Automated video-based assessment of facial bradykinesia in de-novo Parkinson's disease.

Even though hypomimia is a hallmark of Parkinson's disease (PD), objective and easily interpretable tools to capture the disruption of spontaneous and deliberate facial movements are lacking. This study aimed to develop a fully automatic video-based hypomimia assessment tool and estimate the prevalence and characteristics of hypomimia in de-novo PD patients with relation to clinical and dopamine transporter imaging markers. For this cross-sectional study, video samples of spontaneous speech were collected from 91 de-novo, drug-naïve PD participants and 75 age and sex-matched healthy controls. Twelve facial markers covering areas of forehead, nose root, eyebrows, eyes, lateral canthal areas, cheeks, mouth, and jaw were used to quantitatively describe facial dynamics. All patients were evaluated using Movement Disorder Society-Unified PD Rating Scale and Dopamine Transporter Single-Photon Emission Computed Tomography. Newly developed automated facial analysis tool enabled high-accuracy discrimination between PD and controls with area under the curve of 0.87. The prevalence of hypomimia in de-novo PD cohort was 57%, mainly associated with dysfunction of mouth and jaw movements, and decreased variability in forehead and nose root wrinkles (p < 0.001). Strongest correlation was found between reduction of lower lip movements and nigro-putaminal dopaminergic loss (r = 0.32, p = 0.002) as well as limb bradykinesia/rigidity scores (r = -0.37 p < 0.001). Hypomimia represents a frequent, early marker of motor impairment in PD that can be robustly assessed via automatic video-based analysis. Our results support an association between striatal dopaminergic deficit and hypomimia in PD

Cerebral Iron Deposition in Neurodegeneration

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.publishedVersio

Prevention of progression in Parkinson’s disease

Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.Prevention of progression in Parkinson’s diseasepublishedVersio

Articulatory undershoot of vowels in isolated REM sleep behavior disorder and early Parkinson's disease.

Imprecise vowels represent a common deficit associated with hypokinetic dysarthria resulting from a reduced articulatory range of motion in Parkinson's disease (PD). It is not yet unknown whether the vowel articulation impairment is already evident in the prodromal stages of synucleinopathy. We aimed to assess whether vowel articulation abnormalities are present in isolated rapid eye movement sleep behaviour disorder (iRBD) and early-stage PD. A total of 180 male participants, including 60 iRBD, 60 de-novo PD and 60 age-matched healthy controls performed reading of a standardized passage. The first and second formant frequencies of the corner vowels /a/, /i/, and /u/ extracted from predefined words, were utilized to construct articulatory-acoustic measures of Vowel Space Area (VSA) and Vowel Articulation Index (VAI). Compared to controls, VSA was smaller in both iRBD (p = 0.01) and PD (p = 0.001) while VAI was lower only in PD (p = 0.002). iRBD subgroup with abnormal olfactory function had smaller VSA compared to iRBD subgroup with preserved olfactory function (p = 0.02). In PD patients, the extent of bradykinesia and rigidity correlated with VSA (r = -0.33, p = 0.01), while no correlation between axial gait symptoms or tremor and vowel articulation was detected. Vowel articulation impairment represents an early prodromal symptom in the disease process of synucleinopathy. Acoustic assessment of vowel articulation may provide a surrogate marker of synucleinopathy in scenarios where a single robust feature to monitor the dysarthria progression is needed

Treatment strategies in Alzheimer’s disease: a review with focus on selenium supplementation

Alzheimers disease (AD) is a neurodegenerative disorder presenting one of the biggest healthcare challenges in developed countries. No effective treatment exists. In recent years the main focus of AD research has been on the amyloid hypothesis, which postulates that extracellular precipitates of beta amyloid (A beta) derived from amyloid precursor protein (APP) are responsible for the cognitive impairment seen in AD. Treatment strategies have been to reduce A beta production through inhibition of enzymes responsible for its formation, or to promote resolution of existing cerebral A beta plaques. However, these approaches have failed to demonstrate significant cognitive improvements. Intracellular rather than extracellular events may be fundamental in AD pathogenesis. Selenate is a potent inhibitor of tau hyperphosphorylation, a critical step in the formation of neurofibrillary tangles. Some selenium (Se) compounds e.g. selenoprotein P also appear to protect APP against excessive copper and iron deposition. Selenoproteins show anti-inflammatory properties, and protect microtubules in the neuronal cytoskeleton. Optimal function of these selenoenzymes requires higher Se intake than what is common in Europe and also higher intake than traditionally recommended. Supplementary treatment with N-acetylcysteine increases levels of the antioxidative cofactor glutathione and can mediate adjuvant protection. The present review discusses the role of Se in AD treatment and suggests strategies for AD prevention by optimizing selenium intake, in accordance with the metal dysregulation hypothesis. This includes in particular secondary prevention by selenium supplementation to elderly with mild cognitive impairment

