BACKGROUND: Diffuse midline glioma, H3 K27-altered (DMG) is a fatal tumour that arises in the midline structures of the brain. When located in the pons, it is more commonly referred to as diffuse intrinsic pontine glioma (DIPG). DMG/DIPG is usually diagnosed when children are < 10 years, and it has a median overall survival of < 12 months after diagnosis. Radiological imaging is still the gold standard for DIPG diagnosis while the use of biopsy procedures led to our knowledge on its biology, such as with the identification of the canonical histone H3K27M mutation. However, the need to improve survival encourages the development of non-invasive, fast and inexpensive assays on biofluids for optimizing molecular diagnoses in DMG/DIPG. Here, we propose a rapid, new, imaging and epigenetics-based approach to diagnose DMG/DIPG in the plasma of paediatric patients. METHODS: A total of 20 healthy children (mean age: 10.5 years) and 24 children diagnosed with DMG/DIPG (mean age: 8.5 years) were recruited. Individual histones (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2), histone dimers and nucleosomes were assayed in biofluids by means of a new advanced flow cytometry ImageStream(X)-adapted method. RESULTS: We report a significant increase in circulating histone dimers and tetramers (macroH2A1.1/H2B versus control: p value < 0.0001; macroH2A1.2/H2B versus control: p value < 0.0001; H2A/H2B versus control: p value < 0.0001; H3/H4 versus control: p value = 0.008; H2A/H2B/H3/H4 versus control: p value < 0.0001) and a significant downregulation of individual histones (H2B versus control: p value < 0.0001; H3 versus control: p value < 0.0001; H4 versus control: p value < 0.0001). Moreover, histones were also detectable in the cerebrospinal fluid (CSF) of patients with DMG/DIPG and in the supernatant of SF8628, OPBG-DIPG002 and OPBG-DIPG004 DMG/DIPG cell lines, with patterns mostly similar to each other, but distinct compared to blood plasma. CONCLUSIONS: In summary, we identified circulating histone signatures able to detect the presence of DMG/DIPG in biofluids of children, using a rapid and non-invasive ImageStream(X)-based imaging technology, which may improve diagnosis and benefit the patients.
- MeSH
- Diffuse Intrinsic Pontine Glioma genetics diagnosis blood MeSH
- Child MeSH
- Epigenesis, Genetic MeSH
- Glioma genetics diagnosis blood pathology diagnostic imaging MeSH
- Histones * genetics metabolism blood MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation MeSH
- Biomarkers, Tumor blood MeSH
- Brain Stem Neoplasms genetics diagnosis blood diagnostic imaging pathology metabolism MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat-amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient-focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry-associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real-world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m2 (n = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m2 (n = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (n = 116) was -0.9 (-10.8, 9.9) mL/min/1.73 m2/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient-years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real-world Fabry population.
- MeSH
- 1-Deoxynojirimycin * analogs & derivatives therapeutic use MeSH
- alpha-Galactosidase * therapeutic use MeSH
- Adult MeSH
- Fabry Disease * drug therapy MeSH
- Glomerular Filtration Rate * MeSH
- Kidney physiopathology drug effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Prospective Studies MeSH
- Registries * MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Aims: To investigate the efficacy and safety of intravitreal Dexamethasone implant (DEX-I) therapy in the treatment of diabetic macular edema (DME) refractory to intravitreal bevacizumab (IVB). Material and methods: This retrospective and cross-sectional study included 37 eyes of 37 patients who received 3 loading doses of IVB injections for DME with no response and underwent DEX-I implant. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurements and central foveal thickness (CFT) measured by spectral domain optical coherence tomography (SD-OCT) were recorded and compared before DEX-I, at the first week, first, second, third and sixth months. Duration of DME, glycated hemoglobin (HbA1c) levels, DME types and lens status (phakic, pseudophakic) were also recorded. Results: The mean age of the patients was 61.14 ±8.69 years (59.5% male, 40.5% female). 35.1% of the patients had cystoid macular edema, 64.9% had diffuse macular edema and 73 % were phakic and 27% were pseudophakic. BCVA, CFT and IOP values before DEX-I injection were 0.78 ±0.16 LogMAR, 493.73 ±107.6 μm and 13.05 ±2.59 mmHg, respectively. At 6 months after DEX-I, BCVA, CFT and IOP values were 0.64 ±0.11 LogMAR, 397.35 ±59.72 μm and 16.3 ±2.51 mmHg, respectively. In all follow-ups, there was a significant improvement in BCVA, a significant decrease in CFT and a significant increase in IOP compared to pre-injection. Ocular hypertension was observed in 0.8 % of patients and progression of cataract progression in 1% of patients after treatment. Conclusion: DEX-I therapy is an effective and safe treatment option for DME refractory to IVB treatment.
