Volumetric Magnetic Resonance Imaging Analysis Research Articles

Highly demarcated structural alterations in the brain and impaired social incentive learning in Tbx1 heterozygous mice.

Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain's regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.

Brain Magnetic Resonance Imaging in Wilson's Disease-Significance and Practical Aspects-A Narrative Review.

Wilson's disease (WD) is a genetic disorder of copper metabolism with pathological copper accumulation in many organs, resulting in clinical symptoms, mostly hepatic and neuropsychiatric. As copper accumulates in the brain during WD, and almost 50% of WD patients at diagnosis present with neurological symptoms, neuroimaging studies (especially brain magnetic resonance imaging (MRI)) are part of WD diagnosis. The classical sequences (T1, T2, and fluid-attenuated inversion recovery) were used to describe brain MRI; however, with the development of neuroradiology, several papers proposed the use of new MRI sequences and techniques like susceptibility-weighted images, T2*, diffusion MRI, tractography, volumetric assessment and post-processing brain MRI analysis of paramagnetic accumulation-quantitative susceptibility mapping. Based on these neuroradiological data in WD, currently, brain MRI semiquantitative scale and the pathognomonic neuroradiological brain MRI signs in WD were proposed. Further, the volumetric studies and brain iron accumulation MRI analysis suggested brain atrophy and iron accumulation as biomarkers of neurological WD disease severity. All these results highlight the significance of brain MRI examinations in WD. Due to the extreme progress of these studies, based on the available literature, the authors present the current state of knowledge about the significance, practical aspects, and future directions of brain MRI in WD.

Structural Brain Alterations in Metabolic Syndrome: A Comprehensive MRI Volumetric Analysis of Subcortical and Associated Structures.

Objective: This study aims to elucidate the comprehensive effects of metabolic syndrome (MetS) on the structural integrity of subcortical brain regions and associated structures through high-resolution magnetic resonance imaging (MRI) volumetric analysis, thereby contributing to a deeper understanding of the neuroanatomical dimensions of MetS and its potential implications for cognitive functions and overall brain health. Methods: A cross-sectional design was implemented, involving 25 individuals diagnosed with MetS for at least one year and a healthy control group of 15 individuals at a tertiary hospital's family medicine clinic in Eastern Turkey. Participants underwent a high-resolution MRI scan using a 1.5T Siemens Aera scanner. The MRICloud platform was employed for comprehensive segmentation and quantitative analysis of various brain structures. Results: The study revealed significant volumetric reductions in all measured subcortical brain regions among individuals with MetS compared to the control group (all P < 0.05). Notable differences were observed in key structures such as the substantia nigra, corpus callosum, and thalamus. In subcortical structures, the largest volumetric differences were noted in the basal ganglia L (1322.4 mm³), while the most significant percentage differences were seen in the substantia nigra R (25.24%) and caudate nucleus L (21.02%). Conclusion: The findings from this study underscore the significant neuroanatomical changes associated with MetS, manifesting as volumetric reductions in critical subcortical brain areas. These alterations underscore the necessity for further research into the comprehensive influence of MetS on cognitive processes and the potential for early therapeutic interventions.

Long-term effects of SARS-CoV-2 infection in patients with and without chemosensory disorders at disease onset: a psychophysical and magnetic resonance imaging exploratory study

A preserved sense of smell and taste allows us to understand many environmental “messages” and results in meaningfully improvements to quality of life. With the COVID-19 pandemic, it became clear how important these senses are for social and nutritional status and catapulted this niche chemosensory research area towards widespread interest. In the current exploratory work, we assessed two groups of post-COVID-19 patients who reported having had (Group 1) or not (Group 2) a smell/taste impairment at the disease onset. The aim was to compare them using validated smell and taste tests as well as with brain magnetic resonance imaging volumetric analysis. Normative data were used for smell scores comparison and a pool of healthy subjects, recruited before the pandemic, served as controls for taste scores. The majority of patients in both groups showed an olfactory impairment, which was more severe in Group 1 (median UPSIT scores: 24.5 Group 1 vs 31.0 Group 2, p = 0.008), particularly among women (p = 0.014). No significant differences emerged comparing taste scores between Group 1 and Group 2, but dysgeusia was only present in Group 1 patients. However, for taste scores, a significant difference was found between Group 1 and controls (p = 0.005). No MRI anatomical abnormalities emerged in any patients while brain volumetric analysis suggested a significant difference among groups for the right caudate nucleus (p = 0.028), although this was not retained following Benjamini–Hochberg correction. This exploratory study could add new information in COVID-19 chemosensory long-lasting impairment and address future investigations on the post-COVID-19 patients’ research.

