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This meta-analysis examined inhibitory control performance in the antisaccade task across mental disorders. Following PRISMA guidelines, we analyzed data from k = 146 studies (n = 13,807 participants) on antisaccade performance. Effect sizes were estimated using random-effects models and restricted maximum-likelihood estimation, with robustness tests for study heterogeneity and publication bias. Most disorders displayed elevated error rates, with schizophrenia showing the greatest impairments, followed by autism spectrum disorder, bipolar disorder and attention deficit hyperactivity disorder. Small to medium impairments were also found in eating disorders, major depressive disorder, obsessive-compulsive disorder and substance use disorder. Results were robust against corrections for publication bias and largely unaffected by confounding variables. Prolonged latencies were observed in schizophrenia, attention deficit hyperactivity disorder, bipolar disorder and obsessive compulsive disorder, with smaller and less robust effect sizes. Results indicate inhibitory control deficits in the antisaccade task across mental disorders, especially evident for error rates. While present in most disorders, results imply varying degrees of impairments, ranging from small to large in effect sizes, with largest impairments in schizophrenia. Keywords.
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Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.
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Biomarcadores , Transtornos Psicóticos , Acompanhamento Ocular Uniforme , Humanos , Masculino , Feminino , Acompanhamento Ocular Uniforme/fisiologia , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/fisiopatologia , Adulto , Adulto Jovem , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , AdolescenteRESUMO
Patients with persistent postural-perceptual dizziness (PPPD) perceive postural instability larger than the observed sway. It is unknown whether the concept of postural misperception prevails during vestibular stimulation and whether it may account for the unsteadiness patients complain during body movements. We tested the hypothesis of an abnormal sensory-perceptual scaling mechanism in PPPD by recording objective, perceived, and the reproduced postural sway under various standing conditions, modulating visual and proprioceptive input, by binaural galvanic vestibular stimulation (GVS). We related postural sway speed to individual vestibular motion perceptional thresholds and disease-related PPPD questionnaires in 32 patients and 28 age-matched healthy control subjects (HC). All participants showed normal vestibular function tests on quantitative testing at the time of enrollment. The perception threshold of GVS was lower in patients. Compared to HC, patients showed and perceived larger sway on the firm platform. With GVS, posturo-perceptual ratios did not show group differences. The ratio of reproduced to real postural sway showed no group differences indicating normal postural sway perception during vestibular stimulation. Noticeably, only in patients, reproduced postural instability became larger with lower individual thresholds of vestibular motion detection. We conclude that posturo-perceptual (metacognitive) scaling of postural control seems to be largely preserved in PPPD during GVS. Vestibular stimulation does not destabilize patients more than HC, even in challenging postural conditions. Low individual thresholds of vestibular motion perception seem to facilitate instability and postural misperception on solid grounds. This conclusion is important for an effective physical therapy with vestibular exercises in PPPD.
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Tontura , Percepção de Movimento , Equilíbrio Postural , Humanos , Masculino , Feminino , Percepção de Movimento/fisiologia , Pessoa de Meia-Idade , Equilíbrio Postural/fisiologia , Tontura/fisiopatologia , Idoso , Adulto , Estimulação Elétrica , Vestíbulo do Labirinto/fisiologia , Vestíbulo do Labirinto/fisiopatologia , Limiar Sensorial/fisiologia , Postura/fisiologia , Testes de Função Vestibular/métodos , Propriocepção/fisiologiaRESUMO
Persistent postural-perceptual dizziness (PPPD) is a chronic disorder of perceived unsteadiness. Symptoms can be exacerbated in visually complex stationary or moving environment. Visual dependence and increased motion sensitivity are predictors for PPPD but its pathophysiology remains unknown. We hypothesized an abnormal sensory-perceptual scaling mechanism in PPPD and tested visual- and vestibular perceptional thresholds in 32 patients and 28 age-matched healthy control subjects (HC). All participants showed normal vestibular function tests on quantitative testing. Visual motion coherence thresholds were assessed by random dot kinetomatograms. Vestibular perceptional thresholds of egomotion were assessed by binaural galvanic vestibular stimulation (GVS) and passive chair rotation around an earth-vertical axis. Chair rotation trials were contrasted with no-motion (sham) stimulus trials. Mean thresholds of visual motion perception were higher in patients compared to HC. The perception threshold of GVS was lower in patients but the threshold of correctly perceived egomotion during chair rotation did not differ. Interestingly, the number of trials with correct perception in the no-motion condition increased with the threshold of correct responses for rotatory egomotion in patients. Unlike expected, PPPD patients required more coherently moving random dots than HC to perceive visual motion. A poorer complex visual motion recognition, e.g., traffic visual stimuli, may increase anxiety and levels of uncertainty as visuomotor reactions might occur delayed. The vestibular rotatory perception threshold predicted the probability of making false assignments in the sham condition in PPPD, i.e., patients who readily recognize the correct egomotion direction are prone to perceive egomotion in the no-motion condition. As this relation was not found in healthy subjects, it may reflect an abnormal sensory-perceptual scaling feature of PPPD.
