Publications by authors named "Ali Fatemi"

108 Publications

Author Correction: Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2021 Jan 11. Epub 2021 Jan 11.

Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.

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http://dx.doi.org/10.1038/s41588-021-00780-8DOI Listing
January 2021

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

J Inherit Metab Dis 2020 Dec 29. Epub 2020 Dec 29.

Division of Neurogenetics and The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Background: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.

Methods: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.

Results: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI.

Conclusion: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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http://dx.doi.org/10.1002/jimd.12356DOI Listing
December 2020

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

Tensile Behavior of High-Density Polyethylene Including the Effects of Processing Technique, Thickness, Temperature, and Strain Rate.

Polymers (Basel) 2020 Aug 19;12(9). Epub 2020 Aug 19.

Mechanical Engineering, University of Memphis, Memphis, TN 38152, USA.

The primary goal of this study was to investigate the monotonic tensile behavior of high-density polyethylene (HDPE) in its virgin, regrind, and laminated forms. HDPE is the most commonly used polymer in many industries. A variety of tensile tests were performed using plate-type specimens made of rectangular plaques. Several factors can affect the tensile behavior such as thickness, processing technique, temperature, and strain rate. Testing temperatures were chosen at -40, 23 (room temperature, RT), 53, and 82 °C to investigate temperature effect. Tensile properties, including elastic modulus, yield strength, and ultimate tensile strength, were obtained for all conditions. Tensile properties significantly reduced by increasing temperature while elastic modulus and ultimate tensile strength linearly increased at higher strain rates. A significant effect of thickness on tensile properties was observed for injection molding specimens at 23 °C, but no thickness effect was observed for compression molded specimens at either 23 or 82 °C. The aforementioned effects and discussion of their influence on tensile properties are presented in this paper. Polynomial relations for tensile properties, including elastic modulus, yield strength, and ultimate tensile strength, were developed as functions of temperature and strain rate. Such relations can be used to estimate tensile properties of HDPE as a function of temperature and/or strain rate for application in designing parts with this material.
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http://dx.doi.org/10.3390/polym12091857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564066PMC
August 2020

Row-Column-Based Coherence Imaging Using a 2-D Array Transducer: A Row-Based Implementation.

IEEE Trans Ultrason Ferroelectr Freq Control 2020 11 10;67(11):2303-2311. Epub 2020 Jun 10.

Reverberations from tissues around the heart often result in cluttered echocardiograms with reduced diagnostic value. As a consequence, some patients must undergo more expensive and, in some cases, invasive imaging modalities. Coherence-based beamforming can suppress the effect of incoherent reverberations compared with the coherent signal. In some cases, these incoherent reverberations are received by only a part of the aperture. However, the coherence-based techniques, when used on a 1-D array transducer, do not take this into account. We propose an extension of coherence imaging method when using a 2-D array transducer and test a row-based implementation of this extension on two in vitro scenarios and four in vivo cases. The results show that the proposed method improves the lateral resolution compared with the (already improved) resolution with conventional coherence imaging. Furthermore, it gives up to 28% increase in generalized contrast-to-noise ratio (gCNR) (improved detection probability) when incoherent reverberations are partly received by the transducer in the elevation direction.
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http://dx.doi.org/10.1109/TUFFC.2020.3001529DOI Listing
November 2020

Glial restricted precursor delivery of dendrimer N-acetylcysteine promotes migration and differentiation following transplant in mouse white matter injury model.

Nanoscale 2020 Aug 29;12(30):16063-16068. Epub 2020 Jul 29.

Moser Center for Leukodystrophies, Kennedy Krieger Institute, Baltimore, MD, USA.

