Multiple Sclerosis Onset before and after COVID-19 Vaccination: Can HLA Haplotype Be Determinant?

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.

Corticospinal tract hyperintensity in patients with LGI1-antibody encephalitis and other central nervous system disorders with neuroglial antibodies.

The frequency of corticospinal tract (CST) T2/FLAIR hyperintensity in disorders with neuroglial antibodies is unclear. Herein, we retrospectively reviewed brain MRIs of 101 LGI1-antibody encephalitis patients, and observed CST hyperintensity in 30/101 (30%). It was mostly bilateral (93%), not associated with upper motor neuron signs/symptoms (7%), and frequently decreased over time (39%). In a systematic review including patients with other neuroglial antibodies, CST hyperintensity was reported in 110 with neuromyelitis optica (94%), myelin oligodendrocyte glycoprotein-associated disease (2%), Ma2-antibody (3%) and GAD65-antibody paraneoplastic neurological syndrome (1%). CST hyperintensity is not an infrequent finding in LGI1-Ab encephalitis and other disorders with neuroglial antibodies.

Baseline clinical and neuroradiological predictors of outcome in patients with large ischemic core undergoing mechanical thrombectomy: A retrospective multicenter study.

BACKGROUND: Recent randomized trials have shown the benefit of mechanical thrombectomy (MT) also in patients with an established large ischemic core. AIMS: The purpose of this study was to define baseline predictors of clinical outcome in patients with large vessel occlusion (LVO) in the anterior circulation and an Alberta Stroke Program Early CT score (ASPECTS) ⩽ 5, undergoing MT. MATERIAL AND METHODS: The databases of 16 comprehensive stroke centers were retrospectively screened for patients with LVO and ASPECTS ⩽5 that received MT. Baseline clinical and neuroradiological features, including the differential contribution of all ASPECTS regions to the composite score, were collected. Primary clinical outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-2. Statistical analysis used a logistic regression model and random forest algorithm. RESULTS: A total of 408 patients were available for analysis. In multivariate model, among baseline features, lower age (odd ratio (OR) = 0.962, 95% confidence interval (CI) = 0.943-0.982) and lower National Institute of Health Stroke Scale (NIHSS) score (OR = 0.911, 95% CI = 0.862-0.963) were associated with the mRS score 0-2. Involvement of the M2 (OR = 0.398, 95% CI = 0.206-0.770) or M4 (OR = 0.496, 95% CI = 0.260-0.945) ASPECTS regions was associated with an unfavorable outcome. Random forest analysis confirmed that age and baseline NIHSS score are the most important variables influencing clinical outcome, whereas involvement of cortical regions M5, M4, M2, and M1 can have a negative impact. CONCLUSION: Our retrospective analysis shows that, along with age and baseline clinical impairment, presence of early ischemic changes involving cortical areas has a role in clinical outcome in patients with large ischemic core undergoing MT. DATA ACCESS STATEMENT: The data that support the findings of this study are available upon reasonable request.

A microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis.

Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.

Primary headaches prevalence, characteristics, and healthcare utilization in Italian medical students.

BACKGROUND: Among university students, migraine is notably prevalent and is linked to compromised academic performance and daily functioning. Medical students are a particularly vulnerable category due to the demanding nature of their training, as they are often exposed to headache trigger factors. We therefore aimed to determine the prevalence, characteristics, and healthcare-seeking practices of primary headaches among Italian medical students. METHODS: We conducted a cross-sectional study among medical students attending the Università Cattolica del Sacro Cuore in Rome who completed a self-administered questionnaire designed following the International Classification of Headache Disorders-3 criteria. The questionnaire assessed sociodemographic and headache features, healthcare utilization, the use of symptomatic and preventive treatment, and headache trigger factors. RESULTS: Five hundred thirty-six students filled out the questionnaire. The lifetime and last-year prevalence of headache in this cohort was 76.7% (n = 411). Among the students surveyed, migraine had a prevalence of 26.9%, probable migraine of 12.9%, and tension-type headache (TTH)/probable TTH of 36.9%. Two hundred and forty-six students (59.8%) reported that their headache worsened after starting university. All students reporting headache had at least one trigger factor. In students fulfilling the criteria for migraine (n = 144), 137 (95.1%) had previously used acute non-prescription treatments, and eight concurrently used a preventive treatment. Thirty-five students fulfilling the criteria for migraine underwent a brain MRI scan (24.3%), 43 performed a neurological evaluation (29.9%), 36 received a diagnosis of migraine (25%), and 20 (13.9%) accessed the emergency room. DISCUSSION: Migraine and TTH are common among medical students in Italy despite low healthcare resource utilization. These results support the need to promote public health policies and strategies in order to reduce the disability and burden associated with primary headaches among medical students.

