Biometry extraction and probabilistic anatomical atlas of the anterior Visual Pathway using dedicated high-resolution 3-D MRI.

Anterior Visual Pathway (aVP) damage may be linked to diverse inflammatory, degenerative and/or vascular conditions. Currently however, a standardized methodological framework for extracting MRI biomarkers of the aVP is not available. We used high-resolution, 3-D MRI data to generate a probabilistic anatomical atlas of the normal aVP and its intraorbital (iOrb), intracanalicular (iCan), intracranial (iCran), optic chiasm (OC), and tract (OT) subdivisions. We acquired 0.6 mm3 steady-state free-precession images from 24 healthy participants using a 3 T scanner. aVP masks were obtained by manual segmentation of each aVP subdivision. Mask straightening and normalization with cross-sectional area (CSA) preservation were obtained using scripts developed in-house. A probabilistic atlas ("aVP-24") was generated by averaging left and right sides of all subjects. Leave-one-out cross-validation with respect to interindividual variability was performed employing the Dice Similarity Index (DSI). Spatially normalized representations of the aVP subdivisions were generated. Overlapping CSA values before and after normalization demonstrate preservation of the aVP cross-section. Volume, length, CSA, and ellipticity index (ε) biometrics were extracted. The aVP-24 morphology followed previous descriptions from the gross anatomy. Atlas spatial validation DSI scores of 0.85 in 50% and 0.77 in 95% of participants indicated good generalizability across the subjects. The proposed MRI standardization framework allows for previously unavailable, geometrically unbiased biometric data of the entire aVP and provides the base for future spatial-resolved, group-level investigations.

Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.

OBJECTIVE: Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. METHODS: In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. RESULTS: We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. INTERPRETATION: Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy.

Slow wave activity across sleep-night could predict levodopa-induced dyskinesia.

A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID's appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.

Transcranial Magnetic Stimulation Improves Executive Functioning through Modulation of Social Cognitive Networks in Patients with Mild Cognitive Impairment: Preliminary Results.

(1) Background: Patients with mild cognitive impairment (MCI) often present impairment in executive functions (EFs). This study aimed to investigate the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on EFs in patients with MCI. (2) Methods: A prospective trial was conducted on 11 patients with MCI. Participants underwent 25 min of 20 Hz rTMS for ten days on the right temporo-parietal junction (RTPJ) and medial prefrontal cortex (MPFC). Before (T0) and after rTMS treatment (T1), global cognitive profile and EFs were investigated using the Montreal cognitive assessment (MoCA), trial making test (TMT) A and B, and frontal assessment battery (FAB). Depression symptoms were assessed using the geriatric depression scale (GDS). Statistical analysis included Wilcoxon signed-rank test. (3) Results: After treatment, patients showed a significant improvement in the MoCA EFs subtask (T0 vs. T1, p = 0.015) and TMT-B (T0 vs. T1, p = 0.028). Five MCI patients with EF impairment showed full recovery of these deficits. No significant changes in the GDS were observed. (4) Conclusions: rTMS stimulation over the TPJ and MPFC induced significant short-term improvements in EFs in MCI patients. These findings suggest that the TPJ and MPFC may be involved in the attention-executive skills to redirect attention toward behaviorally relevant stimuli.

Effects of Deep Brain Stimulation on Lower Urinary Tract Function in Neurological Patients.

