Journal of Neurology

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PRISMA flow diagram ¹Search cut-off date: 15/02/2022 ²Incorrect outcomes included: a Non-modality-specific hallucinations n = 91; b Limited phenomenological information n = 30; and c Main outcome not prevalence, phenomenology or correlates n = 8.³Pertaining to or combined with other neurological disorder(s)
Prevalence of multisensory hallucinations in Parkinson's disease (n = 45 studies)
  • Wei Lin TohWei Lin Toh
  • Caitlin YollandCaitlin Yolland
  • Caroline GurvichCaroline Gurvich
  • [...]
  • Susan L. RossellSusan L. Rossell
Background Non-visual hallucinations in Parkinson’s disease (PD) can be prevalent and distressing. Most existing research has however, focused on visual hallucinations as well as related risk factors. The current study thus conducted a systematic review to collate existing evidence on non-visual hallucinations in PD, focusing on their prevalence, phenomenology, and clinical-cognitive correlates. Methods Ninety-one relevant studies were included from a systematic search across PsycINFO APA, PubMed, and Web of Science, for peer-reviewed publications in the English language, from 1970 to the present. These comprised a mix of case (30 studies; n = 56) and group design (62 studies; n = 7346) studies, divided into three somewhat overlapping collections to address our three research foci. Results Prevalence estimates for hallucinations were: auditory 1.5–72.0%, olfactory 1.6–21.0%, somatic-tactile 0.4–22.5%, gustatory 1.0–15.0%, and sensed presence 0.9–73.3%. Phenomenological inquiries revealed descriptions of vivid, consuming events replete with elaborate detail, adversely affecting PD patients in different ways. Overt experiences of multisensory hallucinations were also highly variable (0.4–80%) but exceedingly common, reported by almost half of the 45 included prevalence studies. There was some evidence for modality-specific hallucination predictors, but this was largely tentative, pending robust replication. Conclusions Marked prevalence figures coupled with phenomenological descriptions implicating distress denote that non-visual and multisensory hallucinations in PD are of clinical significance. More direct research and clinical attention need to be devoted to the study and management of such hallucinatory experiences.
 
Distribution of the modified Rankin scale score: overall and stratified by the presence of symptomatic intracranial hemorrhage. Horizontal stacked bar graphs show the distribution of modified Rankin scale scores at 90 days. Bars are labeled with proportions. SICH denotes symptomatic intracranial hemorrhage, and NO-SICH without symptomatic intracranial hemorrhage
Analysis of symptomatic intracranial hemorrhage in subgroups. The forest plot shows the effect size in the symptomatic intracranial hemorrhage (adjusted risk ratio were analyzed according to Poisson regression model and adjusted for age, serum glucose, baseline NIHSS, ASPECTS, ASITN/SIR, number of passes, balloon angioplasty, substantial reperfusion, and location of occlusion) across eight subgroups. The thresholds for age, baseline NIHSS score, ASPECTS, and onset to reperfusion time were chosen at the median. ASPECTS Alberta Stroke Program Early CT Score, CI confidence interval, ICA internal carotid artery, LAA large artery atherosclerosis, MCA-M1 or M2 first or second segment of middle cerebral artery, NIHSS denotes National Institutes of Health Stroke Scale, SICH symptomatic intracranial hemorrhage
Background The aim of this study is to investigate the association between intravenous tirofiban and symptomatic intracranial hemorrhage (SICH) in patients with acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO) receiving endovascular thrombectomy (EVT) within 24 h of time last known well (LKW). Methods Patients with AIS-LVO who were randomly assigned to receive intravenous tirofiban or placebo before EVT within 24 h of time LKW and had follow-up brain non-contrast computed tomography within 24 h after stopping tirofiban treatment were derived from “RESCUE BT”: a multicenter, randomized, placebo-controlled, double-blind trial. All eligible patients were divided into SICH and NO-SICH groups. Subgroup analyses were performed to explore for heterogeneity. Results Of 945 patients included in this cohort, there were 76 (8.0%) in the SICH group and 869 (92.0%) in the NO-SICH group. The incidence of SICH was not higher in patients receiving intravenous tirofiban compared with placebo (adjusted risk ratio (RR), 1.51; 95% confidence interval (CI), 0.97–2.36; P = 0.07). Subgroup analyses showed that age greater than 67-year-old (adjusted RR, 2.18; 95% CI 1.18–4.00), NIHSS greater than 16 (adjusted RR, 1.88; 95% CI 1.06–3.34), and cardioembolism (adjusted RR, 3.73; 95% CI 1.66–8.35) were associated with increased SICH risk. Conclusions In patients with acute large vessel occlusion stroke, intravenous tirofiban before EVT within 24 h of time from last known well is not associated with increased risk of SICH. Patients who are older, have more severe neurological deficits, or with cardioembolism are at higher risk of SICH with intravenous tirofiban. Trial registration number URL: http://www.chictr.org.cn; Unique identifier: ChiCTR-INR-17014167.
 
The current understanding of pathogenesis underlying HD and its related blood-based biochemical biomarkers
Huntington’s disease is a progressive neurodegenerative disease caused by mutation of the huntingtin (HTT) gene. The identification of mutation carriers before symptom onset provides an opportunity to intervene in the early stage of the disease course. Optimal biomarkers are of great value to reflect neuropathological and clinical progression and are sensitive to potential disease-modifying treatments. Blood-based biomarkers have the merits of minimal invasiveness, low cost, easy accessibility and safety. In this review, we summarized the updated development of blood-based biomarkers for HD from six aspects, including neuronal injuries, oxidative stress, endocrine functions, immune reactions, metabolism and differentially expressed miRNAs. The blood-based biomarkers presented and discussed in this review were close to clinical applicability and might facilitate clinical design as surrogate endpoints. Exploration and validation of robust blood-based biomarkers require further standard and systemic study design in the future.
 
¹⁸F-FDG PET/CT elaboration using dedicated clinical software (CortexID Suite – GE Healthcare). The cerebellum was chosen as the reference region for intensity normalization. The table on the right reports the regional quantitative results: it shows the quantification of radiopharmaceutical uptake in the patient (left column). and its value assessed in terms of deviations from normal (Z-scores) (right column). The patient presented normal glucose cerebral metabolism (Patient number 2). The upper panel shows the 3D SSP map of FDG uptake in the specific patient (Sokoloff scale reported on the left). The lower panel is a 3D-SSP Z-score image that shows no significant deviation from normal group
¹⁸F-FDG PET/CT elaboration using dedicated clinical software (CortexID Suite – GE Healthcare). The cerebellum was chosen as the reference region for intensity normalization. The table on the right reports the quantification of radiopharmaceutical uptake. assessed in terms of deviations from normal values (Z-scores) in specific regions of interest. As shown by the table. the patient (Patient number 1) presented a hypometabolic pontine area. with a Z-score value of − 2.13 compared to healthy age-matched controls. The images panels show. from left to right. the axial. Coronal and sagiptal views; and from top to bottom PET/CT co-registration images. PET-only images and CT-only images. PET images are depicted in Sokoloff scale. The cursor (and the red arrow in the upper middle panel) points on the pontine pathologic area
¹⁸F-FDG PET/CT elaboration using dedicated clinical software (CortexID Suite – GE Healthcare). The cerebellum was chosen as the reference region for intensity normalization. The table on the right reports the quantification of radiopharmaceutical uptake. assessed in terms of deviations from normal values (Z-scores) in specific regions of interest. As shown by the table. The patient (Patient number 3) presented a significant hypometabolism in the left temporal mesial area. with a Z-score value of − 2.85. compared to healthy age-matched controls. The upper panel shows the 3D SSP map of FDG uptake in the specific patient (Sokoloff scale reported on the left). The lower panel is a 3D-SSP z-score image that shows a significant deviation from age-matched controls in the left temporal mesial area (the golden-brown area pointed by the blue arrow)
¹⁸F-amyloid PET/CT in sagittal and coronal views and PET-only scan in axial views. The slices show increased saturation and abnormal uptake in the superior and middle frontal cortex. pathognomonic of Aβ plaque deposition. ¹⁸F-amyloid PET/CT and PET-only scan in sagittal views. The slice shows intensity of the uptakes in the posterior cingulate. As shown on the left column in each panel. the images are presented in Rainbow scale and are adjusted according to the guidelines of.¹⁸F-flutemetamol PET/TC review (e.g., the color scale to set the pons to approximately 90% maximum intensity)
Emerging evidence indicates that the etiologic agent responsible for coronavirus disease 2019 (COVID-19), can cause neurological complications. COVID-19 may induce cognitive impairment through multiple mechanisms. The aim of the present study was to describe the possible neuropsychological and metabolic neuroimaging consequences of COVID-19 12 months after patients’ hospital discharge. We retrospectively recruited 7 patients (age [mean ± SD] = 56 years ± 12.39, 4 men) who had been hospitalized for COVID-19 with persistent neuropsychological deficits 12 months after hospital discharge. All patients underwent cognitive assessment and brain (¹⁸F-FDG) PET/CT, and one also underwent ¹⁸F-amyloid PET/CT. Of the seven patients studied, four had normal glucose metabolism in the brain. Three patients showed various brain hypometabolism patterns: (1) unilateral left temporal mesial area hypometabolism; (2) pontine involvement; and (3) bilateral prefrontal area abnormalities with asymmetric parietal impairment. The patient who showed the most widespread glucose hypometabolism in the brain underwent an ¹⁸F-amyloid PET/CT to assess the presence of Aβ plaques. This examination showed significant Aβ deposition in the superior and middle frontal cortex, and in the posterior cingulate cortex extending mildly in the rostral and caudal anterior cingulate areas. Although some other reports have already suggested that brain hypometabolism may be associated with cognitive impairment at shorter intervals from SarsCov-2 infection, our study is the first to assess cognitive functions, brain metabolic activity and in a patient also amyloid PET one year after COVID-19, demonstrating that cerebral effects of COVID-19 can largely outlast the acute phase of the disease and even be followed by amyloid deposition.
 
