Abstract High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can ...contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.
Ultrasound of the nerves is an additive diagnostic tool to evaluate polyneuropathy. Recently, the need for standardized scoring systems has widely been discussed; different scores are described so ...far. Therefore, 327 patients with polyneuropathy were analyzed by ultrasound in our laboratory. Consequently, several ultrasound scoring tools were applied, i.e., the nerve pattern classification according to Padua et al. in all patients with CIDP and variants, the Bochum ultrasound score (BUS) and the neuritis ultrasound protocol in immune-mediated neuritis, the ultrasound pattern sum score, the homogeneity score, and the nerve enlargement distribution score in all neuropathies if possible. For all scores good accuracy was found. Most patients with CIDP revealed hypoechoic enlarged nerves (Class 1), the BUS/NUP was useful to identify GBS (sensitivity >85%), MMN (100%) and CIDP (>70%), while the UPSS showed high sensitivity and positive/negative predictive values (N/PPV) in the diagnosis of GBS (>70%), CIDP (>85%) and axonal non-inflammatory neuropathies (>90%). Homogeneous nerves were found in most CMT1 patients (66.7%), while immune-mediated neuropathies mostly show regional nerve enlargement. The HS was suitable to identify CMT patients with an HS ≥5 points. All scores were easily applicable with high accuracy. The former-reported results could be similarly confirmed. However, all sores have some incompleteness concerning unselected polyneuropathy population, particularly rare and focal types. Scoring systems are useful and easily applicable. They show high accuracy in certain neuropathies, but also offer some gaps and can, therefore, only be used in addition to standard diagnostic routines such as electrophysiology.
The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to ...severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
Usage of MR imaging biomarkers is limited to experts. Automatic quantitative reports provide access for clinicians to data analysis. Automated data analysis was tested for usability in a small cohort ...of patients with hereditary spastic paraplegia type 4 (SPG4). We analyzed 3T MRI 3D-T1 datasets of n = 25 SPG4 patients and matched healthy controls using a commercial segmentation tool (AIRAscore structure 2.0.1) and standard VBM. In SPG4 total brain volume was reduced by 27.6 percentiles (p = 0.001) caused mainly by white matter loss (- 30.8th, p < 0.001) and stable total gray matter compared to controls. Brain volume loss occurred in: midbrain (- 41.5th, p = 0.001), pons (- 36.5th, p = 0.02), hippocampus (- 20.9th, p = 0.002), and gray matter of the cingulate gyrus (- 17.0th, p = 0.02). Ventricular volumes increased as indirect measures of atrophy. Group comparisons using percentiles aligned with results from VBM analyses. Quantitative imaging reports proved to work as an easily accessible, fully automatic screening tool for clinicians, even in a small cohort of a rare genetic disorder. We could delineate the involvement of white matter and specify involved brain regions. Group comparisons using percentiles provide comparable results to VBM analysis and are, therefore, a suitable and simple screening tool for all clinicians with and without in-depth knowledge of image processing.
Abstract
Background
Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. ...Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma.
Methods
An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment.
Discussion
The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort.
Trial Registration
NCT05479032.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by ...bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D3 metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D3 substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5.
•Normal values of nerve fascicles might be helpful in analysis and treatment of nerve disorders.•Fascicle enlargement occurs in inherited and inflammatory neuropathies with distinct ...distribution.•Fascicle pattern analysis and - ratios might be suitable to differentiate several polyneuropathies.
Polyneuropathies are increasingly analyzed by ultrasound. Summarizing, diffuse enlargement is typical in Charcot-Marie Tooth type 1 (CMT1a), regional enlargement occurs in inflammatory neuropathies. However, a distinction of subtypes is still challenging. Therefore, this study focused on fascicle size and pattern in controls and distinct neuropathies.
Cross-sectional area (CSA) of the median, ulnar and peroneal nerve (MN, UN, PN) was measured at predefined landmarks in 50 healthy controls, 15 CMT1a and 13 MMN patients. Additionally, largest fascicle size and number of visible fascicles was obtained at the mid-upper arm cross-section of the MN and UN and in the popliteal fossa cross-section of the PN.