BACKGROUND: Deep brain stimulation (DBS) has clear beneficial effects on motor signs in movement disorders, but much less is known about its impact on lower urinary tract (LUT) function. OBJECTIVE: To evaluate the effects of DBS on LUT function in patients affected by movement disorders. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 58 neurological patients affected by movement disorders, who were planned to receive DBS. INTERVENTION: DBS in the globus pallidus internus, ventral intermediate nucleus of the thalamus, or subthalamic nucleus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subjective symptom questionnaires (International Prostate Symptom Score) and objective urodynamic studies were carried out before implantation of the DBS leads and several months after surgery. After DBS surgery, urodynamic investigations were performed with DBS ON as well as DBS OFF. RESULTS AND LIMITATIONS: We enrolled patients suffering from Parkinson's disease (n = 39), dystonia (n = 11), essential tremor (n = 5), Holmes tremor (n = 2), and multiple sclerosis with tremor (n = 1). DBS of the globus pallidus internus resulted in worsening of LUT symptoms in 25% (four of 16) of the cases. DBS of the subthalamic nucleus in patients with Parkinson's disease led to normalization of LUT function in almost 20% (six of 31 patients), while a deterioration was seen in only one (3%) patient. DBS of the ventral intermediate nucleus of the thalamus improved LUT function in two (18%) and deteriorated it in one (9%) patient with tremor. CONCLUSIONS: DBS effects on LUT varied with stimulation location, highly warranting patient counseling prior to DBS surgery. However, more well-designed, large-volume studies are needed to confirm our findings. PATIENT SUMMARY: In this report, we looked at outcomes of deep brain stimulation on lower urinary tract function. We found that outcomes varied with stimulation location, concluding that counseling of patients about the effects on lower urinary tract function is highly recommended prior to surgery.

Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.

Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.

Imagined paralysis reduces motor cortex excitability.

Mental imagery is a powerful capability that engages similar neurophysiological processes that underlie real sensory and motor experiences. Previous studies show that motor cortical excitability can increase during mental imagery of actions. In this study, we focused on possible inhibitory effects of mental imagery on motor functions. We assessed whether imagined arm paralysis modulates motor cortical excitability in healthy participants, as measured by motor evoked potentials (MEPs) of the hand induced by near-threshold transcranial magnetic stimulation (TMS) over the primary motor cortex hand area. We found lower MEP amplitudes during imagined arm paralysis when compared to imagined leg paralysis or baseline stimulation without paralysis imagery. These results show that purely imagined bodily constraints can selectively inhibit basic motor corticospinal functions. The results are discussed in the context of motoric embodiment/disembodiment.

Impairment of sleep homeostasis in cervical dystonia patients.

Alterations in brain plasticity seem to play a role in the pathophysiology of cervical dystonia (CD). Since evidences indicate that sleep regulates brain plasticity, we hypothesized that an alteration in sleep homeostatic mechanisms may be involved in the pathogenesis of CD. We explored sleep in control subjects (CTL) and CD patients before (Tpre-BoNT) and after (Tpost-BoNT) botulinum toxin (BoNT) treatment. A physiological slow wave activity (SWA) power decrease throughout the night was observed in CTL but not in CD at Tpre-BoNT. BoNT restored the physiological SWA decrease in CD at Tpost-BoNT. Furthermore, in the first part of the night, CD at Tpost-BNT showed a frontal increase and parietal decrease in SWA power compared to CD at Tpre-BoNT, with a SWA distribution comparable to that observed in CTL. Our data highlighted a pathophysiological relationship between SWA during sleep and CD and provided novel insight into the transient central plastic effect of BoNT.

Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson's disease.

The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

Consensus Statement on High-Intensity Focused Ultrasound for Functional Neurosurgery in Switzerland.

Background: Magnetic resonance-guided high-intensity focused ultrasound (MRgHiFUS) has evolved into a viable ablative treatment option for functional neurosurgery. However, it is not clear yet, how this new technology should be integrated into current and established clinical practice and a consensus should be found about recommended indications, stereotactic targets, patient selection, and outcome measurements. Objective: To sum up and unify current knowledge and clinical experience of Swiss neurological and neurosurgical communities regarding MRgHiFUS interventions for brain disorders to be published as a national consensus paper. Methods: Eighteen experienced neurosurgeons and neurologists practicing in Switzerland in the field of movement disorders and one health physicist representing 15 departments of 12 Swiss clinical centers and 5 medical societies participated in the workshop and contributed to the consensus paper. All experts have experience with current treatment modalities or with MRgHiFUS. They were invited to participate in two workshops and consensus meetings and one online meeting. As part of workshop preparations, a thorough literature review was undertaken and distributed among participants together with a list of relevant discussion topics. Special emphasis was put on current experience and practice, and areas of controversy regarding clinical application of MRgHiFUS for functional neurosurgery. Results: The recommendations addressed lesioning for treatment of brain disorders in general, and with respect to MRgHiFUS indications, stereotactic targets, treatment alternatives, patient selection and management, standardization of reporting and follow-up, and initialization of a national registry for interventional therapies of movement disorders. Good clinical evidence is presently only available for unilateral thalamic lesioning in treating essential tremor or tremor-dominant Parkinson's disease and, to a minor extent, for unilateral subthalamotomy for Parkinson's disease motor features. However, the workgroup unequivocally recommends further exploration and adaptation of MRgHiFUS-based functional lesioning interventions and confirms the need for outcome-based evaluation of these approaches based on a unified registry. MRgHiFUS and DBS should be evaluated by experts familiar with both methods, as they are mutually complementing therapy options to be appreciated for their distinct advantages and potential. Conclusion: This multidisciplinary consensus paper is a representative current recommendation for safe implementation and standardized practice of MRgHiFUS treatments for functional neurosurgery in Switzerland.