Glymphatic dysfunction potentially contributes to Parkinson's disease (PD) via impaired clearance of metabolic waste products. Obstructive sleep apnea (OSA) can disturb sleep, which is necessary for proper glymphatic function, and is frequent in PD. We investigated the glymphatic function in de novo PD and its relation to OSA. Fifty-four PD patients (mean age 58.9 ± 12.2 years) and 32 controls (mean age 59.4 ± 8.3 years) underwent polysomnography and 3 T magnetic resonance imaging of the brain. Diffusion tensor imaging along the perivascular space (DTI-ALPS) was calculated using atlas-based automatic regions of interest selection. In PD, ALPS-index negatively correlated with apnea-hypopnea index (rho = -0.41; p = 0.002), oxygen desaturation index (rho = -0.38; p = 0.006), sleep stage N1 (rho = -0.42; p = 0.002), and arousal index (rho = -0.24; p = 0.018), while in controls, no such correlations were observed. Glymphatic dysfunction is related to OSA severity in de novo PD but not in controls. We suggest that OSA may contribute to neurodegeneration via glymphatic impairment in PD.
- Publication type
- Journal Article MeSH
PURPOSE: The authors evaluated a cohort of 12 patients with histologically verified pigmented villonodular synovitis of the TMJ between 2018 and 2023. METHODS: The authors evaluated 12 patients (12 women). Only unilateral involvement was present in all patients. The mean age of the patients was 49.5 years. The authors focused on the evaluation of clinical symptoms, imaging findings, and arthroscopic findings. They also evaluated the effect of therapy, including the incidence of recurrence. The evaluation of therapy was performed at a minimum of 12 months after therapy and a maximum of 4.5 years after therapy. RESULTS: Pain was the predominant clinical symptom (12 patients, 100%). Therapy consisted of arthroscopy and open surgery. Radiographs were taken in all patients. In 5 patients (42%) the joint structures were without obvious pathological changes, in 7 patients (58%) there was a finding of irregularities on the joint head. Magnetic resonance imaging was performed in all patients, and in 10 cases (83%) there was a finding of joint space enlargement, effusion. Therapy consisted of TMJ arthroscopy with removal of pathological tissue. If the joint was completely filled with pathological tissue, after histological verification, open surgery with complete removal of joint structures and subsequent reconstruction of the TMJ was indicated. Recurrence of PVNS was not reported in the cohort. CONCLUSION: PVNS is an uncommon benign lesion affecting the TMJ. In the authors' study, pain was the predominant symptom and effusion was the predominant finding on magnetic resonance imaging. Long-term follow-up is appropriate in patients with proven PVNS. This is due to the risk of recurrence, which is also associated with the difficulty of complete repair of the lesion in the anatomically limited space of the TMJ. The authors recommend 1,3,6 months after surgery, and annually for the first 5 years after surgery. One, two, and five years after surgery, they recommend a follow-up MRI. The results of the study support the view that MRI should always be indicated in patients with pain of arthrogenic origin lasting more than 3 months, and if effusion is found, arthroscopy should always be the next step. This procedure will ensure early detection of PVNS.
