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  • Association of subjective cognitive decline with markers of brain pathology in preclinical autosomal dominant Alzheimer’s disease
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-16
    Jennifer R Gatchel; Francisco Lopera; Daniel J Norton; Ana Baena; Edmarie Guzman-Velez; Justin S Sanchez; Federico d’Oleire Uquillas; Aaron Schultz; Patrizia Vannini; Arabiye Artola; Rebecca E Amariglio; Dorene M Rentz; Pierre N Tariot; Eric M Reiman; Keith A Johnson; Reisa A Sperling; Gad A Marshall; Yakeel T Quiroz

    Subjective cognitive decline (SCD) has been implicated as an early marker of subtle cognitive change in preclinical Alzheimer’s disease (AD).1 The relationship between SCD and molecular markers of disease progression in AD is poorly understood. Carriers of the presenilin ( PSEN1 E280A) mutation from the Colombian kindred2 are a compelling group in which to study SCD, as they will develop dementia with certainty, and have a well-characterised disease trajectory from presymptomatic to clinical stages.2 SCD has been associated with markers of AD pathology in older adults at risk for late-onset sporadic AD.3 We showed previously that self-reported subjective memory complaints (SMC), a proxy for SCD, were elevated in cognitively unimpaired PSEN1 mutation carriers, and that study-partner-reported SMCs were correlated with age and negatively correlated with hippocampal volume.4 In the present study, we explored the extent to which SCD relates to markers of brain pathology—in vivo amyloid and/or tau. We hypothesised that SCD would be related to neocortical amyloid and regional tau levels. Findings have the potential to inform whether SCD might be a sensitive marker of AD-related pathology and disease trajectory in the preclinical stage of AD. Participants were 21 PSEN1 E280A mutation carriers and 27 age, sex and education-matched non-carrier family members recruited from the Alzheimer’s Prevention Initiative Registry. All had at least one parent who bore the PSEN1 E280A mutation but were blind to their genetic status, in accordance with cultural norms and ethical regulations in this community. Clinical assessments, including neurological exam and psychiatric questionnaires probing depression and anxiety, were completed at the University of Antioquia. SCD was assessed using both the self-report and study-partner-based versions of the Memory Complaint Scale, Spanish version (online supplementary appendix 1). Positron-emission tomography (PET) imaging was done in Boston, Massachusetts, USA. ### Supplementary data [jnnp-2019-321205supp001.pdf] Exclusion criteria included chronic major neurological …

    更新日期:2020-01-17
  • Hyper-reflexia in Guillain-Barré syndrome: systematic review
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Antonino Uncini; Francesca Notturno; Satoshi Kuwabara

    Areflexia or hyporeflexia is a mandatory clinical criterion for the diagnosis of Guillain-Barré syndrome (GBS). A systematic review of the literature from 1 January 1993 to 30 August 2019 revealed 44 sufficiently detailed patients with GBS and hyper-reflexia, along with one we describe. 73.3% of patients were from Japan, 6.7% from the USA, 6.7% from India, 4.4% from Italy, 4.4% from Turkey, 2.2% from Switzerland and 2.2% from Slovenia, suggesting a considerable geographical variation. Hyper-reflexia was more frequently associated with antecedent diarrhoea (56%) than upper respiratory tract infection (22.2%) and the electrodiagnosis of acute motor axonal neuropathy (56%) than acute inflammatory demyelinating polyneuropathy (4.4%). Antiganglioside antibodies were positive in 89.7% of patients. Hyper-reflexia was generalised in 90.7% of patients and associated with reflex spread in half; it was present from the early progressive phase in 86.7% and disappeared in a few weeks or persisted until 18 months. Ankle clonus or Babinski signs were rarely reported (6.7%); spasticity never developed. 53.3% of patients could walk unaided at nadir, none needed mechanical ventilation or died. 92.9% of patients with limb weakness were able to walk unaided within 6 months. Electrophysiological studies showed high soleus maximal H-reflex amplitude to maximal compound muscle action potential amplitude ratio, suggestive of spinal motoneuron hyperexcitability, and increased central conduction time, suggestive of corticospinal tract involvement, although a structural damage was never demonstrated by MRI. Hyper-reflexia is not inconsistent with the GBS diagnosis and should not delay treatment. All GBS variants and subtypes can present with hyper-reflexia, and this eventuality should be mentioned in future diagnostic criteria for GBS.

    更新日期:2020-01-15
  • Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Lucas Vu; Jiyan An; Tina Kovalik; Tania Gendron; Leonard Petrucelli; Robert Bowser

    Objective Amyotrophic lateral sclerosis (ALS) is a complex disease with numerous pathological mechanisms resulting in a heterogeneous patient population. Using biomarkers for particular disease mechanisms may enrich a homogeneous subset of patients. In this study, we quantified chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1), markers of glial activation, in cerebrospinal fluid (CSF) and plasma and determined the cell types that express CHI3L1 in ALS. Methods Immunoassays were used to quantify Chit-1, CHI3L1 and phosphorylated neurofilament heavy chain levels in longitudinal CSF and matching plasma samples from 118 patients with ALS, 17 disease controls (DCs), and 24 healthy controls (HCs). Immunostaining was performed to identify and quantify CHI3L1-positive cells in tissue sections from ALS, DCs and non-neurological DCs. Results CSF Chit-1 exhibited increased levels in ALS as compared with DCs and HCs. CSF CHI3L1 levels were increased in ALS and DCs compared with HCs. No quantitative differences were noted in plasma for either chitinase. Patients with ALS with fast-progressing disease exhibited higher levels of CSF Chit-1 and CHI3L1 than patients with slow-progressing disease. Increased numbers of CHI3L1-positive cells were observed in postmortem ALS motor cortex as compared with controls, and these cells were identified as a subset of activated astrocytes located predominately in the white matter of the motor cortex and the spinal cord. Conclusions CSF Chit-1 and CHI3L1 are significantly increased in ALS, and CSF Chit-1 and CHI3L1 levels correlate to the rate of disease progression. CHI3L1 is expressed by a subset of activated astrocytes predominately located in white matter.

    更新日期:2020-01-15
  • Chitinases, neuroinflammation and biomarkers in ALS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Michael Swash

    CSF chitinase (Chit-1) and phosphorylated neurofilament heavy chain levels are both raised in patients with amyotrophic lateral sclerosis (ALS), tweaking interest in these proteins as potential disease biomarkers,1 2 for example, in selecting patients for clinical trials. Here, Vu et al 3 show that elevated CSF chitinase levels delineate a subset of fast-progressing ALS. However, although these abnormalities are markers of active disease, they do not change over time and, like other potential biomarkers, they are not specific for ALS. Unlike insects, chitin is not a constituent of mammalian neural or other …

    更新日期:2020-01-15
  • Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Matthew J Morton; Isabel C Hostettler; Nabila Kazmi; Varinder S Alg; Stephen Bonner; Martin M Brown; Andrew Durnford; Benjamin Gaastra; Patrick Garland; Joan Grieve; Neil Kitchen; Daniel Walsh; Ardalan Zolnourian; Henry Houlden; Tom R Gaunt; Diederik O Bulters; David J Werring; Ian Galea

    Objective After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH. Methods The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV. Results The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin. Conclusion The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.

    更新日期:2020-01-15
  • Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Masatoyo Nishizawa; Osamu Onodera; Akihiro Hirakawa; Yoshitaka Shimizu; Masayuki Yamada

    Objective To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD). Methods Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305. Results From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; p=0.029) in the adjusted mean change in the SARA total score. Conclusions Rovatirelin is a potentially effective treatment option for SCD. Trial registration number [NCT01970098][1]; [NCT02889302][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01970098&atom=%2Fjnnp%2Fearly%2F2020%2F01%2F14%2Fjnnp-2019-322168.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02889302&atom=%2Fjnnp%2Fearly%2F2020%2F01%2F14%2Fjnnp-2019-322168.atom

    更新日期:2020-01-15
  • Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Naoki Hayashi; Naoki Atsuta; Daichi Yokoi; Ryoichi Nakamura; Masahiro Nakatochi; Masahisa Katsuno; Yuishin Izumi; Kazuaki Kanai; Nobutaka Hattori; Akira Taniguchi; Mitsuya Morita; Osamu Kano; Kazumoto Shibuya; Satoshi Kuwabara; Naoki Suzuki; Masashi Aoki; Ikuko Aiba; Kouichi Mizoguchi; Masaya Oda; Ryuji Kaji; Gen Sobue

    Objective The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. Methods We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. Results From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. Conclusion We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.

    更新日期:2020-01-15
  • Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-14
    Carolin Heller; Martha S Foiani; Katrina Moore; Rhian Convery; Martina Bocchetta; Mollie Neason; David M Cash; David Thomas; Caroline V Greaves; Ione OC Woollacott; Rachelle Shafei; John C Van Swieten; Fermin Moreno; Raquel Sanchez-Valle; Barbara Borroni; Robert Laforce Jr; Mario Masellis; Maria Carmela Tartaglia; Caroline Graff; Daniela Galimberti; James B Rowe; Elizabeth Finger; Matthis Synofzik; Rik Vandenberghe; Alexandre de Mendonca; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Christopher R Butler; Alex Gerhard; Johannes Levin; Adrian Danek; Giovanni Frisoni; Sandro Sorbi; Markus Otto; Amanda J Heslegrave; Henrik Zetterberg; Jonathan D Rohrer

    Background There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN -related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.