The SleepFit Tablet Application for Home-Based Clinical Data Collection in Parkinson Disease: User-Centric Development and Usability Study.

BACKGROUND: Parkinson disease (PD) is a common, multifaceted neurodegenerative disorder profoundly impacting patients' autonomy and quality of life. Assessment in real-life conditions of subjective symptoms and objective metrics of mobility and nonmotor symptoms such as sleep disturbance is strongly advocated. This information would critically guide the adaptation of antiparkinsonian medications and nonpharmacological interventions. Moreover, since the spread of the COVID-19 pandemic, health care practices are being reshaped toward a more home-based care. New technologies could play a pivotal role in this new approach to clinical care. Nevertheless, devices and information technology tools might be unhandy for PD patients, thus dramatically limiting their widespread employment. OBJECTIVE: The goals of the research were development and usability evaluation of an application, SleepFit, for ecological momentary assessment of objective and subjective clinical metrics at PD patients' homes, and as a remote tool for researchers to monitor patients and integrate and manage data. METHODS: An iterative and user-centric strategy was employed for the development of SleepFit. The core structure of SleepFit consists of (1) an electronic finger-tapping test; (2) motor, sleepiness, and emotional subjective scales; and (3) a sleep diary. Applicable design, ergonomic, and navigation principles have been applied while tailoring the application to the specific patient population. Three progressively enhanced versions of the application (alpha, v1.0, v2.0) were tested by a total of 56 patients with PD who were asked to perform multiple home assessments 4 times per day for 2 weeks. Patient compliance was calculated as the proportion of completed tasks out of the total number of expected tasks. Satisfaction on the latest version (v2.0) was evaluated as potential willingness to use SleepFit again after the end of the study. RESULTS: From alpha to v1.0, SleepFit was improved in graphics, ergonomics, and navigation, with automated flows guiding the patients in performing tasks throughout the 24 hours, and real-time data collection and consultation were made possible thanks to a remote web portal. In v2.0, the kiosk-mode feature restricts the use of the tablet to the SleepFit application only, thus preventing users from accidentally exiting the application. A total of 52 (4 dropouts) patients were included in the analyses. Overall compliance (all versions) was 88.89% (5707/6420). SleepFit was progressively enhanced and compliance increased from 87.86% (2070/2356) to 89.92% (2899/3224; P=.04). Among the patients who used v2.0, 96% (25/26) declared they would use SleepFit again. CONCLUSIONS: SleepFit can be considered a state-of-the-art home-based system that increases compliance in PD patients, ensures high-quality data collection, and works as a handy tool for remote monitoring and data management in clinical research. Thanks to its user-friendliness and modular structure, it could be employed in other clinical studies with minimum adaptation efforts. TRIAL REGISTRATION: ClinicalTrials.gov NCT02723396; https://clinicaltrials.gov/ct2/show/NCT02723396.

Profiling Inflammatory Extracellular Vesicles in Plasma and Cerebrospinal Fluid: An Optimized Diagnostic Model for Parkinson's Disease.