Movement disorders following mechanical thrombectomy resulting in ischemic lesions of the basal ganglia: An emerging clinical entity.

BACKGROUND AND PURPOSE: Post-stroke movement disorders (PMDs) following ischemic lesions of the basal ganglia (BG) are a known entity, but data regarding their incidence are lacking. Ischemic strokes secondary to proximal middle cerebral artery (MCA) occlusion treated with thrombectomy represent a model of selective damage to the BG. The aim of this study was to assess the prevalence and features of movement disorders after selective BG ischemia in patients with successfully reperfused acute ischemic stroke (AIS). METHODS: We enrolled 64 consecutive subjects with AIS due to proximal MCA occlusion treated with thrombectomy. Patients were clinically evaluated by a movement disorders specialist for PMDs onset at baseline, and after 6 and 12 months. RESULTS: None of the patients showed an identifiable movement disorder in the subacute phase of the stroke. At 6 and 12 months, respectively, 7/25 (28%) and 7/13 (53.8%) evaluated patients developed PMDs. The clinical spectrum of PMDs encompassed parkinsonism, dystonia and chorea, either isolated or combined. In most patients, symptoms were contralateral to the lesion, although a subset of patients presented with bilateral involvement and prominent axial signs. CONCLUSION: Post-stroke movement disorders are not uncommon in long-term follow-up of successfully reperfused AIS. Follow-up conducted by a multidisciplinary team is strongly advisable in patients with selective lesions of the BG after AIS, even if asymptomatic at discharge.

Hospital admissions from the emergency department of adult patients affected by myopathies.

BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

A novel risk score predicting 30-day hospital re-admission of patients with acute stroke by machine learning model.

BACKGROUND: The 30-day hospital re-admission rate is a quality measure of hospital care to monitor the efficiency of the healthcare system. The hospital re-admission of acute stroke (AS) patients is often associated with higher mortality rates, greater levels of disability and increased healthcare costs. The aim of our study was to identify predictors of unplanned 30-day hospital re-admissions after discharge of AS patients and define an early re-admission risk score (RRS). METHODS: This observational, retrospective study was performed on AS patients who were discharged between 2014 and 2019. Early re-admission predictors were identified by machine learning models. The performances of these models were assessed by receiver operating characteristic curve analysis. RESULTS: Of 7599 patients with AS, 3699 patients met the inclusion criteria, and 304 patients (8.22%) were re-admitted within 30 days from discharge. After identifying the predictors of early re-admission by logistic regression analysis, RRS was obtained and consisted of seven variables: hemoglobin level, atrial fibrillation, brain hemorrhage, discharge home, chronic obstructive pulmonary disease, one and more than one hospitalization in the previous year. The cohort of patients was then stratified into three risk categories: low (RRS = 0-1), medium (RRS = 2-3) and high (RRS >3) with re-admission rates of 5%, 8% and 14%, respectively. CONCLUSIONS: The identification of risk factors for early re-admission after AS and the elaboration of a score to stratify at discharge time the risk of re-admission can provide a tool for clinicians to plan a personalized follow-up and contain healthcare costs.

Differential profiles of serum cytokines in Parkinson's disease according to disease duration.

OBJECTIVE: Neurodegeneration and neuroinflammation are two intertwined mechanisms contributing to the pathophysiology of Parkinson's disease. Whether circulating biomarkers reflecting those two processes differ according to disease duration remains to be established. The present study was conducted to characterize the biomarkers individuals with PD with short (≤5 years) or long disease duration (>5 years). METHODS: We consecutively enrolled 104 patients with Parkinson's disease and evaluated them using validated clinical scales (MDS-UPDRS, Hoehn and Yahr staging, MMSE). Serum samples were assayed for the following biomarkers: neurofilament light chain (NfL), brain-derived neurotrophic factor (BDNF), interleukin (IL-) 1ß, 4, 5, 6, 10, 17, interferon-γ, and tumor necrosis factor α. RESULTS: Mean age of participants was 66.0 ± 9.6 years and 45 (34%) were women. The average disease duration was 8 ± 5 years (range 1 to 19 years). Patients with short disease duration (≤ 5 years) showed a pro-inflammatory profile, with significantly higher levels of pro-inflammatory IL-1ß and lower concentrations of IL-5, IL-10 and IL-17 (p < 0.05). NfL serum levels showed a positive correlation with disease duration and age (respectively rho = 0.248, p = 0.014 and rho = 0.559, p < 0.001) while an opposite pattern was detected for BDNF (respectively rho -0,187, p = 0.034 and rho = -0.245, p = 0.014). CONCLUSIONS: Our findings suggest that a pro-inflammatory status may be observed in PD patients in the early phases of the disease, independently from age.

