Dementia exacerbates periodontal bone loss in females.

BACKGROUND: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. OBJECTIVE: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. MATERIALS AND METHODS: We induced periodontitis in dementia-like triple-transgenic (3x-Tg) male and female mice and age-matched wild-type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro-CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia-associated Aß42 and p-Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa-Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x-Tg females but not males, compared to wild-type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia-associated Aß42 and p-Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. CONCLUSION: Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.

IL-34 exacerbates pathogenic features of Alzheimer's disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice.

Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aß40 and Aß42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aß40 and Aß42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.

Serum Urate Levels and Ultrasound Characteristics of Carotid Atherosclerosis across Obesity Phenotypes.

BACKGROUND: Existing evidence suggests a close link among high levels of serum urate (SU), obesity and carotid atherosclerosis. The aim of the present study was to evaluate the interrelations between SU levels and carotid atherosclerosis in subjects with different obesity phenotypes. METHODS: In this study, a total of 2076 subjects (mean age 48.1 ± 13.1 years; 1307 women) were recruited: 59 with general obesity, 616 with central obesity, 715 with mixed (general-central) obesity and 686 non-obese. Anthropometric measurements, vascular risk factors, blood biochemistry analysis (including SU levels), and carotid ultrasound were performed. Ultrasound assessment included evaluation of intima-media thickness (IMT) and plaque characteristics, including number, total area and type (vulnerable vs. stable) of plaques. RESULTS: After adjustment for potential confounders, the highest levels of SU were observed in subjects with mixed obesity, followed by subjects with central obesity, general obesity and the non-obese (309.4 ± 82.2 vs. 301.2 ± 73.1 vs. 272.9 ± 61.8 vs. 234.2 ± 59.8 µmol/L, respectively; F = 149.2, post hoc p < 0.001). Similarly, subjects with mixed and central obesity presented higher values of IMT compared to subjects with general obesity and the non-obese (0.68 ± 0.16 vs. 0.67 ± 0.16 vs. 0.62 ± 0.14 vs. 0.57 ± 0.13 mm, respectively; F = 54.2, post hoc p < 0.001). No difference in number, total area and type of plaques among obesity groups were attested (all p > 0.05). Significantly higher IMT values were observed in subjects with increased SU levels compared to subjects with normal SU levels (0.70 ± 0.10 vs. 0.62 ± 0.14 mm, p = 0.02) only within the central obesity group. Increasing levels of SU were associated with a higher frequency of increased IMT only in subjects with central obesity (OR 1.033, 95% CI 1.025-1.041). Similarly, SU levels yielded a satisfactory performance in detecting subjects with increased IMT (AUC 0.65, 95% CI 0.50-0.73, subjects with carotid plaques (0.62, 95% CI 0.55-0.68) and subjects with vulnerable plaque types (0.68, 0.59-0.76) only within the central obesity group. CONCLUSIONS: Among the studied obesity types, the association between SU levels and markers of carotid atherosclerosis was of particular significance in subjects with central obesity.

Maternal antibiotic administration during gestation can affect the memory and brain structure in mouse offspring.

Maternal antibiotics administration (MAA) is among the widely used therapeutic approaches in pregnancy. Although published evidence demonstrates that infants exposed to antibiotics immediately after birth have altered recognition memory responses at one month of age, very little is known about in utero effects of antibiotics on the neuronal function and behavior of children after birth. Therefore, this study aimed to evaluate the impact of MAA at different periods of pregnancy on memory decline and brain structural alterations in young mouse offspring after their first month of life. To study the effects of MAA on 4-week-old offspring, pregnant C57BL/6J mouse dams (2-3-month-old; n = 4/group) were exposed to a cocktail of amoxicillin (205 mg/kg/day) and azithromycin (51 mg/kg/day) in sterile drinking water (daily/1 week) during either the 2nd or 3rd week of pregnancy and stopped after delivery. A control group of pregnant dams was exposed to sterile drinking water alone during all three weeks of pregnancy. Then, the 4-week-old offspring mice were first evaluated for behavioral changes. Using the Morris water maze assay, we revealed that exposure of pregnant mice to antibiotics at the 2nd and 3rd weeks of pregnancy significantly altered spatial reference memory and learning skills in their offspring compared to those delivered from the control group of dams. In contrast, no significant difference in long-term associative memory was detected between offspring groups using the novel object recognition test. Then, we histologically evaluated brain samples from the same offspring individuals using conventional immunofluorescence and electron microscopy assays. To our knowledge, we observed a reduction in the density of the hippocampal CA1 pyramidal neurons and hypomyelination in the corpus callosum in groups of mice in utero exposed to antibiotics at the 2nd and 3rd weeks of gestation. In addition, offspring exposed to antibiotics at the 2nd or 3rd week of gestation demonstrated a decreased astrocyte cell surface area and astrocyte territories or depletion of neurogenesis in the dentate gyrus and hippocampal synaptic loss, respectively. Altogether, this study shows that MAA at different times of pregnancy can pathologically alter cognitive behavior and brain development in offspring at an early age after weaning.