Extracellular vesicles (EVs) play a central role in intercellular communication, which is relevant for inflammatory and immune processes implicated in neurodegenerative disorders, such as Parkinson's Disease (PD). We characterized and compared distinctive cerebrospinal fluid (CSF)-derived EVs in PD and atypical parkinsonisms (AP), aiming to integrate a diagnostic model based on immune profiling of plasma-derived EVs via artificial intelligence. Plasma- and CSF-derived EVs were isolated from patients with PD, multiple system atrophy (MSA), AP with tauopathies (AP-Tau), and healthy controls. Expression levels of 37 EV surface markers were measured by a flow cytometric bead-based platform and a diagnostic model based on expression of EV surface markers was built by supervised learning algorithms. The PD group showed higher amount of CSF-derived EVs than other groups. Among the 17 EV surface markers differentially expressed in plasma, eight were expressed also in CSF of a subgroup of PD, 10 in MSA, and 6 in AP-Tau. A two-level random forest model was built using EV markers co-expressed in plasma and CSF. The model discriminated PD from non-PD patients with high sensitivity (96.6%) and accuracy (92.6%). EV surface marker characterization bolsters the relevance of inflammation in PD and it underscores the role of EVs as pathways/biomarkers for protein aggregation-related neurodegenerative diseases.

Characterisation of advanced Parkinson's disease: OBSERVE-PD observational study - results of the Swiss subgroup.

AIMS OF THE STUDY: Currently, the characterisation of advanced Parkinson’s disease (APD) does not follow standardised diagnostic criteria, which complicates the evaluation of ongoing care and treatment strategies, such as eligibility for device-aided treatment (DAT). Therefore, this study aimed to determine the proportion of APD and non-advanced Parkinson’s disease (non-APD) patients treated at specialised movement disorder centres in Switzerland, to compare clinical characteristics of APD versus non-APD patients and to assess eligibility for and use of DAT. Furthermore, potential differences between the Swiss and international situation should be uncovered. METHODS: OBSERVE-PD was a cross-sectional, international, observational study including 2615 patients from 128 movement disorder centres in 18 countries. For the Swiss subgroup of the study analysed here, which included 134 patients from 5 movement disorder centres, motor and non-motor symptoms, activities of daily living and quality of life were assessed as endpoints. The correlation between physician’s judgement of APD and the Delphi criteria for APD, which were developed by an international expert group, as well as the clinical burden in APD and non-APD patients and eligibility for and use of DAT were evaluated. The results for the Swiss subgroup were subsequently compared with the international full analysis set of the OBSERVE-PD study. RESULTS: Based on physician’s judgement, 69.4% of patients included in the Swiss study suffered from APD. A moderate correlation between physician’s judgement and the Delphi criteria for APD was observed (Κ = 0.480, 95% confidence interval 0.317–0.642). Clinical burden was higher for APD patients, as shown by worse scores for activities of daily living, motor symptom severity, dyskinesia duration/disability, duration of “off” time, non-motor symptoms and quality of life as compared with non-APD patients (p <0.0001 for all). The Swiss data for disease burden were comparable to the international findings, except that the Swiss patients showed less “off” time. Amongst APD patients eligible for DAT, the main reason for no DAT in Switzerland was patient refusal, whereas patients needing more time to decide about it was the most frequent reason in the international analysis. CONCLUSIONS: The study shows that the burden of APD in tertiary care centres in Switzerland is comparable to the international situation. Patient refusal is the main reason for no DAT amongst eligible APD patients in such centres. The identification of standard APD classification parameters and evaluation of the reasons for no DAT are relevant for optimising treatment strategies and the transition to DAT.

Functional connectivity and upper limb function in patients after pediatric arterial ischemic stroke with contralateral corticospinal tract wiring.

To develop individualized motor rehabilitation, knowledge of the relationship between neuroplastic reorganization and motor recovery after pediatric arterial ischemic stroke (AIS) is crucial. Thus, we investigated functional connectivity in patients after AIS with good motor outcome and in patients with hemiparesis compared with typically developing peers. We included 18 patients (n = 9 with hemiparesis, n = 9 with good motor outcome) with pediatric AIS in the chronic phase (≥ 2 years after diagnosis, diagnosed > 16 years) and 18 peers matched by age and gender. Participants underwent a standardized motor assessment, single-pulse transcranial magnetic stimulation to determine the type of corticospinal tract wiring, and resting-state functional magnetic resonance imaging to examine motor network connectivity. Corticospinal tract wiring was contralateral in all participants. Patients with hemiparesis had lower interhemispheric connectivity strength compared with patients with good clinical outcome and peers. Patients with good clinical outcome had higher intrahemispheric connectivity strength compared with peers. Further, higher intrahemispheric connectivity was related to better motor outcome in patients. Our findings suggest that better motor outcome after pediatric AIS is related to higher motor network connectivity strength. Thus, resting-state functional connectivity might be predictive for motor recovery after pediatric AIS.

