Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

A computed tomography-based method for the assessment of canine retrobulbar cone volume for ophthalmic anaesthesia.

OBJECTIVE: To develop a comprehensive formula for calculating the volume of local anaesthetic solution used for retrobulbar anaesthesia in dogs with different skull morphologies. STUDY DESIGN: Retrospective cohort imaging study. ANIMALS: Skull computed tomography (CT) images of 188 dogs of different breeds collected between January 2009 and December 2017. METHODS: Anatomical integrity of the orbit and adjacent structures, presenting complaint, clinical signs and CT findings were verified to exclude ocular abnormalities. The volume of the retrobulbar cone of 376 eyes was calculated using CT scans of the dogs' skulls. Additional data recorded included morphology of the skull, body weight, sex and size of the dogs, all of which were matched for possible association to the retrobulbar cone volume through univariable and multivariable linear regression models. Results of linear regression models were expressed as estimated beta coefficients with the corresponding 95% confidence intervals (95% CIs). RESULTS: Using univariate analysis, the retrobulbar cone volume was positively associated with weight and male sex. In addition, brachycephalic and dolichocephalic dogs showed a larger retrobulbar cone volume than mesocephalic dogs, while sex was no longer significantly associated with the retrobulbar cone volume. In multivariate analysis, when considering all variables in the model, weight emerged as the strongest predictor (beta coefficient: 0.062 mL kg-1, 95% CI: 0.056-0.067 mL kg-1, p < 0.001). CONCLUSIONS: and clinical relevance In the veterinary literature, there is no agreement on the precise volume of local anaesthetic solution that should be used to achieve intraconal retrobulbar anaesthesia in dogs. Here we suggest a formula to calculate the retrobulbar cone volume and, accordingly, the injection volume of local anaesthetic solution for effective retrobulbar anaesthesia.

Biofeedback Rehabilitation and Visual Cortex Response in Stargardt's Disease: A Randomized Controlled Trial.

Purpose: to evaluate the effect of biofeedback (BF) rehabilitation on the visual function and on the activity of primary visual cortex (PVC) in patients with Stargardt's disease owing to mutations in the ABCA4 gene (STGD1). Methods: This was a single-center, controlled, randomized study. Twenty-four patients with STGD1 were randomized into two groups: a treatment group (TG) undergoing BF rehabilitation and a control group (CG). Treatment with BF consisted of a 10-minute session per eye performed weekly for 12 weeks. The subjects underwent a baseline and 3-month follow-up visits, including best-corrected visual acuity (BCVA), reading test, microperimetry, and functional magnetic resonance imaging (fMRI). The fMRI studies were acquired sequentially using a passive viewing condition and an active reading task. The primary outcomes were the change in the fMRI activation of primary visual cortex and the change in reading ability. Results: After treatment, the patients in the TG were able to read smaller characters (P = 0.002) with a greater reading speed (P = 0.014) compared with patients in the CG. The fMRI studies showed a significant effect (P < 0.001) of BF on primary visual cortex activation in the TG compared with the CG. Finally, we observed significant (P < 0.05) improvements of best-corrected visual acuity, macular sensitivity, and fixation stability parameters in the TG compared with the CG. Conclusions: Our study showed that visual rehabilitation using BF improved the usage of residual visual function in patients with STGD1. Translational Relevance: Our findings show that the BF treatment compared with no treatment at all resulted in benefits. The specificity of the treatment could be examined to determine whether BF can be included in clinical practice.

The combined use of conventional MRI and MR spectroscopic imaging increases the diagnostic accuracy in amyotrophic lateral sclerosis.