Craniospinal irradiation of medulloblastoma in the supine position

BackgroundMedulloblastoma, a primitive neuroectodermal tumour growing in the cerebellum, is one of the most sensitive childhood brain tumours to radiation therapy. The most common malignant CNS tumour of children is medulloblastoma with an overall incidence among children aged 0–19 years of 16–20% of all paediatric brain tumours. Radiotherapy is an essential method of treatment for these tumours, but surgery is the primary treatment of choice in medulloblastoma. Postoperative radiation therapy has a significant impact on local control and overall survival.AimMedulloblastoma is the most common malignant brain tumour of children. The tumour is sensitive to chemotherapy and radiotherapy. Radiotherapy is an essential method of treatment for these tumours, but surgery is the primary treatment of choice in medulloblastoma.Materials/MethodsBetween January 1997 and March 2005 there were in this study post-operatively irradiated a total number of 33 paediatric patients aged under 15 years (median age 6.6 years) with medulloblastoma. All tumours were histologically proven and were located infratentorially in the posterior fossa. All of the patients were irradiated with a dose of 24–36 Gy to the whole craniospinal axis and boost with conformal therapy restricted to the tumour bed to the total dose of 50–54 Gy (30–36 Gy “high risk”, 24–30 Gy “standard risk” group). 26 patients (78%) received chemotherapy. Patients with craniospinal irradiation were placed in the supine position and fixed by a vacuum-form body immobilizer and head mask. Irradiation was performed using standard fractionation (5 fractions per week) with a single dose of 1.5–1.8 Gy for craniospinal axis by photon beam (6MV) of the linear accelerator.ResultsThe median overall survival for the whole group was 55.3 months. The median disease-free survival was 20.6 months. The overall survival rate at 5 years was 41%; 8 patients (24%) died. No relationship was found between survival and age, sex or tumour size. Endocrine deficits occurred in 30% (8 patients of the group were hypothyroid, growth retardation occurred in 7 patients).ConclusionsResults of overall and disease-free survival and side-effects of the technique of craniospinal axis irradiation in supine position are comparable with results of the technique in prone position

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes

BRAVE-NET: Fully Automated Arterial Brain Vessel Segmentation in Patients With Cerebrovascular Disease

Introduction: Arterial brain vessel assessment is crucial for the diagnostic process in patients with cerebrovascular disease. Non-invasive neuroimaging techniques, such as time-of-flight (TOF) magnetic resonance angiography (MRA) imaging are applied in the clinical routine to depict arteries. They are, however, only visually assessed. Fully automated vessel segmentation integrated into the clinical routine could facilitate the time-critical diagnosis of vessel abnormalities and might facilitate the identification of valuable biomarkers for cerebrovascular events. In the present work, we developed and validated a new deep learning model for vessel segmentation, coined BRAVE-NET, on a large aggregated dataset of patients with cerebrovascular diseases. Methods: BRAVE-NET is a multiscale 3-D convolutional neural network (CNN) model developed on a dataset of 264 patients from three different studies enrolling patients with cerebrovascular diseases. A context path, dually capturing high- and low-resolution volumes, and deep supervision were implemented. The BRAVE-NET model was compared to a baseline Unet model and variants with only context paths and deep supervision, respectively. The models were developed and validated using high-quality manual labels as ground truth. Next to precision and recall, the performance was assessed quantitatively by Dice coefficient (DSC); average Hausdorff distance (AVD); 95-percentile Hausdorff distance (95HD); and via visual qualitative rating. Results: The BRAVE-NET performance surpassed the other models for arterial brain vessel segmentation with a DSC = 0.931, AVD = 0.165, and 95HD = 29.153. The BRAVE-NET model was also the most resistant toward false labelings as revealed by the visual analysis. The performance improvement is primarily attributed to the integration Hilbert et al. Fully-Automated Arterial Brain Vessel Segmentation of the multiscaling context path into the 3-D Unet and to a lesser extent to the deep supervision architectural component. Discussion: We present a new state-of-the-art of arterial brain vessel segmentation tailored to cerebrovascular pathology. We provide an extensive experimental validation of the model using a large aggregated dataset encompassing a large variability of cerebrovascular disease and an external set of healthy volunteers. The framework provides the technological foundation for improving the clinical workflow and can serve as a biomarker extraction tool in cerebrovascular diseases

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

Background Mitochondrial membrane protein‐associated neurodegeneration is an autosomal‐recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. Objectives The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1H MR spectroscopy in clinically manifesting membrane protein‐associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. Methods We present data of 4 clinically affected membrane protein‐associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age‐matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole‐body system, consisting of whole‐brain gradient‐echo scans and short echo time, single‐volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state‐of‐the‐art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. Results and Conclusion In membrane protein‐associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non‐manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein‐associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein‐associated neurodegeneration patients