Metabolic impact of N2O on cobalamin pathways. Vitamin B12 is the cofactor of two enzymes: the methionine synthase with the methylcobalamin form; and the methylmalonyl-CoA mutase (MMA-CoA mutase) with the adenosylcobalamin form. Cobalamin-dependent methionine synthase (cytosol) is a known target of N2O. Direct impact of N2O on methylmalonyl-CoA mutase (mitochondria) is still debatable
Functional biological markers variation according to N20 consumption. A Plasma homocysteine (µmol/L) according to nitrous oxide consumption. B Plasma methylmalonic acid (µmol/L) according to nitrous oxide consumption. p value is obtained by t test. No: vitamin B12 deficiency without consumption of N20, Yes: consumption of N20. Data are expressed as median ± IQR. Plasma homocysteine increase is defined as > 15 µmol/L. Plasma MMA increase is defined as > 0.4 µmol/L. Serum total vitamin B12 deficiency is defined as < 148 pmol/L
Plasma MMA, homocysteine, and vitamin B12 according to the quantitative consumption of N2O. A Serum vitamin B12 (ng/mL) according to nitrous oxide consumption. B Plasma homocysteine (µmol/L) according to nitrous oxide consumption. C Plasma MMA (µmol/L) according to nitrous oxide consumption. Groups are based on weekly N2O consumption—level 1: one-time use; level 2: 1 to 300 whippits; level 3: 300 to 3000 whippits; level 4: more than 3000 whippits a week. p value and rho were obtained by non-parametric Spearman rank test. Data are expressed as median ± IQR. Plasma homocysteine increase is defined as > 15 µmol/L. Plasma MMA increase is defined as > 0.4 µmol/L. Serum total vitamin B12 deficiency is defined as < 148 pmol/L
Plasma MMA, HCYS, and B12 according to clinical severity of N2O abuse. A Serum vitamin B12 (ng/mL) according to clinical severity. B Plasma homocysteine (µmol/L) according to clinical severity. C Plasma MMA (µmol/L) according to clinical severity. Groups are based on the severity of their clinical symptoms (based on Peripheral Neuropathy Disability (PND) score—level 1: paresthesia or PND I; level 2: gait disorders or PND II; level 3: thrombosis or combined subacute degeneration of spinal cord or PND III or IV. p value and rho were obtained by non-parametric spearman rank test. Data are expressed as median ± IQR. Plasma homocysteine increase is defined as > 15 µmol/L. Plasma MMA increase is defined as > 0.4 µmol/L. Serum total vitamin B12 deficiency is defined as < 148 pmol/L
Background Recreational use of nitrous oxide (N2O) leads to neurological disorders including combined subacute degeneration of spinal cord, psychological disorders, and thrombosis. Serum or urine N2O assays could not be routinely performed. Hence, it is necessary to investigate other biological markers such as metabolic markers. We aimed here to challenge the three main biological markers used for the diagnosis of nitrous oxide abuse as total vitamin B12, homocysteine, and methylmalonic acid.Methods We retrospectively collected clinical and biological data from 52 patients with known, documented chronic N2O abuse and associated clinical signs (peripheral neuropathy disability score or thrombosis event). Sera and plasma total vitamin B12, methylmalonic acid (MMA), and homocysteine were performed to identify the most specific marker of chronic N2O intoxication and related clinical outcomes.ResultsPlasma homocysteine was almost consistently increased in case of N2O chronic consumption, whereas MMA increase and total vitamin B12 decrease are not systematically found. Our results showed that none of the markers are correlated with levels of N2O consumptions. However, homocysteine and MMA are correlated with clinical severity, but MMA seems to be a better marker of clinical severity.Conclusion There is no specific marker of nitrous oxide abuse according to levels of consumption, total vitamin B12 decrease could not be used either as consumption or as severity marker. However, we showed that homocysteine is consistently increased and could be used as marker of recent N2O consumption. On the other hand, we showed that MMA could be used as a marker of clinical gravity.
 
Atypical parkinsonian syndromes are neurodegenerative conditions, characterised by rapid disease progression and shorter life expectancy compared to idiopathic Parkinson’s disease. These conditions inflict substantial physical and psychosocial burden on patients and their families; hence, there is a clear rationale for a palliative care approach from diagnosis. An interdisciplinary care model has been shown to improve symptom burden, quality of life and engagement with advance care planning, in a heterogeneous group of neurodegenerative conditions. In this update, we summarise how the landscape for treating these patients has changed and the questions that still need to be resolved.
 
Representative recordings of torsional eye motion during head oscillation in the roll plane in progressive supranuclear palsy (PSP), Parkinson’s disease (PD), multiple system atrophy (MSA), and normal control
Comparison of the amplitude of torsional quick phases of eye movements during torsional vestibulo-ocular reflex (VOR) and visually enhanced VOR (VVOR) among the patients with progressive supranuclear palsy (PSP), Parkinson’s disease (PD), and multiple system atrophy (MSA), and normal controls
Comparison of the gain of the torsional vestibulo-ocular reflex (VOR) and visually enhanced VOR (VVOR) among the patients with progressive supranuclear palsy (PSP), Parkinson’s disease (PD), and multiple system atrophy (MSA), and normal controls
Background and objectivesEven though impaired horizontal and vertical saccades are well-known features of progressive supranuclear palsy (PSP), abnormalities of torsional quick phases of eye movements have not been defined in PSP and other Parkinsonian syndromes. This study aims to determine the diagnostic value of decreased torsional quick phases during head oscillations in the roll plane in patients with PSP.Methods Using video-oculography, we recorded the head and eye motion during passive head oscillations in the roll plane and determined the decrease of torsional quick phases in patients with PSP (n = 13) in comparison to normal controls (n = 13) and those with multiple system atrophy (MSA, n = 17) or idiopathic Parkinson’s disease (PD, n = 6).ResultsTorsional quick phases were absent during the torsional vestibulo-ocular reflex (VOR) in 78.6% (11/13) of the patients with PSP, but only in 11.8% (2/17) of those with MSA and none with idiopathic PD or of normal controls (Chi-square tests, p < 0.001) while gains of the torsional VOR did not differ among the groups (Chi-square tests, p > 0.05). Furthermore, the torsional quick phases were smaller even when observed in patients with PSP. Conclusion Loss of torsional quick phases is an early biological marker for diagnosis of PSP, and may be ascribed to degeneration of the rostral interstitial nucleus of the medial longitudinal fasciculus that contains the burst neurons for torsional as well as vertical saccades.
 
Classification for different types of physical activity. The diagram displays the classification for each subtype of physical activity
PRISMA flowchart for systematic review and meta-analysis. Flowchart of the literature search according to Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA). ALS amyotrophic lateral sclerosis
Forest plot of the risk in ALS with PA. The forest plot displays meta-analysis results on the risk in ALS with different types of PA compared with controls. OR odds ratio, CI confidence intervals, ALS amyotrophic lateral sclerosis, VPA vigorous physical activity. A vigorous physical activity, B occupational-related activity, C leisure time activity, D sport-related activity, E unclassified physical activity
Forest plot of the risk in ALS who engaged in professional sports in cohort study. The forest plot displays meta-analysis pooled results on the risk in ALS who engaged in professional sports in cohort study. OR odds ratio, SMR standardized mortality rate, SIR standardized incidence rate, CI confidence intervals, ALS amyotrophic lateral sclerosis. A professional athletes (SMR), B professional athletes (SIR)
Objective Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with rapid progression and high mortality. Physical activity (PA) has been identified as a major risk factor for ALS. However, the results across studies are still controversial. We aimed to explore the association between different types of PA and ALS.Methods The PubMed, EMBASE, Cochrane and Web of Science databases were systematically searched for case–control and cohort studies which explored the relationship between PA and ALS from inception to October 2022. The data were analyzed to generate a pooled effect and 95% confidence interval (CI).ResultsA total of 16,686 articles were included in the systematic search. After filtering, 28 studies from online database and 6 studies from references of relevant articles remained in the analysis. Individuals with a history of vigorous physical activity (OR 1.26, 95% CI 1.06–1.49), occupational-related activity (OR 1.14, 95% CI 1.04–1.25), leisure time activity (OR 1.08, 95% CI 1.04–1.12), unclassified PA (OR 1.05 95% CI 1.02–1.09) and professional athletes (SMR 5.23, 95% CI 2.67–10.25; SIR 2.54, 95% CI 1.37–4.69) were in higher risk of developing ALS. In contrast, sport-related activity (OR 0.97, 95% CI 0.76–1.26) was not associated with ALS.Conclusions Vigorous physical activity, occupational-related activity, leisure time activity, unclassified PA and professional athletes were associated with a higher risk of ALS, while sport-related activity showed no association with ALS. Our findings clarified the relation between different types of PA and ALS and provided some practicable advice for the lifestyle of high-risk populations.
 
Graphic representation of the improvement of the Burke-Fahn-Marsden Dystonia Rating Scale (BMF) [total score (top, left); motor score (top, right); disability score (bottom, left)] and Eq-5d score (bottom, right) in individual patients during the follow-up period, as assessed at 6, 12, and 24 months (24 months not available for pts 6 and 9)
Graphic representation of the mean improvement of the Burke-Fahn-Marsden Dystonia Rating Scale [total score; motor score; disability score] and Eq-5d score
continued)
Summary of the stimulation settings of patients included in the study, at their last available appointment
Background Deep brain stimulation (DBS) is an established treatment for dystonia and tremor. However, there is no consensus about the best surgical targeting strategy in patients with concomitant tremor and dystonia. Both the thalamic ventral intermediate nucleus (VIM) and the globus pallidus pars interna (GPi) have been proposed as targets. Few cases using them together in a double-target approach have also been reported. Methods We reviewed the literature on this topic, summarizing results of different target choices. Additionally, we retrospectively report a case series of nine patients with sporadic dystonia and severe tremor treated with a double-target strategy at our center. Outcome measures were the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) and Eq-5d scale. Results In published studies of patients with dystonia and tremor, VIM-DBS is highly effective on tremor but raise some concerns about dystonia’s control, while GPi-DBS is more effective on dystonia but does not always relieve tremor. GPi + VIM-DBS shows good efficacy but is rarely reported and reserved for selected patients. In our patients, the double-target strategy obtained a significant and durable improvement in tremor, dystonia, and quality of life. Additionally, compared with a cohort of patients with tremor treated with VIM-DBS only, significantly lower frequency and intensity of VIM stimulation were required to control tremor. Conclusion Our findings and published evidence seem to support the double-targeting approach as a safe and effective option in selected patients with tremor-dominant dystonia. This strategy appears to provide a more extensive control of either dystonia or tremor and may have a potential for limiting stimulation-related side effects.
 