Oligodendrocyte replacement using glial restricted precursors (GRPs) is a promising avenue for the treatment of acquired or genetic white matter disorders; however, limited long-term survival of these cells post-transplant may impede maximal recovery. Nanotherapeutic approaches can facilitate stem cell delivery while simultaneously delivering factors aimed at enhancing and nourishing stem cells en route to, and at, the target site. Hydroxyl polyamidoamine (PAMAM) dendrimer nanoparticles have been used in a variety of models to deliver therapeutics in a targeted manner to injury sites at low doses. Here, survival and migration of GRPs was assessed in a mouse model of neonatal white matter injury with different methods of dendrimer nanoparticle support. Our findings demonstrate the ability of GRPs to take up nanoparticle-drug conjugates and for these conjugates to act beyond the injury site in vivo. Compared to GRPs alone, mice receiving dendrimer-drug in parallel to GRPs, or via GRPs as the delivery vector, showed improved migration and differentiation of cells 8 weeks post-transplant. These studies demonstrate that drug-conjugated nanoparticles can enhance transplanted progenitor cell survival and migration, and suggest that combination therapies may allow engraftment without overt immunosuppression.
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http://dx.doi.org/10.1039/c9nr10804aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448752PMC
August 2020

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

Am J Hum Genet 2020 08 20;107(2):352-363. Epub 2020 Jul 20.

GeneDx, Inc., Gaithersburg, MD 20877, USA.

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413887PMC
August 2020

Characterization and Analysis of Porosities in High Pressure Die Cast Aluminum by Using Metallography, X-Ray Radiography, and Micro-Computed Tomography.

Materials (Basel) 2020 Jul 9;13(14). Epub 2020 Jul 9.

Department of Mechanical Engineering, University of Memphis, Memphis, TN 38152, USA.

Mechanical performance of cast aluminum alloys is strongly affected by the defects formed during solidification. For example, fractography studies of the fatigue specimens have shown that fatigue failure in aluminum castings containing defects is almost always initiated from defects, among which pores are most detrimental. However, elimination of these pores is neither always economically nor technically possible. This work characterizes defects in high pressure die cast aluminum alloy as an illustrative material, but the methods used can be applicable to other types of castings and defects. The defects were evaluated using metallography as well as micro-computed tomography techniques. The variability of defects between the specimens of two sizes as well as different porosity levels are studied statistically. The distributions of defects based on location within the specimens are also analyzed. Moreover, the maximum defect size within the specimens are estimated using extreme value statistics, which can be used as an input to fatigue life prediction models. Extreme value statistics is applied on both 2D and 3D defect data. The accuracy of each approach is verified by comparing the estimated maximum defect size within the specimens with the maximum observed defects on fracture surfaces of fatigue specimens.
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http://dx.doi.org/10.3390/ma13143068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412358PMC
July 2020

Towards Deterministic Computation of Internal Stresses in Additively Manufactured Materials under Fatigue Loading: Part I.

Materials (Basel) 2020 May 18;13(10). Epub 2020 May 18.

Department of Materials Test Engineering (WPT), TU Dortmund University, Baroper Str. 303, D-44227 Dortmund, Germany.

The ongoing studies of the influence of internal defects on fatigue strength of additively manufactured metals adopted an internal crack or notch-like model at which the threshold stress intensity factor is the driving mechanism of fatigue failure. The current article highlights a shortcoming of this approach and offers an alternative based on X-ray microcomputed tomography and cyclic plasticity with a hybrid formulation of Chaboche and Armstrong-Frederick material laws. The presented tessellation and geometrical transformation scheme enabled a significantly more realistic morphological representation of internal defects that yielded a cyclic strain within 2% of the experimental values. This means that cyclic plasticity models have an accurate prediction of mechanical properties without repeating a full set of experiments for additively manufactured arbitrary microstructures. The coupling with a material law that is oriented towards the treatment of cyclic hardening and softening enabled more accurate computation of internal stresses under cyclic loading than ever before owing to the maturity of tessellation and numerical tools since then. The resulting stress-strain distributions were used as input to the Fatemi-Socie damage model, based on which a successful calculation of fatigue lifetime became possible. Furthermore, acting stresses on the internal pores were shown to be more than 450% concerning the applied remote stress amplitude. The results are a pretext to a scale bridging numerical solution that accounts for the short crack formation stage based on microstructural damage.
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http://dx.doi.org/10.3390/ma13102318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287919PMC
May 2020

Expansion of the genetic landscape of ERLIN2-related disorders.