Six years of the Angels Initiative: Aims, achievements, and future directions to improve stroke care worldwide.

The rate of stroke-related death and disability is four times higher in low- and middle-income countries (LMICs) than in high-income countries (HICs), yet stroke units exist in only 18% of LMICs, compared with 91% of HICs. In order to ensure universal and equitable access to timely, guideline-recommended stroke care, multidisciplinary stroke-ready hospitals with coordinated teams of healthcare professionals and appropriate facilities are essential.Established in 2016, the Angels Initiative is an international, not-for-profit, public-private partnership. It is run in collaboration with the World Stroke Organization, European Stroke Organisation, and regional and national stroke societies in over 50 countries. The Angels Initiative aims to increase the global number of stroke-ready hospitals and to optimize the quality of existing stroke units. It does this through the work of dedicated consultants, who help to standardize care procedures and build coordinated, informed communities of stroke professionals. Angels consultants also establish quality monitoring frameworks using online audit platforms such as the Registry of Stroke Care Quality (RES-Q), which forms the basis of the Angels award system (gold/platinum/diamond) for all stroke-ready hospitals across the world.The Angels Initiative has supported over 1700 hospitals (>1000 in LMICs) that did not previously treat stroke patients to become "stroke ready." Since its inception in 2016, the Angels Initiative has impacted the health outcomes of an estimated 7.46 million stroke patients globally (including an estimated 4.68 million patients in LMICs). The Angels Initiative has increased the number of stroke-ready hospitals in many countries (e.g. in South Africa: 5 stroke-ready hospitals in 2015 vs 185 in 2021), reduced "door to treatment time" (e.g. in Egypt: 50% reduction vs baseline), and increased quality monitoring substantially.The focus of the work of the Angels Initiative has now expanded from the hyperacute phase of stroke treatment to the pre-hospital setting, as well as to the early post-acute setting. A continued and coordinated global effort is needed to achieve the target of the Angels Initiative of >10,000 stroke-ready hospitals by 2030, and >7500 of these in LMICs.

Characterisation of the Antibody Response in Sinopharm (BBIBP-CorV) Recipients and COVID-19 Convalescent Sera from the Republic of Moldova.

The early availability of effective vaccines against SARS-CoV-2, the aetiologic cause of COVID-19, has been at the cornerstone of the global recovery from the pandemic. This study aimed to assess the antispike RBD IgG antibody titres and neutralisation potential of COVID-19 convalescent plasma and the sera of Moldovan adults vaccinated with the Sinopharm BBIBP-CorV vaccine. An IgG ELISA with recombinant SARS-CoV-2 spike RBD and two pseudovirus-based neutralisation assays have been developed to evaluate neutralising antibodies against SARS-CoV-2 in biosafety level 2 containment facilities. A significant moderate correlation was observed between IgG titres and the overall neutralising levels for each neutralisation assay (ρ = 0.64, p < 0.001; ρ = 0.52, p < 0.001). A separate analysis of convalescent and vaccinated individuals showed a higher correlation of neutralising and IgG titres in convalescent individuals (ρ = 0.68, p < 0.001, ρ = 0.45, p < 0.001) compared with vaccinated individuals (ρ = 0.58, p < 0.001; ρ = 0.53, p < 0.001). It can be concluded that individuals who recovered from infection developed higher levels of antispike RBD IgG antibodies. In comparison, the Sinopharm-vaccinated individuals produced higher levels of neutralising antibodies than convalescent plasma.