NOVEL ADJUVANT TARGETED APPROACH FOR PTEN MUTATED CHOROID PLEXUS CARCINOMA IN ADULTS: CASE REPORT AND LITERATURE REVIEW

Abstract Choroid plexus carcinoma (CPC) is a malignant primary brain tumor that is extremely rare in adults. Previous literature has reported a median overall survival of 2.7 years among pediatric and adult cases. However, data regarding adult CPC's genomic profile by next-generation sequencing (NGS), pathogenesis, and adjuvant treatments after maximum safe resection and radiotherapy remains limited. CASE DESCRIPTION: A 53-year-old female was diagnosed with CPC and found with PTEN and PREX2 mutations by NGS. She underwent near total resection and craniospinal irradiation, followed by a novel mTOR-targeted chemotherapy with everolimus for 12 months. She has remained in remission with no evidence of tumor growth upon follow-up magnetic resonance imaging (MRI). There are notable MRI T2-fluid-attenuated inversion recovery (FLAIR) signal changes likely due to radiation effects. Currently, the patient is doing well with mild cognitive impairments and an overall survival of 5.2 years. DISCUSSION: Since PTEN and PREX2 are involved with the mTOR pathway, this case provides insight into the pathogenesis of adult CPC and evidence of a viable adjuvant treatment. Treatments such as stem cell transplants and ifosfamide, carboplatin, and etoposide chemotherapy have not shown to prevent recurrence. This is also the first study to calculate CPC's natural growth rate using MRI volumetric analysis with a 7.74% tumor growth in 51 days. Further studies are warranted in prospective clinical trials to assess everolimus' efficacy as an adjuvant therapy. NGS focusing on mTOR pathway abnormalities are also recommended to expand the present knowledge of this rare tumor.

Massive Left Ventricular Aneurysm After Inferior Infarction

True ventricular aneurysm is a rare complication of myocardial infarction. After a 53-year-old man presented late with an inferior ST-segment elevation myocardial infarction, he was found to have a massive posterobasal left ventricular aneurysm. Cardiac magnetic resonance imaging volumetric analysis highlighted the hemodynamic significance of the aneurysm. As the result of persistent symptomatic heart failure, the patient underwent surgical resection of the aneurysm and placement of a pericardial patch with excellent results at follow-up.

Analysis of Imaging Results for Semisitting Compared with Supine Positioning in the Retrosigmoid Approach for Resection of Cerebellopontine Angle Vestibular Schwannomas.

To compare the completeness of resection of vestibular schwannomas using three-dimensional segmented volumetric analysis of pre- and postoperative magnetic resonance imaging (MRI) of patients undergoing supine and semisitting positioning for the retrosigmoid approach. Retrospective chart review. Tertiary medical center. Patients with vestibular schwannomas undergoing surgical resection via the retrosigmoid approach. Tumor resection via the retrosigmoid approach with different patient positioning: standard supine versus semisitting. Preoperative versus postoperative three-dimensional segmented volumetric MRI analysis of vestibular schwannomas. A total of 43 patients (15 supine and 28 semisitting) underwent retrosigmoid craniotomy for resection of vestibular schwannomas. For the conventional supine and semisitting positioning, mean preoperative tumor volumes were 12.65 and 8.73 cm 3 ( p = 0.15), respectively. Postoperative mean tumor volumes for the supine and semisitting positions were 2.09 and 0.48 cm 3 ( p = 0.13), respectively. There were 11 cases of postoperative sigmoid sinus thrombosis, 3 in the conventional supine group and 8 in the semisitting groups, and there were 6 cases of postoperative cerebrospinal fluid leaks, all in the semisitting group. The mean House-Brackmann scores for the supine and semisitting groups were 2.9 and 2.3, respectively. There was no statistically significant difference between groups in the rates of these or any other postoperative complications. The semisitting position for the suboccipital retrosigmoid approach for vestibular schwannoma resection does not compromise the ability to adequately resect the tumor as seen by volumetric MRI results. Further studies are needed to establish the safety of this position compared with the traditional supine approach.

Longitudinal Natural History of Pediatric Subjects Affected with Mucopolysaccharidosis IIIB

To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB. Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects. The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6years. Development quotients for both cognition and adaptive behaviorfollow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24months by age 8years on average and by 13.5years at the latest. All tested subjects (n=22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26mL of brain volume (-2.7%) over 48weeks, owing entirely to a loss of cortical gray matter (32mL; -6.5%). MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior. ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.

Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study.

Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4–24.0) and 23.9 (20.6–29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies.