Ann Clin Transl Neurol 2020 04 8;7(4):573-578. Epub 2020 Mar 8.

Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

ERLIN2-related disorders are rare conditions of the motor system and clinical details are limited to a small number of prior descriptions. We here presented clinical and genetic details in five individuals (four different families) where three subjects carried a common homozygous p.Asn292ArgfsX26, associated also with sensorineural hearing loss in one child. One further subject had a de novo p.Gln63Lys and one harbors the homozygous p.Val136Gly because of maternal isodisomy of chromosome 8. Overall, we expanded the clinical and genetic spectrum of ERLIN2-related disorders and we reiterate that autosomal-dominant transmission is a potential mode of inheritance. Future research will elucidate disease mechanisms.
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http://dx.doi.org/10.1002/acn3.51007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187699PMC
April 2020

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.

Hum Mutat 2020 Jun 11;41(6):1131-1137. Epub 2020 Mar 11.

Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Melbourne, Australia.

Alexander disease results from gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.
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http://dx.doi.org/10.1002/humu.24008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491703PMC
June 2020

Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.

Neuron 2020 04 24;106(2):246-255.e6. Epub 2020 Feb 24.

Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. Electronic address:

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.
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http://dx.doi.org/10.1016/j.neuron.2020.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255387PMC
April 2020

X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies.

Int J Dev Neurosci 2020 Feb 26;80(1):52-72. Epub 2020 Jan 26.

Hugo W Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.

Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long-chain fatty acid (VLCFA) chain length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
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http://dx.doi.org/10.1002/jdn.10003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041623PMC
February 2020

Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption.

Exp Neurol 2020 04 27;326:113164. Epub 2019 Dec 27.

Moser Center for Leukodystrophies, Kennedy Krieger Institute, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (mt-AspRS, or DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brainstem, and spinal cord, the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease. Here, Dars2 disruption in CamKIIα-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at five months, and culminating by nine months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation. Interestingly, RNAseq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and defense response regulation. RNA transcript analysis demonstrates that activation of immune and cell stress pathways are initiated in advance of a behavioral phenotype and cerebral deficits. An understanding of these pathways and their contribution to significant neuronal loss in CamKII-Dars2 deficient mice may aid in deciphering mechanisms of LBSL pathology.
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http://dx.doi.org/10.1016/j.expneurol.2019.113164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448750PMC
April 2020

Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.

J Neurodev Disord 2019 12 16;11(1):29. Epub 2019 Dec 16.

Moser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, MD, 21205, USA.

Background: The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. BODY: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum.

Conclusion: The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.
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http://dx.doi.org/10.1186/s11689-019-9292-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913031PMC
December 2019

X-linked Adrenoleukodystrophy: Pathology, Pathophysiology, Diagnostic Testing, Newborn Screening, and Therapies.

Int J Dev Neurosci 2019 Nov 25. Epub 2019 Nov 25.

Hugo W Moser Research Institute, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, USA. Electronic address:

Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific role of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials, and the advent of newborn screening in the United States. In ALD, very long chain fatty acid (VLCFA) chain-length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
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http://dx.doi.org/10.1016/j.ijdevneu.2019.11.002DOI Listing
November 2019

X-linked Adrenoleukodystrophy: Pathology, Pathophysiology, Diagnostic Testing, Newborn Screening, and Therapies.

Int J Dev Neurosci 2019 Nov 25. Epub 2019 Nov 25.

Hugo W Moser Research Institute, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, USA. Electronic address:

Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific role of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials, and the advent of newborn screening in the United States. In ALD, very long chain fatty acid (VLCFA) chain-length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
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http://dx.doi.org/10.1016/j.ijdevneu.2019.11.002DOI Listing
November 2019

Evaluating the accuracy of geometrical distortion correction of magnetic resonance images for use in intracranial brain tumor radiotherapy.

