Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.

BACKGROUND: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. OBJECTIVE: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. METHODS: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. RESULTS: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. CONCLUSIONS: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A multi-network model of Parkinson's disease tremor: exploring the finger-dimmer-switch theory and role of dopamine in thalamic self-inhibition.

BACKGROUND: Tremor is a cardinal symptom of Parkinson's disease (PD) that manifests itself through complex oscillatory activity across multiple neuronal populations. According to the finger-dimmer-switch (FDS) theory, tremor is triggered by transient pathological activity in the basal ganglia-thalamo-cortical (BTC) network (the finger) and transitions into an oscillatory form within the inner circuitry of the thalamus (the switch). The cerebello-thalamo-cortical (CTC) network (the dimmer) is then involved in sustaining and amplifying tremor amplitude. In this study, we aimed to investigate the generation and progression dynamics of PD tremor oscillations by developing a comprehensive and interacting FDS model that transitions sequentially from healthy to PD to tremor and then to tremor-off state. Methods: We constructed a computational model consisting of 700 neurons in 11 regions of BTC, CTC, and thalamic networks. Transition from healthy to PD state was simulated through modulating dopaminergic synaptic connections; and further from PD to tremor and tremor-off by modulating projections between the thalamic reticular nucleus (TRN), anterior ventrolateral nucleus (VLa), and posterior ventrolateral nucleus (VLp). Results: Sustained oscillations in the frequency range of PD tremor emerged in thalamic VLp (5 Hz) and cerebellar dentate nucleus (3 Hz). Increasing self-inhibition in the thalamus through dopaminergic modulation significantly decreased tremor amplitude. Conclusion/Significance: Our results confirm the mechanistic power of the FDS theory in describing the PD tremor phenomenon and emphasize the role of dopaminergic modulation on thalamic self-inhibition. These insights pave the way for novel therapeutic strategies aimed at reducing the tremor by strengthening thalamic self-inhibition, particularly in dopamine-resistant patients.

GPi/GPe borderland- a potential sweet spot for deep brain stimulation for chorea in Huntington's disease?

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington's disease (HD). OBJECTIVES: To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations. METHODS: We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated. RESULTS: The chorea subscore (p < 0.001) and UHDRS total motor score was significantly reduced postoperatively (p = 0.019). Pallidal DBS did not improve other motor symptoms. Activation of the lateral GPi/GPe was associated with improvement in choreatic symptoms (p = 0.048; r = 0.90). CONCLUSIONS: Our findings indicate that stimulation of the lateral GPi has a stable effect on choreatic symptoms. The modulation of the electrical field is relevant for motor outcome.

Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease.

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.

DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery.

Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) shows variable expressivity and reduced penetrance of ~ 50%. Since THAP1 encodes a transcription factor, modifiers influencing this variability likely operate at the gene expression level. This study aimed to assess the transferability of differentially expressed genes (DEGs) in neuronal cells related to pathogenic variants in the THAP1 gene, which were previously identified by transcriptome analyses. For this, we performed quantitative (qPCR) and Digital PCR (dPCR) in cultured fibroblasts. RNA was extracted from THAP1 manifesting (MMCs) and non-manifesting mutation carriers (NMCs) as well as from healthy controls. The expression profiles of ten of 14 known neuronal DEGs demonstrated differences in fibroblasts between these three groups. This included transcription factors and targets (ATF4, CLN3, EIF2A, RRM1, YY1), genes involved in G protein-coupled receptor signaling (BDKRB2, LPAR1), and a gene linked to apoptosis and DNA replication/repair (CRADD), which all showed higher expression levels in MMCs and NMCs than in controls. Moreover, the analysis of genes linked to neurological disorders (STXBP1, TOR1A) unveiled differences in expression patterns between MMCs and controls. Notably, the genes CUEDC2, DRD4, ECH1, and SIX2 were not statistically significantly differentially expressed in fibroblast cultures. With > 70% of the tested genes being DEGs also in fibroblasts, fibroblasts seem to be a suitable model for DYT-THAP1 research despite some restrictions. Furthermore, at least some of these DEGs may potentially also serve as biomarkers of DYT-THAP1 and influence its penetrance and expressivity.

Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Smaller Cerebellar Lobule VIIb is Associated with Tremor Severity in Parkinson's Disease.

Alterations in the cerebellum's morphology in Parkinson's disease (PD) point to its pathophysiological involvement in this movement disorder. Such abnormalities have previously been attributed to different PD motor subtypes. The aim of the study was to relate volumes of specific cerebellar lobules to motor symptom severity, in particular tremor (TR), bradykinesia/rigidity (BR), and postural instability and gait disorders (PIGD) in PD. We performed a volumetric analysis based on T1-weighted MRI images of 55 participants with PD (22 females, median age 65 years, Hoehn and Yahr stage 2). Multiple regression models were fitted to investigate associations between volumes of cerebellar lobules with clinical symptom severity based on MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score and sub-scores for TR, BR, and PIGD; adjusted for age, sex, disease duration, and intercranial volume as cofactors. Smaller volume of lobule VIIb was associated with higher tremor severity (P = 0.004). No structure-function relationships were detected for other lobules or other motor symptoms. This distinct structural association denotes the involvement of the cerebellum in PD tremor. Characterizing morphological features of the cerebellum leads to a better understanding of its role in the spectrum of motor symptoms in PD and contributes further to identifying potential biological markers.