Volumetric MRI is a promising outcome measure of muscle reinnervation

The development of outcome measures that can track the recovery of reinnervated muscle would benefit the clinical investigation of new therapies which hope to enhance peripheral nerve repair. The primary objective of this study was to assess the validity of volumetric Magnetic Resonance Imaging (MRI) as an outcome measure of muscle reinnervation by testing its reproducibility, responsiveness and relationship with clinical indices of muscular function. Over a 3-year period 25 patients who underwent nerve transfer to reinnervate elbow flexor muscles were assessed using intramuscular electromyography (EMG) and MRI (median post-operative assessment time of 258 days, ranging from 86 days pre-operatively to 1698 days post- operatively). Muscle power (Medical Research Council (MRC) grade) and Stanmore Percentage of Normal Elbow Assessment (SPONEA) assessment was also recorded for all patients. Sub-analysis of peak volitional force (PVF), muscular fatigue and co-contraction was performed in those patients with MRC > 3. The responsiveness of each parameter was compared using Pearson or Spearman correlation. A Hierarchical Gaussian Process (HGP) was implemented to determine the ability of volumetric MRI measurements to predict the recovery of muscular function. Reinnervated muscle volume per unit Body Mass Index (BMI) demonstrated good responsiveness (R2 = 0.73, p < 0.001). Using the temporal and muscle volume per unit BMI data, a HGP model was able to predict MRC grade and SPONEA with a mean absolute error (MAE) of 0.73 and 1.7 respectively. Muscle volume per unit BMI demonstrated moderate to good positive correlations with patient reported impairments of reinnervated muscle; co- contraction (R2 = 0.63, p = 0.02) and muscle fatigue (R2 = 0.64, p = 0.04). In summary, volumetric MRI analysis of reinnervated muscle is highly reproducible, responsive to post-operative time and demonstrates correlation with clinical indices of muscle function. This encourages the view that volumetric MRI is a promising outcome measure for muscle reinnervation which will drive advancements in motor recovery therapy.

Volumetric magnetic resonance imaging analysis of multilevel upper airway surgery effects on pharyngeal structure.

The Sleep Apnea Multilevel Surgery (SAMS) trial found that modified uvulopalatopharyngoplasty with tonsillectomy (if tonsils present) combined with radiofrequency tongue ablation reduced obstructive sleep apnea (OSA) severity and daytime sleepiness in moderate-severe OSA. This study aimed to investigate mechanisms of effect on apnea-hypopnea index (AHI) reduction by assessing changes in upper airway volumes (airway space, soft palate, tongue, and intra-tongue fat). This is a case series analysis of 43 participants of 51 randomized to the surgical arm of the SAMS trial who underwent repeat magnetic resonance imaging (MRI). Upper airway volume, length, and cross-sectional area, soft palate and tongue volumes, and tongue fat were measured. Relationships between changes in anatomical structures and AHI were assessed. The participant sample was predominantly male (79%); mean ± SD age 42.7 ± 13.3 years, body mass index 30.8 ± 4.1 kg/m2, and AHI 47.0 ± 22.3 events/hour. There were no, or minor, overall volumetric changes in the airway, soft palate, total tongue, or tongue fat volume. Post-surgery there was an increase in the minimum cross-sectional area by 0.1 cm2 (95% confidence interval 0.04-0.2 cm2) in the pharyngeal airway, but not statistically significant on corrected analysis. There was no association between anatomical changes and AHI improvement. This contemporary multilevel upper airway surgery has been shown to be an effective OSA treatment. The current anatomical investigation suggests there are not significant post-operative volumetric changes associated with OSA improvement 6-month post-surgery. This suggests that effect on OSA improvement is achieved without notable deformation of airway volume. Reduced need for neuromuscular compensation during wake following anatomical improvement via surgery could explain the lack of measurable volume change. Further research to understand the mechanisms of action of multilevel surgery is required. This manuscript presents a planned image analysis of participants randomized to the surgical arm or the clinical trial multilevel airway surgery in patients with moderate-severe obstructive sleep apnea (OSA) who have failed medical management to assess change in OSA events and daytime sleepiness. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=266019&isReview=true%20Australian%20New%20Zealand%20Clinical%20Trials%20Registry%20ACTRN12514000338662, prospectively registered on March 31, 2014.