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Tontura , Percepção de Movimento , Humanos , Percepção de Movimento/fisiologia , Masculino , Feminino , Tontura/fisiopatologia , Pessoa de Meia-Idade , Adulto , Idoso , Vestíbulo do Labirinto/fisiopatologia , Vestíbulo do Labirinto/fisiologia , Limiar Sensorial/fisiologia , Equilíbrio Postural/fisiologia , Transtornos da Percepção/fisiopatologia , Transtornos da Percepção/etiologia , Rotação , Estimulação Luminosa/métodosRESUMO
The efficacy of transcranial electric stimulation (tES) to effectively modulate neuronal activity depends critically on the spatial orientation of the targeted neuronal population. Therefore, precise estimation of target orientation is of utmost importance. Different beamforming algorithms provide orientation estimates; however, a systematic analysis of their performance is still lacking. For fixed brain locations, EEG and MEG data from sources with randomized orientations were simulated. The orientation was then estimated (1) with an EEG and (2) with a combined EEG-MEG approach. Three commonly used beamformer algorithms were evaluated with respect to their abilities to estimate the correct orientation: Unit-Gain (UG), Unit-Noise-Gain (UNG), and Array-Gain (AG) beamformer. Performance depends on the signal-to-noise ratios for the modalities and on the chosen beamformer. Overall, the UNG and AG beamformers appear as the most reliable. With increasing noise, the UG estimate converges to a vector determined by the leadfield, thus leading to insufficient orientation estimates.
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The neural networks subserving smooth pursuit eye movements (SPEM) provide an ideal model for investigating the interaction of sensory processing and motor control during ongoing movements. To better understand core plasticity aspects of sensorimotor processing for SPEM, normative sham, anodal or cathodal transcranial direct current stimulation (tDCS) was applied over visual area V5 and frontal eye fields (FEF) in sixty healthy participants. The identical within-subject paradigm was used to assess SPEM modulations by practice. While no specific tDCS effects were revealed, within- and between-session practice effects indicate plasticity of top-down extraretinal mechanisms that mainly affect SPEM in the absence of visual input and during SPEM initiation. To explore the potential of tDCS effects, individual electric field simulations were computed based on calibrated finite element head models and individual functional localization of V5 and FEF location (using functional MRI) and orientation (using combined EEG/MEG) was conducted. Simulations revealed only limited electric field target intensities induced by the applied normative tDCS montages but indicate the potential efficacy of personalized tDCS for the modulation of SPEM. In sum, results indicate the potential susceptibility of extraretinal SPEM control to targeted external neuromodulation (e.g., personalized tDCS) and intrinsic learning protocols.
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Estimulação Transcraniana por Corrente Contínua , Humanos , Estimulação Transcraniana por Corrente Contínua/métodos , Acompanhamento Ocular Uniforme , Lobo Frontal , Imageamento por Ressonância Magnética/métodosRESUMO
A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.
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Background: Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as important endophenotypes associated with inherited risk. We tested the familiality of sensorimotor impairments in ASD across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Methods: Fifty-eight autistic individuals (probands), 109 parents, and 89 control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid, feedforward control and sustained, sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results: Probands with BAP- parents (BAP- probands) showed rapid manual motor and oculomotor deficits, while BAP+ probands showed sustained motor impairments compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Atypical rapid oculomotor impairments also were familial. Limitations: Larger samples of ASD families including greater samples of probands with BAP+ parents are needed. Genetic studies also are needed to link sensorimotor endophenotype findings directly to genes. Conclusions: Results indicate rapid sensorimotor behaviors are selectively impacted in BAP- probands and their parents and may reflect familial liabilities for ASD that are independent of familial autistic traits. Sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents re ecting familial traits that may only confer risk when combined with parental autistic trait liabilities. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of ASD risk that demonstrate unique interactions with mechanisms related to parental autistic traits.
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BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease. METHODS: Twenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs. RESULTS: The error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients. CONCLUSIONS: Despite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson's disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.