Rep Pract Oncol Radiother 2019 Nov-Dec;24(6):606-613. Epub 2019 Oct 19.

Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39216, United States.

Aim: Determine the 1) effectiveness of correction for gradient-non-linearity and susceptibility effects on both QUASAR GRID and CIRS phantoms; and 2) the magnitude and location of regions of residual distortion before and after correction.

Background: Using magnetic resonance imaging (MRI) as a primary dataset for radiotherapy planning requires correction for geometrical distortion and non-uniform intensity.

Materials And Methods: MRI, computed tomography (CT) and cone beam CT images of QUASAR GRID and CIRS head phantoms were acquired. Ten patients were MRI-scanned for stereotactic radiosurgery treatment. Two magnitude and one phase difference image were acquired to create a field map. A MATLAB program was used to calculate geometrical distortion in the frequency encoding direction, and 3D interpolation was applied to resize it to match 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images. MPRAGE images were warped according to the interpolated field map in the frequency encoding direction. The corrected and uncorrected MRI images were fused, deformable registered, and a difference distortion map generated.

Results: Maximum deviation improvements: , 0.27 mm y-direction, 0.07 mm z-direction, 0.23 mm x-direction. , 0.34 mm, 0.1 mm and 0.09 mm at 20-, 40- and 60-mm diameters from the isocenter. Patient data show corrections from 0.2 to 1.2 mm, based on location. The most-distorted areas are around air cavities, e.g. sinuses.

Conclusions: The phantom data show the validity of our fast distortion correction algorithm. Patient-specific data are acquired in <2 min and analyzed and available for planning in less than a minute.
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http://dx.doi.org/10.1016/j.rpor.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807066PMC
October 2019

STrategically Acquired Gradient Echo (STAGE) imaging, part III: Technical advances and clinical applications of a rapid multi-contrast multi-parametric brain imaging method.

Magn Reson Imaging 2020 01 16;65:15-26. Epub 2019 Oct 16.

Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

One major thrust in radiology today is image standardization with a focus on rapidly acquired quantitative multi-contrast information. This is critical for multi-center trials, for the collection of big data and for the use of artificial intelligence in evaluating the data. Strategically acquired gradient echo (STAGE) imaging is one such method that can provide 8 qualitative and 7 quantitative pieces of information in 5 min or less at 3 T. STAGE provides qualitative images in the form of proton density weighted images, T1 weighted images, T2* weighted images and simulated double inversion recovery (DIR) images. STAGE also provides quantitative data in the form of proton spin density, T1, T2* and susceptibility maps as well as segmentation of white matter, gray matter and cerebrospinal fluid. STAGE uses vendors' product gradient echo sequences. It can be applied from 0.35 T to 7 T across all manufacturers producing similar results in contrast and quantification of the data. In this paper, we discuss the strengths and weaknesses of STAGE, demonstrate its contrast-to-noise (CNR) behavior relative to a large clinical data set and introduce a few new image contrasts derived from STAGE, including DIR images and a new concept referred to as true susceptibility weighted imaging (tSWI) linked to fluid attenuated inversion recovery (FLAIR) or tSWI-FLAIR for the evaluation of multiple sclerosis lesions. The robustness of STAGE T1 mapping was tested using the NIST/NIH phantom, while the reproducibility was tested by scanning a given individual ten times in one session and the same subject scanned once a week over a 12-week period. Assessment of the CNR for the enhanced T1W image (T1WE) showed a significantly better contrast between gray matter and white matter than conventional T1W images in both patients with Parkinson's disease and healthy controls. We also present some clinical cases using STAGE imaging in patients with stroke, metastasis, multiple sclerosis and a fetus with ventriculomegaly. Overall, STAGE is a comprehensive protocol that provides the clinician with numerous qualitative and quantitative images.
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http://dx.doi.org/10.1016/j.mri.2019.09.006DOI Listing
January 2020

Gamma Knife icon CBCT offers improved localization workflow for frame-based treatment.