Solid Component Volume as a Proxy to Identify Distinct Hemangioblastoma Populations

Posterior fossa hemangioblastomas usually consist of a small solid nodule with a large cyst, while more rarely they present as a large solid mass with a small or absent cyst, which can be surgically challenging. We sought to investigate the potential existence of multiple distinct hemangioblastoma populations using tumor volumetric data as an indicator. We conducted a retrospective review of surgically treated hemangioblastomas between 2005 and 2019 in our unit, including clinical notes, preoperative magnetic resonance imaging volumetric analysis of the solid component of the tumor, and pathology. Finite Gaussian mixture modeling was applied on the solid component volume dataset to identify potential underlying Gaussian distributions with their associated characteristics. Nonparametric Mann-Whitney U tests were used to investigate significance of differences (P < 0.05) in solid component volume and different variables (Von Hippel-Lindau disease, extent of resection, outcome). A total of 68 consecutive patients were included. Solid component volumes followed a multimodal distribution (median= 1287 mm3, interquartile range of 3428 mm3). The best-fit finite Gaussian mixture modeling model identified 3 statistically significant different (P= 0.001) potential mixture components: X1 (219 ± 187 mm3), X2 (2686 ± 1299 mm3), and X3 (10,800 ± 5514 mm3). The second-best model detected 2 significantly different (P= 9.99e-08) mixture components Y1 (222 ± 189 mm3) and Y2 (5391 ± 5094 mm3). A significant difference in solid component volume was found between patients with favorable and unfavorable outcome (P= 0.002). This study has shown preliminary evidence that large solid hemangioblastomas may constitute a completely distinct population, rather than a variant of one large group of hemangioblastomas.

Volumetric brain magnetic resonance imaging analysis in children with obstructive sleep apnea

ObjectivesPediatric Obstructive Sleep Apnea (OSA) is associated with neurocognitive deficits. Cerebral structural alterations in the frontal cortex, cerebellum, and hippocampus have been reported in adult OSA patients. These brain areas are important for executive functioning, motor regulation of breathing, and memory function, respectively. Corresponding evidence comparing cerebral structures in pediatric OSA patients is limited. The objective of this study is to investigate MRI differences in cortical thickness and cortical volume in children with and without OSA. Study designProspective, single institutional case-control study. MethodsForty-five children were recruited at a pediatric tertiary care center (27 with OSA; mean age 9.9 ± 1.9 years, and 18 controls; mean age 10.5 ± 1.0 years). The OSA group underwent magnetic resonance imaging (MRI), polysomnography (PSG) and completed the Pediatric Daytime Sleepiness Scale (PDSS) and the Child's Sleep Habits Questionnaire (CSHQ). High-resolution T1-weighted MRI was utilized to examine cortical thickness and gray and white matter volume in children with OSA compared to a healthy group of demographically-comparable children without OSA selected from a pre-existing MRI dataset. ResultsChildren with OSA showed multiple regions of cortical thinning primarily in the left hemisphere. Reduced gray matter (GM) volume was noted in the OSA group in multiple frontal regions of the left hemisphere (superior frontal, rostral medial frontal, and caudal medial frontal regions). Reduced white matter (WM) volume in both the left and right hemisphere was observed in regions of the frontal, parietal, and occipital lobes in children with OSA. ConclusionThis study noted differences in cortical thickness and GM and WM regional brain volumes in children with OSA. These findings are consistent with other pediatric studies, which also report differences between healthy children and those with OSA. We found that the severity of OSA does not correlate with the extent of MRI alterations.

Sydenham Chorea: Putaminal Enlargement

Our aim in this study was to evaluate the efficacy of magnetic resonance imaging (MRI) studies in the detection of brain regions effected by Sydenham chorea and to determine whether they provided data regarding the pathogenesis of Sydenham chorea. To this end, we assessed basal ganglia structures in Sydenham chorea patients and control group by quantitative MRI volumetric analysis. Patients with a recent onset of chorea and control subjects matched for age and gender were included in the study. Medical history, laboratory tests, and physical and neurologic examinations were reviewed. All MRIs were considered within normal limits. High-resolution T1-weighted 3D magnetization-prepared rapid acquisition of gradient echo scans were used for quantitative volumetric assessment of the brain via the "volBrain" method. Twenty-four subjects with Sydenham chorea (16 girls and 8 boys, aged between 7 and 16 years) and 35 control subjects were evaluated. Mean age was 11.25 ± 2.89 years for Sydenham chorea patients and 10.58 ± 2.53 years for the controls. No significant difference was found relative to globus pallidus, caudate, and thalamic volumes between patients with Sydenham chorea and controls. The relative mean total, left, and right putamen volumes were significantly larger in patients with Sydenham chorea compared to controls (P = .003, P = .018, P = .001, respectively). Selective neuroanatomic differences in putamen among other basal ganglia structures and significant increases in size are consistent with a hypothesis of a cross-reactive antibody-mediated inflammation of the putamen as being the pathophysiologic mechanism for this disorder.