    更新日期:2020-01-15
  • Guillain-Barré syndrome: looking back… and forward
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Richard A C Hughes

    In 1988, in the first large-scale prospective study of Guillain-Barré syndrome (GBS), John Winer and colleagues collected and followed 100 patients from the London area.1 A year later, 20% of the patients were still unable to walk, and an additional 13% had died, 10% directly from the disease. The series was probably biased towards more severely affected patients. At that time only supportive treatment was available, plasma exchange was rarely used and intravenous immunoglobulin (IVIg) never. There have been many subsequent prospective studies of GBS but all have now been trumped by the International GBS Outcome Study (IGOS) which has collected more than 1800 patients.2 In an analysis of the first 1000 included patients, 8% were unable to walk and 7% had died after a year, with the prognosis being much worse in Bangladesh than in Europe/the Americas and the rest of Asia.3 It is likely that this study was also biased towards more severe disease as most patients were collected from large referral hospitals: this was confirmed in Denmark where the average severity was less in the population as a whole than in those captured by IGOS.4 In the series of Winer and colleagues, factors which predicted a worse prognosis were rapidity of onset, need for ventilation, older age and small distally evoked compound muscle action potentials.1 A Dutch study of 397 patients identified older age, more severe weakness …

    更新日期:2020-01-10
  • Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Christine Verboon; Bianca van den Berg; David R Cornblath; Esmee Venema; Kenneth C Gorson; Michael P Lunn; Hester Lingsma; Peter Van den Bergh; Thomas Harbo; Kathleen Bateman; Yann Pereon; Søren H Sindrup; Susumu Kusunoki; James Miller; Zhahirul Islam; Hans-Peter Hartung; Govindsinh Chavada; Bart C Jacobs; Richard A C Hughes; Pieter A van Doorn

    Objective To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. Methods From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. Results Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an ‘early’ second IVIg course (1–2 weeks after start of the first IVIg course) and 18 patients a ‘late’ second IVIg course (2–4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. Conclusions This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

    更新日期:2020-01-10
  • Is the future of symptomatic intracranial atherosclerotic stenosis management promising?
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Dacheng Liu; Jingyi Liu; Yuan Cai; Ka Sing Lawrence Wong; Liping Liu

    Intracranial atherosclerotic stenosis (ICAS) is one of most common causes of stroke; it has the highest rate of recurrence compared with other aetiologies.1 ICAS is especially more prevalent among the Asians.2 The results of the Chinese Intracranial Atherosclerosis Study indicated that the prevalence of symptomatic ICAS (sICAS) is as high as 46%.1 The 1-year stroke recurrence rate with sICAS is reported to be 12.2% and 15%.3 4 We understand, the following pathological reasons could account for the high recurrence rate in sICAS. First, patients with ICAS are prone to encounter hypoperfusion haemodynamics, especially under poor collateral conditions.5 Studies on the association of blood pressure (BP) control in the acute stage and clinical outcomes are contradictory, supporting this hypothesis.6 Second, plaques in stenotic arteries are usually highly vulnerable (due to large lipid cores, thin fibrous caps and intraplaque haemorrhage).7 These plaques are prone to rupture into downstream arteries, leading to embolic stroke in the territory of the responsible artery.5 Furthermore, these patients are often comorbid with heightened risk factors strongly correlated with stroke recurrence, including hypertension, metabolic disorders, dyslipidaemia.8 Therefore, there is an urgent need to standardise assessment and management of sICAS. The treatment of sICAS nowadays primarily focuses on secondary prevention to reduce stroke recurrence. Therapeutic methods include antiplatelet therapy, interventional therapy and control of risk factors.9 Two milestone trials, the Warfarin Aspirin Symptomatic Intracranial Disease (WASID)3 Trial and the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)4 Trial aim to provide an updated strategy for clinical practice. The WASID Trial, with a double-blind, multicentre, randomised control clinical trial design, aimed to evaluate the efficacy and safety of warfarin over aspirin among patients with 50%–99% degree of ICAS. Aspirin proved to be equally efficient …

    更新日期:2020-01-10
  • In vivo tracking of TDP43 in ALS: cognition as a new biomarker for brain pathology
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Dorothée E Lulé; Albert C Ludolph

    There is a lack of in vivo readout measures to track changes in brain pathology during the course of amyotrophic lateral sclerosis (ALS) which might support the measurement of therapeutic effects in clinical trials. For this, biomarkers need to be specific, reproducible and sensitive to changes in the course of the disease. Established clinical markers of motor deficits are the ALS functional rating scale (ALSFRS-R) and survival. Markers such as neurofilament light chain levels and MRI have been shown to be powerful candidates but have not been introduced into routine yet. Phosphorylated TDP43 (pTDP43) accumulations are reliable postmortem biomarkers of disease pathology in the majority of ALS autopsies and are related to cell death.1 Molecular pTDP43 load has limited use as a biomarker for clinical trials as it can be retrieved post mortem only and not in biological fluids. A completely new …

    更新日期:2020-01-10
  • Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Yan Ge; Ding Ding; Guoxing Zhu; Patrick Kwan; Wenzhi Wang; Zhen Hong; Josemir W Sander

    Objective Sudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified. Methods We performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP. Results After the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles. Conclusions These three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

    更新日期:2020-01-10
  • Peripheral blood helper T cell profiles and their clinical relevance in MOG-IgG-associated and AQP4-IgG-associated disorders and MS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Jia Liu; Masahiro Mori; Kazuo Sugimoto; Akiyuki Uzawa; Hiroki Masuda; Tomohiko Uchida; Ryohei Ohtani; Satoshi Kuwabara

    Objective To investigate the immunological characteristics and their clinical relevance in anti-myelin oligodendrocyte glycoprotein (MOG)-IgG-associated and anti-aquaporin-4 (AQP4)-IgG-associated disorders (MOGAD and AQPAD) and multiple sclerosis (MS). Methods We measured peripheral blood helper T cell subsets (Th1, Th2, Th17 and regulatory T cell (Treg)) in patients with MOGAD (n=26), AQPAD (n=32) and MS (n=28) in the attack and remission phases by flow cytometry with intracellular cytokine staining. We also studied their correlation with clinical parameters. Ten normal subjects served as healthy controls. Results In all the three disorders, Th17 significantly increased at attack, and downregulated in the remission phases, although still elevated compare with healthy controls. MOGAD and AQPAD patients shared the common T cell profiles, while the extent of Th17 shift was more prominent in AQPAD. Patients with MS showed decreased Th2 than ones with MOGAD and AQPAD at attack. In terms of clinical correlation, MS patients showed that higher Th1 and Th17 proportion was associated with more frequent relapse and more severe clinical disability, whereas in MOGAD, higher Treg was associated with milder clinical severity. In AQPAD, no obvious correlation of Th profiles with clinical manifestation was found. Conclusions The present study first investigated intracellular cytokine levels among MOGAD, AQPAD and MS. The different patterns and extent of helper T cell profiles could reflect the pathogenesis of each disorders, and may affect disease severity and activity.

    更新日期:2020-01-10
  • Multifocal motor neuropathy: controversies and priorities
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Wei Zhen Yeh; P James Dyck; Leonard H van den Berg; Matthew C Kiernan; Bruce V Taylor

    Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy.

    更新日期:2020-01-10
  • Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Jenna M Gregory; Karina McDade; Thomas H Bak; Suvankar Pal; Siddharthan Chandran; Colin Smith; Sharon Abrahams

    Objective Approximately 35% of patients with amyotrophic lateral sclerosis (ALS) exhibit mild cognitive deficits in executive functions, language and fluency, without dementia. The precise pathology of these extramotor symptoms has remained unknown. This study aimed to determine the pathological correlate of cognitive impairment in patients with non-demented ALS. Methods In-depth neuropathological analysis of 27 patients with non-demented ALS who had undergone cognitive testing (Edinburgh Cognitive and Behaviour ALS Screen (ECAS)) during life. Analysis involved assessing 43 kDa Tar-DNA binding protein (TDP-43) accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology. Results All patients with cognitive impairment had TDP-43 pathology in extramotor brain regions (positive predictive value of 100%). The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases. Conclusions Cognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. The profile of mild cognitive deficits specifically predicts regional cerebral involvement. These findings highlight the utility of the ECAS in accurately assessing the pathological burden of disease.

    更新日期:2020-01-10
  • Association between midlife dementia risk factors and longitudinal brain atrophy: the PREVENT-Dementia study
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    John T O'Brien; Michael J Firbank; Karen Ritchie; Katie Wells; Guy B Williams; Craig W Ritchie; Li Su

    Background Increased rates of brain atrophy on serial MRI are frequently used as a surrogate marker of disease progression in Alzheimer’s disease and other dementias. However, the extent to which they are associated with future risk of dementia in asymptomatic subjects is not clear. In this study, we investigated the relationship between the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score and longitudinal atrophy in middle-aged subjects. Materials and methods A sample of 167 subjects (aged 40–59 at baseline) from the PREVENT-Dementia programme underwent MRI scans on two separate occasions (mean interval 735 days; SD 44 days). We measured longitudinal rates of brain atrophy using the FSL Siena toolbox. Results Annual percentage rates of brain volume and ventricular volume change were greater in those with a high (>6) vs low CAIDE score—absolute brain volume percentage loss 0.17% (CI 0.07 to 0.27) and absolute ventricular enlargement 1.78% (CI 1.14 to 2.92) higher in the at risk group. Atrophy rates did not differ between subjects with and without a parental history of dementia, but were significantly correlated with age. Using linear regression, with covariates of age, sex and education, CAIDE score >6 was the only significant predictor of whole brain atrophy rates (p=0.025) while age (p=0.009), sex (p=0.002) and CAIDE>6 (p=0.017) all predicted ventricular expansion rate. Conclusion Our results show that progressive brain atrophy is associated with increased risk of future dementia in asymptomatic middle-aged subjects, two decades before dementia onset.

    更新日期:2020-01-10
  • Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Emily P McCann; Jennifer A Fifita; Natalie Grima; Jasmin Galper; Prachi Mehta; Sarah E Freckleton; Katharine Y Zhang; Lyndal Henden; Alison L Hogan; Sandrine Chan Moi Fat; Sharlynn SL Wu; Cyril J Jagaraj; Britt A Berning; Kelly Louise Williams; Natalie A Twine; Denis Bauer; Olivier Piguet; John Hodges; John B J Kwok; Glenda M Halliday; Matthew C Kiernan; Julie Atkin; Dominic B Rowe; Garth A Nicholson; Adam K Walker; Ian P Blair; Shu Yang

    Objective Since the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia. Methods Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10 . CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology. Results No causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease. Conclusions Genetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.

    更新日期:2020-01-10
  • Pure tone audiometry and cerebral pathology in healthy older adults
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Thomas Parker; David M Cash; Chris Lane; Kirsty Lu; Ian B Malone; Jennifer M Nicholas; Sarah James; Ashvini Keshavan; Heidi Murray-Smith; Andrew Wong; Sarah Buchannan; Sarah Keuss; Carole H Sudre; David Thomas; Sebastian Crutch; Doris-Eva Bamiou; Jason D Warren; Nick C Fox; Marcus Richards; Jonathan M Schott

    Background Hearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations. Methods Data from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults. Results There was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase. Conclusion Pure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.