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner.

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

Cerebellar Modulation of Sensorimotor Associative Plasticity Is Impaired in Cervical Dystonia.

BACKGROUND: In recent years, cervical dystonia (CD) has been recognized as a network disorder that involves not only the basal ganglia but other brain regions, such as the primary motor and somatosensory cortex, brainstem, and cerebellum. So far, the role of the cerebellum in the pathophysiology of dystonia is only poorly understood. OBJECTIVE: The objective of this study was to investigate the role of the cerebellum on sensorimotor associative plasticity in patients with CD. METHODS: Sixteen patients with CD and 13 healthy subjects received cerebellar transcranial direct current stimulation (ctDCS) followed by a paired associative stimulation (PAS) protocol based on transcranial magnetic stimulation that induces sensorimotor associative plasticity. Across three sessions the participants received excitatory anodal, inhibitory cathodal, and sham ctDCS in a double-blind crossover design. Before and after the intervention, motor cortical excitability and motor symptom severity were assessed. RESULTS: PAS induced an increase in motor cortical excitability in both healthy control subjects and patients with CD. In healthy subjects this effect was attenuated by both anodal and cathodal ctDCS with a stronger effect of cathodal stimulation. In patients with CD, anodal stimulation suppressed the PAS effect, whereas cathodal stimulation had no influence on PAS. Motor symptom severity was unchanged after the intervention. CONCLUSIONS: Cerebellar modulation with cathodal ctDCS had no effect on sensorimotor associative plasticity in patients with CD, in contrast with the net inhibitory effect in healthy subjects. This is further evidence that the cerebello-thalamo-cortical network plays a role in the pathophysiology of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disability and persistent motor deficits are linked to structural crossed cerebellar diaschisis in chronic stroke.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited. In this cross-sectional study, structural MRI and clinical data were analyzed from 32 chronic stroke patients, at least 6 months after the event. We quantified lobule-specific contralesional atrophy, as a surrogate of structural CCD, in patients and healthy controls. Volumetric data were integrated with clinical scores of disability and motor deficits. Diaschisis-outcome models were adjusted for the covariables age, lesion volume, and damage to the corticospinal tract. We found that structural CCD was evident for the whole cerebellum, and particularly for lobules V and VI. Lobule VI diaschisis was significantly correlated with clinical scores, that is, volume reductions in contralesional lobule VI were associated with higher levels of disability and motor deficits. Lobule V and the whole cerebellum did not show similar diaschisis-outcome relationships across the spectrum of the clinical scores. These results provide novel insights into stroke-related cerebellar plasticity and might thereby promote lobule VI as a key area prone to structural CCD and potentially involved in recovery and residual motor functioning.

Perception-Action Integration Is Altered in Functional Movement Disorders.

BACKGROUND: Although functional neurological movement disorders (FMD) are characterized by motor symptoms, sensory processing has also been shown to be disturbed. However, how the integration of perception and motor processes, essential for the control of goal-directed behavior, is altered in patients with FMD is less clear. A detailed investigation of these processes is crucial to foster a better understanding of the pathophysiology of FMD and can systematically be achieved in the framework of the theory of event coding (TEC). OBJECTIVE: The aim was to investigate perception-action integration processes on a behavioral and neurophysiological level in patients with FMD. METHODS: A total of 21 patients and 21 controls were investigated with a TEC-related task, including concomitant electroencephalogram (EEG) recording. We focused on EEG correlates established to reflect perception-action integration processes. Temporal decomposition allowed to distinguish between EEG codes reflecting sensory (S-cluster), motor (R-cluster), and integrated sensory-motor processing (C-cluster). We also applied source localization analyses. RESULTS: Behaviorally, patients revealed stronger binding between perception and action, as evidenced by difficulties in reconfiguring previously established stimulus-response associations. Such hyperbinding was paralleled by a modulation of neuronal activity clusters, including reduced C-cluster modulations of the inferior parietal cortex and altered R-cluster modulations in the inferior frontal gyrus. Correlations of these modulations with symptom severity were also evident. CONCLUSIONS: Our study shows that FMD is characterized by altered integration of sensory information with motor processes. Relations between clinical severity and both behavioral performance and neurophysiological abnormalities indicate that perception-action integration processes are central and a promising concept for the understanding of FMD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-phenotype correlation and treatment effects in young patients with GNAO1-associated disorders.

