Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.

The Influence of Packaging Color on Consumer Perceptions of Healthfulness: A Systematic Review and Theoretical Framework.

When consumers evaluate a new product, packaging design plays a critical role. In particular, packaging color is a dominant design cue that influences consumer perception of a product. Several studies have investigated the influence of color on taste. However, there is limited research on the influence of packaging color on consumer health perception. As healthy eating is a focus for many consumers and public decision-makers, more knowledge is needed. The aim of this review is to provide an overview of empirical studies that have investigated the influence of packaging color on consumers' health perceptions and to provide a psychological explanation for the observed effects. The systematic review includes 20 empirical studies across different product groups. The results show that packaging color influences consumers' health perceptions. We argue that the influence of packaging color on consumer health perceptions can be explained by the following mechanisms, which are not mutually exclusive: (1) consumers rely on a color as an explicit signal for health; (2) colors are associated with beliefs that indirectly influence health assessments; and (3) colors trigger mental simulations that influence health assessments. In addition, we provide suggestions for further research that will contribute to a better understanding of when and how packaging color can help consumers make healthier food choices.

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Long-term organotypic brain slices cultured on collagen-based microcontact prints: A perspective for a brain-on-a-chip.

Organotypic brain slices are three-dimensional 150 µm-thick sections of a postnatal day 10 mouse and can be cultured for several weeks in vitro. In such brain slices the complex cellular connections are preserved with a high viability. These brain slices can be connected to collagen-loaded microcontact prints to develop a simple brain-on-a-chip model. Using the microcontact printing technique, many peptides or proteins can be printed onto a semipermeable membrane and linked to brain slices. On these microcontact prints, brain-derived nerve fibers grow out, or microglia can get activated and migrate out, or also new brain vessels can be formed. Such a brain-on-a-chip model may allow to develop new drugs or a diagnostic method for neurodegenerative diseases.

Circulation as a Visual Practice.

This special issue looks at some of the ways that images are adopted, co-opted, and adapted in the life sciences and beyond. It brings together papers that investigate the role of visualization in scientific knowledge-production with contributions that focus on the distribution and dissemination of knowledge to a broader audience. A commentary provides a critical perspective. In this editorial we introduce circulation as a practice to better understand scientific images. Along two themes, we highlight connections across the papers. First, the social life of scientific representation follows the contexts, settings, and spaces through which images circulate. Second, authorship, expertise, and trust inform the capacity and the failure of images to circulate. Altogether, this volume raises a set of new questions about circulation as practice in the historiography of images in the life sciences.

Study protocol: effects of treatment expectation toward repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder-a randomized controlled clinical trial.

BACKGROUND: Patients' expectations toward any given treatment are highly important for the effectiveness of such treatment, as has been demonstrated for several disorders. In particular, in major depressive disorder (MDD), one of the most frequent and most serious mental disorders with severe consequences for the affected, the augmentation of available treatment options could mean a ground-breaking success. Repetitive transcranial magnetic stimulation (rTMS), a new, non-invasive, and well-tolerated intervention with proven effects in the treatment of MDD, appears particularly suitable in this context as it is assumed to exert its effect via structures implicated in networks relevant for both expectation and depression. METHODS: All patients will receive rTMS according to its approval. Half of the patients will be randomized to a psychological intervention, which is a comprehensive medical consultation aiming to improve positive treatment expectations; the control group will receive a conventional informed consent discussion (in the sense of a treatment-as-usual condition). As outcome parameters, instruments for both self-assessment and external assessment of depression symptoms will be applied. Furthermore, psycho-immunological parameters such as inflammation markers and the cortisol awakening response in saliva will be investigated. Resting-state functional magnetic resonance imaging (rs fMRI) will be performed to analyze functional connectivity, including the cerebellum, and to identify neuronal predictors of expectation effects. In addition, possible cerebellar involvement will be assessed based on a cerebellar-dependent motor learning paradigm (i.e., eyeblink conditioning). DISCUSSION: In this study, the effects of treatment expectations towards rTMS are investigated in patients with MDD. The aim of this study is to identify the mechanisms underlying the expectation effects and, beyond that, to expand the potential of non-invasive and well-tolerated treatments of MDD. TRIAL REGISTRATION: German Registry of Clinical Studies (DRKS DRKS00028017. Registered on 2022/03/07. URL: https://www.drks.de/drks_web/ .