Dynamic flexibility and controllability of network communities in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common syndrome within the idiopathic generalized epilepsy spectrum, manifested by myoclonic and generalized tonic-clonic seizures and spike-and-wave discharges (SWDs) on electroencephalography (EEG). Currently, the pathophysiological concepts addressing SWD generation in JME are still incomplete. In this work, we characterize the temporal and spatial organization of functional networks and their dynamic properties as derived from high-density EEG (hdEEG) recordings and MRI in 40 JME patients (25.4 ± 7.6 years, 25 females). The adopted approach allows for the construction of a precise dynamic model of ictal transformation in JME at the cortical and deep brain nuclei source levels. We implement Louvain algorithm to attribute brain regions with similar topological properties to modules during separate time windows before and during SWD generation. Afterwards, we quantify how modular assignments evolve and steer through different states towards the ictal state by measuring characteristics of flexibility and controllability. We find antagonistic dynamics of flexibility and controllability within network modules as they evolve towards and undergo ictal transformation. Prior to SWD generation, we observe concomitantly increasing flexibility (F(1,39) = 25.3, corrected p < 0.001) and decreasing controllability (F(1,39) = 55.3, p < 0.001) within the fronto-parietal module in γ-band. On a step further, during interictal SWDs as compared to preceding time windows, we notice decreasing flexibility (F(1,39) = 11.9, p < 0.001) and increasing controllability (F(1,39) = 10.1, p < 0.001) within the fronto-temporal module in γ-band. During ictal SWDs as compared to prior time windows, we demonstrate significantly decreasing flexibility (F(1,14) = 31.6; p < 0.001) and increasing controllability (F(1,14) = 44.7, p < 0.001) within the basal ganglia module. Furthermore, we show that flexibility and controllability within the fronto-temporal module of the interictal SWDs relate to seizure frequency and cognitive performance in JME patients. Our results demonstrate that detection of network modules and quantification of their dynamic properties is relevant to track the generation of SWDs. The observed flexibility and controllability dynamics reflect the reorganization of de-/synchronized connections and the ability of evolving network modules to reach a seizure-free state, respectively. These findings may advance the elaboration of network-based biomarkers and more targeted therapeutic neuromodulatory approaches in JME.

Dissecting the Spectrum of Stroke Risk Factors in an Apparently Healthy Population: Paving the Roadmap to Primary Stroke Prevention.

We aimed to investigate, for the first time, the spectrum of stroke risk factors specific to the population of the Republic of Moldova. The subjects were examined according to a pre-established protocol of risk factor estimation. The study involved 300 subjects, including 60% women and 40% men, with a mean age of 49.9 ± 14.5 years. The most common risk factor was abdominal obesity, identified in 75% of subjects; general obesity was detected in 48%, while 32% of subjects were overweight and 20% were normally weighted. Hypertension was observed in 44%; 8% of those examined had atrial fibrillation, and 9% had diabetes mellitus. Left myocardial hypertrophy on ECG was present in 53% of subjects, and acute ischemic changes in 2%. Laboratory observations detected that glycosylated hemoglobin increased by 7%, and >50% had dyslipidemia. Total cholesterol was significantly elevated by 58%, LDL-cholesterol was increased by 32%, and HDL-cholesterol was decreased by 9%. Homocysteine was increased in 55% and high-sensitivity C-reactive protein in 28% of subjects. These results indicate the presence of modifiable risk factors and the necessity to elaborate on the primary prevention strategies aimed at minimizing the burden of stroke in the population of the Republic of Moldova.

Genome Sequences of SARS-CoV-2 Strains from the Republic of Moldova.

The whole-genome sequences of 15 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains from nasopharyngeal swab samples collected in the Republic of Moldova in June 2020 to September 2021 were determined. Little variability was observed in the early stages, when mostly clade 19A was circulating, followed by clade 20B. Later, multiple introductions of SARS-CoV-2 lineages B.1.1., B.1.1.7, and B.1.1.525 were detected. The B.1.1.7 lineage became predominant between December 2020 and June 2021, followed by the Delta variant.