Long-term safety and efficacy of frameless subthalamic deep brain stimulation in Parkinson's disease.

BACKGROUND: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is standard of care for Parkinson's disease (PD) patients and a correct lead placement is crucial to obtain good clinical outcomes. Evidence demonstrating the targeting accuracy of the frameless technique for DBS, along with the advantages for patients and clinicians, is solid, while data reporting long-term clinical outcomes for PD patients are still lacking. OBJECTIVES: The study aims to assess the clinical safety and efficacy of frameless bilateral STN-DBS in PD patients at 5 years from surgery. METHODS: Consecutive PD patients undergoing bilateral STN-DBS with a frameless system were included in this single-center retrospective study. Clinical features, including the Unified Parkinson's Disease Rating Scale (UPDRS) in its total motor score and axial sub-scores, and pharmacological regimen were assessed at baseline, 1 year, 3 years, and 5 years after surgery. The adverse events related to the procedure, stimulation, or the presence of the hardware were systematically collected. RESULTS: Forty-one PD patients undergone bilateral STN-DBS implantation were included in the study and fifteen patients already completed the 5-year observation. No complications occurred during surgery and the perioperative phase, and no unexpected serious adverse event occurred during the entire follow-up period. At 5 years from surgery, there was a sustained motor efficacy of STN stimulation: STN-DBS significantly improved the off-stim UPDRS III score at 5 years by 37.6% (P < 0.001), while the dopaminergic medications remained significantly reduced compared to baseline (- 21.6% versus baseline LEDD; P = 0.036). CONCLUSIONS: Our data support the use of the frameless system for STN-DBS in PD patients, as a safe and well-tolerated technique, with long-term clinical benefits and persistent motor efficacy at 5 years from the surgery.

A multiple hits hypothesis for memory dysfunction in Parkinson disease.

Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of α-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.

Neuroplasticity in levodopa-induced dyskinesias: An overview on pathophysiology and therapeutic targets.

Levodopa-induced dyskinesias (LIDs) are a common complication in patients with Parkinson's disease (PD). A complex cascade of electrophysiological and molecular events that induce aberrant plasticity in the cortico-basal ganglia system plays a key role in the pathophysiology of LIDs. In the striatum, multiple neurotransmitters regulate the different forms of physiological synaptic plasticity to provide it in a bidirectional and Hebbian manner. In PD, impairment of both long-term potentiation (LTP) and long-term depression (LTD) progresses with disease and dopaminergic denervation of striatum. The altered balance between LTP and LTD processes leads to unidirectional changes in plasticity that cause network dysregulation and the development of involuntary movements. These alterations have been documented, in both experimental models and PD patients, not only in deep brain structures but also at motor cortex. Invasive and non-invasive neuromodulation treatments, as deep brain stimulation, transcranial magnetic stimulation, or transcranial direct current stimulation, may provide strategies to modulate the aberrant plasticity in the cortico-basal ganglia network of patients affected by LIDs, thus restoring normal neurophysiological functioning and treating dyskinesias. In this review, we discuss the evidence for neuroplasticity impairment in experimental PD models and in patients affected by LIDs, and potential neuromodulation strategies that may modulate aberrant plasticity.

Predictors of parenchymal hematoma and clinical outcome after mechanical thrombectomy in patients with large ischemic core due to large vessel occlusion: a retrospective multicenter study.