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Distonia , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Transtornos da Motilidade Ocular , Humanos , Distúrbios Distônicos/complicações , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Distonia/genética , Encéfalo , Transtornos da Motilidade Ocular/etiologiaRESUMO
PURPOSE: As measures of association between an adverse drug reaction (ADR) and exposure to a drug the reporting odds ratio (ROR) and the information component (IC) can be used. We sought to test the reliability of signal detection with these. METHODS: We simulated ADR counts as binomially distributed random numbers for different expected ADR frequencies and theoretical reporting odds ratios (RORs). We then calculated the empirical IC and the empirical ROR and their confidence intervals. The rate of signals that was detected despite a theoretical ROR of 1 represented the false positive rate, and represented the sensitivity if the ROR was >1. RESULTS: For expected case counts below 1 the false positive rate oscillates from 0.01 to 0.1 even though 0.025 were intended. Even beyond expected case counts of 5 oscillations can cover a range of 0.018 to 0.035. The first n oscillations with the largest amplitude are eliminated if a minimum case count of n is required. To detect an ROR of 2 with a sensitivity of 0.8, a minimum of 12 expected ADRs are required. In contrast, 2 expected ADRs suffice to detect an ROR of 4. CONCLUSION: Summaries of measures for disproportionality should include the expected number of cases in the group of interest if a signal was detected. If no signal was detected the sensitivity for the detection of a representative ROR or the minimum ROR that could be detected with probability 0.8 should be reported.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Razão de Chances , Reprodutibilidade dos Testes , Bases de Dados Factuais , FarmacovigilânciaRESUMO
BACKGROUND: Hemispatial neglect is a disabling cognitive disorder following stroke and effective therapies are required. OBJECTIVES: To evaluate the effects of combined optokinetic stimulation (OKS) and cueing-assisted reading therapy (READ) on the remission of hemispatial neglect following stroke. METHODS: Randomized, controlled, two-period, crossover trial conducted at a German neurorehabilitation center. Twenty participants with left neglect following right hemispheric stroke (mean age 66 years (SD 11), mean time since stroke 50 days (SD 33)) finished the trial (12 received OKSREAD first, 8 CONTROL first). The intervention consisted of 15 daily sessions of OKS (20 min) and text reading assisted by a therapist providing cues (20 min). The control treatment was a same-number, same-length neuropsychological treatment not targeting visuospatial attention. Primary outcomes were the change in performance of a customized neuropsychological test battery for neglect (0% worst - 100% best) and a test of neglect-related functional disability (Catherine Bergego Scale, 0 no impairment - 30 severest impairment), assessed before and after each treatment period. Secondary outcomes were performance in the 6 single tests composing the battery (e.g., omissions in text reading, center of cancellation in the Bells test, spatial bias of fixations when freely viewing photographs) and a clinical test of anosognosia. RESULTS: Overall performance in the neglect test battery improved slightly more after OKSREAD than after CONTROL (d=6%; p=0.002). The remission of neglect-related functional disability did not differ between treatments (d=-2; p=0.291). Ipsilesional fixation bias during free viewing was the only secondary outcome that was improved by OKSREAD as compared to CONTROL (d= -2.8°; p=0.005). CONCLUSION: At the applied intensity, the combined OKSREAD intervention slightly attenuated the ipsilesional attention bias in persons with neglect, but it did not improve neglect-related functional disability, anosognosia, or other neglect symptoms to a clinically meaningful degree. CLINICAL TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04273620.
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Agnosia , Transtornos da Percepção , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Idoso , Sinais (Psicologia) , Estudos Cross-Over , Leitura , Testes NeuropsicológicosRESUMO
In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.
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Distúrbios Distônicos , Doenças Neurodegenerativas , Adulto , Humanos , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Distúrbios Distônicos/complicações , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/patologia , Atrofia/patologia , FerroRESUMO
BACKGROUND: Hemispatial neglect results from unilateral brain damage and represents a disabling unawareness for objects in the hemispace opposite the brain lesion (contralesional). The patients' attentional bias for ipsilesional hemispace represents a hallmark of neglect, which results from an imbalanced attentional priority map in the brain. The aim of this study was to investigate whether gaze-contingent display (GCD) technology, reducing the visual salience of objects in ipsilesional hemispace, is able to rebalance this map and increase awareness and exploration of objects in the neglected contralesional hemispace. METHODS: Using remote eye-tracking, we recorded gaze positions in 19 patients with left hemispatial neglect following right-hemisphere stroke and 22 healthy control subjects, while they were watching static naturalistic scenes. There were two task conditions, free viewing (FV) or goal-directed visual search (VS), and four modification conditions including the unmodified original picture, a purely static modification and two differently strong modifications with an additional gaze-contingent mask (GC-LOW, GC-HIGH), that continuously reduced color saturation and contrast of objects in the right hemispace. RESULTS: The patients' median gaze position (Center of Fixation) in the original pictures was markedly deviated to the right in both tasks (FV: 6.8° ± 0.8; VS: 5.5° ± 0.7), reflecting the neglect-typical ipsilesional attention bias. GC modification significantly reduced this bias in FV (GC-HIGH: d = - 3.2 ± 0.4°; p < 0.001). Furthermore, in FV and VS, GC modification increased the likelihood to start visual exploration in the (neglected) left hemifield by about 20%. This alleviation of the ipsilesional fixation bias was not associated with an improvement in detecting left-side targets, in contrast, the GC mask even decreased and slowed the detection of right-side targets. Subjectively, patients found the intervention pleasant and most of the patients did not notice any modification. CONCLUSIONS: GCD technology can be used to positively influence visual exploration patterns in patients with hemispatial neglect. Despite an alleviation of the neglect-related ipsilesional fixation bias, a concomitant functional benefit (improved detection of contralesional targets) was not achieved. Future studies may investigate individualized GCD-based modifications as augmented reality applications during the activities of daily living.