    更新日期:2020-01-10
  • Pain and the immune system: emerging concepts of IgG-mediated autoimmune pain and immunotherapies
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Min Xu; David L H Bennett; Luis Antonio Querol; Long-Jun Wu; Sarosh R Irani; James C Watson; Sean J Pittock; Christopher J Klein

    The immune system has long been recognised important in pain regulation through inflammatory cytokine modulation of peripheral nociceptive fibres. Recently, cytokine interactions in brain and spinal cord glia as well as dorsal root ganglia satellite glia have been identified important— in pain modulation. The result of these interactions is central and peripheral sensitisation of nociceptive processing. Additionally, new insights and the term ‘autoimmune pain’ have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability. Other discovered IgGs heighten pain indirectly by T-cell-mediated inflammation or destruction of targets within the nociceptive pathways. Notable identified IgGs in pain include those against the components of channels and receptors involved in inhibitory or excitatory somatosensory synapses or their pathways: nodal and paranodal proteins (LGI1, CASPR1, CASPR2); glutamate detection (AMPA-R); GABA regulation and release (GAD65, amphiphysin); glycine receptors (GLY-R); water channels (AQP4). These disorders have other neurological manifestations of central/peripheral hyperexcitabability including seizures, encephalopathy, myoclonus, tremor and spasticity, with immunotherapy responsiveness. Other pain disorders, like complex regional pain disorder, have been associated with IgGs against β2-adrenergic receptor, muscarinic-2 receptors, AChR-nicotinic ganglionic α-3 receptors and calcium channels (N and P/Q types), but less consistently with immune treatment response. Here, we outline how the immune system contributes to development and regulation of pain, review specific IgG-mediated pain disorders and summarise recent development in therapy approaches. Biological agents to treat pain (anti-calcitonin gene-related peptide and anti-nerve growth factor) are also discussed.

    更新日期:2020-01-10
  • Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Junus M. van der Wal; Isidoor O. Bergfeld; Anja Lok; Mariska Mantione; Martijn Figee; Peter Notten; Guus Beute; Ferdinand Horst; Pepijn van den Munckhof; P. Rick Schuurman; Damiaan Denys

    Objective Deep brain stimulation (DBS) reduces depressive symptoms in approximately 40%–60% of patients with treatment-resistant depression (TRD), but data on long-term efficacy and safety are scarce. Our objective was to assess the efficacy and safety of DBS targeted at the ventral anterior limb of the internal capsule (vALIC) in 25 patients with TRD during a 1-year, open-label, maintenance period, which followed a 1-year optimisation period. Methods Depression severity was measured using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Montgomery-Asberg Depression Rating Scale (MADRS) and self-reported Inventory of Depressive Symptomatology (IDS-SR). Primary outcomes were response rate (≥50% HAM-D-17 score reduction) after the maintenance phase, approximately 2 years after DBS surgery, and changes in depression scores and occurrence of adverse events during the maintenance phase. Results Of 25 operated patients, 21 entered and 18 completed the maintenance phase. After the maintenance phase, eight patients were classified as responder (observed response rate: 44.4%; intention-to-treat: 32.0%). During the maintenance phase, HAM-D-17 and MADRS scores did not change, but the mean IDS-SR score decreased from 38.8 (95% CI 31.2 to 46.5) to 35.0 (95% CI 26.1 to 43.8) (p=0.008). Non-responders after optimisation did not improve during the maintenance phase. Four non-DBS-related serious adverse events occurred, including one suicide attempt. Conclusions vALIC DBS for TRD showed continued efficacy 2 years after surgery, with symptoms remaining stable after optimisation as rated by clinicians and with patient ratings improving. This supports DBS as a viable treatment option for patients with TRD. Trial registration number NTR2118.

    更新日期:2020-01-10
  • Structural network changes in cerebral small vessel disease
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Anil M Tuladhar; Jonathan Tay; Esther van Leijsen; Andrew J Lawrence; Ingeborg Wilhelmina Maria van Uden; Mayra Bergkamp; Ellen van der Holst; Roy P C Kessels; David Norris; Hugh S Markus; Frank-Erik De Leeuw

    Objectives To investigate whether longitudinal structural network efficiency is associated with cognitive decline and whether baseline network efficiency predicts mortality in cerebral small vessel disease (SVD). Methods A prospective, single-centre cohort consisting of 277 non-demented individuals with SVD was conducted. In 2011 and 2015, all participants were scanned with MRI and underwent neuropsychological assessment. We computed network properties using graph theory from probabilistic tractography and calculated changes in psychomotor speed and overall cognitive index. Multiple linear regressions were performed, while adjusting for potential confounders. We divided the group into mild-to-moderate white matter hyperintensities (WMH) and severe WMH group based on median split on WMH volume. Results The decline in global efficiency was significantly associated with a decline in psychomotor speed in the group with severe WMH (β=0.18, p=0.03) and a trend with change in cognitive index (β=0.14, p=0.068), which diminished after adjusting for imaging markers for SVD. Baseline global efficiency was associated with all-cause mortality (HR per decrease of 1 SD 0.43, 95% CI 0.23 to 0.80, p=0.008, C-statistic 0.76). Conclusion Disruption of the network efficiency, a metric assessing the efficiency of network information transfer, plays an important role in explaining cognitive decline in SVD, which was however not independent of imaging markers of SVD. Furthermore, baseline network efficiency predicts risk of mortality in SVD that may reflect the global health status of the brain in SVD. This emphasises the importance of structural network analysis in the context of SVD research and the use of network measures as surrogate markers in research setting.

    更新日期:2020-01-10
  • Intensive Statin Treatment in Acute Ischaemic Stroke Patients with Intracranial Atherosclerosis: a High-Resolution Magnetic Resonance Imaging study (STAMINA-MRI Study)
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Jong-Won Chung; Jihoon Cha; Mi Ji Lee; In-Wu Yu; Moo-Seok Park; Woo-Keun Seo; Sung Tae Kim; Oh Young Bang

    Objective Intracranial atherosclerosis is a major cause of ischaemic stroke worldwide. A number of studies have shown the effects of statin treatment on coronary and carotid artery plaques, but there is little evidence on the effects of statin treatment on intracranial atherosclerotic plaques. Methods The Intensive Statin Treatment in Acute Ischaemic Stroke Patients with Intracranial Atherosclerosis - High-Resolution Magnetic Resonance Imaging (STAMINA-MRI) Trial is a single-arm, prospective, observational study monitoring imaging and clinical outcomes of high-dose statin treatment among statin-naive patients with acute ischaemic stroke caused by symptomatic intracranial atherosclerosis. The primary outcome was the change in vascular remodelling and plaque characteristics before and after 6 months (median: 179 days, IQR 163–189 days) of statin treatment measured by high-resolution MRI (HR-MRI). Results A total of 77 patients (mean age: 62.6±13.7 years, 61.0% women) were included in this study. Low-density lipoprotein cholesterol (LDL-C) levels (mg/dL) at initial and follow-up assessments were 125.81±35.69 and 60.95±19.28, respectively. Overall, statin treatment significantly decreased enhancement of plaque volume (mm3, 32.07±39.15 vs 17.06±34.53, p=0.013), the wall area index (7.50±4.28 vs 5.86±4.05, p=0.016) and stenosis degree (%, 76.47±20.23 vs 64.05±21.29, p<0.001), but not the remodelling index (p=0.195). However, 35% patients showed no change or increased enhancement volume and stenosis degree after statin treatment. Higher reduction of LDL-C and longer duration of statin treatment were associated with decreased enhancement volume after statin treatment. Conclusions High-dose statin treatment effectively stabilised symptomatic intracranial atherosclerotic plaques as documented by HR-MRI. Further study is needed to determine laboratory and genetic factors associated with poor response to statins and alternative therapeutic options, such as proprotein convertase subtilisin-kexin type 9 inhibitors, for these patients. Trial registration number ClinicalTrials.gov [NCT02458755][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02458755&atom=%2Fjnnp%2F91%2F2%2F204.atom

    更新日期:2020-01-10
  • Abnormal coagulation parameters are a common non-neuromuscular feature in patients with spinal muscular atrophy
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Camiel A Wijngaarde; Albert Huisman; Renske I Wadman; Inge Cuppen; Marloes Stam; Katja M J Heitink-Pollé; Ewout J N Groen; Roger E G Schutgens; W-Ludo van der Pol

    Hereditary proximal spinal muscular atrophy (SMA) is caused by survival motor neuron (SMN) protein deficiency due to homozygous loss of SMN1 gene function. Residual SMN protein levels are produced by the SMN2 gene and SMN protein is expressed ubiquitously. Its deficiency causes alpha motor neuron loss.1 Observations in animal models suggest other tissues, for example heart, peripheral vascular system, liver and pancreas, may also require SMN protein above specific threshold levels. This is further supported by case reports of severely affected patients but it remains to be established whether multisystem pathology is actually part of the patient phenotype.2 3 This is even more relevant now that SMN-augmenting therapies have become available. We here report a systematic characterisation of coagulation in patients with SMA, which we studied for several reasons. First, we observed abnormal coagulation screening results frequently during the course of clinical trials and nusinersen treatment. Second, local thrombotic small vessel occlusions and peripheral vascular dysfunction have been suggested to play a role in causing some of the observed non-neuromuscular pathology. Third, relatively high levels of SMN protein are found in platelets.2 Here, we find activated partial thromboplastin time (APTT) to be significantly and consistently prolonged in patients with SMA. Prothrombin time, platelet count, von Willebrand Factor (vWF) antigen and activity also differ significantly from reference values. These findings represent a common functional defect outside the nervous system in patients with SMA. We enrolled patients with SMA types 1–4 and analysed blood samples to …

    更新日期:2020-01-10
  • Plasma pNfH levels differentiate SBMA from ALS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Vittoria Lombardi; Alessandro Bombaci; Luca Zampedri; Ching-Hua Lu; Bilal Malik; Henrik Zetterberg; Amanda J Heslegrave; Carlo Rinaldi; Linda Greensmith; Michael G Hanna; Andrea Malaspina; Pietro Fratta