Age-related differences of cerebellar cortex and nuclei: MRI findings in healthy controls and its application to spinocerebellar ataxia (SCA6) patients.

Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 - 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 - 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals.

Beta-Amyloid Enhances Vessel Formation in Organotypic Brain Slices Connected to Microcontact Prints.

In Alzheimer's disease, the blood-brain barrier breakdown, blood vessel damage and re-organization are early events. Deposits of the small toxic peptide beta-amyloid (Aß) cause the formation of extracellular plaques and accumulate in vessels disrupting the blood flow but may also play a role in blood clotting. In the present study, we aim to explore the impact of Aß on the migration of endothelial cells and subsequent vessel formation. We use organotypic brain slices of postnatal day 10 wildtype mice (C57BL/6) and connect them to small microcontact prints (µCPs) of collagen. Our data show that laminin-positive endothelial cells migrate onto collagen µCPs, but without any vessel formation after 4 weeks. When the µCPs are loaded with human Aß40, (aggregated) human Aß42 and mouse Aß42 peptides, the number and migration distance of endothelial cells are significantly reduced, but with a more pronounced subsequent vessel formation. The vessel formation is verified by zonula occludens (ZO)-1 and -2 stainings and confocal microscopy. In addition, the vessel formation is accompanied by a stronger GFAP-positive astroglial formation. Finally, we show that vessels can grow towards convergence when two opposed slices are connected via microcontact-printed lanes. In conclusion, our data show that Aß promotes vessel formation, and organotypic brain slices connected to collagen µCPs provide a potent tool to study vessel formation.

Effects of Ischemia on the Migratory Capacity of Microglia Along Collagen Microcontact Prints on Organotypic Mouse Cortex Brain Slices.

Ischemic stroke is a severe insult in the brain causing cell death, inflammation, and activation of microglia. Microglia are the immune cells of the brain and play a role in any inflammatory process during neurodegeneration. Microglia are round ameboid and migrate to the lesion site, where they differentiate into ramified forms and activated phagocytic microglia. On the other hand, microglia can also release growth factors to repair degeneration. The aim of the present study is to explore the migratory capacity of microglia after ischemic insults. Organotypic brain slices of the mouse cortex (300 µm) were prepared. In order to study migration, the slices were connected to collagen-loaded microcontact prints (with or without monocyte chemoattractant protein-1, MCP-1) on the membranes. Slices were stimulated with lipopolysaccharide (LPS) for maximal microglial activation. Ischemic insults were simulated with oxygen-glucose deprivation (OGD) and acidosis (pH 6.5) for 3 days. After 3 weeks in culture, slices were fixed and immunohistochemically stained for the microglial markers Iba1, CD11b and macrophage-like antigen. Our data show that Iba1+ microglia migrated along the microcontact prints, differentiate and phagocyte 1.0 µm fluorescent microbeads. LPS significantly enhanced the number of round ameboid migrating microglia, while OGD and acidosis enhanced the number of ramified activated microglia. The effect was not visible on slices without any µCP and was most potent in µCP with MCP-1. We conclude that OGD and acidosis activate ramification and exhibit a similar mechanism, while LPS only activates round ameboid microglia. Collagen-loaded microcontact prints connected to mouse brain slices are a potent method to study activation and migration of microglia ex vivo.

Novel Synthetic Opioids (NSO) Use in Opioid Dependents Entering Detoxification Treatment.