Cut-off normal values for fascicle size in the MN, UN and PN were defined (<4.8mm2, <2.8mm2 and <3.5mm2). In CMT1a CSA and fascicle values are significantly enlarged in all nerves, while in MMN CSA and fascicles are regionally enlarged with predominance in the upper arm nerves. The ratio of enlarged fascicles and all fascicles was significantly increased in CMT1a (>50%) in all nerves (p<0.0001), representing diffuse fascicle enlargement, and moderately increased in MMN (>20%), representing differential fascicle enlargement (enlarged and normal fascicles at the same location) sparing the peroneal nerve (regional fascicle enlargement). Based on these findings distinct fascicle patterns were defined.
Normal values for fascicle size could be evaluated; while CMT1a features diffuse fascicle enlargement, MMN shows regional and differential predominance with enlarged fascicles as single pathology.
Pattern analysis of fascicles might facilitate distinction of several otherwise similar neuropathies.
Vertigo and dizziness comprise a multisensory and multidisciplinary syndrome of different etiologies. The term "cerebellar vertigo and dizziness" comprises a heterogenous group of disorders with ...clinical signs of cerebellar dysfunction and is caused by vestibulo-cerebellar, vestibulo-spinal or cerebellar systems. About 10 % of patients in an outpatient clinic for vertigo and balance disorders suffer from cerebellar vertigo and dizziness. According to the course of the symptoms, one can considers 3 types: permanent complaints, recurrent episodes of vertigo and balance disorders, or an acute onset of complaints. The most common diagnoses in patients with cerebellar vertigo and dizziness were as follows: degenerative disease, hereditary forms and acquired forms. In a subgroup of patients with cerebellar vertigo, central cerebellar oculomotor dysfunction is indeed the only clinical correlate of the described symptoms. 81 % of patients with cerebellar vertigo suffer from permanent, persistent vertigo and dizziness, 31 % from vertigo attacks, and 21 % from both. Typical clinical cerebellar signs, including gait and limb ataxia or dysarthria, were found less frequently. Key to diagnosis is a focused history as well as a thorough clinical examination with particular attention to oculomotor function. Regarding oculomotor examination, the most common findings were saccadic smooth pursuit, gaze-evoked nystagmus, provocation nystagmus, rebound nystagmus, central fixation nystagmus, most commonly downbeat nystagmus, and disturbances of saccades. Thus, oculomotor examination is very sensitive in diagnosing cerebellar vertigo and dizziness, but not specific in distinguishing different etiologies. Laboratory examinations using posturography and a standardized gait analysis can support the diagnosis, but also help to estimate the risk of falls and to quantify the course and possible symptomatic treatment effects. Patients with cerebellar vertigo and dizziness should receive multimodal treatment.
Face pareidolia in schizophrenia Rolf, Rebecca; Sokolov, Alexander N.; Rattay, Tim W. ...
Schizophrenia research,
04/2020, Letnik:
218
Journal Article
Recenzirano
Faces convey valuable daily life social signals. As in most psychiatric conditions, non-verbal social cognition or its components including face processing may be aberrant in schizophrenia (SZ). ...Social participation of individuals with SZ is vital for their quality of life, and remediation of social abilities in this population is of high relevance both for society and clinical care.
Tuning to faces in non-face images such as shadows, grilled toasts, or ink blots is called face pareidolia. Humans possess high sensitivity to facial signals: even fetuses and infants are well tuned to coarse face cues. Here we assessed face tuning in individuals with SZ and person-by-person matched controls by using a new experimental tool, a set of food-plate images bordering on the Giuseppe Arcimboldo style. The key benefit of these images is that single components do not trigger face processing.
The outcome indicates that individuals with SZ exhibit aberrant face tuning in face-like non-face images (χ2(1) = 17.44, p = 0.0001) that can hamper adaptive interaction with peers and social participation hindering, in turn, clinical remediation. Face response rate in SZ patients was related to the scores on the event arrangement task tapping social cognition (Pearson product-moment correlation, r = 0.602, p = 0.01) and on picture completion task assessing visual perceptual organization (Spearman's rho = 0.614, p = 0.009). Therefore, poor performance on the face tuning task is unlikely to be accounted for by deviant general cognitive abilities, but rather by impairments in perceptual integration and social cognition. Comparison of these findings with data in autism and other neuropsychiatric conditions provides novel insights on the origins of face tuning in SZ and triggers brain imaging research.
Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the ...corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml interquartile range (IQR) 683-1113 to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
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