J Appl Clin Med Phys 2019 Nov 6;20(11):95-103. Epub 2019 Oct 6.

Radiation Oncology, University of Mississippi Medical Center, Jackson, MS, USA.

Object: The purpose of this study was to compare two methods of stereotactic localization in Gamma Knife treatment planning: cone beam computed tomography (CBCT) or fiducial. While the fiducial method is the traditional method of localization, CBCT is now available for use with the Gamma Knife Icon. This study seeks to determine whether a difference exists between the two methods and then whether one is better than the other regarding accuracy and workflow optimization.

Methods: Cone beam computed tomography was used to define stereotactic space around the Elekta Film Pinprick phantom and then treated with film in place. The same phantom was offset known amounts from center and then imaged with CBCT and registered with the reference CBCT image to determine if measured offsets matched those known. Ten frameless and 10 frame-based magnetic resonance imaging (MRI) to CBCT patient fusions were retrospectively evaluated using the TG-132 TRE method. The stereotactic coordinates defined by CBCT and traditional fiducials were compared on the Elekta 8 cm Ball phantom, an anthropomorphic phantom, and actual patient data. Offsets were introduced to the anthropomorphic phantom in the stereotactic frame and CBCT's ability to detect those offsets was determined.

Results: Cone beam computed tomography defines stereotactic space well within the established limits of the mechanical alignment system. The CBCT to CBCT registration can detect offsets accurately to within 0.1 mm and 0.5°. In all cases, some disagreement existed between fiducial localization and that of CBCT which in some cases was small, but also was as high as 0.43 mm in the phantom domain and as much as 1.54 mm in actual patients.

Conclusion: Cone beam computed tomography demonstrates consistent accuracy in defining stereotactic space. Since both localization methods do not agree with each other consistently, the more reliable method must be identified. Cone beam computed tomography can accurately determine offsets occurring within stereotactic space that would be nondiscernible utilizing the fiducial method and seems to be more reliable. Using CBCT localization offers the opportunity to streamline workflow both from a patient and clinic perspective and also shows patient position immediately prior to treatment.
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http://dx.doi.org/10.1002/acm2.12745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839378PMC
November 2019

Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network.

Biol Blood Marrow Transplant 2019 12 6;25(12):e363-e374. Epub 2019 Sep 6.

Pediatric Transplant and Cellular Therapy, Duke University, Durham, North Carolina.

The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.003DOI Listing
December 2019

A new approach to automatic fetal brain extraction from MRI using a variational level set method.

Med Phys 2019 Nov 12;46(11):4983-4991. Epub 2019 Sep 12.

Department of Radiation Oncology and Radiology, University of Mississippi Medical Center (UMMC), Jackson, MS, USA.

Background And Purpose: Appropriate images extracted from the MRI of mothers' wombs can be of great help in the medical diagnosis of fetal abnormalities. As maternal tissue may appear in such images, affecting visualization of myelination of the fetal brain, it is not possible to use methods routinely used for extraction of adult brains for fetal brains. The aim of the present study was to use a variational level set approach to extract fetal brain from T2-weighted MR images of the womb.

Methods: Coronal T2-weighted images were acquired using fast MRI protocols (to avoid artifacts). The database includes 105 MR images from eight subjects. After correcting the inhomogeneity of the images, the fetal eyes were located, and from that information, the location of the fetus brain was automatically determined. Then, the variational level set was used for fetus brain extraction. The results were analyzed by a clinical specialist (radiologist) and the similarity (Dice and Jaccard coefficients), sensitivity and specificity were calculated.

Results And Conclusions: The means of the statistical analysis for the Dice and Jaccard coefficients, sensitivity and specificity, were 99.56%, 96.89%, 95.71%, and 97.96%, respectively. Thus, extraction of fetal brain from MR images was confirmed, both statistically and visually through cross-validation.
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http://dx.doi.org/10.1002/mp.13766DOI Listing
November 2019

De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.