    Spinal and bulbar muscular atrophy (SBMA), known as Kennedy disease (KD), is a slowly progressive adult-onset X-linked neuromuscular disorder with no effective treatment. It is characterised by progressive limb and bulbar muscle weakness, associated with metabolic and endocrine alterations.1 2 SBMA is caused by the expansion of a CAG repeat in exon 1 of the androgen receptor ( AR ) gene; more than 37 repeats are pathogenic.1 While the genetic test is diagnostic, biomarkers would aid the initial differential diagnosis, and furthermore, there is a strong need for disease activity and progression markers to inform effective clinical trials design. Neurofilaments (Nfs), both light and heavy chains, are now becoming a widely accepted marker of neuronal damage and a prognostic biomarker for amyotrophic lateral sclerosis (ALS) and other neurodegenerative disease.3–7 Recently, plasma neurofilament light chain (NfL) levels were unexpectedly found not to be raised in patients with SBMA.8 This finding supports other lines of evidence, including an increase in plasma muscle damage markers, myopathic changes in biopsies and a series of genetic experiments in mouse models, that point to a primary myopathic involvement in SBMA.2 9 10 We here used the highly sensitive single molecule array (SIMOA) platform to investigate plasma levels of phosphorylated neurofilament heavy chain (pNfH), another well-established marker of neuronal damage, in patients with SBMA and in a rodent model of disease. We have undertaken cross-sectional pNfH analysis using the SIMOA platform in plasma from 46 patients with SBMA, 50 patients with ALS (25 ALS-Fast and 25 ALS-Slow, as previously described)8 and 50 healthy controls (HCs) previously tested for NfL. Participant’s demographic and clinical data are summarised in figure 1A, and detailed methods and statistical analysis are listed in the online supplementary file 1. ### Supplementary data [jnnp-2019-320624supp001.pdf] Figure 1 (A) Cohort demographic, genetic information, pNfH and clinical …

    更新日期:2020-01-10
  • Cerebellum is more concerned about visceral than somatic pain
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Jens Claassen; Laura Ricarda Koenen; Thomas M Ernst; Franziska Labrenz; Nina Theysohn; Michael Forsting; Ulrike Bingel; Dagmar Timmann; Sigrid Elsenbruch

    Chronic pain disorders are extremely common, including chronic back pain and headaches, but also chronic visceral pain disorders, such as irritable bowel syndrome. Treatment is notoriously difficult. A detailed understanding of the neural pain circuitry is a prerequisite for the development of new treatment options. The cerebellum has become an interesting target for non-invasive and invasive brain stimulations in a wide range of brain disorders and may be a future option in treating chronic pain. The possible contribution of the cerebellum to the pathophysiology of chronic pain has become of interest only recently.1 Although the cerebellum has frequently been shown to respond to painful stimuli, knowledge about the specific contributions of the cerebellum to pain processing remains elusive. Electrophysiological studies in rodents provide evidence that the cerebellum receives afferent input coming from cutaneous and visceral nociceptors.2 Our group and others have found that neural processing of somatic and visceral pain is partly overlapping but reveals also significant differences.3 As yet, however, it is unknown to what extent cerebellar responses differ between visceral and somatic pain. To address this question, we compared pain-related activations of the cerebellum between carefully matched rectal distensions and cutaneous heat stimuli. Functional MRI (fMRI) data were acquired in 22 healthy female participants as part of a previous study.3 fMRI data were reanalysed using a normalising method optimised for the cerebellum. Participants were on average 24.4±0.6 years old with a mean body mass index of 21.9±0.5. Questionnaires confirmed lack …

    更新日期:2020-01-10
  • Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Takashi Kurashige; Hiroyuki Morino; Yukiko Matsuda; Tomoya Mukai; Tomomi Murao; Megumi Toko; Kodai Kume; Ryosuke Ohsawa; Tsuyoshi Torii; Hiroshi Tokinobu; Hirofumi Maruyama; Hideshi Kawakami

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of both upper and lower motor neurons. Approximately 10% of patients with ALS have a family history of the disease, and 22 genes have already been reported to be implicated in ALS.1 In previous reports, some of the genes implicated in ALS were associated with visual dysfunctions; however, no cases have yet reported patients presenting clinically both ALS and ocular abnormalities.1 Recently, a large case-controlled genome-wide association study (GWAS) of ALS revealed cilia and flagella-associated protein 410 ( CFAP410 ), previously called as C21orf2 .2 CFAP410 is causative for axial spondylometaphyseal dysplasia (SMDAX), which presents with retinitis pigmentosa (RP), and retinal dystrophy (RD) with or without macular staphyloma.3 However, no hereditary ALS cases have yet reported CFAP410 variants. In this letter, we provide the first description of siblings with RP and ALS with the causative CFAP410 mutation. They showed RP until their fourth decade and muscle weakness of the extremities started more than 10 years after the diagnosis of RP. The pedigree chart of the affected family is presented in figure 1A. Their parents (I-1 and I-2) were consanguineous and neurologically healthy. Figure 1 (A) Pedigree chart of the affected family. Shaded boxes represent affected members. Symbols having diagonal lines represent deceased individuals. Unaffected family members exhibited no abnormalities during their medical examinations. (B) Sanger sequencing revealed that the patients had exon 4 of a CFAP410 homozygous variant (c.319T>C, p.Y107H) and that the non-affected sibling had a heterozygous variant of CFAP410 . (C) Heterozygous CFAP410 variants of amyotrophic lateral sclerosis (ALS) (black) were previously detected except for exon 2. On the other hand, causative …

    更新日期:2020-01-10
  • Familial flail leg ALS caused by PFN1 mutation
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-02-01
    Zhang-Yu Zou; Shi-Dong Chen; Shu-Yan Feng; Chang-Yun Liu; Mei Cui; Shu-fen Chen; Shu-Man Feng; Qiang Dong; Huapin Huang; Jin-Tai Yu

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting from loss of motor neurons in the motor cortex, brainstem and spinal cord. Despite a characterised rapidly progressive clinical course with upper and lower motor neuron signs and symptoms in classical ALS, unusual presentations can restrict to a specific spinal or bulbar segment for several years. Flail leg syndrome (FLS) is an atypical variant of ALS characterised by progressive distal onset weakness and atrophy of lower limbs with reduced or absent reflexes. Patients should not present with significant weakness or wasting in upper limbs and bulbar within 12 months after onset.1 Mutations in more than 20 genes have been linked to ALS.2 However, genetic cause familial FLS has never been reported. We have identified a missense mutation in PFN1 gene in a FLS family by whole-exome sequencing (WES). The proband (III-7) of the FLS pedigree was chosen for WES using the Illumina Hiseq sequencing platform and screening for presence of the GGGGCC expansions in the C9orf72 gene. All three exons of the PFN1 (NM_005022) gene were amplified by PCR and directly sequenced (online supplementary file 1) in additional 15 patients with familial ALS (FALS) indexes and 275 patients with sporadic ALS (SALS) (173 male, 117 female, mean age of onset±SD 55.3±11.6 years) referred to Fujian Medical Union Hospital and Henan Provincial People's Hospital between January 2017 and December 2018. A diagnosis of definite, probable or laboratory supported probable ALS was established using the revised El Escorial criteria. Blood samples were collected after the individuals had signed an informed consent document. ### Supplementary data [jnnp-2019-321366supp001.pdf] The proband (III-7) …

    更新日期:2020-01-10
  • Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-10
    Isabel Charlotte Hostettler; Matthew J Morton; Gareth Ambler; Nabila Kazmi; Tom Gaunt; Duncan Wilson; Clare Shakeshaft; H R Jäger; Hannah Cohen; Tarek A Yousry; Rustam Al-Shahi Salman; Gregory Lip; Martin M Brown; Keith Muir; Henry Houlden; Diederik O Bulters; Ian Galea; David J Werring

    Objective Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH. Methods We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1–1, 2–1 or 2–2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3–6). Results We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume. Conclusion The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study.

    更新日期:2020-01-10
  • Sleep problems and risk of all-cause cognitive decline or dementia: an updated systematic review and meta-analysis
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-26
    Wei Xu; Chen-Chen Tan; Juan-Juan Zou; Xi-Peng Cao; Lan Tan

    Objectives To conduct an updated systematic review and meta-analysis of association between sleep and all-cause cognitive disorders. Methods PubMed and EMBASE were searched from inception to 18 February 2019. Cohort studies exploring longitudinal associations of sleep with cognitive decline or dementia were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment. The robust error meta-regression model was used to conduct the dose–response meta-analysis for sleep duration. Results 11 155 reports were searched and 51 eligible cohorts with 15 sleep problems were included for our meta-analyses. Ten types of sleep conditions or parameters, including six (insomnia, fragmentation, daytime dysfunction, prolonged latency, rapid eye movement sleep behaviour disorder and excessive time in bed) with moderate-to-high levels of evidence, were linked to higher risk of all-cause cognitive disorders. Furthermore, a U-shaped relationship was revealed for the associations with sleep duration. Conclusions Sleep management might serve as a promising target for dementia prevention.

    更新日期:2019-12-27
  • Neuropsychiatric history influences cognition and behaviour in MND
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-23
    Matthew Jones

    The spectrum of cognitive and behavioural changes occurring in patients with motor neuron disease (MND) has become an area of great research interest over recent years. In addition to the well-known association with frontotemporal dementia (FTD), which occurs in approximately 15% of patients, many more have evidence of milder behavioural and/or cognitive impairment.1 As a result of this increased awareness, patients with MND are now much more likely to have their cognition assessed as part of the routine care they receive in clinic. Standardised tools such as the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) are making this …

    更新日期:2019-12-23
  • Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-23
    Umberto Manera; Andrea Calvo; Margherita Daviddi; Antonio Canosa; Rosario Vasta; Maria Claudia Torrieri; Maurizio Grassano; Maura Brunetti; Sandra D'Alfonso; Lucia Corrado; Fabiola De Marchi; Cristina Moglia; Fabrizio D'Ovidio; Gabriele Mora; Letizia Mazzini; Adriano Chiò

    Objective The lack of prognostic biomarkers in patients with amyotrophic lateral sclerosis (ALS) induced researchers to develop clinical evaluation tools for stratification and survival prediction. We assessed the correlation between patterns of functional involvement, considered as a cumulative number of body regions involved, and overall survival in a population-based series of patients with ALS (PARALS). Methods We derived the functional involvement of four body regions at diagnosis using ALSFRS-R subscores for bulbar, upper limbs, lower limbs and respiratory/thoracic regions. We analysed the effect of number of body regions involved (NBRI) at diagnosis on overall survival, adjusting for age at onset, sex, site of onset, diagnostic delay, forced vital capacity, body mass index, mutational status, cognition and comparing it with King’s staging system. Results The NBRI was strongly related to survival, with a progressive increase of death/tracheostomy risk among groups (two body regions HR=1.24, 95% CI 1.06 to 1.45, p=0007; three body regions HR=1.65, 95% CI 1.38 to 1.98, p<0.001; four body regions HR=2.68, 95% CI 2.11 to 3.39, p<0.001). Using ALSFRS-R score, the consistency between the number of regions involved and King’s clinical stage at diagnosis was very high (81%). The evaluation of respiratory/thoracic region and cognition allowed to subdivide patients into different prognostic categories. Regional spreading of the disease is associated with survival, independently from the initial region involved. Conclusions The evaluation of NBRI, with the inclusion of initial respiratory/thoracic involvement and cognition, can be useful in many research fields, improving the stratification of patients. Our findings highlight the importance of the spatial spreading of functional impairment in the prediction of ALS outcome.