Bilateral pallidal stimulation improves cervical dystonia for more than a decade.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment in medically resistant cervical dystonia (CD) with a documented therapeutic effect. Long term outcome beyond a decade, however, has not been studied systematically. METHODS: To investigate the impact of pallidal DBS beyond 10 years in CD we followed a series of five consecutive patients with severe medication-resistant CD. Severity of head and neck deviation, disability, and pain related to dystonia were assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in the frame of a prospective study. The primary endpoint of this study was a change in the TWSTRS total score. Secondary endpoints were changes in the subscores of the TWSTRS. RESULTS: The mean follow-up time was 11.5 years (range 10-12.8). Comparing baseline and the last follow-up, CD improved by 53% on the total TWSTRS score, by 54.1% on the severity score, and by 70.1% on the disability score, while pain did not improve significantly. Improvement was stable over time. Patients with a tonic pattern of CD responded less to DBS than patients with a phasic pattern. DBS had no significant effect on mood and cognition. Two patients underwent electrode revisions. One patient had an infection of the proximal cable two years after surgery. CONCLUSIONS: Chronic bilateral pallidal stimulation improves severity of dystonia and disability over more than a decade in treatment resistant CD. Results may vary among individual patients.

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease.

OBJECTIVE: To develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform. METHODS: Plasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort. RESULTS: Distinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations. CONCLUSIONS: Immune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP.

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core.

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer's and Parkinson's diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a "dying back" pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson's disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function.

The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state.

Corrigendum to "Protoporphyrin IX tracer fluorescence modulation for improved brain tumor cell lines visualization".

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase (FECH) and heme oxygenase-1 (HO-1) and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).

Corticospinal Control of Human Locomotion as a New Determinant of Age-Related Sarcopenia: An Exploratory Study.

Sarcopenia is a muscle disease listed within the ICD-10 classification. Several operational definitions have been created for sarcopenia screening; however, an international consensus is lacking. The Centers for Disease Control and Prevention have recently recognized that sarcopenia detection requires improved diagnosis and screening measures. Mounting evidence hints towards changes in the corticospinal communication system where corticomuscular coherence (CMC) reflects an effective mechanism of corticospinal interaction. CMC can be assessed during locomotion by means of simultaneously measuring Electroencephalography (EEG) and Electromyography (EMG). The aim of this study was to perform sarcopenia screening in community-dwelling older adults and explore the possibility of using CMC assessed during gait to discriminate between sarcopenic and non-sarcopenic older adults. Receiver Operating Characteristic (ROC) curves showed high sensitivity, precision and accuracy of CMC assessed from EEG Cz sensor and EMG sensors located over Musculus Vastus Medialis [Cz-VM; AUC (95.0%CI): 0.98 (0.92-1.04), sensitivity: 1.00, 1-specificity: 0.89, p < 0.001] and with Musculus Biceps Femoris [Cz-BF; AUC (95.0%CI): 0.86 (0.68-1.03), sensitivity: 1.00, 1-specificity: 0.70, p < 0.001]. These muscles showed significant differences with large magnitude of effect between sarcopenic and non-sarcopenic older adults [Hedge's g (95.0%CI): 2.2 (1.3-3.1), p = 0.005 and Hedge's g (95.0%CI): 1.5 (0.7-2.2), p = 0.010; respectively]. The novelty of this exploratory investigation is the hint toward a novel possible determinant of age-related sarcopenia, derived from corticospinal control of locomotion and shown by the observed large differences in CMC when sarcopenic and non-sarcopenic older adults are compared. This, in turn, might represent in future a potential treatment target to counteract sarcopenia as well as a parameter to monitor the progression of the disease and/or the potential recovery following other treatment interventions.