Am J Hum Genet 2019 08 18;105(2):413-424. Epub 2019 Jul 18.

NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892-1851, USA. Electronic address:

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699142PMC
August 2019

Evaluation of the Geometric and Dosimetric Accuracy of Synthetic Computed Tomography Images for Magnetic Resonance Imaging-only Stereotactic Radiosurgery.

Cureus 2019 Apr 8;11(4):e4404. Epub 2019 Apr 8.

Radiation Oncology, University of Mississippi Medical Center, Jackson, USA.

Introduction Stereotactic radiosurgery (SRS) plans created using synthetic computed tomography (CT) images derived from magnetic resonance imaging (MRI) data may offer the advantage of inhomogeneity correction by convolution algorithms, as is done for CT-based plans. We sought to determine and validate the clinical significance and accuracy of synthetic CT images for inhomogeneity correction in MRI-only stereotactic radiosurgery plans for treatment of brain tumors. Methods In this retrospective study, data from two patients with brain metastases and one with meningioma who underwent imaging with multiple modalities and received frameless SRS treatment were analyzed. The SRS plans were generated using a convolution algorithm to account for brain inhomogeneity using CT and synthetic CT images and compared with the original clinical TMR10 plans created using MRI images. Results Synthetic CT-derived SRS plans are comparable with CT-based plans using convolution algorithm, and for some targets, based on location, they provided better coverage and a lower maximum dose. Conclusions The results suggest similar dose delivery results for CT and synthetic CT-based treatment plans. Synthetic CT plans offered a noticeable improvement in target dose coverage and a more gradual dose fall-off relative to TMR10 MRI-based plans. The major disadvantage is a slightly increased dose (by 0.37%) to nearby healthy tissue (brainstem) for synthetic CT-based plans relative to those created using clinical MRI images, which may be a problem for patients undergoing high-dose treatment.
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http://dx.doi.org/10.7759/cureus.4404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559689PMC
April 2019

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.

Neurotherapeutics 2019 10;16(4):1167-1182

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.
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http://dx.doi.org/10.1007/s13311-019-00735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985062PMC
October 2019

Studying the Origin of Reverberation Clutter in Echocardiography: In Vitro Experiments and In Vivo Demonstrations.

Ultrasound Med Biol 2019 07 30;45(7):1799-1813. Epub 2019 Apr 30.

Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.

Clutter in echocardiography hinders the visualization of the heart and reduces the diagnostic value of the images. The detailed mechanisms that generate clutter are, however, not well understood. We present five different hypotheses for generation of clutter based on reverberation artifact with a focus on apical four-chamber view echocardiograms. We demonstrate the plausibility of our hypotheses by in vitro experiments and by comparing the results with in vivo recordings from four volunteers. The results show that clutter in echocardiography can be originated both at structures that lie in the ultrasound beam path and at those that are outside the imaging plane. We show that reverberations from echogenic structures outside the imaging plane can make clutter over the image if the ultrasound beam gets deflected out of its intended path by specular reflection at the ribs. Different clutter types in the in vivo examples show that the appearance of clutter varies, depending on the tissue from which it originates. The results of this work can be applied to improve clutter reduction techniques or to design ultrasound transducers that give higher quality cardiac images. The results can also help cardiologists have a better understanding of clutter in echocardiograms and acquire better images based on the type and the source of the clutter.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.01.010DOI Listing
July 2019

In vivo high-resolution diffusion tensor imaging of the developing neonatal rat cortex and its relationship to glial and dendritic maturation.

Brain Struct Funct 2019 Jun 22;224(5):1815-1829. Epub 2019 Apr 22.

Department of Radiology, New York University School of Medicine, 660 First Avenue, Room 207, New York, NY, 10016, USA.