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Viés de Atenção , Transtornos da Percepção , Acidente Vascular Cerebral , Humanos , Atividades Cotidianas , Lateralidade Funcional , Transtornos da Percepção/diagnóstico , Acidente Vascular Cerebral/complicações , TecnologiaRESUMO
Background and Objectives: Lesions of the cerebellar flocculus cause enduring downbeat nystagmus (DBN) with unrelenting oscillopsia. Unlike most patients with DBN, the flocculus is structurally spared in nonalcoholic Wernicke encephalopathy (nWE) with chronic DBN. The objective was to study the effects of alcohol in nWE. Methods: We recorded eye movements of a unique patient with nWE under controlled alcohol consumption who said his oscillopsia disappeared with a few drinks of alcohol. Results: His DBN was markedly diminished by alcohol (by 77.4%), although he remained alert with normal saccades. Discussion: This striking observation may be caused by the differential effect of alcohol on the perihypoglossal complex and the paramedian tract neurons, which control the level of activity in the flocculus, with opposite (inhibition and excitation, respectively) effects. The finding suggests new ideas about the treatment and pathophysiology of DBN with a structurally intact cerebellum.
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Background: "Central dizziness" due to acute bilateral midline cerebellar disease sparing the posterior vermis has specific oculomotor signs. The oculomotor region of the cerebellar fastigial nucleus (FOR) crucially controls the accuracy of horizontal visually-guided saccades and smooth pursuit eye movements. Bilateral FOR lesions elicit bilateral saccade hypermetria with preserved pursuit. It is unknown whether the initial acceleration of smooth pursuit is impaired in patients with bilateral FOR lesions. Objective: We studied the effect of a cerebellar lesion affecting the deep cerebellar nuclei on the initial horizontal pursuit acceleration and investigated whether saccade dysmetria also affects other types of volitional saccades, i.e., memory-guided saccades and anti-saccades, which are not performed in immediate response to the visual target. Methods: We recorded eye movements during a sinusoidal and step-ramp target motion paradigm as well as visually-guided saccades, memory-guided saccades, and anti-saccades in one patient with a circumscribed cerebellar hemorrhage and 18 healthy control subjects using a video-based eye tracker. Results: The lesion comprised the FOR bilaterally but spared the posterior vermis. The initial pursuit acceleration was low but not significantly different from the healthy control subjects and sinusoidal pursuit was normal. Bilateral saccade hypermetria was not only seen with visually-guided saccades but also with anti-saccades and memory-guided saccades. The final eye position remained accurate. Conclusion: We provide new insights into the contribution of the bilateral deep cerebellar nuclei on the initial acceleration of human smooth pursuit in midline cerebellar lesions. In line with experimental bilateral FOR lesion data in non-human primates, the initial pursuit acceleration in our patient was not significantly reduced, in contrast to the effects of unilateral experimental FOR lesions. Working memory and neural representation of target locations seem to remain unimpaired. Our data argue against an impaired common command feeding the circuits controlling saccadic and pursuit eye movements and support the hypothesis of independent influences on the neural processes generating both types of eye movements in the deep cerebellar nuclei.
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BACKGROUND: Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease-modifying therapies at a time point where progressive neurodegeneration can still be modified. OBJECTIVES: The objective of this study was to determine whether motor or non-motor signs of the disease occur as indicators of a prodromal phase of X-linked dystonia-parkinsonism (XDP), a highly-penetrant monogenic movement disorder with striking basal ganglia pathology. METHODS: In addition to a comprehensive clinical assessment, sensor-based balance and gait analyses were performed in non-manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient-boosted trees (GBT) methodology was utilized to classify groups of interest. RESULTS: There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best-performing GBT-based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group. CONCLUSIONS: Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.