BACKGROUND: The aim of our study was to find predictors of parenchymal hematoma (PH) and clinical outcome after mechanical thrombectomy (MT) in patients with large vessel occlusion (LVO) and baseline large infarct. METHODS: The databases of 16 stroke centers were retrospectively screened for patients with anterior circulation LVO and baseline Alberta Stroke Program Early CT Score (ASPECTS) ≤5 that received MT. Procedural parameters, including the number of passes during first and second technique of MT, were recorded. Outcome measures were occurrence of PH type 2 and any type of PH after MT, and the 90-day modified Rankin Scale (mRS) score of 0-3 and 0-2. RESULTS: In total, 408 patients were available for analysis. A higher number of passes in the second technique was predictive of PH type 2 (odds ratio (OR) - 3.204, 95% confidence interval (CI) 1.140 to 9.005), whereas procedure conducted under general anesthesia was associated with lower risk (OR 0.127, 95% CI 0.002 to 0.808). The modified thrombolysis in cerebral infarction grade 2c-3 was associated with the mRS score 0-3 (OR 3.373, 95% CI 1.891 to 6.017), whereas occurrence of PH type 2 was predictive of unfavorable outcome (OR 0.221, 95% CI 0.063 to 0.773). Similar results were found for the mRS score 0-2 outcome measure. CONCLUSION: In patients with large ischemic core, a higher number of passes during MT and procedure not conducted under general anesthesia are associated with increased rate of PH type 2, that negatively impact the clinical outcome. Our data outline a delicate balance between the need of a complete recanalization and the risk of PH following MT.

Effects of deep brain stimulation of the subthalamic nucleus on patients with Parkinson's disease: a machine-learning voice analysis.

Introduction: Deep brain stimulation of the subthalamic nucleus (STN-DBS) can exert relevant effects on the voice of patients with Parkinson's disease (PD). In this study, we used artificial intelligence to objectively analyze the voices of PD patients with STN-DBS. Materials and methods: In a cross-sectional study, we enrolled 108 controls and 101 patients with PD. The cohort of PD was divided into two groups: the first group included 50 patients with STN-DBS, and the second group included 51 patients receiving the best medical treatment. The voices were clinically evaluated using the Unified Parkinson's Disease Rating Scale part-III subitem for voice (UPDRS-III-v). We recorded and then analyzed voices using specific machine-learning algorithms. The likelihood ratio (LR) was also calculated as an objective measure for clinical-instrumental correlations. Results: Clinically, voice impairment was greater in STN-DBS patients than in those who received oral treatment. Using machine learning, we objectively and accurately distinguished between the voices of STN-DBS patients and those under oral treatments. We also found significant clinical-instrumental correlations since the greater the LRs, the higher the UPDRS-III-v scores. Discussion: STN-DBS deteriorates speech in patients with PD, as objectively demonstrated by machine-learning voice analysis.

Cerebrospinal fluid neurofilament light chain and total-tau as biomarkers of neurodegeneration in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: CSF Neurofilament light chain(NfL) is a promising biomarker of neurodegeneration, but its utility in discriminating between Alzheimer's disease(AD) and frontotemporal dementia(FTD) is limited. METHODS: 105 patients with clinical-biological diagnosis of mild cognitive impairment(MCI) due to AD (N = 72) or clinical diagnosis of FTD (N = 33) underwent neuropsychological assessment and CSF Aß42/40, p-tau181, total-tau and NfL quantification. Group comparisons, correlations between continuous variables and ROC curve analysis were carried out to assess NfL role in discriminating between MCI due to AD and FTD, exploring the associations between NfL, ATN biomarkers and neuropsychological measures. RESULTS: NfL levels were significantly lower in the AD group, while levels of total-tau were higher. In the FTD group, significant correlations were found between NfL, p-tau181 and total-tau, and between NfL and cognitive performances. In the AD group, NfL levels were directly correlated with total-tau and p-tau181; Aß42/40 ratio was inversely correlated with total-tau and p-tau181, but not with NfL. Moreover, p-tau181 and t-tau levels were found to be associated with episodic memory and lexical-semantic impairment. Total-tau/NfL ratio differentiated prodromal-AD from FTD with an AUC of 0.951, higher than the individual measures. DISCUSSION & CONCLUSIONS: The results support that NfL and total-tau levels reflect distinct pathophysiological neurodegeneration mechanisms, independent and dependent of Aß pathology, respectively, Combining them may enhance both markers reliability, their ratio showing high accuracy in distinguishing MCI due to AD from FTD. Moreover, our results revealed associations between NfL and disease severity in FTD and between tauopathy and episodic memory and lexical-semantic impairment in prodromal-AD.