Introduction: Over the last decade, the use of New/Novel Synthetic Opioids (NSO) has emerged as an increasing problem, and especially so in the USA. However, only little is known about the prevalence and history of NSO use in European heroin dependents. Method: A cross-sectional multicenter study, carried out with the means of both standardized interviews and urine toxicology enhanced screening, in a sample of opioid addicted patients referred for an in-patient detoxification treatment. Results: Sample size included here n = 256 patients; prior to admission, 63.7% were prescribed with an opioid maintenance treatment. Lifetime use of heroin and opioid analgesics was reported by 99.2 and 30.4%, respectively. Lifetime NSO/fentanyl use was reported by 8.7% (n = 22); a regular use was reported by 1.6% (n = 4), and ingestion over the 30 days prior to admission by 0.8% (n = 2). Most typically, patients had started with a regular consumption of heroin, followed by maintenance opioids; opioid analgesics; and by NSO. Self-reported data were corroborated by the toxicology screenings carried out; no evidence was here identified for the presence of heroin being contaminated by fentanyl/derivatives. Discussion: NSO and also opioid analgesics did not play a relevant role in the development and the course of opioid/opioid use disorders in German patients referred for an inpatient detoxification treatment.

Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias.

The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich's ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich's ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich's ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

Motor training-related brain reorganization in patients with cerebellar degeneration.

Cerebellar degeneration progressively impairs motor function. Recent research showed that cerebellar patients can improve motor performance with practice, but the optimal feedback type (visual, proprioceptive, verbal) for such learning and the underlying neuroplastic changes are unknown. Here, patients with cerebellar degeneration (N = 40) and age- and sex-matched healthy controls (N = 40) practiced single-joint, goal-directed forearm movements for 5 days. Cerebellar patients improved performance during visuomotor practice, but a training focusing on either proprioceptive feedback, or explicit verbal feedback and instruction did not show additional benefits. Voxel-based morphometry revealed that after training gray matter volume (GMV) was increased prominently in the visual association cortices of controls, whereas cerebellar patients exhibited GMV increase predominantly in premotor cortex. The premotor cortex as a recipient of cerebellar efferents appears to be an important hub in compensatory remodeling following damage of the cerebro-cerebellar motor system.

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial.

Importance: Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances. Objective: To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia. Design, Setting, and Participants: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020. Interventions: Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site. Main Outcomes and Measures: Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6. Results: Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]). Conclusions and Relevance: In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia. Trial Registration: EudraCT 2015-000460-34.

Microcontact Printing of Cholinergic Neurons in Organotypic Brain Slices.

Alzheimer's disease is a severe neurodegenerative disorder of the brain, characterized by beta-amyloid plaques, tau pathology, and cell death of cholinergic neurons, resulting in loss of memory. The reasons for the damage of the cholinergic neurons are not clear, but the nerve growth factor (NGF) is the most potent trophic factor to support the survival of these neurons. In the present study we aim to microprint NGF onto semipermeable 0.4 µm pore membranes and couple them with organotypic brain slices of the basal nucleus of Meynert and to characterize neuronal survival and axonal growth. The brain slices were prepared from postnatal day 10 wildtype mice (C57BL6), cultured on membranes for 2-6 weeks, stained, and characterized for choline acetyltransferase (ChAT). The NGF was microcontact printed in 28 lines, each with 35 µm width, 35 µm space between them, and with a length of 8 mm. As NGF alone could not be printed on the membranes, NGF was embedded into collagen hydrogels and the brain slices were placed at the center of the microprints and the cholinergic neurons that survived. The ChAT+ processes were found to grow along with the NGF microcontact prints, but cells also migrated. Within the brain slices, some form of re-organization along the NGF microcontact prints occurred, especially the glial fibrillary acidic protein (GFAP)+ astrocytes. In conclusion, we provided a novel innovative microcontact printing technique on semipermeable membranes which can be coupled with brain slices. Collagen was used as a loading substance and allowed the microcontact printing of nearly any protein of interest.

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

BACKGROUND: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. OBJECTIVE: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). METHODS: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. RESULTS: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. CONCLUSIONS: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection.

BACKGROUND: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies. METHODS: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients. RESULTS: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood-brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested. CONCLUSION: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.

Neurostructural changes and declining sensorimotor function due to cerebellar cortical degeneration.

Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex.NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.