CONSORT diagram. Consolidated Standards of Reporting Trials flow diagram showing study participants screening, eligibility and inclusion
Measurement of the PVSs and ventricles areas by MRI. (A) Representative T2 axial MRI scans of PVSs in the bilateral frontal cortex and the bilateral basal ganglia of the NCs. The irregular regions within the closed yellow contour represent the frontal cortex or bilateral basal ganglia. The irregular red regions represent the PVSs. Representative T2 axial MRI scans of the bilateral lateral ventricle of the NCs. The irregular blue regions represent the bilateral lateral ventricles. The irregular regions within the closed yellow contour represent the total brain area at the level of the lateral ventricle. Representative images of the fourth ventricle of the NCs. The irregular blue regions represent the fourth ventricle. The irregular regions within the closed yellow contour represent the total cerebellum area at the level of the fourth ventricle. Scale bar, 20 mm. (B) Representative T2 axial MRI scans of PVSs in the bilateral frontal cortex and the bilateral basal ganglia, and the bilateral lateral ventricle and the fourth ventricle of the OSA. Scale bar, 20 mm. (C) Comparison of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles between the NCs (n = 28) and OSA (n = 31) groups (Mann–Whitney U-test). (D) ROC curves of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles for distinguishing OSA (n = 31) from NCs (n = 28). (E) Comparison of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles between the mild-moderate OSA (n = 17) and severe OSA (n = 11) groups (Mann–Whitney U-test). (F) ROC curves of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles for distinguishing severe OSA (n = 11) from mild-moderate OSA (n = 17). (G) Comparison of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles between the OSA with mild hypoxemia (n = 18) and OSA with severe hypoxemia (n = 10) groups (Mann–Whitney U-test). (H) ROC curves of the relative area ratios of the bilateral frontal cortex, basal ganglia, lateral ventricle and the fourth ventricles for distinguishing OSA with severe hypoxemia (n = 10) from OSA with mild hypoxemia (n = 18)
Measurement of fluid flow of PVSs by DCE-MRI. (A) K-means cluster outcome of all CTCs in the bilateral frontal cortex of the NCs (n = 236) and before-CPAP-treatment OSA (n = 253) groups. The red drops represent type I CTCs. The blue triangles represent type II CTCs. (B) Average CTCs based on the cluster analysis of totaling 489 CTCs from the NCs (n = 236) and before-CPAP-treatment OSA (n = 253) groups. (C) The proportions of the type I and type II CTCs in NCs (n = 236) and before-CPAP-treatment OSA (n = 253) groups. (D) The numbers of type I CTCs for each subject of NCs (n = 236) and before-CPAP-treatment OSA (n = 253) groups. (E) The average CTCs of the NCs and before-CPAP-treatment OSA groups. (F) ROC curves of peak concentration values wash-in rate values, and wash-out rate values of all CTCs in frontal cortex for distinguishing type II CTCs (n = 314) from type I CTCs (n = 175). (G) Comparison of peak concentration values wash-in rate values, and wash-out rate values of the type I CTCs in the frontal cortex between NCs (n = 70) and before-CPAP-treatment OSA (n = 105) groups (Mann–Whitney U-test). (H) Comparison of peak concentration values, wash-in rate values, and wash-out rate values of the type II CTCs in the frontal cortex between NCs (n = 166) and before-CPAP-treatment OSA (n = 148) groups (Mann–Whitney U-test). (I) K-means cluster outcome of all CTCs in the bilateral frontal cortex of the NCs (n = 236) and after-CPAP-treatment OSA (n = 253) groups. The red drops represent type I CTCs. The blue triangles represent type II CTCs. (J) Average CTCs based on the cluster analysis of totaling 489 CTCs from the NCs (n = 236) and after-CPAP-treatment OSA (n = 253) groups. (K) The proportions of the type I and type II CTCs in NCs (n = 236) and after-CPAP-treatment OSA (n = 253) groups. (L) The numbers of type I CTCs for each subject of NCs (n = 236) and after-CPAP-treatment OSA (n = 253) groups. (M) The average CTCs of the NCs and after-CPAP-treatment OSA groups. (N) ROC curves of peak concentration values wash-in rate values, and wash-out rate values of all CTCs in frontal cortex for distinguishing type II CTCs (n = 314) from type I CTCs (n = 175). (O) Comparison of peak concentration values wash-in rate values, and wash-out rate values of the type I CTCs in the frontal cortex between NCs (n = 70) and after-CPAP-treatment OSA (n = 105) groups (Mann–Whitney U-test). (P) Comparison of peak concentration values wash-in rate values, and wash-out rate values of the type II CTCs in the frontal cortex between NCs (n = 166) and after-CPAP-treatment OSA (n = 148) groups (Mann–Whitney U-test)
Spearman correlations between imaging parameters and clinical manifestation. (A) Heatmap of Spearman correlations among morphological changes of PVSs, ventricle enlargement, the AHI, the ODI, the MMSE scores, the MoCA scores, the PSQI scores and the ESS scores. The circle size and color intensity represent the magnitude of correlation. (B) Heatmap of Spearman correlations among wash-out rate values of type I CTCs of frontal cortex, the AHI, the ODI, the MMSE scores and the MoCA scores. The circle size and color intensity represent the magnitude of correlation
Obstructive sleep apnea (OSA) is highly prevalent but easily undiagnosed and is an independent risk factor for cognitive impairment. However, it remains unclear how OSA is linked to cognitive impairment. In the present study, we found the correlation between morphological changes of perivascular spaces (PVSs) and cognitive impairment in OSA patients. Moreover, we developed a novel set of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) methods to evaluate the fluid dynamics of glymphatic drainage system. We found that the inflow and outflow parameters of the glymphatic drainage system in patients with OSA were obviously changed, indicating impairment of glymphatic drainage due to excessive perfusion accompanied with deficient drainage in OSA patients. Moreover, parameters of the outflow were associated with the degree of cognitive impairment, as well as the hypoxia level. In addition, continuous positive airway pressure (CPAP) enhances performance of the glymphatic drainage system after 1 month treatment in OSA patients. We proposed that ventilation improvement might be a new strategy to ameliorate the impaired drainage of glymphatic drainage system due to OSA-induced chronic intermittent hypoxia, and consequently improved the cognitive decline.
 
Background and objectiveDespite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system’s morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction.Methods196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization.ResultsCOVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group.Conclusions Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology.Graphical abstract
 
Identification of rare variants in IMPDH2 in families with dystonia. A Pedigree of the families with rare IMPDH2 variants co-segregated. Symbols are defined as follows: black symbols: individuals affected by dystonia; circles: women; squares: men; arrows: probands; slashes: deceases; m1, p.Ser508Leu; m2, c.1296-1G>T; wt, wild type; N/A: no DNA sample available. B Locations of the newly identified and previously reported IMPDH2 variants on protein level. Red: variants identified in the current study; black: variants reported by previous studies. CBS cystathionine-β-synthase
Enrichment analysis of rare variants in IMPDH2 in dystonia. All rare variants and rare damaging variants with MAF < 1% and MAF < 1‰ were analyzed separately. P values, OR, and 95% confidence intervals (CI) were calculated using Fisher’s exact test
Study objectivesRecently, IMPDH2 has been linked to dystonia. However, no replication study from other cohorts has been conducted to confirm the association. We aimed to systematically evaluate the genetic associations of IMPDH2 with dystonia in a large dystonia cohort.Methods We analyzed rare variants (minor allele frequency < 0.01) of IMPDH2 in 688 Chinese dystonia patients with whole exome sequencing. The over-representation of rare variants in patients was examined with Fisher’s exact test at allele and gene levels.ResultsFour rare variants were detected in IMPDH2 in four patients with dystonia in our cohort, including three missense variants (p.Ser508Leu, p.Ala396Thr, and p.Phe24Val) and one splice acceptor variant (c.1296-1G>T). Two of them (c.1296-1G>T and p.Ser508Leu) were co-segregated in the family co-segregation analysis and were classified as pathogenic and likely pathogenic variant according to the American College of Medical Genetics and Genomics (ACMG) guidelines, respectively. Gene burden analysis revealed enrichment of rare variants in IMPDH2 in dystonia.Conclusions Our work supplemented the evidence on the role of IMPDH2 in autosomal dominant dystonia in Chinese population, and expanded the genetic and phenotypic spectrum of IMPDH2, paving way for future studies.
 
Distribution of Hughes Functional Grading Scale. Circles indicate the values for each case. Black bars indicate average values. Hughes functional grading scale (HFGS) 4 patients were the most common in both the super-elderly and control groups. The super-elderly group contained many severe cases with grades HFGS 4 or higher overall, but the control group was polarized into severe and mild cases
Background Japan has the world’s largest super-aging population, and the number of elderly patients with various diseases is increasing. Herein, we reported the characteristics of super-elderly patients, aged over 80 years, with Guillain-Barré syndrome (GBS), a typical neuroimmune disease. Methods During the period 2019–2021, 74 patients over the age of 80 years diagnosed with GBS at Kindai university were analyzed as the super-elderly group patients. The control group comprised 74 consecutive patients aged < 79 years, under the same conditions. GBS was diagnosed using Brighton diagnostic criteria. Electrophysiology was assessed using the Ho criteria. Results The mean age was 83.5 years in the super-elderly group and 51.7 years in the control group. Prior infection was recognized in 50% of cases in the super-elderly group and 77% of cases in the control group with fewer cases in the super-elderly group. The mean number of days until peak symptom presentation was longer in the super-elderly group. The percentage who required a ventilator was significantly higher among the super-elderly group than among the control group. Hughes functional grading scale was more severe in the super-elderly group. Electrophysiological examination revealed the demyelinating form was particularly common in the super-elderly group. Intravenous immunoglobulin was the most common treatment in both the groups, with no difference in efficacy. Conclusions Super-elderly onset GBS tends to be severe, therefore it is important to diagnose and treat appropriately, even in the absence of prior episodes of infection.
 
A Auditory temporal discrimination threshold (Z-score) in healthy controls and patients with laryngeal dystonia (LD). The horizontal red line indicated the cut-off abnormal Z-scores ≥ 2.0. B Olfactory ITD (identification, threshold, discrimination) score in healthy controls and LD patients. The horizontal red line indicated the cut-off score ≤ 15 for anosmia. Boxplots show the distribution of individual Z-score A and ITD B values; each participant is represented as a dot; the bold line indicates the median of the group; the dotted line indicates the mean of the group. For the range of values, see Table 2. C The correlation plot between olfactory threshold and Burke–Fahn–Marsden dystonia rating scale (BFMDRS) scores in LD patients
Abnormal sensory discriminatory processing has been implicated as an endophenotypic marker of isolated dystonia. However, the extent of alterations across the different sensory domains and their commonality in different forms of dystonia are unclear. Based on the previous findings of abnormal temporal but not spatial discrimination in patients with laryngeal dystonia, we investigated sensory processing in the auditory and olfactory domains as potentially additional contributors to the disorder pathophysiology. We tested auditory temporal discrimination and olfactory function, including odor identification, threshold, and discrimination, in 102 laryngeal dystonia patients and 44 healthy controls, using dichotically presented pure tones and the extended Sniffin’ Sticks smell test protocol, respectively. Statistical significance was assessed using analysis of variance with non-parametric bootstrapping. Patients had a lower mean auditory temporal discrimination threshold, with abnormal values found in three patients. Hyposmia was found in 64 patients and anosmia in 2 patients. However, there were no statistically significant differences in either auditory temporal discrimination threshold or olfactory identification, threshold, and discrimination between the groups. A significant positive relationship was found between olfactory threshold and disorder severity based on the Burke–Fahn–Marsden dystonia rating scale. Our findings demonstrate that, contrary to altered visual temporal discrimination, auditory temporal discrimination and olfactory function are likely not candidate endophenotypic markers of laryngeal dystonia.
 