PURPOSE: We aimed to assess, in amyotrophic lateral sclerosis (ALS), the diagnostic accuracy of the combined use of conventional MRI signal changes (namely, hypointensity of the precentral cortex and hyperintensity of the corticospinal tracts on T2-weighted images), and N-Acetyl-Aspartate (NAA) reduction in the motor cortex at Magnetic Resonance Spectroscopy (MRS), which are affected by limited diagnostic accuracy when used separately. METHODS: T2-hypointensity and NAA/(Choline+Creatine) ratio of the precentral gyrus and T2-hyperintensity of the corticospinal tracts were measured in 84 ALS patients and 28 healthy controls, using a Region-of-Interest approach. Sensitivity and specificity values were calculated using Fisher stepwise discriminant analysis, and cross-validated using the leave-one-out method. RESULTS: Precentral gyrus T2 signal intensity (p<10(-4)) and NAA peak (p<10(-6)) were significantly reduced in patients, and their values did not correlate significantly to each other both in patients and controls, while no significant differences were obtained in terms of T2-hyperintensity of the corticospinal tract. Sensitivity and specificity of the two discriminant variables, taken alone, were 71.4% and 75.0%, for NAA peak, and 63.1% and 71.4% for T2-hypointensity, respectively. When using these two variables in combination, a significant increase in sensitivity (78.6%) and specificity (82.1%) was achieved. CONCLUSIONS: Precentral gyrus T2-hypointensity and NAA peak are not significantly correlated in ALS patients, suggesting that they reflect relatively independent phenomena. The combined use of these measures improves the diagnostic accuracy of MRI in ALS diagnosis.

Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3'-deoxy-3'-[18F]-fluorothymidine positron emission tomography.

PURPOSE: MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC. EXPERIMENTAL DESIGN: H1993 and H820 NSCLC cells with high and low levels of MET amplification, respectively, and HCC827-expressing MET, but without gene amplification, were tested for the effects of MET inhibitors on the EGFR pathway and proliferation both in vitro and in vivo. Nude mice bearing NSCLCs with and without MET amplification were subjected to [(18)F]FLT PET/CT before and after treatment with crizotinib or erlotinib (50 mg/kg and 100 mg/kg p.o. for 3 days). RESULTS: H1993 cells showed high responsiveness to MET inhibitors and were resistant to erlotinib. Conversely, HCC827 cells showed high sensitivity to erlotinib and were resistant to MET inhibitors. Accordingly, H1993 tumors bearing MET amplification showed a mean reduction in [(18)F]FLT uptake of 28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [(18)F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [(18)F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [(18)F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections. CONCLUSIONS: [(18)F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC.

Assessment of dual-energy x-ray absorptiometry for use in evaluating the effects of dietary and environmental management on Hermann's tortoises (Testudo hermanni).

OBJECTIVE: To assess dual-energy x-ray absorptiometry (DXA) for evaluating effects of diet and environment on bone mineral density in Hermann's tortoises (Testudo hermanni). ANIMALS: 26 Hermann's tortoises within 1 month after hatching. PROCEDURES: Group 1 was housed in an artificial setting and fed naturally growing vegetation. Group 2 was housed in an artificial setting and fed vegetables grown for human consumption. Group 3 was maintained in an outside enclosure and fed naturally growing vegetation. After 10 months, pyramidal growth, body weight, and adverse conditions were assessed. Bone mineral density (BMD) of the axial and appendicular skeleton, shell, vertebral column, and pelvis was measured via DXA. RESULTS: Group 2 had the highest mean ± SD body weight (65.42 ± 30.85 g), followed by group 1 (51.08 ± 22.92 g) and group 3 (35.74 ± 7.13 g). Mean BMD of the shell varied significantly among groups (group 1, 0.05 ± 0.03 g/cm(2)•m; group 2, 0.09 ± 0.15 g/cm(2)•m; and group 3, undetectable). The BMD of the axial and appendicular skeleton, vertebral column, and pelvis did not differ significantly among groups. Pyramidal growth was highest in group 1 and not evident in group 3. CONCLUSIONS AND CLINICAL RELEVANCE: Tortoises raised in artificial conditions did not have deficits in BMD, compared with results for outdoor-housed hibernating tortoises. Supplemental calcium was apparently not necessary when an adequate photothermal habitat and plant-based diet were provided. Higher BMD of captive-raised tortoises was morphologically associated with a higher incidence of pyramidal growth in captive-raised groups.

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.

Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy.

A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing-remitting multiple sclerosis patients, aged 18-50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 microg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.