EVs vs. EVs: MSCs and Tregs as a source of invisible possibilities.

Extracellular vesicles (EVs) are produced by various cells and exist in most biological fluids. They play an important role in cell-cell signaling, immune response, and tumor metastasis, and also have theranostic potential. They deliver many functional biomolecules, including DNA, microRNAs (miRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), lipids, and proteins, thus affecting different physiological processes in target cells. Decreased immunogenicity compared to liposomes or viral vectors and the ability to cross through physiological barriers such as the blood-brain barrier make them an attractive and innovative option as diagnostic biomarkers and therapeutic carriers. Here, we highlighted two types of cells that can produce functional EVs, namely, mesenchymal stem/stromal cells (MSCs) and regulatory T cells (Tregs), discussing MSC/Treg-derived EV-based therapies for some specific diseases including acute respiratory distress syndrome (ARDS), autoimmune diseases, and cancer.

Altered grey matter integrity and network vulnerability relate to epilepsy occurrence in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy. METHODS: From 3-T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver-operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients. RESULTS: Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p < 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p < 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p < 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p < 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67-0.91]) in discriminating between MSE and MS patients. CONCLUSIONS: High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS.

Molecular Mechanisms of SARS-CoV-2/COVID-19 Pathogenicity on the Central Nervous System: Bridging Experimental Probes to Clinical Evidence and Therapeutic Interventions.

The coronavirus disease 2019 (COVID-19) pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has dramatically impacted the global healthcare systems, constantly challenging both research and clinical practice. Although it was initially believed that the SARS-CoV-2 infection is limited merely to the respiratory system, emerging evidence indicates that COVID-19 affects multiple other systems including the central nervous system (CNS). Furthermore, most of the published clinical studies indicate that the confirmed CNS inflammatory manifestations in COVID-19 patients are meningitis, encephalitis, acute necrotizing encephalopathy, acute transverse myelitis, and acute disseminated encephalomyelitis. In addition, the neuroinflammation along with accelerated neurosenescence and susceptible genetic signatures in COVID-19 patients might prime the CNS to neurodegeneration and precipitate the occurrence of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Thus, this review provides a critical evaluation and interpretive analysis of existing published preclinical as well as clinical studies on the key molecular mechanisms modulating neuroinflammation and neurodegeneration induced by the SARS-CoV-2. In addition, the essential age- and gender-dependent impacts of SARS-CoV-2 on the CNS of COVID-19 patients are also discussed.

Clinical and Radiological Deterioration in a Case of Creutzfeldt-Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration.

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt-Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19.

Increased migraine-free intervals with multifocal repetitive transcranial magnetic stimulation.

INTRODUCTION: Episodic migraine is a debilitating condition associated with vast impairments of health, daily living, and life quality. Several prophylactic treatments exist, having a moderate ratio of action related to side effects and therapy costs. Repetitive transcranial magnetic stimulation (rTMS) is an evidence based therapy in several neuropsychiatric conditions, showing robust efficacy in alleviating specific symptoms. However, its efficacy in migraine disorders is unequivocal and might be tightly linked to the applied rTMS protocol. We hypothesized that multifocal rTMS paradigm could improve clinical outcomes in patients with episodic migraine by reducing the number of migraine days, frequency and intensity of migraine attacks, and improve the quality of life. METHODS: We conducted an experimental, double-blind, randomized controlled study by applying a multifocal rTMS paradigm. Patients with episodic migraine with or without aura were enrolled in two centers from August 2018, to December 2019, and randomized to receive either real (n = 37) or sham (sham coil stimulation, n = 28) multifocal rTMS for six sessions over two weeks. Patients, physicians, and raters were blinded to the applied protocol. The experimental multifocal rTMS protocol included two components; first, swipe stimulation of 13 trains of 140 pulses/train, 67 Hz, 60% of RMT, and 2s intertrain interval and second, spot burst stimulation of 33 trains of 15 pulses/train, 67 Hz, 85% of RMT, and 8s intertrain interval. Reduction >50% from the baseline in migraine days (as primary outcome) and frequency and intensity of migraine attacks (as key secondary outcomes) over a 12-week period were assessed. To balance the baseline variables between the treatment arms, we applied the propensity score matching through the logistic regression. RESULTS: Among 65 randomized patients, sixty (age 39.7 ± 11.6; 52 females; real rTMS n = 33 and sham rTMS n = 27) completed the trial and five patients dropped out. Over 12 weeks, the responder's rate in the number of migraine days was significantly higher in the real rTMS compared to the sham group (42% vs. 26%, p < 0.05). The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group, resulting in a difference with real vs. sham rTMS of -3.2 days (p < 0.05). Similarly, over the 12-week period, the responder's rate in the reduction of migraine attacks frequency was higher in the real rTMS compared to the sham group (42% vs 33%, p < 0.05). No serious adverse events were observed. CONCLUSION: Our pilot study shows compelling evidence in a double placebo-controlled trial that multifocal rTMS is an effective and well-tolerated preventive treatment in patients with episodic migraine.