Study flow diagram
Distribution of stroke lesions. BG basal ganglia; PL of IC = posterior limb of internal capsule
Lesion overlay map shows the stroke lesions in 45 patients with unilateral supratentorial infarction presenting acute vestibular symptoms (A) including 14 with acute vertigo (B), 10 with isolated vestibular symptoms (C), and 5 with isolated vertigo (D) on a 2 mm brain atlas. The color scale represents the number of subjects that had a lesion in the represented area on the map. All four groups have lesions widespread across the cortex or subcortex with no clear correlation between acute vestibular symptoms and involvement of specific vestibular cortex
MRI lesions of 11 patients with unilateral stroke presenting isolated vestibular symptoms
The incidence and characteristics of acute vestibular symptoms, responsible structures, and lateralization of the causative lesions in supratentorial stroke remain unknown. This study aimed to determine the incidence, clinical features, and anatomical correlation of acute vestibular symptoms in supratentorial stroke. We performed a prospective, multicenter, observational study that had recruited patients with supratentorial stroke from the neurology clinics of referral-based four university hospitals in Korea. All patients received a constructed neuro-otological evaluations, and neuroimaging. We analyzed the incidence of acute vestibular symptoms, abnormal ocular motor and vestibular function tests, and stroke lesions. Of 1301 patients with supratentorial stroke, 48 (3.7%) presented with acute vestibular symptoms, and 13 of them (1%) had the vestibular symptoms in isolation. In patients with acute vestibular symptoms, abnormal findings included spontaneous nystagmus (5%), impaired horizontal smooth pursuit (41%), and abnormal tilt of the subjective visual vertical (SVV) (20%). Video head impulse and caloric tests were normal in all the patients. There was no clear correlation between acute vestibular symptoms and involvement of specific vestibular cortex. In patients with unilateral stroke, there was also no lateralization of the causative lesions of acute vestibular symptoms (left vs. right; 52 vs. 48%), even in patients with vertigo (left vs. right; 58 vs. 42%). This study demonstrates that the incidence of acute vestibular symptoms in supratentorial stroke is 3.7%, with being isolated in 1%. The widespread lesions responsible for acute vestibular symptoms implicate diffuse multisensory cortical–subcortical networks in the cerebral hemispheres without a lateralization.
 
a Percentage of caregivers currently employed by PD severity. b Number of hours per day caring for person with PD by PD severity. p-values for pairwise comparisons using Sidak’s method to adjust for multiple comparisons. PD Parkinson’s disease
Caregiver perceived burden by Parkinson’s disease severity
Background Caring for a partner or family member with Parkinson’s disease (PD) negatively affects the caregiver’s own physical and emotional well-being, especially those caring for people with advanced PD (APD). This study was designed to examine the impact of APD on caregiver perceived burden, quality of life (QoL), and health status. Methods Dyads of people with PD and their primary caregivers were identified from the Adelphi Parkinson’s Disease Specific Program (DSP™) using real-world data from the United States, Japan and five European countries. Questionnaires were used to capture measures of clinical burden (people with PD) and caregiver burden (caregivers). Results Data from 721 patient-caregiver dyads in seven countries were captured. Caregivers had a mean age 62.6 years, 71.6% were female, and 70.4% were a spouse. Caregivers for people with APD had a greater perceived burden, were more likely to take medication and had lower caregiver treatment satisfaction than those caring for people with early or intermediate PD; similar findings were observed for caregivers of people with intermediate versus early PD. Caregivers for people with intermediate PD were also less likely to be employed than those with early PD (25.3% vs 42.4%) and spent more time caring (6.6 vs 3.2 h/day). Conclusions This real-world study demonstrates that caregivers of people with APD experience a greater burden than those caring for people with early PD. This highlights the importance of including caregiver-centric measures in future studies, and emphasizes the need for implementing treatments that reduce caregiver burden in APD. Trial registration: N/A.
 
Flowchart illustrating the literature search strategy
Overall standardized mean difference (SMD) for each region of interest model in comparison between PSP and HCs (a), PSP and PD (b), PSP and AD (c), and PSP and CBS (d)
Objectives To evaluate the difference of tau burden between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs) or other neurodegenerative diseases using tau-positron emission tomography (PET) imaging.MethodsA systematic search on PubMed, Embase, and Web of Science databases was performed for tau-PET studies in PSP patients, up to April 1, 2022. Standardized mean differences (SMDs) of tau tracer uptake were calculated using random-effects models. Subgroup analysis based on the type of tau tracers, meta-regression, and sensitivity analysis were conducted.ResultsTwenty-seven studies comprising 553 PSP, 626 HCs, and 406 other neurodegenerative diseases were included. Compared with HCs, PSP patients showed elevated tau binding in basal ganglia, midbrain, dentate nucleus, cerebellar white matter, and frontal lobe with decreasing SMD (SMD: 0.390–1.698). Compared with Parkinson’s disease patients, increased tau binding was identified in the midbrain, basal ganglia, dentate nucleus, and frontal and parietal lobe in PSP patients with decreasing SMD (SMD: 0.503–1.853). PSP patients showed higher tau binding in the subthalamic nucleus (SMD = 1.351) and globus pallidus (SMD = 1.000), and lower binding in the cortex and parahippocampal gyrus than Alzheimer’s disease patients (SMD: − 2.976 to − 1.018). PSP patients showed higher midbrain tau binding than multiple system atrophy patients (SMD = 1.269).Conclusion Tau PET imaging indicates different topography of tau deposition between PSP patients and HCs or other neurodegenerative disorders. The affinity and selectivity of tracers for 4R-tau and the off-target binding of tracers should be considered when interpreting the results.
 
Flow-chart of the literature search and selection strategy. N, number of studies
Prevalence of Charcot–Marie–Tooth diseases and related inherited peripheral neuropathies (CMT&RIPNs) in different countries (× 10–5). The prevalence rates and the cases (in the brackets) shown in the figure were from populations involving all subtypes of CMT&RIPNs reported in the latest publication for each country. *All-age; # ≥ 18 years old; & ≥ 16 years old; ⁺Age or sex standardized
Forest plot showing the arcsine transformed prevalence of Charcot–Marie–Tooth diseases. After back transformed, the overall prevalence was 17.69/100,000 (95% CI 12.32—24.33). N’ the number of general populations, n the number of surviving CMT&RIPNs cases, CI confidence interval, DL DerSimoninan–Laird method
Sensitivity analysis of the transformed prevalence of Charcot–Marie–Tooth diseases. The prevalence was arcsine transformed and magnified by 100 times to generate the picture
Age-specific prevalence of Charcot-Marie-Tooth diseases in different studies
Background Charcot–Marie–Tooth disease and related inherited peripheral neuropathies (CMT&RIPNs) brings great suffering and heavy burden to patients, but its global prevalence rates have not been well described. Methods We searched major English and Chinese databases for studies reporting the prevalence of CMT&RIPNs from the establishment of the databases to September 26, 2022. Based on the age, gender, study design, study region, and disease subtype, the included studies were correspondingly synthesized for meta-analyses on the overall prevalence and/or the subgroup analyses by using pool arcsine transformed proportions in the random-effects model. Results Of the finally included 31 studies, 21 studied the whole age population and various types of CMT&RIPNs, and the others reported specific disease subtype(s) or adult or non-adult populations. The pooled prevalence was 17.69/100,000 (95% CI 12.32–24.33) for the whole age population and significantly higher for CMT1 [10.61/100,000 (95% CI 7.06–14.64)] than for other subtypes (P’ < 0.001). Without statistical significance, the prevalence seemed higher in those aged ≥ 16 or 18 years (21.02/100,000) than in those aged < 16 years (16.13/100,000), in males (22.50/100,000) than in females (17.95/100,000), and in Northern Europe (30.97/100,000) than in other regions. Conclusion CMT&RIPNs are relatively more prevalent as CMT1 in the disease subtypes, and probably prevalent in older ages, males, and Northern Europe. More studies on the epidemiological characteristics of CMT&RIPNs with well-defined diagnosis criteria are needed to improve the prevalence evaluation and to arouse more attention to health care support.
 
Associations of regional cortical volumes with OCT measures and with measures of disability. The effect size, expressed as standardized beta (β), is graphically displayed for each of the Desikan-Killiany atlas regions presenting significant association after multiple comparisons correction. Abbreviations: pRNFL peripapillary retinal nerve fiber layer; GCIPL ganglion cell-inner plexiform layer; INL inner nuclear layer; EDSS, Expanded Disability Status Scale; SDMT Symbol Digit Modalities Test; β standardized regression coefficient
Associations of MRI measures with OCT measures and with measures of disability. The effect size, expressed as standardized beta (β), is graphically displayed for each brain volume presenting significant association after multiple comparisons correction. Abbreviations: EDSS, Expanded Disability Status Scale; SDMT Symbol Digit Modalities Test; pRNFL peripapillary retinal nerve fiber layer; GCIPL ganglion cell-inner plexiform layer; INL inner nuclear layer; β standardized regression coefficient; GM gray matter; WM white matter
Background Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS). Objective To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS. Methods 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models. Results In PwMS, pRNFL and GCIPL were associated with the volume of whole brain ( p < 0.04), total gray matter ( p < 0.002), thalamus ( p ≤ 0.04), and cerebral cortex ( p ≤ 0.003) –both globally and regionally–, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations ( p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL. Conclusions In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis.
 