- MeSH
- Arthroscopy MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Temporomandibular Joint Disorders * surgery diagnostic imaging pathology MeSH
- Recurrence MeSH
- Retrospective Studies MeSH
- Synovitis, Pigmented Villonodular * surgery diagnostic imaging pathology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Myoepithelial neoplasms of the skin and soft tissue still represent a confusing and somewhat controversial field in pathology as it appears that this category includes several different entities. However, recent studies have suggested that both apocrine mixed tumors (AMT) and cutaneous myoepitheliomas (CM) harbor identical chromosomal rearrangements involving the PLAG1 gene and hence may represent a morphological spectrum. The aim of the present study was to share our institutional experience with these tumors and specifically focus on studying their immunohistochemical and molecular features to further assess their relatedness. Eleven cases of AMT and 7 cases of CM were collected and analyzed using immunohistochemistry (IHC), PLAG1 FISH, and Archer FusionPlex assay. There were 14 male and 4 female patients with ages ranging from 26 to 85 years (median 55.8 years, mean 58.5 years). AMTs were mainly located in the head and neck (n = 10), while CMs were mainly located in the acral sites (n = 5). PLAG1 IHC was diffusely strongly positive in 14/17 (82%) cases, whereas a single case of AMT diffusely expressed HMGA2. Both tumor groups showed PLAG1 gene fusions which were detected in 6/13 analyzable samples (AMT, n = 4 and CM, n = 2), and included TRPS1::PLAG1 (n = 3), NDRG1::PLAG1 (n = 1), CTNNB1::PLAG1 (n = 1) and a novel PXDNL::PLAG1 fusion (n = 1). The remaining 5 cases were negative, 5 were not analyzable and the single case positive for HMGA2 by IHC revealed a potential HMGA2 gene rearrangement. The cases were further studied by FISH, with 12/17 cases showing PLAG1 gene rearrangement (AMT, n = 8 and CM, n = 4). Altogether, 14/18 cases showed PLAG1 gene rearrangement by at least one of the methods. PLAG1 immunohistochemistry had a 92% specificity and sensitivity. Our study provided additional data to suggest that AMT and CM share overlapping morphological and immunohistochemical features as well as molecular background characterized by PLAG1 gene fusions and thus represent a morphological spectrum. In addition, we identified a novel PXDNL::PLAG1 fusion and suggested that rare cases may harbor HMGA2 gene alterations which seem to be mutually exclusive with PLAG1 gene fusions. The relatedness of these tumors to salivary gland myoepithelial neoplasms and distinctness from eccrine mixed tumors and other skin and soft tissue myoepithelial neoplasms with EWSR1/FUS fusions is discussed.
- MeSH
- DNA-Binding Proteins * genetics MeSH
- Adult MeSH
- Gene Rearrangement * MeSH
- In Situ Hybridization, Fluorescence MeSH
- Immunohistochemistry * MeSH
- Middle Aged MeSH
- Humans MeSH
- Myoepithelioma * genetics pathology MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Neoplasms, Complex and Mixed genetics pathology chemistry MeSH
- Skin Neoplasms * genetics pathology MeSH
- Sweat Gland Neoplasms genetics pathology MeSH
- HMGA2 Protein * genetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Dementia with Lewy bodies often presents with cholinergic degeneration and varying degrees of cerebrovascular disease. There is a lack of radiological methods for evaluating cholinergic degeneration in dementia with Lewy bodies. We investigated the potential of the Cholinergic Pathway Hyperintensities Scale (CHIPS) in identifying cerebrovascular disease-related disruptions in cholinergic white matter pathways, offering a practical and accessible method for assessing cholinergic integrity in neurodegenerative diseases. We assessed the associations of CHIPS with regional brain atrophy, Alzheimer's disease co-pathology and clinical phenotype. Additionally, we compared its diagnostic performance to that of other manual and automated evaluation methods. We included 82 