BACKGROUND: Patients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations. METHODS: To improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients. RESULTS: The main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype. CONCLUSION: The broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.

Tremor is associated with familial clustering of dystonia.

INTRODUCTION: Dystonia is a movement disorder of variable etiology and clinical presentation and is accompanied by tremor in about 50% of cases. Monogenic causes in dystonia are rare, but also in the group of non-monogenic dystonias 10-30% of patients report a family history of dystonia. This points to a number of patients currently classified as idiopathic that have at least in part an underlying genetic contribution. The present study aims to identify clinical and demographic features associated with heritability of yet idiopathic dystonia. METHODS: Seven hundred thirty-three datasets were obtained from the DysTract dystonia registry, patients with acquired dystonia or monogenic causes were excluded. Affected individuals were assigned to a familial and sporadic group, and clinical features were compared across these groups. Additionally, the history of movement disorders was also counted in family members. RESULTS: 18.2% of patients reported a family history of dystonia. Groups differed in age at onset, disease duration and presence of tremor on a descriptive level. Logistic regression analysis revealed that tremor was the only predictor for a positive family history of dystonia (OR 2.49, CI = 1.54-4.11, p < 0.001). Tremor turned out to be the most common movement disorder in available relatives of patients, and presence of tremor in relatives was associated with tremor in index patients (X2(1) = 16.2, p < 0.001). CONCLUSIONS: Tremor is associated with an increased risk of familial clustering of dystonia and with a family history of tremor itself. This indicates a hereditable dystonia-tremor syndrome with a clinical spectrum ranging from tremor-predominant diseases to dystonia.

Characterisation and differential diagnosis of neurological complications in adults with phenylketonuria: literature review and expert opinion.

OBJECTIVE: Phenylketonuria (PKU) is a rare inherited metabolic disorder characterised by elevated phenylalanine (Phe) concentrations that can exert neurotoxic effects if untreated or upon treatment discontinuation. This systematic review supported by expert opinion aims to raise awareness among the neurological community on neurological complications experienced by adults with PKU (AwPKU). METHODS: The PubMed database was searched for articles on neurological signs and symptoms in AwPKU published before March 2022. In addition, two virtual advisory boards were held with a panel of seven neurologists and two metabolic physicians from Germany and Austria. Findings are supported by three illustrative patient cases. RESULTS: Thirty-nine articles were included. Despite early diagnosis and treatment, neurological signs and symptoms (e.g. ataxia, brisk tendon reflexes, tremor, visual impairment) can emerge in adulthood, especially if treatment has been discontinued after childhood. In PKU, late-onset neurological deficits often co-occur with cognitive impairment and psychiatric symptoms, all of which can be completely or partially reversed through resumption of treatment. CONCLUSION: Ideally, neurologists should be part of the PKU multidisciplinary team, either to bring lost to follow-up patients back to clinic or to manage symptoms in referred patients, considering that symptoms are often reversible upon regaining metabolic control. The current findings have been combined in a leaflet that will be disseminated among neurologists in Germany and Austria to create awareness.

Impaired Metacognition of Voluntary Movement in Functional Movement Disorder.

BACKGROUND: Motor symptoms in functional movement disorders (FMDs) are experienced as involuntary but share characteristics of voluntary action. Clinical and experimental evidence indicate alterations in monitoring, control, and subjective experience of self-performed movements. OBJECTIVE: The objective of this study was to test the prediction that FMDs are associated with a reduced ability to make accurate (metacognitive) judgments about self-performed movements. METHODS: We compared 24 patients with FMD (including functional gait disturbance, functional tremor, and functional tics) with 24 age- and sex-matched healthy control subjects in a novel visuomotor-metacognitive paradigm. Participants performed target-directed movements on a graphics tablet with restricted visual feedback, decided which of two visually presented trajectories was closer to their preceding movement, and reported their confidence in the visuomotor decision. We quantified individual metacognitive performance as participants' ability to assign high confidence preferentially to correct visuomotor decisions. RESULTS: Patients and control subjects showed comparable motor performance, response accuracy, and use of the confidence scale. However, visuomotor sensitivity in the trajectory judgment was reduced in patients with FMD compared with healthy control subjects. Moreover, metacognitive performance was impaired in patients, that is, their confidence ratings were less predictive of the correctness of visuomotor decisions. Exploratory subgroup analyses suggest metacognitive deficits to be most pronounced in patients with a functional gait disturbance or functional tremor. CONCLUSIONS: Patients with FMD exhibited deficits both when making visuomotor decisions about their own movements and in the metacognitive evaluation of these decisions. Reduced metacognitive insight into voluntary motor control may play a role in FMD pathophysiology and could lay the groundwork for new treatment strategies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Structural cerebellar reserve positively influences outcome after severe stroke.

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume (P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke.