nucleus is a spherical dual-membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the "nucleoplasmic reticulum." Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer's disease. While the presence of pore-lined, cytoplasm-filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau-induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau-induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies.

Correction: Test-retest reliability of myelin imaging in the human spinal cord: Measurement errors versus region- and aging-induced variations.

[This corrects the article DOI: 10.1371/journal.pone.0189944.].

Test-retest reliability of myelin imaging in the human spinal cord: Measurement errors versus region- and aging-induced variations.

PURPOSE: To implement a statistical framework for assessing the precision of several quantitative MRI metrics sensitive to myelin in the human spinal cord: T1, Magnetization Transfer Ratio (MTR), saturation imposed by an off-resonance pulse (MTsat) and Macromolecular Tissue Volume (MTV). METHODS: Thirty-three healthy subjects within two age groups (young, elderly) were scanned at 3T. Among them, 16 underwent the protocol twice to assess repeatability. Statistical reliability indexes such as the Minimal Detectable Change (MDC) were compared across metrics quantified within different cervical levels and white matter (WM) sub-regions. The differences between pathways and age groups were quantified and interpreted in context of the test-retest repeatability of the measurements. RESULTS: The MDC was respectively 105.7ms, 2.77%, 0.37% and 4.08% for T1, MTR, MTsat and MTV when quantified over all WM, while the standard-deviation across subjects was 70.5ms, 1.34%, 0.20% and 2.44%. Even though particular WM regions did exhibit significant differences, these differences were on the same order as test-retest errors. No significant difference was found between age groups for all metrics. CONCLUSION: While T1-based metrics (T1 and MTV) exhibited better reliability than MT-based measurements (MTR and MTsat), the observed differences between subjects or WM regions were comparable to (and often smaller than) the MDC. This makes it difficult to determine if observed changes are due to variations in myelin content, or simply due to measurement error. Measurement error remains a challenge in spinal cord myelin imaging, but this study provides statistical guidelines to standardize the field and make it possible to conduct large-scale multi-center studies.