Study cohort (March 2014–April 2022). RT-QuIC real-time quaking-induced conversion, sCJD sporadic Creutzfeldt–Jakob disease, sFI sporadic fatal insomnia. aNo or insufficient clinical data for case classification available. bDefinite and probable sCJD according to WHO criteria [10, 11]. cProbable sCJD according to amended criteria based on RT-QuIC [12], not meeting previous criteria
False-positive CSF RT-QuIC fluorescence signals in control patients. A The images show fluorescence signal (relative fluorescence units, y-axis) development over time (until 80 h after test initiation, x-axis). According to our test protocol, each patient was analyzed in triplets. An example of a typical RT-QuIC reaction is shown in the upper left corner. The false-positive sample from a patient with brain sinus thrombosis is shown in the upper right corner (FP 1). Four patients with encephalitis are shown below (FP2–FP5). B The bar chart includes categories of differential (non-prion) diagnoses. Light gray: Cases without positive signal. Dark gray: Positive RT-QuIC signal in one of the three replicates. Black: Positive signal in at least two of the three replicates. aFisher’s exact test on distribution of positive (> 1/3) and negative (≤ 1/3) RT-QuIC tests among patients with and without inflammatory brain diseases. bFisher’s exact test on distribution of at least partial (> 0/3) and no (0/3) detection of PrPSc seeding activity reactions among patients with and without inflammatory brain diseases. cOne patient with false-positive RT-QuIC and inflammatory CSF and transient response to immune-therapy had also evidence for a (FUS-positive) neurodegenerative disease in biopsy
Annual incidence of sporadic CJD in Germany (2006–2021). The figure displays the development of the annual German sCJD-Incidence (black line) and the according incidence when all RT-QuIC-positive patients were considered (black dots) in cases per million person-years (left y-axis). Before 2018, the discrepancy is mostly due to application of pre-RT-QuIC criteria. Other reasons were positive RT-QuIC tests without available clinical data for case classification (in total n = 84 since 2014) and very few false-positive patients (n = 5 since 2014). In addition, the figure indicates the number of all performed CSF RT-QuIC analyses (gray line, right y-axis)
Background Evaluation of the application of CSF real-time quaking-induced conversion in Creutzfeldt–Jakob disease surveillance to investigate test accuracy, influencing factors, and associations with disease incidence. Methods In a prospective surveillance study, CSF real-time quaking-induced conversion was performed in patients with clinical suspicion of prion disease (2014–2022). Clinically or histochemically characterized patients with sporadic Creutzfeldt–Jakob disease ( n = 888) and patients with final diagnosis of non-prion disease ( n = 371) were included for accuracy and association studies. Results The overall test sensitivity for sporadic Creutzfeldt–Jakob disease was 90% and the specificity 99%. Lower sensitivity was associated with early disease stage ( p = 0.029) and longer survival ( p < 0.001). The frequency of false positives was significantly higher in patients with inflammatory CNS diseases (3.7%) than in other diagnoses (0.4%, p = 0.027). The incidence increased from 1.7 per million person-years (2006–2017) to 2.0 after the test was added to diagnostic the criteria (2018–2021). Conclusion We validated high diagnostic accuracy of CSF real-time quaking-induced conversion but identified inflammatory brain disease as a potential source of (rare) false-positive results, indicating thorough consideration of this condition in the differential diagnosis of Creutzfeldt–Jakob disease. The surveillance improved after amendment of the diagnostic criteria, whereas the incidence showed no suggestive alterations during the COVID-19 pandemic.
 
A NfL in patients with serum NfL < 60 pg/ml and controls, B in all patients and controls. Sample: Status epilepticus = SE patients from this study, Popgen = Popgen control sample measured on the same instrument concomitantly with the epilepsy samples, BiDirect, and MEMO: additional control samples measured on an identical but not the same instrument using the same Simoa kit. Blue interrupted line: NfL per age regression line for the joint control sample, gray band: standard error for the mean of the NfL per age regression line. Green interrupted lines: 95% prediction interval for the NfL per age regression, meaning that the linear model predicts that 95% of all population control samples will show NfL concentrations within these limits
NfL versus A status duration and B status onset time to LP. r Pearson correlation coefficient, p p value for the correlation
NfL in convulsive SE and NCSE according to: A ILAE classification, B alternative classification. p p value, LM linear model (equivalent to t test), LMadj linear model adjusted for status duration and status onset time to LP. Serum NfL concentrations were multiplied by the factor 60 to allow plotting them side by side with the CSF NfL concentrations
NfL in A patients who survived or died, B versus EMSE-EAC score. p p value, LM linear model (equivalent to t test), LMadj linear model adjusted for status duration and status onset time to LP. Serum NfL concentrations were multiplied by the factor 60 to allow plotting them side by side with the CSF NfL concentrations
Objective We explored the potential of neurofilament light chain (NfL) in serum and cerebrospinal fluid as a biomarker for neurodestruction in status epilepticus. Methods In a retrospective analysis, we measured NfL in serum and cerebrospinal fluid samples of patients with status epilepticus using a highly sensitive single-molecule array technique (Simoa). Status epilepticus was diagnosed according to ILAE criteria. Additionally, we employed an alternative classification with more emphasis on the course of status epilepticus. We used data from three large control groups to compare NfL in status epilepticus versus neurologically healthy controls. Results We included 28 patients (mean age: 69.4 years, SD: 15 years) with a median status duration of 44 h (IQR: 80 h). Twenty-one patients (75%) suffered from convulsive status epilepticus and seven (25%) from non-convulsive status epilepticus. Six patients died (21%). Cerebrospinal fluid and serum NfL concentrations showed a high correlation ( r = 0.73, p < 0.001, Pearson). The main determinant of NfL concentration was the status duration. NfL concentrations did not differ between convulsive status epilepticus and convulsive status epilepticus classified according to the ILAE or to the alternative classification without and with adjusting for status duration and time between status onset and sampling. We found no association of NfL concentration with death, treatment refractoriness, or prognostic scores. Conclusion The results suggest that neurodestruction in status epilepticus measured by NfL is mainly determined by status duration, not status type nor therapy refractoriness. Therefore, our results suggest that regarding neurodestruction convulsive and non-convulsive status epilepticus are both neurological emergencies of comparable urgency.
 
Heat map of 22 upregulated and 21 downregulated mRNAs in Dataset 1. Red and cyan indicate upregulation and downregulation respectively. FDR false discovery rate, AD Alzheimer’s disease
Measurements of mRNAs in Dataset 2. MTRNR2L1 (a), HBB (b), TPT1 (c), FTH1 (d), RPLP2 (e), and B2M (f) were increased in patients with AD, whereas NEMF (g), PTPRD (h), PCBD2 (i), ANKRD28 (j), ARF6 (k), and HBA2 (l) were decreased in AD. AD Alzheimer’s disease, FC fold change
Establishment of a diagnostic panel for AD. a ROC curve analysis of the six-mRNA panel (upregulated: HBB, TPT1, FTH1, RPLP2, and B2M; downregulated: PCBD2). b ROC analysis of 12 individual mRNAs. AD Alzheimer’s disease, ROC receiver operating characteristic, AUC area under the curve
Measurements of mRNAs in control, AD, VaD, PDD, bvFTD, and DLB. HBB (a), TPT1 (b), FTH1 (c), RPLP2 (d), B2M (e), and PCBD2 (f) were measured. AD Alzheimer’s disease, VaD vascular dementia, PDD Parkinson’s disease dementia, bvFTD behavioral variant frontotemporal dementia, DLB dementia with Lewy body, FC fold change
ROC curve analysis in Dataset 3. The ROCs of AD versus controls (a), AD versus other types of dementia (b), and AD versus non-AD (c), Non-AD indicates a combination of controls and other types of dementia. Other types of dementia include VaD, PDD, bvFTD, and DLB. ROC receiver operating characteristic, AD Alzheimer’s disease, VaD vascular dementia, PDD Parkinson’s disease dementia, bvFTD behavioral variant frontotemporal dementia, DLB dementia with Lewy body, AUC area under the curve. ***P < 0.001
Background Messenger RNAs (mRNAs) have been reported to be associated with Alzheimer’s disease (AD). In this study, we investigated whether plasma-based mRNAs could distinguish AD from cognitively normal controls and other types of dementia, including vascular dementia (VaD), Parkinson’s disease dementia (PDD), behavioral variant frontotemporal dementia (bvFTD), and dementia with Lewy body (DLB).Methods Plasma mRNA expression was measured in three independent datasets. Dataset 1 (n = 40; controls, 20; AD, 20) was used to identify the differentially expressed mRNAs. Dataset 2 (n = 122; controls: 60; AD: 62) was used to develop a diagnostic AD model using an mRNA panel. Furthermore, we applied the model to Dataset 3 (n = 334; control, 57; AD, 58; VaD, 55; PDD, 54; bvFTD, 55; DLB, 55) to verify its ability to identify AD and other types of dementia.ResultsDataset 1 showed 22 upregulated and 21 downregulated mRNAs. A panel of six mRNAs distinguished AD from the control group in Dataset 2. The panel was used to successfully differentiate AD from other types of dementia in Dataset 3.Conclusions An AD-specific panel of six mRNAs was created that can be used for AD diagnosis.
 
Objective Essential tremor (ET) is the second most common movement disorder; however, the pathophysiological mechanism of ET is unclear. We aimed to investigate the microstructural degeneration of gray matter (GM) and white matter (WM) and their correlations with cognition and tremor in patients with ET.Methods The participants were 63 patients with ET and 63 matched healthy controls (HCs) who underwent 3D-T1 weighted and diffusion kurtosis images (DKI). Microstructural degeneration was measured using high-level diffusion parameters derived from DKI. A voxel-wise analysis of the means of the GM-based spatial statistics and tract-based spatial statistics were conducted to assess differences in diffusion parameters between the ET and HC groups. The volume differences between the two groups were also assessed, and tremor severity and multi-domain cognitive performance were evaluated. Finally, the relationship between microstructural degeneration and clinical characteristics were assessed.ResultsThe ET group had significantly lower mean kurtosis of the temporal, parietal, and occipital lobes and the cerebellum and lower radial kurtosis in several tracts. These microstructural changes in GM and WM were correlated with tremor and cognitive scores. However, no significant difference in volume was found between the groups.Conclusion Our findings suggest that ET entails extensive GM and WM microstructural alterations, which support the neurodegenerative hypothesis of ET. Our study contributes to a better understanding of the mechanisms underlying tremor and cognitive impairment in ET.
 
There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod—a novel neonatal Fc receptor inhibitor—was well tolerated and that acetylcholine receptor antibody–positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up–only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.
 
Objectives To investigate the relationship between the initiation time of anticoagulation after endovascular treatment (EVT) and the outcomes in atrial fibrillation (AF)-related acute ischemic stroke (AIS) patients. Methods In this prospective registry study, from March 2013 to June 2022, patients with anterior circulation territories AF-related AIS who underwent EVT within 24 h were included. The primary outcome was favorable [modified Rankin Scale (mRS) 0–1) at ninety days and the secondary outcome was hemorrhage events after anticoagulants. Factors affecting the outcomes were pooled into multivariate regression and ROC curve analysis. Results Of 234 eligible patients, there were 63 (26.9%) patients achieved a favorable outcome. The symptomatic intracranial hemorrhage (sICH), ICH, and systemic hemorrhage events after anticoagulants occurred in 8 (3.4%), 28 (12.0%), and 39 (16.7%) patients, severally. A longer EVT to anticoagulation time (p = 0.033) was associated with an unfavorable outcome (mRS 3–6). An earlier EVT to anticoagulation time was the independent risk factor of sICH (p = 0.043), ICH (p = 0.005), and systemic hemorrhage (p = 0.005). There was no significant difference in recurrent AIS/ transient ischemic attack (TIA) or mortality among patients who started anticoagulation at ≤ 4 days, ≥ 15 days, or 4 to 15 days. The optimum cut-off for initiating anticoagulants to predict a favorable outcome and hemorrhage events was 4.5 days and 3.5 days after EVT, respectively. Conclusions In AF-related AIS, the time of EVT to anticoagulation is an independent factor of the functional outcome and hemorrhage events after anticoagulation. The optimal initiate time of anticoagulant after EVT is 4.5 days. ClinicalTrialRegister NCT03754738.
 
