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Cohort profile: the Oxford Parkinson's Disease Centre Discovery Cohort MRI substudy (OPDC-MRI).
PURPOSE: The Oxford Parkinson's Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson's, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and function, and develop, together with the clinical data, biomarkers to stratify, predict and chart progression in early-stage Parkinson's and at-risk individuals. PARTICIPANTS: Participants are recruited from the OPDC Discovery Cohort, a prospective, longitudinal study. Baseline MRI data are currently available for 290 participants: 119 patients with early idiopathic Parkinson's, 15 Parkinson's patients with pathogenic mutations of the leucine-rich repeat kinase 2 or glucocerebrosidase (GBA) genes, 68 healthy controls and 87 individuals at risk of Parkinson's (asymptomatic carriers of GBA mutation and patients with idiopathic rapid eye movement sleep behaviour disorder-RBD). FINDINGS TO DATE: Differences in brain structure in early Parkinson's were found to be subtle, with small changes in the shape of the globus pallidus and evidence of alterations in microstructural integrity in the prefrontal cortex that correlated with performance on executive function tests. Brain function, as assayed with resting fMRI yielded more substantial differences, with basal ganglia connectivity reduced in early Parkinson'sand RBD. Imaging of the substantia nigra with the more recent adoption of sequences sensitive to iron and neuromelanin content shows promising results in identifying early signs of Parkinsonian disease. FUTURE PLANS: Ongoing studies include the integration of multimodal MRI measures to improve discrimination power. Follow-up clinical data are now accumulating and will allow us to correlate baseline imaging measures to clinical disease progression. Follow-up MRI scanning started in 2015 and is currently ongoing, providing the opportunity for future longitudinal imaging analyses with parallel clinical phenotyping.
Altered network stability in progressive supranuclear palsy.
The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states.
Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline
AbstractObjectivesRapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near‐term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility‐weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits.MethodsSWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson’s patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty‐two RBD patients were also imaged with 123I‐ioflupane single‐photon emission computed tomography (DaT SPECT/CT).ResultsConsensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson’s patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P < 0.001).InterpretationOver one quarter of RBD patients have abnormal substantia nigra SWI reminiscent of Parkinson’s, which is associated with a greater dopaminergic deficit. This modality may help enrich neuroprotective trials with early converters.
Longitudinal Changes in Parkinson's Disease Symptoms with and Without Rapid Eye Movement Sleep Behavior Disorder: The Oxford Discovery Cohort Study.
BACKGROUND: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype. OBJECTIVE: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD. METHODS: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores. RESULTS: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60). CONCLUSIONS: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society.
Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging
AbstractA key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We developed a QSM processing pipeline to estimate magnetic susceptibility of multiple brain structures in 35,885 subjects from the UK Biobank prospective epidemiological study. We identified phenotypic associations of magnetic susceptibility that include body iron, disease, diet, and alcohol consumption. Genome-wide associations related magnetic susceptibility to genetic variants with biological functions involving iron, calcium, myelin, and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers world-wide, creating potential to discover novel, non-invasive markers of brain health.
Impulse control disorders in Parkinson disease and RBD: A longitudinal study of severity.
OBJECTIVE: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls. METHODS: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinson's Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinson's Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations. RESULTS: Data from 921 cases of PD at baseline, 768 cases at 18 months, and 531 cases at 36 months were included, with 21% to 25% screening positive for ICBs at each visit. Interviews of ICB screen-positive individuals revealed that 10% met formal criteria for impulse control disorders (ICD), while 33% had subsyndromal ICD (ICB symptoms without reaching the formal diagnostic criteria for ICD). When these data were combined through the use of multiple imputation, the prevalence of PD-ICB was estimated at 19.1% (95% confidence interval 10.1-28.2). On follow-up, 24% of cases of subsyndromal ICD had developed full symptoms of an ICD. PD-ICD was associated with dopamine agonist use, motor complications, and apathy but not PD-RBD. ICD prevalence in the RBD group (1%) was similar to that in controls (0.7%). CONCLUSIONS: ICBs occur in 19.1% of patients with early PD, many persisting or worsening over time. RBD is not associated with increased ICD risk. Psychosocial drivers, including mood and support networks, affect severity.
Predictors of motor complications in early Parkinson's disease: A prospective cohort study.