Distinct patterns of hippocampal subfield volume loss in left and right mesial temporal lobe epilepsy.

To investigate the pattern and severity of hippocampal subfield volume loss in patients with left and right mesial temporal lobe epilepsy (mTLE) using quantitative MRI volumetric analysis. A total of 21 left and 14 right mTLE subjects, as well as 15 healthy controls, were enrolled in this cross-sectional study. A publically available magnetic resonance imaging (MRI) brain volumetry system (volBrain) was used for volumetric analysis of hippocampal subfields. The T1-weighted images were processed with a HIPS pipeline. A distinct pattern of hippocampal subfield atrophy was found between left and right mTLE patients when compared with controls. Patients with left mTLE exhibited ipsilateral hippocampal atrophy and segmental volume depletion of the Cornu Ammonis (CA) 2/CA3, CA4/dentate gyrus (DG), and strata radiatum-lacunosum-moleculare (SR-SL-SM). Those with right mTLE exhibited similar ipsilateral hippocampal atrophy but with additional segmental CA1 volume depletion. More extensive bilateral subfield volume loss was apparent with right mTLE patients. We demonstrate that left and right mTLE patients show a dissimilar pattern of hippocampal subfield atrophy, suggesting the pathophysiology of epileptogenesis in left and right mTLE to be different.

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Late-onset oro-facial dyskinesia in Spinocerebellar Ataxia type 2: a case report

BackgroundGenetic familiar causes of oro-facial dyskinesia are usually restricted to Huntington’s disease, whereas other causes are often missed or underestimated. Here, we report the case of late-onset oro-facial dyskinesia in an elderly patient with a genetic diagnosis of Spinocerebellar Ataxia type 2 (SCA2).Case presentationA 75-year-old man complained of progressive balance difficulty since the age of 60 years, associated with involuntary movements of the mouth and tongue over the last 3 months. No exposure to anti-dopaminergic agents, other neuroleptics, antidepressants, or other drugs was reported. Family history was positive for SCA2 (brother and the son of the brother). At rest, involuntary movements of the mouth and tongue were noted; they appeared partially suppressible and became more evident during stress and voluntary movements. Cognitive examination revealed frontal-executive dysfunction, memory impairment, and attention deficit. Brain magnetic resonance imaging (MRI) disclosed signs of posterior periventricular chronic cerebrovascular disease and a marked ponto-cerebellar atrophy, as confirmed by volumetric MRI analysis. A dopamine transporter imaging scan demonstrated a bilaterally reduced putamen and caudate nucleus uptake. Ataxin-2 (ATXN2) gene analysis revealed a 36 cytosine-adenine-guanine (CAG) repeat expansion, confirming the diagnosis of SCA2.ConclusionsSCA2 should be considered among the possible causes of adult-onset oro-facial dyskinesia, especially when the family history suggests an inherited cerebellar disorder. Additional clinical features, including parkinsonism and motor neuron disease, may represent relevant cues for an early diagnosis and adequate management.

Magnetic resonance imaging volumetric analysis in patients with Alternating hemiplegia of childhood: A pilot study.

Quantitative MRI is increasingly being used as a biomarker in neurological disorders. Cerebellar atrophy occurs in some Alternating Hemiplegia of Childhood (AHC) patients. However, it is not known if cerebellar atrophy can be a potential biomarker in AHC or if quantitative MRI is a reliable method to address this question. Here we determine the reproducibility of an MRI-volumetrics method to investigate brain volumes in AHC and apply it to a population of 14 consecutive AHC patients (ages 4-11 years). We studied method reproducibility in the first 11 patients and then performed correlation of cerebellar volumes, relative to published normal population means, with age in all 14. We used FreeSurfer 6.0.0 to automatically segment MRI images, then performed manual resegmentation correction by two different observers. No significant differences were observed in any of ten brain regions between the two reviewers: p>.591 and interclass Correlation Coefficient (ICC) ≥0.975 in all comparisons. Additionally, there were no significant differences between the means of the two reviewers and the automatic segmentation values: p≥.106 and ICC ≥0.994 in all comparisons. We found a negative correlation between cerebellar volume and age (R=-0.631, p=.037), even though only one patient showed any cerebellar atrophy upon formal readings of the MRIs by neuroradiology. Sample size did not allow us to rule out potential confounding variables. Thus, findings from this cross-sectional study should be considered as exploratory. Our study supports the prospective investigation of quantitative MRI-volumetrics of the cerebellum as a potential biomarker in AHC.

Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.