Systems-level perspective on neural connections. A network of connections between regions (either structural or functional) can be conceptualised along a continuum—segregated networks contain tight-knit communities that resemble interactions within faculties of a university, whereas integrated networks dissolve these boundaries, similar to the way that scientists and clinicians interact at academic conferences; B brain state trajectories can be conceptualised as landscapes, in which defines the energy required to move between different brain states is linked to the height/depth of the landscape
The ascending arousal system orchestrates systems-level neural activity. Through intrinsic second-messenger cascades, noradrenaline released by the locus coeruleus (middle) changes the gain of individual neurons: i.e., changes the amount that input (current) is translated into firing rate outputs (Q; left). This is analogous to the way in which a bow resonates the strings of a violin, causing changes in the timbre of the sounds emergent in the violin (right)
The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, we argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level. Specifically, we will highlight the role of the neuromodulatory arousal system, which is uniquely positioned to coordinate the brain’s ability to flexibly integrate the otherwise segregated structures required to support higher cognitive functions. Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer’s and Parkinson’s disease. We will review studies that implicate the dysfunctional interactions amongst distributed brain regions as a side-effect of pathological involvement of the neuromodulatory arousal system in these neurodegenerative disorders. From this perspective, we will argue that future work in clinical neuroscience should attempt to consider the inherent complexity in the brain and employ analytic techniques that do not solely focus on regional functional impairments, but rather captures the brain as an inherently dynamic, distributed, multi-scale system. Through this lens, we hope that we will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.
 
Objectives To evaluate the effects of rituximab treatment on innate immune cell activation in primary progressive multiple sclerosis (PPMS).MethodsA 48-year-old woman with PPMS was started on rituximab shortly after diagnosis. [11C]PK11195 PET imaging was employed to assess innate immune cell activation with special interest in the white matter around chronic lesions. PET, MRI, and disability measurements were performed at baseline and after 18 months of rituximab treatment. Specific binding of [11C]PK11195 was quantified using mean distribution volume ratios (DVRs), and at voxel-level based on proportions of active voxels.ResultsThe PPMS patient had higher PK11195 DVRs and higher proportions of active voxels in the thalamus and the normal appearing white matter compared to the healthy control group. The thalamic and perilesional white matter DVRs and the proportions of active voxels decreased after rituximab treatment. The patient remained clinically stable during the 5-years follow-up.Conclusions This case suggests that while a degree of smoldering activity persists, high efficacy B-cell-targeting therapy may contribute to reduced innate immune cell activation in PPMS brain areas relevant for disease progression. This case supports the therapeutic concept that controlling smoldering brain inflammation is beneficial for slowing down progression independent of relapses.
 
The main central nervous system pathways implicated in gait and balance alterations in the major neurodegenerative disorders. CD cerebrovascular disease, CC corpus callosum, CST corticospinal tract, FWM frontal white matter, iNPH idiopathic normal pressure hydrocephalus, MS multiple sclerosis, MSA-C multiple system atrophy cerebellar type, MSA-P multiple system atrophy parkinsonian type, PD Parkinson’s disease, PSP progressive supranuclear palsy, WM white matter
Gait and balance disorders are common signs in several neurodegenerative diseases such as Parkinson’s disease, atypical parkinsonism, idiopathic normal pressure hydrocephalus, cerebrovascular disease, dementing disorders and multiple sclerosis. According to each condition, patients present with different gait and balance alterations depending on the structural and functional brain changes through the disease course. In this review, we will summarize the main clinical characteristics of gait and balance disorders in the major neurodegenerative conditions, providing an overview of the significant structural and functional MRI brain alterations underlying these deficits. We also will discuss the role of neurorehabilitation strategies in promoting brain plasticity and gait/balance improvements in these patients.
 
Flowcharts of participants selection
Heterogeneous associations between apathy and incident AD in cognitively unimpaired men and women
Heterogeneous associations between depression and incident AD in cognitively unimpaired men and women
Heterogeneous associations between agitation and incident AD in cognitively unimpaired men and women
Objective To examine whether associations between individual neuropsychiatric symptoms (NPS) and incident Alzheimer’s dementia (AD) differ in men versus women. Methods Data were acquired from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. Two sets of older (≥ 60 years) participants were formed: one of cognitively unimpaired (CU) individuals, and one of participants with mild cognitive impairment (MCI). NPS were assessed using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models examined associations between individual NPS and AD incidence separately for each participant set. These models featured individual NPS, sex, NPS by sex interactions as well as a number of covariates. Results The analysis involved 9,854 CU individuals followed for 5.5 ± 3.8 years and 6,369 participants with MCI followed for 3.8 ± 3.0 years. NPS were comparably associated with future AD in men and women with MCI. Regarding CU participants, the following significant sex by NPS interactions were noted: female sex moderated the risk conferred by moderate/severe apathy (HR = 7.36, 3.25–16.64) by 74%, mitigated the risk conferred by moderate/severe depression (HR = 3.61, 2.08–6.28) by 52%, and augmented the risks conferred by mild depression (HR = 1.00, 0.60–1.68) and agitation (HR = 0.81, 0.40–1.64) by 83% and 243%, respectively. Conclusions Apathy, depression and agitation were differentially associated with incident AD in CU men and women. No individual NPS was associated with different risks of future AD in men versus women with MCI.
 
z-scores of hippocampal subfield volumes, hippocampal head–body–tail segmentation volumes and entorhinal–parahippocampal gyrus cortical thickness; *p value < 0.05; **p value < 0.01; ***p value < 0.001
Introduction Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer’s disease (AD). Typical amnestic AD is characterized by early selective hippocampal atrophy. The profile of hippocampal atrophy in AD patients presenting as CBS (CBS-AD), compared to CBS patients of non-AD pathologies (CBS-nAD) and amnestic AD patients, has not been studied. Objectives To compare hippocampal subfield atrophy patterns between CBS-AD, CBS-nAD, typical amnestic AD patients, and control subjects. Methods Automated hippocampal subfield volumetry was performed via the hippocampal subfield segmentation pipeline of Freesurfer 6.0 on 3D T1-weighted images. CBS patients were classified as CBS-AD or CBS-nAD based on CSF AD biomarkers by applying the AT(N) classification system. Mean volumes of nine hippocampal subfields, head–body–tail segments, total hippocampus, and entorhinal and parahippocampal gyrus cortical thickness were measured. Results Eighty-three subjects were included (CBS-AD: n = 14; CBS-nAD: n = 17; amnestic AD: n = 29; controls: n = 23). CBS-AD patients had greater whole hippocampal and hippocampal subfield atrophy compared to CBS-nAD. CBS-AD and amnestic AD patients did not differ in subfield volumes. CBS-nAD did not exhibit hippocampal atrophy compared to controls, with the exception of fimbria. (Cohen’s d = 1.27; p = 0.038). Presubiculum (Cohen’s d = 1.00; p = 0.002) and hippocampal body (Cohen’s d = 0.95; p = 0.001) volumes exhibited the greatest differences between CBS-AD and CBS-nAD. Hippocampal subfield volume provided combined sensitivity and specificity < 80% for the discrimination of CBS-AD from CBS-nAD. Conclusion CBS-AD and amnestic AD patients exhibit comparable, and significantly greater hippocampal atrophy compared to CBS-nAD patients. Hippocampal subfield volumetry in CBS is indicative of an AD underlying pathology.
 
HRs for time to first rituximab discontinuation among patients on rituximab (at least two doses). a Reference female. b Reference White. c Reference seropositivity. d Reference 30-49 years. e Reference > 5 years. f Reference ARR < 0.25. g Reference ON, ON + BR.
Relapse phenotype frequency
Objective Neuromyelitis optica spectrum disorders (NMOSD) represent rare autoimmune diseases of the central nervous system largely targeting optic nerve(s) and spinal cord. The present analysis used real-world data to identify clinical and epidemiological correlates of treatment change in patients with NMOSD. Methods CIRCLES is a longitudinal, observational study of NMOSD conducted at 15 centers across North America. Patients with ≥ 60 days of follow-up and receiving on-study maintenance treatment were evaluated. The mean annual relapse rate (ARR) was estimated using negative binomial models; the likelihood of treatment change was estimated using Cox proportional hazards models. Relapses were included as time-varying covariates to estimate the relationship to treatment change. Results Of 542 patients included, 171 (31.5%) experienced ≥ 1 relapse on the study and 133 patients (24.5%) had ≥ 1 change in the treatment regimen. Two categories of variables significantly correlated with the likelihood of treatment change: (1) relapse: any on-study relapse (hazard ratio [HR] = 2.91; p < 0.001), relapse phenotypes (HR range = 2.15–5.49; p < 0.001), and pre-study ARR > 0.75 (HR 2.28; p < 0.001); 2) disease phenotype: brain syndrome only vs transverse myelitis involvement at onset (HR 2.44; p = 0.008), disease duration < 1 vs > 5 years (HR 1.66; p = 0.028), or autoimmune comorbidity (HR 1.55; p = 0.015). A subset of these factors significantly correlated with shorter time to first rituximab discontinuation. Conclusions In CIRCLES, relapse patterns and disease phenotype significantly correlated with changes in the maintenance treatment regimen. Such findings may facilitate the identification of patients with NMOSD who are likely to benefit from treatment change to reduce relapse risk or disease burden and enhance the quality of life.
 
Flowchart of participants
Examples of posterior circulation stroke and their vestibular test results. Abnormalities are marked by red asterisk. In the Right posterior inferior cerebellar artery stroke (PICA) stroke (right panel), there was contralateral reduced horizontal canal (HC) VOR gain with catchups and patchy vertical canal decreased VOR gain. The VEMPs were normal, but the SVH showed large contralesional mean deviation of 18 degrees. In the left anterior inferior cerebellar stroke (AICA) stroke (middle panel), there is left-sided reduction of all canal gains with catch of saccades, with reduced left cVEMP response and ipsilesional mean SVH deviation of 9 degrees. The right superior cerebellar artery (SCA) stroke (right panel) has normal HC VOR gains on vHIT, but reduced contralateral posterior canal gain with normal VEMP and SVH responses
Distribution of vestibular tests with vestibular neuritis (VN) subtypes. Red bars denote vestibular end-organs supplied by superior vestibular nerve. Blue bars denote vestibular end-organs supplied by inferior vestibular nerve. Superior VN involves end-organs supplied by the superior vestibular nerve with 10–20% having cVEMP involvement. Inferior VN patients universally had posterior canal vHIT involvement, with 60–80% having cVEMP, AC oVEMP, and SVH abnormality. Pan VN patients had more involvement of cVEMP, oVEMP, SVH and anterior and posterior canal involvement on vHIT, compared to superior VN patients
Vestibular neuritis (VN) patient examples and their vestibular test results. Abnormalities are marked by black asterisk. All vestibular neuritis patients had symmetrical audiometry and ipsilesional subjective visual horizontal (SVH) deviation. In superior VN, the ipsilesional horizontal and anterior canal vHIT VOR gains are markedly reduced with catch-up saccades. In the right pan VN, all ipsilesional vHIT canals are reduced with catch-up saccades. In the right inferior VN, only the ipsilesional posterior canal has reduced VOR gain on vHIT. Both ipsilesional cVEMP and oVEMP responses are reduced in Pan VN. Whereas only the oVEMP is reduced in superior VN and only the cVEMP response is reduced in inferior VN
Objectives To separate posterior-circulation stroke (PCS) and vestibular-neuritis (VN) using quantitative vestibular tests.Methods Patients were prospectively recruited from the emergency room within 72 h of presentation. Video-nystagmography (VNG), three-dimensional video head-impulse testing (vHIT), vestibular-evoked myogenic potentials (VEMPs), and subjective visual-horizontal (SVH) were performed.ResultsThere were 128 PCS and 134 VN patients. Common stroke-territories were: posterior–inferior cerebellar artery, basilar-perforators, multi-territory and anterior–inferior cerebellar artery (41.4%, 21.1%, 14.1%, 7.8%). VN included superior, inferior and pan-neuritis (53.3%, 4.2%, and 41.5%). Most VN and stroke patients presented with acute vestibular syndrome (96.6%, 61.7%). In VN, we recorded horizontal (98.5%) or vertical/torsional spontaneous nystagmus (1.5%) and in PCS, absent-nystagmus (53.9%), horizontal (32%) or vertical/torsional (14.1%) nystagmus. The mean slow-phase velocity of horizontal nystagmus was faster in VN than PCS (11.8 ± 7.2 and 5.2 ± 3.0°/s, p < 0.01). Ipsilesional horizontal-canal (HC) vHIT-gain was lower in VN than in stroke (0.47 ± 0.24, 0.92 ± 0.20, p < 0.001). Ipsilesional catch-up saccades occurred earlier, and their amplitude, prevalence, and velocity were greater in VN than PCS (p < 0.01). Ipsilesional SVH deviation > 2.5° occurred more often in VN than in stroke (97.6% and 24.3%, p < 0.01). Abnormal bone-conducted ocular-VEMP asymmetry ratio was more common in VN than PCS (50% and 14.4%, p < 0.01). Using the ten best discriminators (VNG, vHIT, SVH, and oVEMP metrics), VN was separated from PCS with a sensitivity of 92.9% and specificity of 89.8%. Adding VNG and vHIT to the bedside head-impulse-nystagmus-and-test-of-skew (HINTS) test enhanced sensitivity and specificity from 95.3% and 63.4% to 96.5% and 80.6%.Conclusion Quantitative vestibular testing helps separate stroke from vestibular neuritis and, when used, could improve diagnostic accuracy in the emergency room.
 
CSF Pleocytosis at the diagnostic lumbar puncture is not associated worse progression indices as seen with higher yearly change in EDSS (annualised change in EDSS = ΔEDSS/yr) (A); and Multiple Sclerosis Severity Score (MSSS) (B). CSF pleocytosis is represented by green dataset and No-CSF pleocytosis group by blue dataset. None of the correlation coefficients studied were statistically significant. Spearman coefficients for between CSF count and ΔEDSS/yr (r = 0.082, p = 0.59); and MSSS (r = − 0.16, p = 0.21) for CSF Pleocytosis group; and CSF count and ΔEDSS/yr (r = − 0.026, p = 0.71); and MSSS (r = − 0.11, p = 0.09) for No-CSF Pleocytosis group
Objective The role of CSF lymphocytic pleocytosis in predicting the clinical outcome of multiple sclerosis is unclear. We explored the impact of CSF pleocytosis at diagnosis on long-term disease progression in a large UK cohort. Methods We extracted demographic, clinical and CSF data of people with MS attending the MS clinics between 1996 and 2014 at two MS centres from the English Midlands. We compared EDSS at onset, follow up EDSS and progression indices Multiple Sclerosis Severity Score (MSSS), annualized change in EDSS and transition to secondary progression in the presence/absence of pleocytosis. Two-tailed student t -test, Mann–Whitney U test, Chi-Square or Fisher’s exact tests were used for detecting the differences. Results A total of 247 patients with MS (178 females; mean age 42.4; 217 with relapsing onset) were followed up for an average of 13.56 years (median 12 years). Almost 18% had lymphocytic CSF ≥ 5 per microliter. CSF pleocytosis was not associated with higher EDSS at the time of LP or at follow up, and other progression indices like MSSS, annualized change in EDSS or transition to secondary progression. Discussion CSF pleocytosis at MS diagnosis does not predict higher long-term disability and has no long-term prognostic value in routine clinical circumstances. Differences between MS populations and potential differences in disease activity at the time of CSF analysis may account for differences between studies.
 
Levels of adiponectin (a), resistin (b) and leptin (c) in healthy controls versus people with multiple sclerosis (PwMS) and levels of adiponectin (d), resistin (e) and leptin (f) in PwMS stratified by sex. Each dot in the scatter box-plot represents a sample. p values were calculated with a general linear model, adjusted for sex, BMI, diabetes mellitus (yes/no), statin use (yes/no) and hyperlipidemia (yes/no). F female, HC healthy controls, M male, MS multiple sclerosis
Adiponectin levels in healthy controls and people with multiple sclerosis, stratified by sex and MS subtype. Each dot in the scatter box-plot represents a sample. p values were calculated with a general linear model (adjusted for BMI, diabetes status, statin use and hyperlipidemia) followed by post-hoc analyses, Bonferroni corrected. HC healthy control, PPMS primary progressive multiple sclerosis, RRMS relapsing remitting multiple sclerosis, SPMS secondary progressive multiple sclerosis
Scatterplot of resistin levels and total brain volume (a) deep gray matter volume (b) and thalamic volume (c) in primary progressive multiple sclerosis. Dashed lines indicate the 95% confidence intervals for the regression line. PPMS primary progressive multiple sclerosis
Background An imbalance of adipokines, hormones secreted by white adipose tissue, is suggested to play a role in the immunopathology of multiple sclerosis (MS). In people with MS (PwMS) of the same age, we aimed to determine whether the adipokines adiponectin, leptin, and resistin are associated with MS disease severity. Furthermore, we aimed to investigate whether these adipokines mediate the association between body mass index (BMI) and MS disease severity. Methods Adiponectin, resistin, and leptin were determined in serum using ELISA. 288 PwMS and 125 healthy controls (HC) were included from the Project Y cohort, a population-based cross-sectional study of people with MS born in the Netherlands in 1966, and age and sex-matched HC. Adipokine levels and BMI were related to demographic, clinical and disability measures, and MRI-based brain volumes. Results Adiponectin levels were 1.2 fold higher in PwMS vs. HC, especially in secondary progressive MS. Furthermore, we found a sex-specific increase in adiponectin levels in primary progressive (PP) male patients compared to male controls. Leptin and resistin levels did not differ between PwMS and HC, however, leptin levels were associated with higher disability (EDSS) and resistin strongly related to brain volumes in progressive patients, especially in several grey matter regions in PPMS. Importantly, correction for BMI did not significantly change the results. Conclusion In PwMS of the same age, we found associations between adipokines (adiponectin, leptin, and resistin) and a range of clinical and radiological metrics. These associations were independent of BMI, indicating distinct mechanisms.
 
Flow chart of study selection
Alzheimer’s disease (AD) to control group ratio for salivary Aβ1–42, t-tau, p-tau and AChE. Forest plot of salivary biomarkers (Aβ1–42, t-tau, p-tau and AChE) concentrations in AD vs control: a Ratio of mean (RoM) of salivary Aβ1–42 in Alzheimer’s disease (AD) to control group; b RoM of t-tau in AD vs control group; c RoM of p-tau in AD vs control group; d RoM of AChE in AD vs control group. CI confidence interval, IV inverse variance methods, M–H Mantel–Haenszel
Objective Alzheimer’s disease (AD) is the most prevalent form of dementia among the aging population. Cumulative studies aim to find non-invasive biomarkers in the early stages of AD. Saliva can be obtained easily, and salivary biomarkers have been proven effective in detecting neurodegenerative diseases. To find effective biomarkers in saliva and to help the diagnosis of AD, we performed a meta-analysis focusing on the salivary biomarkers (β-amyloid 1–42 (Aβ1–42), total tau (t-tau), phosphorylated tau (p-tau) and acetylcholinesterase (AChE)) in AD.Methods We conducted a systematic online search for eligible studies reporting data on salivary biomarkers reflecting Aβ1–42, t-tau, p-tau, and AChE in AD cohorts versus controls. Biomarkers’ performance was assessed in a random-effects meta-analysis with the ratio of mean (RoM).ResultsA total of thirteen studies were included in the meta-analysis, of them seven involved salivary Aβ1–42 (271 AD and 489 controls), five involved salivary t-tau (324 AD and 252 controls), four involved salivary p-tau (130 AD and 161 controls), and three involved salivary AChE (81 AD and 54 controls). AD showed significantly higher salivary Aβ1–42 levels than control (ROM = 1.90 (95% CI 1.28–2.81, P = 0.001), while AD and control did not differ significantly on salivary t-tau, p-tau and AChE (ROM = 0.94, 95% CI 0.67–1.31, P = 0.72; ROM = 0.91, 95% CI 0.56–1.45, P = 0.68; ROM = 0.83, 95% CI 0.24–2.88, P = 0.77; respectively).Conclusion The pooled results provide evidence that salivary Aβ1–42 may serve as a sensitive biomarker for AD; nevertheless, larger AD cohorts are required to further confirm the sensitivity and specificity of salivary Aβ1–42 for AD diagnosis.
 