OBJECTIVE: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. METHODS: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. RESULTS: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). CONCLUSIONS: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Myasthenia gravis in 2025: five new things and four hopes for the future
Abstract The last 10 years has brought transformative developments in the effective treatment of myasthenia gravis (MG). Beginning with the randomized trial of thymectomy in myasthenia gravis that demonstrated efficacy of thymectomy in nonthymomatous MG, several new treatment approaches have completed successful clinical trials and regulatory launch. These modalities, including B cell depletion, complement inhibition, and blockade of the neonatal Fc receptor, are now in use, offering prospects of sustained remission and neuromuscular protection in what is a long-term disease. In this review, we update our clinico-immunological review of 2016 with these important advances, examine their role in treatment algorithms, and focus attention on key issues of biomarkers for prognostication and the growing cohort of older patients, both those with long-term disease, and late-onset MG (‘LOMG’). We close by expressing our four hopes for the next 5–10 years: improvements in laboratory medicine to facilitate rapid diagnosis, effective strategies for neuromuscular protection, more research into and better understanding of pathophysiology and treatment response in older individuals, and the potentially transformative role of therapies aimed at delivering a durable response such as chimeric antigen receptor (CAR) T cells. Our postscript summarizes some emerging themes in the field of serological and online biomarkers, which may develop greater stature in the next epoch.
Gliosarcoma associated with bilateral hippocampal sclerosis in a cat presenting complex partial seizures with orofacial involvement: A case report.
KEY CLINICAL MESSAGE: Gliosarcoma, a rare cerebral neoplasm, has not been linked to hippocampal changes in cats. We report a case of complex partial seizures with orofacial involvement, revealing gliosarcoma concurrent with bilateral hippocampal sclerosis. ABSTRACT: A 16-year-old neutered female domestic shorthair cat presented with acute inappetence, ataxia, disorientation, and vacant staring. Brain MRI revealed an ill-defined, round, intra-axial mass in the right piriform lobe, showing hyperintensity on T2W, T2-FLAIR, and T2*W, and hypointensity on T1W images. The lesion exhibited mass effect and contrast enhancement in its center. Bilateral hyperintensity on T2-FLAIR images and contrast enhancement were observed in the hippocampus. Brain histologic and immunohistochemical analysis revealed cerebral gliosarcoma with concurrent hippocampal sclerosis. Feline LGI1-antibody testing on the serum and/or CSF was not performed due to insufficient biomaterial. Although retrospective testing on brain tissue was considered, it ultimately proved unfeasible, preventing us from ruling out antibody-associated limbic encephalitis. In conclusion, cerebral gliosarcoma should be included in feline intracranial tumor differentials, warranting brain MRI and feline LGI1-antibody testing in cats showing complex partial seizures with orofacial involvement. In our case, the prognosis remained poor due to the presence of a high-grade glioma.
Established, new and future disease modifying therapies for MS
Over recent years the pace of therapeutic development in multiple sclerosis has increased, and there are now 10 disease-modifying therapies available. In this review the authors discuss the evidence supporting the use of these drugs and consider which new treatments may be available in the future.
HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis
IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.
Capturing what matters: Patient‐reported LGI1‐ANTibody encephalitis outcome RatiNg scale (LANTERN)
AbstractBackgroundLGI1‐antibody encephalitis (LGI1‐Ab‐E) is a common form of autoimmune encephalitis where most patients demonstrate ‘good’ clinician‐rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1‐Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease‐specific patient‐reported outcome measure (PROM), adhering to FDA guidelines.MethodsA participant‐driven mixed‐methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi‐structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.ResultsFrom 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89‐question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three‐factor symptom‐burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85–0.91), correlations with relative‐completed questionnaires (R = 0.73–0.85; p < 0.001), good‐to‐excellent intraclass re‐testing correlations (0.81–0.98; n = 19) and strong associations with numerous predefined external measures.DiscussionLANTERN represents a PROM for LGI1‐Ab‐E, with initial content, structural and construct validity and test–retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1‐Ab‐E, both in clinical practice and trials.
Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model.
BACKGROUND AND OBJECTIVE: Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart. METHODS: We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors. RESULTS: The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p
LGI1-antibody encephalitis: how to approach this highly treatable dementia mimic in memory and mental health services
Leucine-rich glioma-inactivated 1-antibody-encephalitis is a treatable and potentially reversible cause of cognitive and psychiatric presentations, and may mimic cognitive decline, rapidly progressive dementia and complex psychosis in older patients. This aetiology is of immediate relevance given the alternative treatment pathway required, compared with other conditions presenting with cognitive deficits.
Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.