    更新日期:2019-12-23
  • Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-23
    Caroline A McHutchison; Danielle Jane Leighton; Andrew McIntosh; Elaine Cleary; Jon Warner; Mary Porteous; Siddharthan Chandran; Suvankar Pal; Sharon Abrahams

    Objective In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neuron disease (MND). Methods People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. We identified patients with cognitive impairment (motor neuron disease with cognitive impairment (MNDci)), behavioural impairment (motor neuron disease with behavioural impairment (MNDbi), both (motor neuron disease with cognitive and behavioural impairment (MNDcbi)) or motor neuron disease–frontotemporal dementia (MND-FTD). Results Data were available for 305 pwMND (mean age at diagnosis=62.26 years, SD=11.40), of which 60 (19.7%) had a neuropsychiatric disorder. A family history of neuropsychiatric disorders was present in 36/231 (15.58%) of patients. Patient premorbid mood disorders were associated with increased apathy (OR=2.78, 95% CI 1.083 to 7.169). A family history of any neuropsychiatric disorder was associated with poorer visuospatial scores, MNDbi (OR=3.14, 95% CI 1.09 to 8.99) and MND-FTD (OR=5.08, 95% CI 1.26 to 20.40). A family history of mood disorders was associated with poorer overall cognition (exp(b)=0.725, p=0.026), language, verbal fluency and visuospatial scores, and MND-FTD (OR=7.57, 95% CI 1.55 to 46.87). A family history of neurotic disorders was associated with poorer language (exp(b)=0.362, p<0.001), visuospatial scores (exp(b)=0.625, p<0.009) and MND-FTD (OR=13.75, 95% CI 1.71 to 110.86). Conclusion Neuropsychiatric disorders in patients and their families are associated with cognitive and behavioural changes post-MND diagnosis, with many occurring independently of MND-FTD and C9orf72 status. These findings support an overlap between MND, frontotemporal dementia and neuropsychiatric disorders, particularly mood disorders.

    更新日期:2019-12-23
  • Steno-occlusive cerebral arteriopathy in patients with glycogen storage disease type I
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-18
    Yuehui Hong; Yuheng Yuan; Shi Shu; Bo Hou; Yi Dai; Jun Ni; Feng Feng; Zhengqing Qiu; Bin Peng

    Glycogen storage disease type I (GSDI) is a rare genetic metabolic disorder caused by a deficiency of the glucose-6-phosphatase (GSDIa) or glucose-6-phosphate translocase enzyme (GSDIb).1 Cerebrovascular disorders associated with GSDI have been reported in seven cases but have not been well studied. Here we investigated the prevalence, characteristics and pathophysiology of cerebrovascular disorders in patients with GSDI in a Chinese referral centre. Between September 2014 and January 2019, among 175 patients with genetically confirmed GSDI (140 and 35 subjects with GSDIa and GSDIb respectively) at Peking Union Medical College Hospital, 34 with cranial magnetic resonance angiography (MRA) were included in this study. The indications for neuroimaging included headache, dizziness, intellectual impairment or stroke/transient ischaemic attack (TIA). Stroke was defined as an acute neurological deficit with neuroimaging showing brain infarction or haemorrhage, conforming to known arterial territory(ies). TIA was defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia, without infarction on neuroimage or lasting less than 24 hours. None of the subjects had cranial irradiation, varicella-zoster virus infection, sickle cell disease, or neurofibromatosis type I, which were recognised causes of cerebral arteriopathy. The GSDI related data (eg, GSD subtype/genotype, metabolic control status, complications and treatment) and cerebrovascular related data (eg, neurological presentation and risk factors) were collected. Arteriopathy was diagnosed if MRA showed the imaging appearance of an in situ arterial abnormality not attributable to an exogenous thrombus or normal developmental …

    更新日期:2019-12-19
  • Jewels in the crown: a century of achievement for the Journal of Neurology, Neurosurgery & Psychiatry
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Matthew C Kiernan

    ![][1] Welcome to 2020—a year in which the Journal of Neurology, Neurosurgery and Psychiatry reaches its century. It would be interesting to jump into the time machine, to turn back the clock to 1920 and ask the foundation editor, Kinnier Wilson, what he anticipated when he launched the journal. On reflection, it would seem difficult to predict the astounding advancements in clinical neuroscience to which the past century has borne witness. No doubt Kinnier Wilson would have been proud of the many contributions the JNNP has made and the citation classics it has generated over that time. How could he have predicted the path his journal would forge—from understanding the circuitry of memory,1 unlocking disease pathophysiology,2 3 the creation of rating scales (some with citation counts >48 000 to date)4 the role of neurosurgery,5 to the advent of new therapies,6 comprehending quality of life,7 addressing patient outcomes8 and establishing disease criteria.9 These mere samples in the phenomenal history of the journal mark … [1]: /embed/graphic-1.gif

    更新日期:2019-12-18
  • Multiple system atrophy: the nature of the beast revisited
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Niall Quinn

    ![][1] It is now 50 years since Graham and Oppenheimer first coined the term multiple system atrophy (MSA).1 Twenty years later, I wrote an extensive review of MSA entitled ‘The nature of the beast’.2 This alluded to blindfolded men examining an elephant from different directions and coming away with different perceptions (figure 1). Not long ago, a propos of MSA, my uroneurologist friend Clare Fowler (personal communication), commented, “You know, it all makes sense now, but 30 years ago that was far from being the case.” Figure 1 The MSA Elephant. I got hooked on neurology, and on movement disorders in particular, in my first neurology post as SHO to David Marsden at King’s College Hospital. Later, I worked for Roger Bannister at Queen Square, where I encountered a number of severely affected inpatients with MSA. I read the papers of Dejerine and Thomas3 on sporadic olivopontocerebellar degeneration (sOPCA, now MSA-C), Bradbury and Eggleston4 on postural hypotension, Shy and Drager (1960) on their syndrome (Shy-Drager5 syndrome; SDS), and of Adams et al 6 on striatonigral degeneration (SND now MSA-P). Other key developments in the busy 1960s (which I still think of as the decade of the basal ganglia) were the introduction of levodopa in 1967, Hoehn and Yahr’s landmark (pre-levodopa) 1967 paper7 on a large cohort with Parkinson’s disease and parkinsonism, Steele et al ’s description of their syndrome,8 later called progressive supranuclear palsy (PSP) and Rebeiz et al ’s paper on corticodentatonigral degeneration, now called corticobasal degeneration (CBD).9 Later, in 1972, Bannister and Oppenheimer had described in Brain 10 16 pathologically confirmed cases of neurogenic autonomic … [1]: /embed/graphic-1.gif

    更新日期:2019-12-18
  • Using clinically stable disease (NEDA 2) as a proxy for disease impact and employment in MS paints an incomplete picture
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Sharon Roman

    Multiple sclerosis (MS) has long been associated with high rates of unemployment.1 While in many countries, patients are entitled to ask for reasonable accommodations,2 the duty to accommodate still operates within the confines of being able to fulfil the job requirements. Fluctuations in disease and pseudo exacerbations can confound meeting these requirements, making permanent and meaningful employment out of reach for many, as most people with MS are not free of all disease activity.3 Obstacles to employment are multifactorial and can be independent of clinically stable disease, a measurement used in the paper by Ameri et al . …

    更新日期:2019-12-18
  • Keeping people with MS in the workforce through effective treatment
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Steve Simpson

    The clinical pathogenesis of multiple sclerosis (MS) can be profoundly deleterious to employment, with disability and fatigue leading to reduced employment hours, changes to less demanding job tasks, and early retirement.1 Given the typical onset of MS in the 20–40 years old range, these effects on employment occur in the prime years when people are typically establishing their careers. MS clinical progression leads directly to reduced or lost income and forced patients to rely on disability pension supports, and thus becoming a significant cost for society. Until recently, treatment options to reduce MS progression were limited. Symptom-specific treatments could ameliorate some elements like spasticity, incontinence and fatigue but did …

    更新日期:2019-12-18
  • Stay at home with the amyotrophic lateral sclerosis functional rating scale
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Christopher J McDermott

    In this issue, Bakker and colleagues report on the development and assessment of the performance of a self-administered version of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R).1 The ALSFRS, subsequently revised to ALSFRS-R is a functional outcome measure for ALS trials and has been shown to correlate with survival and muscle strength.2 As an outcome measure, it is not without its problems including multidimensionality, non-linearity, poor sensitivity to change in latter stages of disease and the absence of a cognitive function domain.3 4 Survival has traditionally been seen as the gold standard outcome measure; however, such trials are long and expensive. This has led to …

    更新日期:2019-12-18
  • FGFR3 autoantibodies in sensory neuronopathy
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Norman Latov

    FGFR3 antibodies have been associated with sensory neuropathy, but many questions remain regarding their use in clinical practice.

    更新日期:2019-12-18
  • Case for a new corticosteroid treatment trial in optic neuritis: review of updated evidence
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Axel Petzold; Tasanee Braithwaite; Bob W van Oosten; Lisanne Balk; Elena H Martinez-Lapiscina; Russell Wheeler; Nils Wiegerinck; Christiaan Waters; Gordon T Plant

    Optic neuritis (ON) is a condition that causes loss of vision. Most frequently, ON affects one eye, but occasionally, simultaneous bilateral loss of vision occurs. Typically, a variable degree of spontaneous recovery takes place within about 3 months and can continue for up to 1 year. There are a number of triggers for ON, ranging from postvaccination episodes to any type of inflammation and specific autoimmune conditions such as multiple sclerosis (MS), neuromyelitis optica (NMO), and myelin oligodendrocyte glycoprotein (MOG) ON among1 2 others. In about 5% of patients, there is risk of severe permanent loss of vision and blindness. A major challenge is that it is not possible to know the subtype of ON at presentation. While certain demographic features, symptoms and clinical signs are suggestive, more definitive results from blood tests and neuroimaging can take days or weeks to obtain. Furthermore, negative findings in the blood tests do not rule out non-multiple sclerosis-associated optic neuritis (MSON). The clinical management of patients who suffer from MSON has been profoundly influenced by the 1992 US Optic Neuritis Treatment Trial (ONTT).3 This trial recommended intravenous corticosteroids, not to improve the final outcome but to speed up visual recovery.4 There were, however, limitations to the ONTT protocol, which may have influenced the findings.5 First, the ONTT used a vague definition of ‘symptom onset’. This is relevant because loss of vision (used in the ONTT) is frequently preceded by several days of pain from inflammation.6 Second, there was delayed treatment initiation, at a mean of 5.0±1.6 days, which was timed from the visual loss but not from the onset of pain. Third, by contemporary standards, the trial primary outcome measure of high-contrast visual acuity (HCVA) was relatively crude. Fourth, the ONTT recruited a heterogeneous cohort of ON types, including a …

    更新日期:2019-12-18
  • Psychosis and longitudinal outcomes in Huntington disease: the COHORT Study
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Michael H Connors; Armando Teixeira-Pinto; Clement T Loy

    Objective Huntington disease (HD) is an autosomal dominant neurodegenerative disease involving motor disturbances, cognitive decline and psychiatric symptoms. Psychotic symptoms occur in a significant proportion of patients. We sought to characterise the clinical outcomes of this group of patients. Methods Data were drawn from the Cooperative Huntington Observational Research Trial, a prospective, multi-centre observational study. 1082 patients with HD were recruited. Measures of cognition, function, behavioural disturbance and motor function were completed annually over 5 years. Results Overall, 190 patients (17.6%) displayed psychotic symptoms. These patients demonstrated worse cognition, function and behavioural disturbances than patients without psychosis over time. Patients with psychosis also demonstrated lower levels of chorea than patients without psychosis, despite adjusting for concurrent antipsychotic and tetrabenazine use. Conclusions Psychosis in HD is associated with poorer outcomes in cognition, function and behavioural symptoms. Patients with psychotic symptoms may also have less chorea. Altogether, the findings suggest patients with psychosis have a distinct clinical course.

    更新日期:2019-12-18
  • Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Shuang Bai; Wenliang Guo; Yangyang Feng; Hong Deng; Gaigai Li; Hao Nie; Guangyu Guo; Haihan Yu; Yang Ma; Jiahui Wang; Shiling Chen; Jie Jing; Jingfei Yang; Yingxin Tang; Zhouping Tang

    Objectives To systematically review the efficacy and safety of anti-inflammatory agents for patients with major depressive disorders. Methods We searched the literature to identify potentially relevant randomised controlled trials (RCTs) up to 1 January 2019. The primary outcome was efficacy, measured by mean changes in depression score from baseline to endpoint. Secondary outcomes included response and remission rates and quality of life (QoL). Safety was evaluated by incidence of classified adverse events. Heterogeneity was examined using the I2 and Q statistic. Pooled standard mean differences (SMDs) and risk ratios (RRs) were calculated. Subgroup meta-analyses were conducted based on type of treatment, type of anti-inflammatory agents, sex, sponsor type and quality of studies. Results Thirty RCTs with 1610 participants were included in the quantitative analysis. The overall analysis pooling from 26 of the RCTs suggested that anti-inflammatory agents reduced depressive symptoms (SMD −0.55, 95% CI −0.75 to −0.35, I2=71%) compared with placebo. Higher response (RR 1.52, 95% CI 1.30 to 1.79, I2=29%) and remission rates (RR 1.79, 95% CI 1.29 to 2.49, I2=41%) were seen in the group receiving anti-inflammatory agents than in those receiving placebo. Subgroup analysis showed a greater reduction in symptom severity in both the monotherapy and adjunctive treatment groups. Subgroup analysis of non-steroidal anti-inflammatory drugs, omega-3 fatty acids, statins and minocyclines, respectively, disclosed significant antidepressant effects for major depressive disorder (MDD). For women-only trials, no difference in changes of depression severity was found between groups. Subanalysis stratified by sponsor type and study quality led to the same outcomes in favour of anti-inflammatory agents in both subgroups. Changes of QoL showed no difference between the groups. Gastrointestinal events were the only significant differences between groups in the treatment periods. Conclusions Results of this systematic review suggest that anti-inflammatory agents play an antidepressant role in patients with MDD and are reasonably safe.

    更新日期:2019-12-18
  • Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Susan Peters; Anne E Visser; Fabrizio D'Ovidio; Jelle Vlaanderen; Lützen Portengen; Ettore Beghi; Adriano Chio; Giancarlo Logroscino; Orla Hardiman; Elisabetta Pupillo; Jan H Veldink; Roel Vermeulen; Leonard H van den Berg

    Background We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case–control studies and explored the independent effects of intensity, duration and time-since-quitting. Methods ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models. Results Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (ptrend=0.001) rather than intensity (ptrend=0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (ptrend<0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration. Conclusions Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.

    更新日期:2019-12-18
  • CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer’s disease
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Sarah Teuber-Hanselmann; Jan Rekowski; Jonathan Vogelgsang; Christine von Arnim; Kathrin Reetz; Andreas Stang; Karl-Heinz Jöckel; Jens Wiltfang; Herrmann Esselmann; Markus Otto; Hayrettin Tumani; Arne Herring; Kathy Keyvani

    Objective There is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of Alzheimer’s disease (AD). Previous work in our lab has identified Kallikrein-8 (KLK8) as a potential candidate since it shows an excessive increase in human brain in preclinical disease stages. The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) and blood KLK8 for AD and mild cognitive impairment (MCI) due to AD. Methods In this multi-centre trans-sectional study, clinical and laboratory data as well as CSF and/or blood serum samples of 237 participants, including 98 patients with mild AD, 21 with MCI due to AD and 118 controls were collected. CSF and/or serum KLK8 levels were analysed by ELISA. The diagnostic accuracy of KLK8 in CSF and blood was determined using receiver operating characteristic (ROC) analyses and compared with that of CSF core biomarkers Aβ42, P-tau and T-tau. Results The diagnostic accuracy of CSF KLK8 was as good as that of core CSF biomarkers for AD (area under the curve (AUC)=0.89) and in case of MCI (AUC=0.97) even superior to CSF Aβ42. Blood KLK8 was a similarly strong discriminator for MCI (AUC=0.94) but slightly weaker for AD (AUC=0.83). Conclusions This is the first study to demonstrate the potential clinical utility of blood and CSF KLK8 as a biomarker for incipient AD. Future prospective validation studies are warranted.

    更新日期:2019-12-18
  • Clinical characterisation of sensory neuropathy with anti-FGFR3 autoantibodies
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Yannick Tholance; Christian Peter Moritz; Carole Rosier; Karine Ferraud; François Lassablière; Evelyne Reynaud-Federspiel; Marcondes C França Jr; Alberto R M Martinez; Jean-Philippe Camdessanché; Jean-Christophe Antoine

    Objective Sensory neuropathies (SNs) are often classified as idiopathic even if immunological mechanisms can be suspected. Antibodies against the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) possibly identify a subgroup of SN affecting mostly the dorsal root ganglion (DRG). The aim of this study was to identify the frequency of anti-FGFR3 antibodies and the associated clinical pattern in a large cohort of patients with SN. Methods A prospective, multicentric, European and Brazilian study included adults with pure SN. Serum anti-FGRF3 antibodies were analysed by ELISA. Detailed clinical and paraclinical data were collected for each anti-FGFR3-positive patient and as control for anti-FGFR3-negative patients from the same centres (‘center-matched’). Results Sixty-five patients out of 426 (15%) had anti-FGFR3 antibodies, which were the only identified autoimmune markers in 43 patients (66%). The neuropathy was non-length dependent in 89% and classified as sensory neuronopathy in 64%, non-length-dependent small fibre neuropathy in 17% and other neuropathy in 19%. Specific clinical features occurred after 5–6 years of evolution including frequent paresthesia, predominant clinical and electrophysiological involvement of the lower limbs, and a less frequent mixed large and small fibre involvement. Brazilians had a higher frequency of anti-FGFR3 antibodies than Europeans (36% vs 13%, p<0.001), and a more frequent asymmetrical distribution of symptoms (OR 169, 95% CI 3.4 to 8424). Conclusions Anti-FGFR3 antibodies occur in a subgroup of SN probably predominantly affecting the DRG. Differences between Europeans and Brazilians could suggest involvement of genetic or environmental factors.

    更新日期:2019-12-18
  • Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIGMS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Kumaran Deiva; Peter Huppke; Brenda Banwell; Tanuja Chitnis; Jutta Gärtner; Lauren Krupp; Emmanuelle Waubant; Tracy Stites; Gregory Lewis Pearce; Martin Merschhemke

    Background In PARADIG MS , a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) β-1a. Objectives To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression. Methods ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc. Results In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF β-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%–94.6%. Twice as many IFN β-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively. Conclusions Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN β-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years. Trial registration number [NCT01892722][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01892722&atom=%2Fjnnp%2F91%2F1%2F58.atom

    更新日期:2019-12-18
  • Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Thor Ameri Chalmer; Mathias Buron; Zsolt Illes; Viktoria Papp; Asta Theodorsdottir; Jakob Schäfer; Victoria Hansen; Nasrin Asgari; Pernille Bro Skejø; Henrik Boye Jensen; Per Soelberg Sørensen; Melinda Magyari

    Objective To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT). Methods Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks. Results We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0–5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5–10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01). Conclusion Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.