individuals (41 patients in the Lewy body continuum with either probable dementia with Lewy bodies or mild cognitive impairment with Lewy bodies, and 41 healthy controls) from the Sant Pau Initiative on Neurodegeneration cohort. We used CHIPS to assess cholinergic white matter signal abnormalities (WMSA) on MRI, while tractography mean diffusivity provided a complementary measure of cholinergic WMSA. For global WMSA evaluation, we used the Fazekas scale and FreeSurfer. CHIPS successfully identified cerebrovascular disease-related disruptions in cholinergic white matter pathways, as evidenced by its association with tractography and global WMSA markers (P < 0.005 for all associations). Lewy body patients showed a significantly higher degree of WMSA in the external capsule cholinergic pathway despite no significant differences in global WMSA compared to controls. CHIPS score in the posterior external capsule and the mean diffusivity in the external capsule and cingulum exceeded the threshold for an optimal biomarker (sensitivity and specificity values above 80%) in discriminating Lewy body patients from controls. Furthermore, higher CHIPS scores, Fazekas scale and tractography mean diffusivity were associated with more pronounced frontal atrophy in Lewy body patients but not in controls. No associations were found for the four WMSA and integrity methods with the core clinical features, clinical or cognitive measures, or CSF biomarkers. In conclusion, cholinergic WMSA were more pronounced in Lewy body patients compared to healthy controls, independently of global WMSA. Our findings indicate that cerebrovascular disease-related disruptions in cholinergic white matter may be linked to frontal atrophy in Lewy body patients. Clinically, we demonstrate the potential of CHIPS to assess cholinergic WMSA using widely available MRI sequences. Our data suggest cerebrovascular disease co-pathology could drive the cholinergic degeneration in Lewy body patients, opening opportunities for therapeutic interventions targeting vascular health from mild cognitive impairment with Lewy bodies through manifest dementia with Lewy bodies.
- Publication type
- Journal Article MeSH
BACKGROUND AND PURPOSE: The primary objective was to compare diffusion tensor imaging (DTI) scalar parameters of peripheral nerves between subjects with type 2 diabetes mellitus (T2DM) and those without diabetes. Secondarily, we aimed to correlate DTI scalar parameters with nerve morphometric properties. METHODS: Median, tibial, and sural nerves were harvested from 34 male cadavers (17 T2DM, 17 nondiabetic). Each nerve was divided into three segments. The initial segment was scanned using 9.4 Tesla MRI system (three-dimensional pulsed-gradient spin-echo sequence). DTI scalars were calculated from region-average diffusion-weighted signals. Second segment was optically cleared, acquired with optical projection tomography (OPT), and analyzed for morphometrical properties. Toluidine-stained sections were prepared from last segment, and axon- and myelin-related properties were evaluated. RESULTS: DTI scalar parameters of median and tibial nerves were comparable between the groups, while sural nerves of T2DM exhibited on average 41% higher mean diffusivity (MD) (p = 0.03), 38% higher radial diffusivity (RD) (p = 0.03), and 27% lower fractional anisotropy (FA) (p = 0.005). Significant differences in toluidine-evaluated parameters of sural nerves were observed between the groups, with a positive correlation between FA with fiber density (p = 0.0001) and with myelin proportion (p < 0.0001) and an inverse correlation between RD and myelin proportion (p = 0.003). OPT-measured morphometric properties did not correlate with DTI scalar parameters. CONCLUSIONS: High-field DTI shows promise as an imaging technique for detecting axonal and myelin-related changes in small sural nerves ex vivo. The reduced fiber density and decreased myelin content, which can be observed in T2DM, likely contribute to observed FA reduction and increased MD/RD.