Diffusion tensor imaging (DTI) is increasingly utilized as a sensitive tool for studying brain maturation and injuries during the neonatal period. In this study, we acquired high resolution in vivo DTI data from neonatal rat brains from postnatal day 2 (P2) to P10 and correlated temporal changes in DTI derived markers with microstructural organization of glia, axons, and dendrites during this critical period of brain development. Group average images showed dramatic temporal changes in brain morphology, fractional anisotropy (FA) and mean diffusivity (MD). Most cortical regions showed a monotonous decline in FA and an initial increase in MD from P2 to P8 that declined slightly by P10. Qualitative histology revealed rapid maturation of the glial and dendritic networks in the developing cortex. In the cingulate and motor cortex, the decreases in FA over time significantly correlated with structural anisotropy values computed from histological sections stained with glial and dendritic markers. However, in the sensory and visual cortex, other factors probably contributed to the observed decreases in FA. We did not observe any significant correlations between FA and structural anisotropy computed from the axonal histological marker.
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http://dx.doi.org/10.1007/s00429-019-01878-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565480PMC
June 2019

The Effect of Dynamic Range Alterations in the Estimation of Contrast.

IEEE Trans Ultrason Ferroelectr Freq Control 2019 07 15;66(7):1198-1208. Epub 2019 Apr 15.

Many adaptive beamformers claim to produce images with increased contrast, a feature that could enable a better detection of lesions and anatomical structures. Contrast is often quantified using the contrast ratio (CR) and the contrast-to-noise ratio (CNR). The estimation of CR and CNR can be affected by dynamic range alterations (DRAs), such as those produced by a trivial gray-level transformation. Thus, we can form the hypothesis that contrast improvements from adaptive beamformers can, partly, be due to DRA. In this paper, we confirm this hypothesis. We show evidence on the influence of DRA on the estimation of CR and CNR and on the fact that several methods in the state of the art do alter the DR. To study this phenomenon, we propose a DR test (DRT) to estimate the degree of DRA and we apply it to seven beamforming methods. We show that CR improvements correlate with DRT with [Formula: see text] in simulated data and [Formula: see text] in experiments. We also show that DRA may lead to increased CNR values, under some circumstances. These results suggest that claims on lesion detectability, based on CR and CNR values, should be revised.
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http://dx.doi.org/10.1109/TUFFC.2019.2911267DOI Listing
July 2019

Phantom Validation of DCE-MRI Magnitude and Phase-Based Vascular Input Function Measurements.

Tomography 2019 03;5(1):77-89

TECHNA Institute, University Health Network, Toronto, ON, Canada.

Accurate, patient-specific measurement of arterial input functions (AIF) may improve model-based analysis of vascular permeability. This study investigated factors affecting AIF measurements from magnetic resonance imaging (MRI) magnitude (AIF) and phase (AIF) signals, and compared them against computed tomography (CT) (AIF), under controlled conditions relevant to clinical protocols using a multimodality flow phantom. The flow phantom was applied at flip angles of 20° and 30°, flow rates (3-7.5 mL/s), and peak bolus concentrations (0.5-10 mM), for in-plane and through-plane flow. Spatial 3D-FLASH signal and variable flip angle T1 profiles were measured to investigate in-flow and radiofrequency-related biases, and magnitude- and phase-derived Gd-DTPA concentrations were compared. MRI AIF performance was tested against AIF via Pearson correlation analysis. AIF was sensitive to imaging orientation, spatial location, flip angle, and flow rate, and it grossly underestimated AIF peak concentrations. Conversion to Gd-DTPA concentration using T1 taken at the same orientation and flow rate as the dynamic contrast-enhanced acquisition improved AIF accuracy; yet, AIF metrics remained variable and significantly reduced from AIF at concentrations above 2.5 mM. AIF performed equivalently within 1 mM to AIF across all tested conditions. AIF, but not AIF, reported equivalent measurements to AIF across the range of tested conditions. AIF showed superior robustness.
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http://dx.doi.org/10.18383/j.tom.2019.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403037PMC
March 2019