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors. METHODS: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020). RESULTS: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium. CONCLUSIONS: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.

Extensive cerebellar involvement and cognitive impairment in COVID-19-associated acute necrotizing encephalopathy.

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.

Enhancing and accelerating stroke treatment in Eastern European region: Methods and achievement of the ESO EAST program.

INTRODUCTION: Despite the availability of prevention and therapies of stroke, their implementation in clinical practice, even of low-cost ones, remains poor. In 2015, the European Stroke Organisation (ESO) initiated the ESO Enhancing and Accelerating Stroke Treatment (EAST) program, which aims to improve stroke care quality, primarily in Eastern Europe. Here, we describe its methods and milestones. PATIENTS AND METHODS: The ESO EAST program is using an implementation strategy based on a 'detecting-understanding-reducing disparities' conceptual framework: stroke care quality is first measured (after developing a platform for data collection), gaps are identified in the current service delivery, and ultimately feedback is provided to participating hospitals, followed by the application of interventions to reduce disparities. The ESO EAST program is carried out by establishing a stroke quality registry, stroke management infrastructure, and creating education and training opportunities for healthcare professionals. RESULTS: Program management and leadership infrastructure has been established in 19 countries (Country Representatives in 22 countries, National Steering Committee in 19 countries). A software platform for data collection and analysis: Registry of Stroke Care Quality was developed, and launched in 2016, and has been used to collect data from over 90,000 patients from >750 hospitals and 56 countries between September 2016 and May 2019. Training in thrombolysis, nursing and research skills has been initiated. DISCUSSION: ESO EAST is the first pan-Eastern European (and beyond) multifaceted quality improvement intervention putting evidence-informed policies into practice. Continuous monitoring of stroke care quality allows hospital-to-hospital and country-to-country benchmarking and identification of the gaps and needs in health care.

An update on MSA: premotor and non-motor features open a window of opportunities for early diagnosis and intervention.

In this review, we describe the wide clinical spectrum of features that can be seen in multiple system atrophy (MSA) with a focus on the premotor phase and the non-motor symptoms providing an up-to-date overview of the current understanding in this fast-growing field. First, we highlight the non-motor features at disease onset when MSA can be indistinguishable from pure autonomic failure or other chronic neurodegenerative conditions. We describe the progression of clinical features to aid the diagnosis of MSA early in the disease course. We go on to describe the levels of diagnostic certainty and we discuss MSA subtypes that do not fit into the current diagnostic criteria, highlighting the complexity of the disease as well as the need for revised diagnostic tools. Second, we describe the pathology, clinical description, and investigations of cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, and respiratory and REM-sleep behavior disorders, which may precede the motor presentation by months or years. Their presence at presentation, even in the absence of ataxia and parkinsonism, should be regarded as highly suggestive of the premotor phase of MSA. Finally, we discuss how the recognition of the broader spectrum of clinical features of MSA and especially the non-motor features at disease onset represent a window of opportunity for disease-modifying interventions.

MYORG-related disease is associated with central pontine calcifications and atypical parkinsonism.

OBJECTIVE: To identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations. METHODS: Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here. RESULTS: We identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases. CONCLUSIONS: This large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.