- MeSH
- Diabetes Mellitus, Type 2 * diagnostic imaging pathology MeSH
- Diabetic Neuropathies diagnostic imaging pathology MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Cadaver * MeSH
- Median Nerve diagnostic imaging pathology MeSH
- Sural Nerve * diagnostic imaging pathology MeSH
- Tibial Nerve diagnostic imaging pathology MeSH
- Reproducibility of Results MeSH
- Aged MeSH
- Sensitivity and Specificity MeSH
- Diffusion Tensor Imaging * methods MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
BACKGROUND AND PURPOSE: White matter changes assessed by DTI typically reflect tract functionality. This study aimed to investigate DTI parameter alterations in important regions pre- and postshunt implantation in patients with idiopathic normal pressure hydrocephalus (iNPH), alongside assessing the relationship between DTI parameters and clinical improvement. MATERIALS AND METHODS: Patients with probable iNPH underwent prospective preoperative MRI and comprehensive clinical work-up between 2017-2022. Patients with clinical symptoms of iNPH, positive result on a lumbar infusion test, and/or gait improvement after 120-hour lumbar drainage were diagnosed with iNPH and underwent shunt-placement surgery. Fractional anisotropy and mean diffusivity values for individual regions of interest were extracted from preoperative and postoperative MRI. These values were correlated with the clinical picture of individual patients. RESULTS: A total of 32 patients (73.59 ± 4.59 years) with definite iNPH were analyzed. Preoperative DTI characteristics of internal capsule and corona radiata correlated with the 1-year improvement in the Dutch Gait Scale postoperatively (all P < .036). Cognitive domain improvement after surgery in memory and psychomotor speed correlated with preoperative DTI values of cingulate gyrus (P = .050), uncinate fasciculus (P = .029), superior longitudinal fasciculus (P = .020), or corpus callosum (P < .045). CONCLUSIONS: DTI characteristics of white matter regions reflect clinical improvement after shunt surgery in patients with iNPH. They tend to improve toward physiologic DTI values, thus further accentuating the benefit of shunt surgery in both clinical and radiologic pictures.
- MeSH
- Anisotropy MeSH
- White Matter diagnostic imaging MeSH
- Middle Aged MeSH
- Humans MeSH
- Hydrocephalus, Normal Pressure * surgery diagnostic imaging MeSH
- Prospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Cerebrospinal Fluid Shunts * MeSH
- Treatment Outcome MeSH
- Diffusion Tensor Imaging * methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: The clinical diversity of schizophrenia is reflected by structural brain variability. It remains unclear how this variability manifests across different gray and white matter features. In this meta- and mega-analysis, the authors investigated how brain heterogeneity in schizophrenia is distributed across multimodal structural indicators. METHODS: The authors used the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6,037 individuals for a given brain measure. Variability and mean values of cortical thickness, cortical surface area, cortical folding index, subcortical volume, and fractional anisotropy were examined in individuals with schizophrenia and healthy control subjects. RESULTS: Individuals with schizophrenia showed greater variability in cortical thickness, cortical surface area, subcortical volume, and fractional anisotropy within the frontotemporal and subcortical network. This increased structural variability was mainly associated with psychopathological symptom domains, and the schizophrenia group frequently displayed lower mean values in the respective structural measures. Unexpectedly, folding patterns were more uniform in individuals with schizophrenia, particularly in the right caudal anterior cingulate region. The mean folding values of the right caudal anterior cingulate region did not differ between the schizophrenia and healthy control groups, and folding patterns in this region were not associated with disease-related parameters. CONCLUSIONS: In patients with schizophrenia, uniform folding patterns in the right caudal anterior cingulate region contrasted with the multimodal variability in the frontotemporal and subcortical network. While variability in the frontotemporal and subcortical network was associated with disease-related diversity, uniform folding may indicate a less flexible interplay between genetic and environmental factors during neurodevelopment.
- MeSH
- Anisotropy MeSH
- White Matter pathology diagnostic imaging MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain * pathology diagnostic imaging MeSH
- Schizophrenia * pathology diagnostic imaging MeSH
- Gray Matter pathology diagnostic imaging MeSH
- Diffusion Tensor Imaging MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