    更新日期:2019-12-18
  • Development and assessment of the inter-rater and intra-rater reproducibility of a self-administration version of the ALSFRS-R
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Leonhard A Bakker; Carin D Schröder; Harold H G Tan; Simone M A G Vugts; Ruben P A van Eijk; Michael A van Es; Johanna M A Visser-Meily; Leonard H van den Berg

    Objective The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is widely applied to assess disease severity and progression in patients with motor neuron disease (MND). The objective of the study is to assess the inter-rater and intra-rater reproducibility, i.e., the inter-rater and intra-rater reliability and agreement, of a self-administration version of the ALSFRS-R for use in apps, online platforms, clinical care and trials. Methods The self-administration version of the ALSFRS-R was developed based on both patient and expert feedback. To assess the inter-rater reproducibility, 59 patients with MND filled out the ALSFRS-R online and were subsequently assessed on the ALSFRS-R by three raters. To assess the intra-rater reproducibility, patients were invited on two occasions to complete the ALSFRS-R online. Reliability was assessed with intraclass correlation coefficients, agreement was assessed with Bland-Altman plots and paired samples t -tests, and internal consistency was examined with Cronbach’s coefficient alpha. Results The self-administration version of the ALSFRS-R demonstrated excellent inter-rater and intra-rater reliability. The assessment of inter-rater agreement demonstrated small systematic differences between patients and raters and acceptable limits of agreement. The assessment of intra-rater agreement demonstrated no systematic changes between time points; limits of agreement were 4.3 points for the total score and ranged from 1.6 to 2.4 points for the domain scores. Coefficient alpha values were acceptable. Discussion The self-administration version of the ALSFRS-R demonstrates high reproducibility and can be used in apps and online portals for both individual comparisons, facilitating the management of clinical care and group comparisons in clinical trials.

    更新日期:2019-12-18
  • Haematoma evacuation in cerebellar intracerebral haemorrhage: systematic review
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Sanjula Dhillon Singh; Hens Bart Brouwers; Jasper Rudolf Senff; Marco Pasi; Joshua Goldstein; Anand Viswanathan; Catharina J M Klijn; Gabriël Johannes Engelmundus Rinkel

    Background Guidelines regarding recommendations for surgical treatment of spontaneous cerebellar intracerebral haemorrhage (ICH) differ. We aimed to systematically review the literature to assess treatment strategies and outcomes. Methods We searched PubMed and Embase between 1970 and 2019 for randomised or otherwise controlled studies and observational cohort studies. We included studies according to predefined selection criteria and assessed their quality according to the Newcastle-Ottawa Scale (NOS) and risk of bias according to a predefined scale. We assessed case fatality and functional outcome in patients treated conservatively or with haematoma evacuation. Favourable functional outcome was defined as a modified Rankin Scale score of 0–2 or a Glasgow Outcome Scale score of 4–5. Results We included 41 observational cohort studies describing 2062 patients (40% female) with spontaneous cerebellar ICH. A total of 1171 patients (57%) underwent haematoma evacuation. Ten studies described a cohort of surgically treated patients (n=533) and 31 cohorts with both surgically and conservatively treated patients (n=638 and n=891, respectively). There were no randomised clinical trials nor studies comparing outcome between the groups after adjustment for differences in baseline characteristics. The median NOS score (IQR) was 5 (4–6) out of 8 points and the bias score was 2 (1–3) out of 8, indicative of high risk of bias. Case fatality at discharge was 21% (95% CI 17% to 25%) after conservative treatment and 24% (95% CI 19% to 29%) after haematoma evacuation. At ≥6 months after conservative treatment, case fatality was 30% (95% CI 25% to 30%) and favourable functional outcome was 45% (95% CI 40% to 50%) and after haematoma evacuation, case fatality was 34% (95% CI 30% to 38%) and 42% (95% CI 37% to 47%). Conclusions Controlled studies on the effect of neurosurgical treatment in patients with spontaneous cerebellar ICH are lacking, and the risk of bias in published series is high. Due to substantial differences in patient characteristics between conservatively and surgically treated patients, and high variability in treatment indications, a meaningful comparison in outcomes could not be made. There is no good published evidence to support treatment recommendations and controlled, preferably randomised studies are warranted in order to formulate evidence-based treatment guidelines for patients with cerebellar ICH.

    更新日期:2019-12-18
  • Disentangling the multiple links between renal dysfunction and cerebrovascular disease
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Dearbhla Kelly; Peter Malcolm Rothwell

    Chronic kidney disease (CKD) has a rapidly rising global prevalence, affecting as many as one-third of the population over the age of 75 years. CKD is a well-known risk factor for cardiovascular disease and, in particular, there is a strong association with stroke. Cohort studies and trials indicate that reduced glomerular filtration rate increases the risk of stroke by about 40% and that proteinuria increases the risk by about 70%. In addition, CKD is also strongly associated with subclinical cerebrovascular abnormalities, vascular cognitive impairment and dementia. The mechanisms responsible for these associations are currently unclear. CKD is associated with traditional risk factors such as hypertension, diabetes mellitus and atrial fibrillation, but non-traditional risk factors such as uraemia, oxidative stress, mineral and bone abnormalities, and dialysis-related factors, such as changes in cerebral blood flow or cardiac structure, are also postulated to play a role. Kidney disease can also impact and complicate the treatments used in acute stroke and in secondary prevention. In this review, we will outline our current understanding of the epidemiology and pathophysiology of cerebrovascular disease in CKD.

    更新日期:2019-12-18
  • Midbrain MRI assessments in progressive supranuclear palsy subtypes
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Marina Picillo; Maria Francesca Tepedino; Filomena Abate; Roberto Erro; Sara Ponticorvo; Salvatore Tartaglione; Giampiero Volpe; Daniela Frosini; Paolo Cecchi; Mirco Cosottini; Roberto Ceravolo; Fabrizio Esposito; Maria Teresa Pellecchia; Paolo Barone; Renzo Manara

    Objectives To explore the role of the available midbrain-based MRI morphometric assessments in (1) differentiating among progressive supranuclear palsy (PSP) subtypes (PSP Richardson’s syndrome (PSP-RS), PSP with predominant parkinsonism (PSP-P) and the other variant syndromes of PSP (vPSP)), and (2) supporting the diagnosis of PSP subtypes compared with Parkinson’s disease (PD) and healthy controls (HC). Methods Seventy-eight patients with PSP (38 PSP-RS, 21 PSP-P and 19 vPSP), 35 PD and 38 HC were included in the present analysis. Available midbrain-based MRI morphometric assessments were calculated for all participants. Results Current MRI midbrain-based assessments do not display an adequate sensitivity and specificity profile in differentiating PSP subtypes. On the other hand, we confirmed MR Parkinsonism Index (MRPI) and pons area to midbrain area ratio (P/M) have adequate diagnostic value to support PSP-RS clinical diagnosis compared with both PD and HC, but low sensitivity and specificity profile in differentiating PSP-P from PD as well as from HC. The same measures show acceptable sensitivity and specificity profile in supporting clinical diagnosis of vPSP versus HC but not versus PD. Similar findings were detected for the newer MRPI and P/M versions. Conclusions Further studies are warranted to identify neuroimaging biomarkers supporting the clinical phenotypic categorisation of patients with PSP. MRPI and P/M have diagnostic value in supporting the clinical diagnosis of PSP-RS. Classification of evidence This study provides class III evidence that available MRI midbrain-based assessments do not have diagnostic value in differentiating the Movement Disorder Society PSP subtypes.

    更新日期:2019-12-18
  • Burden of brain disorders in Europe in 2017 and comparison with other non-communicable disease groups
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Alberto Raggi; Matilde Leonardi

    Brain disorders, together with other non-communicable diseases (NCDs), such as musculoskeletal disorders, cardiovascular disorders and tumours, are leading burdensome diseases. These four groups in fact account for 65.5% of the burden associated with NCDs, and 40.7% of the all-cause burden.1 As shown in the recently published Global Burden of Disease (GBD) 2017 estimates, the burden of mental and neurological conditions increased by 13.5%–20.5% between 1990 and 2017, mostly because of population ageing.1 However, research into brain disorders is fragmented, and the appreciation of their size and burden is still limited.2 3 In Europe, brain disorders accounted for 35% of the burden in 20002 and for 26.6% in 2010.3 These figures need to be updated given European population ageing (see online supplementary materials) and because some leading burdensome conditions, for example, stroke and dementias, typically occur in older age. ### Supplementary data [jnnp-2019-320466supp001.pdf] The aims of this paper are to present the updated burden of brain disorders in Europe relying on GBD 2017 data, and to compare it to that of other burdensome diseases, namely tumours, musculoskeletal and cardiovascular. We used the GBD 2017 data made available by the Institute for Health Metrics and Evaluation (available at http://ghdx.healthdata.org/gbd-results-tool) referred to EU-28 with the addition of Iceland, Norway and Switzerland. The overall population of these countries comprised 521.4 million citizens, 441.0 million aged 15+ years (see online supplementary table 1). …

    更新日期:2019-12-18
  • Longitudinal (18F)AV-1451 PET imaging in a patient with frontotemporal dementia due to a Q351R MAPT mutation
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Rhian S Convery; Jieqing Jiao; Mica T M Clarke; Katrina M Moore; Carolin A M Koriath; Ione O C Woollacott; Philip S J Weston; Roger Gunn; Ilan Rabiner; David M Cash; Martin N Rossor; Jason D Warren; Nick C Fox; Sebastien Ourselin; Martina Bocchetta; Jonathan D Rohrer

    Mutations in the microtubule associated protein tau ( MAPT ) gene are a common cause of inherited frontotemporal dementia (FTD) and result in the deposition of pathological tau protein in the brain.1 Tau positron emission tomography (PET) may enhance in vivo diagnosis and testing of tau-based therapies in FTD, however, few tau ligands have been validated in FTD. The (18F)AV-1451 ligand was developed to assess in vivo tau accumulation and has consistently been shown to bind to tau in individuals with Alzheimer’s disease (AD) but less work has focused on the non-AD tauopathies, including FTD. Autoradiography studies of (18F)AV-1451 have shown strong binding in regions of neurofibrillary tangles matching the pattern of paired helical filament (PHF) immunochemistry but have not shown strong binding to non-PHF-tau.2 In (18F)AV-1451 studies conducted in FTD spectrum disorders, not only does the ligand not bind strongly to non-PHF tau, but there is significant in vivo binding reported in conditions where no tau is expected at all, for example, in patients with semantic variant primary progressive aphasia and with C9orf72 expansions where TDP-43 pathology is usually found.3 4 (18F)AV-1451 also displays both off-target binding in the basal ganglia and an age-related increase in binding in cognitively healthy controls.3 Nevertheless, this ligand has shown strong binding in a subset of FTD-causing MAPT mutations, including V337M and R406W that are associated with PHF-tau pathology.1 5 (18F)AV-1451 may therefore be useful in detecting tau pathology in some genetic forms of FTD that result in similar structural conformations of tau to that of AD. Here we describe longitudinal (18F)AV-1451 PET imaging from a patient with FTD due to a Q351R mutation located on exon 12 of the MAPT gene.6 ### Participants A patient with a Q351R MAPT mutation in her mid-60s as …