The differenetiate diagnosis of suspicious process of vestibular migraine (VM) and Meniere’s disease (MD) patients
Meniere’s disease (MD) represents one of the vertigo disorders characterized by triad symptoms (recurrent vertigo, fluctuating hearing loss, tinnitus or ear fullness). The diagnosis of MD relies on the accurate and detailed taking of medical history, and the differentiation between MD and vestibular migraine (VM) is of critical importance from the perspective of the treatment efficacy. VM is a highly prevalent vertigo condition and its typical symptoms (headache, vestibular symptoms, cochlear symptoms) mimic those of MD. Furthermore, the misdiagnosis in MD and VM could lead to VM patients mistakenly receiving the traumatic treatment protocol designed for MD, and sustaining unnecessary damage to the inner ear. Fortunately, thanks to the advances in examination technologies, the barriers to their differentiation are being gradually removed. These advances enhance the diagnostic accuracy of vertigo diseases, especially VM and MD. This review focused on the differentiation of VM and MD, with an attempt to synthesize existing data on the relevant battery of differentiation diagnosis (covering core symptoms, auxiliary tests [audiometry, vestibular tests, endolymphatic hydrops tests]) and longitudinal follow-up. Since the two illnesses are overlapped in all aspects, no single test is sufficiently specific on its own, however, patterns containing all or at least some features boost specificity.
 
Impact of the SARS-CoV-2-pandemic—key points
Study appointments vs. telephone interviews during the pandemic period
Introduction SARS-CoV-2 pandemic is especially compromising for patients with autoimmune diseases with or without immunomodulatory treatment. This study aimed to investigate the longitudinal changes in the health care of patients with immune-mediated neuropathies during the COVID-19 pandemic. Methods We performed a longitudinal study using questionnaires in a prospective cohort of patients with immune-mediated neuropathies at two timepoints of the pandemic: May–July 2021 and May–July 2022. Results The cohort consisted of 73 patients (55 male), mean age 62 years, 68 patients with CIDP, 5 with other immune neuropathies. In 2021, 19.2% of the patients reported a reduced number of physician–patient-contacts, while 13.7% reported this in 2022. Nevertheless, the overall health-care situation worsened from 2021 to 2022: 15.1% reported reduced overall healthcare in 2021, 26.0% in 2022. In 2021, 29.4% of patients reported absence of physio-/occupational therapy, while 34.4% reported this in 2022. Switching immunomodulatory treatment and stretching of treatment intervals occurred more often in 2022 (38.4%) than in 2021 (27.4%). 12 COVID-19-infections occurred overall, with typical only mild symptoms. The rate of fully vaccinated patients was 61.6% and 98.6% in May–July 2021 and 2022, respectively. Only minor side-effects after vaccination were reported. Conclusion Despite mitigation of COVID-19 restrictions from 2021 to 2022, the health-care situation of patients worsened in this time. Reasons could be the international shortage of immunoglobulins during the pandemic and reduced physio/ergotherapy due to lingering regulatory restrictions. Vaccination rate was high in our cohort of patients compared to the general German population and CIDP did not seem to be a risk factor for severe SARS-CoV-2 infections.
 
Proportional distribution of the terms psychogenic, somatization, somatoform, medically unexplained symptoms, hysteria, conversion disorder, functional neurological disorder, and dissociative in the medical literature during successive 5-year periods, from 1960 to 2020. Top panel: distribution in PubMed database. Bottom panel: distribution in PsycINFO database
Disciplinary field associations of the terms psychogenic, somatization, somatoform, medically unexplained symptoms, hysteria, conversion disorder, functional disorder, and dissociative with psychiatry and neurology in the literature of the last decade
Proportion of highly cited papers obtained by calculating the ratio of each term’s H-index to the total number of entries retrieved by the term
Background Functional neurological disorders (FND), a subtype of functional disorders (FD), are a frequent motive for neurology referrals. The various presentations and the unknown physiopathology of FD have led to the multiplication of terms describing these disorders over the years.Methods We examined the FD-related articles published from 1960 to 2020 in PubMed and PsycINFO databases. We searched for: psychogenic, somatization, somatoform, medically unexplained symptoms, hysteria, conversion disorder, dissociative, functional neurological disorder, and functional disorder. Use rates in the title, abstract, keyword, or MeSH fields were collected over successive 5-year periods. After correcting for off-topic results, we examined proportional distribution over time, term associations, and disciplinary fields (neurology and psychiatry). Term impact was estimated via H-index and number of citations.ResultsWe found that none of the terms is prevailing in the recent medical literature. We observed three trends in the use rates: stability, increase, and decrease of use over time. While most of the terms were present in a stable proportion of the publications, hysteria and psychogenic lost popularity over time. We found a differential preference for terminology between disciplines. Functional neurological disorder showed the highest citation impact, yielding 10% of highly cited publications.Conclusion We found a dynamic and evolving use of the different terms describing FD in the last 60 years. Despite the tendency to use the term functional in the recent highly cited publications, its low prevalence and coexistence with several other terms suggest that a precise, explanatory and non-offensive term remains yet to be found.
 
Life space of one day of an example participant with an area of the convex hull (red) and area of a standard deviational ellipse (blue) based on GNSS fixes
Visualization of the regression outcomes showing the unstandardized regression coefficients (B) and 95%-CIs of the models for the log-transformed convex hull area. The vertical line indicates the null value. mRS Modified Rankin Scale, NIHSS National Institutes of Health Stroke Scale, TUG Timed up-and-go test
Visualization of the regression outcomes showing the unstandardized regression coefficients (B) and 95%-CIs of the models for the LSA score. The vertical line indicates the null value. mRS Modified Rankin Scale, NIHSS National Institutes of Health Stroke Scale, TUG Timed up-and-go test
Background Stroke is a common cause of mobility limitation, including a reduction in life space. Life space is defined as the spatial extent in which a person moves within a specified period of time. We aimed to analyze patients’ objective and self-reported life space and clinical stroke characteristics. Methods MOBITEC-Stroke is a prospective observational cohort study addressing poststroke mobility. This cross-sectional analysis refers to 3-month data. Life space was assessed by a portable tracking device (7 consecutive days) and by self-report (Life-Space Assessment; LSA). We analysed the timed up-and-go (TUG) test, stroke severity (National Institutes of Health Stroke Scale; NIHSS), and the level of functional outcome (modified Rankin Scale; mRS) in relation to participants’ objective (distance- and area-related life-space parameters) and self-reported (LSA) life space by multivariable linear regression analyses, adjusted for age, sex, and residential area. Results We included 41 patients, mean age 70.7 (SD11.0) years, 29.3% female, NIHSS score 1.76 (SD1.68). We found a positive relationship between TUG performance and maximum distance from home ( p = 0.006), convex hull area (i.e. area enclosing all Global Navigation Satellite System [GNSS] fixes, represented as a polygon linking the outermost points; p = 0.009), perimeter of the convex hull area (i.e. total length of the boundary of the convex hull area; p = 0.008), as well as the standard ellipse area (i.e. the two-dimensional ellipse containing approximately 63% of GNSS points; p = 0.023), in multivariable regression analyses. Conclusion The TUG, an easily applicable bedside test, seems to be a useful indicator for patients’ life space 3 months poststroke and may be a clinically useful measure to document the motor rehabilitative process.
 
Background For ischemic stroke patients with concomitant unruptured aneurysm, intravenous thrombolysis therapy (IVT) remains a disputable decision. We hence performed a meta-analysis to identify the related brain hemorrhage rate of unruptured aneurysms and the risk ratio for their rupture comparing to stroke patients who do not have aneurysms.MethodsA comprehensive search was conducted to identify the studies from the online database from 2000 to September 1st, 2022. Cohort studies were included and assessed by Newcastle–Ottawa Scale (NOS) for quality. The research procedures were subjected to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Fixed-effects model was used based on the heterogeneity tests.ResultsIn 10 eligible studies, 7238 ischemic stroke patients were screened, a total of 302 patients with 348 aneurysms were included. 10 studies were eligible for ICH rate analysis, 8 for SAH rate analysis and 7 for risk ratio of stroke patients with unruptured aneurysms. The pooled any ICH rate was 16% (95% CI 11–21%), symptomatic ICH rate was 4% (95% CI 1–7%, I2 = 0.00%, p = 0.90), and 0% (95% CI 0–1%) for aneurysm-related ICH. Subarachnoid hemorrhage was as low as 2% (95% CI 0–5%), while 0% (95% CI 0–2%) directly related to the aneurysm rupture. The risk ratio of ICH in stroke patients with aneurysms was 1.18 (95% CI 0.79–1.77). Additionally, the hemorrhage rate difference was not evident between saccular and fusiform aneurysms due to a lack of details.ConclusionsIVT is unlikely to induce hemorrhage of pre-existing unruptured aneurysms in stroke patients. Further randomized control studies are warranted to validate these conclusions.Graphical abstract
 
Background Primary angiitis of the central nervous system (PACNS) is a rare disease, for which no validated guidelines exist. We report the findings of a survey on the clinical practice of physicians who manage adults with PACNS. Methods An online survey was distributed through neurology, internal medicine, and rheumatology societies in Canada and Europe. Participants who were directly involved as treating physicians for at least two adult patients with PACNS were eligible for the survey. Results Ninety-six physicians completed the survey. Most participants were neurologists (n = 38, 40%), internists (n = 34, 35%) or rheumatologists (n = 22, 23%). Participants obtained a CNS biopsy in a median of 25% (IQR: 5–50%) of suspected PACNS cases. When determining the degree to which eight scenarios justified a CNS biopsy, participants achieved fair inter-rater agreement (Gwet’s AC2 0.30, 95% CI 0.23–0.41). For induction therapy, 81 (84%) participants reported using glucocorticoids and cyclophosphamide in > 50% of patients. After obtaining remission, 85 (89%) participants systematically introduced or maintained immunosuppressive therapy. Glucocorticoids were prescribed for a median of 12 months. Maintenance therapy with another immunosuppressant was continued for a median of 24 months. In patients who achieved remission, we explored how eight scenarios with different imaging and CSF results supported an increase in treatment. Inter-rater agreement was substantial if the patient was symptomatic (0.66, 95% CI 0.58–0.80) and moderate (0.50, 95% CI 0.45–0.60) if asymptomatic. Conclusion This survey illustrates current real-world management of PACNS and emphasizes several areas for which physicians still lack study-based evidence and/or clinical practice guidelines.
 
a Left perisylvian regions included in the MR imaging analysis are shown in this artificial representation of the lateral surface of the brain, with the insula and supratemporal region shown in darker blue to represent that they are deeper structures within the sylvian fissure, and b region of interest volumes in each genetic group as a percent-
The percentage of participants in each of the groups who score 0 = absent, 0.5 = very mild/questionable, 1 = mild, 2 = moderate, or 3 = severe for each linguistic symptom. Values along the x-axis rep-
Background Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. Methods Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. Results 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72 , 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. Conclusions Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
 
Top-cited authors
Bas Bloem
  • Radboud University Medical Centre (Radboudumc)
Marianne Dieterich
  • Ludwig-Maximilians-University München Germany
Benedikt Schoser
  • Ludwig-Maximilians-University of Munich
Sven Jarius
  • Universität Heidelberg
Angelo Antonini
  • University of Padova