Neuropsychological predictors of conversion from mild cognitive impairment to dementia at different timepoints.

INTRODUCTION: Impairment of episodic memory is largely considered the main cognitive marker of prodromic Alzheimer's disease (AD). Nevertheless, the neuropathological process in AD starts several years before and, apart from biomarkers well defined in the Amyloid (A), Tauopathy (T), Neurodegeneration (N) framework, early clinical and neuropsychological markers able to detect mild cognitive impairment (MCI) due to AD before the appearance of memory disorders are lacking in clinical practice. Investigations on semantic memory have shown promising results in providing an earlier marker of dementia in MCI patients. METHODS: A total of 253 MCI subjects were followed up every 6 months for 6 years-186 converted to dementia and 67 remained stable at the sixth year of follow-up. Twenty-seven patients progressed in the first 2 years (fast converters), 107 in the third to fourth year (intermediate converters), and 51 after the fourth year of follow-up (slow converters). RESULTS: Stable MCI subjects performed better than fast decliners in Mini-Mental State Examination (MMSE), several long-term memory scores, and category verbal fluency test (CFT); stable and intermediate converters differ only in MMSE and CFT tests; and stable and slow converters differ only in MMSE and phonological/semantic discrepancy score. CONCLUSION: Early impairment of semantic memory could predict the evolution to AD before the onset of episodic memory disorders, and the discrepancy between phonological and semantic verbal fluency could be able to detect this impairment in advance in respect of simple CFT tests. The assessment of different aspects of semantic memory and its degradation could represent an early cognitive marker to intercept MCI due to AD in clinical practice.

Intensive exercise ameliorates motor and cognitive symptoms in experimental Parkinson's disease restoring striatal synaptic plasticity.

Intensive physical activity improves motor functions in patients with Parkinson's disease (PD) at early stages. However, the mechanisms underlying the beneficial effects of exercise on PD-associated neuronal alterations have not been fully clarified yet. Here, we tested the hypothesis that an intensive treadmill training program rescues alterations in striatal plasticity and early motor and cognitive deficits in rats receiving an intrastriatal injection of alpha-synuclein (α-syn) preformed fibrils. Improved motor control and visuospatial learning in active animals were associated with a recovery of dendritic spine density alterations and a lasting rescue of a physiological corticostriatal long-term potentiation (LTP). Pharmacological analyses of LTP show that modulations of N-methyl-d-aspartate receptors bearing GluN2B subunits and tropomyosin receptor kinase B, the main brain-derived neurotrophic factor receptor, are involved in these beneficial effects. We demonstrate that intensive exercise training has effects on the early plastic alterations induced by α-syn aggregates and reduces the spread of toxic α-syn species to other vulnerable brain areas.

Perturbation of serine enantiomers homeostasis in the striatum of MPTP-lesioned monkeys and mice reflects the extent of dopaminergic midbrain degeneration.

Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.

Basal ganglia ischaemic infarction after thrombectomy: cognitive impairment at acute stage.

BACKGROUND AND PURPOSE: After successful mechanical thrombectomy for middle cerebral artery occlusion, basal ganglia infarction is commonly detectable. Whilst the functional outcome of these patients is often good, less knowledge is available about the cognitive outcome. The aim of our study was to assess the presence of cognitive impairment within 1 week after thrombectomy. METHODS: In all, 43 subjects underwent a general cognitive assessment using the Montreal Cognitive Assessment and an extensive battery of tests. Patients were classified as cognitively impaired (CImp) or not (noCImp) according to a Montreal Cognitive Assessment score below 18. RESULTS: Cognitively impaired and noCImp subjects did not differ either in their National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at admittance, or in their Fazekas score and Alberta Stroke Program Early Computed Tomography Score. At discharge, CImp subjects showed higher scores than noCImp subjects on NIHSS (p = 0.002) and mRS (p < 0.001). The percentage of pathological performances on each neuropsychological test in the whole sample and in CImp and noCImp patients shows a similar cognitive profile between the groups. CONCLUSIONS: Some patients who underwent thrombectomy experienced a detectable cognitive impairment that probably led to worse NIHSS and mRS. The neuropsychological profile of such cognitive impairment at the acute stage consists of wide deficits in numerous cognitive domains, suggesting that basal ganglia damage may lead to complex functional impairments.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.