    更新日期:2019-12-18
  • CSF tau proteins correlate with an atypical clinical presentation in dementia with Lewy bodies
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2020-01-01
    Rita Di Censo; Carla Abdelnour; Frederic Blanc; Olivier Bousiges; Afina W Lemstra; Inger van Steenoven; Marco Onofrj; Dag Aarsland; Laura Bonanni

    A cerebrospinal fluid (CSF) Alzheimer’s disease (AD) profile, that is, decreased amyloid-β1-42 (Aβ42) and increased total tau protein (t-tau) and/or phosphorylated tau at threonine-181 (p-tau),1 has been identified in a substantial number of dementia with Lewy bodies (DLB) patients, and it has been related to a more rapid cognitive decline.1 We investigated the association between AD CSF biomarkers and DLB core clinical features to better understand in vivo how AD pathology influences DLB clinical presentation. We included 171 subjects with a clinical diagnosis of probable DLB2 3 from the European DLB consortium (E-DLB). The centres involved are summarised in online supplementary table 1. Clinical examination was performed as previously reported.1 Dopamine transporter (DAT) single-photon emission CT scans (123I-FP-CIT-SPECT) were performed in 80 patients.### Supplementary data [jnnp-2019-320980supp001.pdf] CSF samples were collected at each centre according to the procedures detailed in online supplementary table 1. An AD CSF profile was defined as low Aβ42 combined with high t-tau or p-tau.1 Information about pharmacological treatments of patients were not available at each centre. Statistical analyses were performed using SPSS V.24. Association between CSF biomarkers (normal or abnormal), and each core features (present or absent), were tested with χ2 test. Associations between single CSF biomarkers and groups of subjects with different core clinical features’ number (1–4) were tested with Armitage test for trend. Local ethics committees approved the study. All patients gave their written consent for the use of their …

    更新日期:2019-12-18
  • Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-17
    Brian D Berman; Christopher L Groth; Stefan H Sillau; Sarah Pirio Richardson; Scott A Norris; Johanna Junker; Norbert Brüggemann; Pinky Agarwal; Richard L Barbano; Alberto J Espay; Joaquin A Vizcarra; Christine Klein; Tobias Bäumer; Sebastian Loens; Stephen G Reich; Marie Vidailhet; Cecilia Bonnet; Emmanuel Rose; Hyder A Jinnah; Joel S Perlmutter

    Objective Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients. Methods Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread. Results 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009). Conclusions Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.

    更新日期:2019-12-18
  • Revascularisation surgery improves cognition in adult patients with moyamoya disease
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-13
    Toshihiko Ando; Yasuyoshi Shimada; Shunrou Fujiwara; Kenji Yoshida; Masakazu Kobayashi; Yoshitaka Kubo; Kazunori Terasaki; Satoshi Ando; Kuniaki Ogasawara

    One-(2-18F-fluoro-1-(hydroxymethyl)ethoxy) methyl-2-nitroimidazole (18F-FRP170) is a marker of hypoxic but viable tissue in the human brain and is used in positron emission tomography (PET).1 Neural tissues showing elevated 18F-FRP170 uptake exist in brain areas with chronic cerebral ischaemia with a combination of increased oxygen extraction fraction, namely misery perfusion and moderately reduced cerebral metabolic rate of oxygen (CMRO2) due to atherosclerotic stenosis or occlusion of the internal carotid artery.1 These hypoxic neural tissues decrease after cerebral perfusion and restored following carotid endarterectomy, leading to postoperative cognitive improvement after surgery.2 Adults with ischaemic moyamoya disease (MMD) sometimes experience cognitive improvement after revascularisation surgery.3 The present prospective study was aimed to determine whether the resolution of hypoxia in neural tissue and recovery of cerebral oxygen metabolism on PET after revascularisation surgery such as a combination of the superficial temporal artery–middle cerebral artery anastomosis and encephalo-duro-myo-synangiosis are related to postoperatively improved cognition in adults with ischaemic MMD. Patients with the following criteria were prospectively included in this study: (1) bilateral MMD confirmed by angiography via arterial catheterisation; (2) histories of ischaemic symptoms in unilateral carotid artery territory ≤3 months before visiting our hospital; (3) ≥30 years and <60 years; (4) preoperative modified Rankin disability scale, 0 or 1; (5) no cortical infarct or presence of infarcts that did not occupy the entire cortical area …

    更新日期:2019-12-17
  • Phenotypic presentations of paraneoplastic neuropathies associated with MAP1B-IgG
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-04
    Jiraporn Jitprapaikulsan, C J Klein, Sean J Pittock, Avi Gadoth, Andrew McKeon, John R Mills, Divyanshu Dubey

    Purkinje cell cytoplasmic antibody type-2 (PCA2-IgG) was first defined as a paraneoplastic biomarker based on a unique immunofluorescence pattern seen on a mouse composite brain tissue assay.1 Lung and breast cancer are the most common malignancies associated with PCA2-IgG seropositivity.2 In 2017, microtubule-associated protein 1B (MAP1B) protein was identified as the autoantigen target for PCA2-IgG.2 Clinical presentation associated with MAP1B-IgG is variable including neuropathy, encephalopathy, cognitive dysfunction, brainstem syndrome, ophthalmic involvement and cerebellar ataxia.1 2 Despite neuropathy being the most common neurological accompaniment earlier reports lack details of those neuropathies.2 Here, we describe the neuropathy phenotypes in patients affected by MAP1B-IgG autoimmunity. Although rare, recognition of this paraneoplastic neuropathy phenotype may aid early detection of underlying malignancy. We reviewed the Mayo Clinic Neuroimmunology laboratory database (1 January 1995 and 30 September 2018) for patients tested for paraneoplastic panel by indirect immunofluorescence assay (IFA) and western blot (WB) analysis of rat cerebellar and cortical extracts (online supplementary methods).2 All PCA2-IgG stored samples were also tested and confirmed positive on MAP1B fragment WB. Study inclusion criteria: (1) MAP1B-IgG seropositivity by IFA and MAP1B WB, (2) presence of somatic and autonomic peripheral neuropathies and (3) exclusion of alternative aetiologies including chemotherapy-induced neuropathies, diabetes mellitus, nutritional deficiency, systemic vasculitis, lymphoma and paraproteinemia as deemed clinically appropriate. Clinical outcomes were evaluated by improvement in modified Rankin Scale (≥1) and 5-year mortality rate. Anti-Neuronal Nuclear Antibody type-1 (ANNA1 aka anti-Hu-IgG) seropositive neuropathy cases evaluated at Mayo Clinic (2000–2018), were utilised to evaluate phenotype and survival outcome comparison. All patients with ANNA1-IgG neuropathy in the comparison group were negative for MAP1B-IgG. ### Supplementary data [jnnp-2019-322175supp001.pdf] Indirect IFA using MAP1B-IgG neuropathy patients’ serum showed staining of rat dorsal root ganglia, sciatic nerves, sympathetic ganglia and spinal cord, along with typical staining of cerebellum and myenteric …

    更新日期:2019-12-04
  • IgM-gammopathy strongly favours immune treatable MMN and MADSAM over ALS
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-03
    Shahar Shelly, John R Mills, Jennifer M Martinez-Thompson, Matt M Rofforth, Sean J Pittock, Jay Mandrekar, James Douglas Triplett, Michelle Mauermann, Divyanshu Dubey, C J Klein

    The early diagnosis of amyotrophic lateral sclerosis (ALS) is often difficult as not all patients meet clinical and electrophysiological criteria.1 Additionally a small per cent of patients have a divergent diagnosis, most commonly multifocal motor neuropathy (MMN) or motor-predominant multifocal acquired demyelinating sensory and motor neuropathy (MADSAM).2 Although motor conduction blocks distinguish MMN and MADSAM from ALS, it is often difficult to find these conduction abnormalities when present at the roots or plexus. Currently biomarkers to assist in the diagnosis of ALS versus MMN and MADSAM are inadequate. Specifically, GM1 (ganglioside monosialo-asialo) autoantibodies can be present in all these disorders, although typically of lower values in ALS. Recently, IgM-gammopathy was suggested to be more common in MMN (7%) compared with healthy (2%) and ALS (1%) controls.3 If true, IgM-gammopathy may forebode for an immune treatment refractory disorder as described in other IgM-gammopathy neuropathies.4 Herein, we address: (1) the occurrence of an IgM-gammopathy in MMN and MADSAM compared with ALS and (2) evaluate the immune treatment response of MMN and MADSAM IgM-monoclonal-gammopathy. ### Clinical characteristics We identified 78 MADSAM, 65 MMN cases and 412 ALS patients matched in gender and age. ALS was considered in the differential diagnosis of 51% (40/78) of MADSAM and 64% (42/65) of MMN patients due to motor predominant progressive symptoms. IgM-gammopathy was significantly (p<0.001; OR estimate of 33, 95% CI) more common in MADSAM 23% (18/78) and MMN 17% (11/65) compared with ALS<1% (2/412) (figure 1). IgM-Kappa was the most …

    更新日期:2019-12-04
  • Untangling neuroinflammation in amyotrophic lateral sclerosis
    J. Neurol. Neurosurg. Psychiatry (IF 8.272) Pub Date : 2019-12-01
    Alexander Guy Thompson, Martin R Turner

    A broad body of evidence supports both pathogenic and neuroprotective roles for inflammation in amyotrophic lateral sclerosis (ALS)1 but trials of several immunomodulatory drugs have not yielded a beneficial effect in an increasingly complex disorder with multiple upstream cellular causes.2 There has been interest in proteins involved in the microglial response as potential biomarkers for well over a decade.3 4 Recently this has focused on a group of three chitinase proteins, thought to be macrophage-derived, identified in proteomic analysis of cerebrospinal fluid (CSF) taken from ALS patients.5 6 Chitinases have also been studied the pathologically related disorder frontotemporal dementia (FTD).7 8 Although chitin is not produced by mammals, it is suggested that chitinases might act on N -acetylglucosamine-containing extracellular matrix polymers, such as hyaluronan or keratan sulfate, …

    更新日期:2019-11-14
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