Sex Differences in Dystonia.

BACKGROUND: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. OBJECTIVES: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. METHODS: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. RESULTS: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). CONCLUSIONS: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics.

PET Quantification of [18F]VAT in Human Brain and Its Test-Retest Reproducibility and Age Dependence.

Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[18F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([18F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [18F]VAT. [3H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BPND). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [18F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [3H]VAT autoradiography-specific binding and PET [18F]VAT uptake were low in white matter. [18F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BPND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BPND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BPND calculations and demonstrate the viability, reproducibility, and utility of using the [18F]VAT tracer in humans to quantify cholinergic pathways.

The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action.

The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ~ 45,000), to precisely examine red nucleus functional connectivity. Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a 'motor' structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.

An Empirical Comparison of Commonly Used Universal Rating Scales for Dystonia.

Background: There are several widely used clinical rating scales for documenting the severity and distribution of various types of dystonia. Objectives: The goal of this study was to evaluate the performance of the most commonly used scales in a large group of adults with the most common types of isolated dystonia. Methods: Global Dystonia Rating Scale (GDRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) scores were obtained for 3067 participants. Most had focal or segmental dystonia, with smaller numbers of multifocal or generalized dystonia. These scales were also compared for 209 adults with cervical dystonia that had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and 210 adults with blepharospasm that had Blepharospasm Severity Scale (BSRS) scores. Results: There were strong correlations between the GDRS and BFM total scores (r = 0.79) and moderate correlations for their sub scores (r > 0.5). Scores for both scales showed positive skew, with an overabundance of low scores. BFM sub-scores were not normally distributed, due to artifacts caused by the provoking factor. Relevant sub-scores of the GDRS and BFM also showed moderate correlations with the TWSTRS (r > 0.5) for cervical dystonia and the BSRS (r > 0.5) for blepharospasm. Conclusions: The BFM is more widely used than the GDRS, but these results suggest the GDRS may be preferable for focal and segmental dystonias. The overabundance of very low scores for both scales highlights challenges associated with discriminating very mild dystonia from other abnormal movements or variants of normal behavior.

A somato-cognitive action network alternates with effector regions in motor cortex.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

OBJECTIVE: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. METHODS: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. RESULTS: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. INTERPRETATION: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.

The Future of Functional Neuroimaging in Parkinsonism: Prove It!

This Viewpoint discusses the current lack of evidence of functional neuroimaging affecting patient outcomes in parkinsonian conditions.

A tissue-fraction estimation-based segmentation method for quantitative dopamine transporter SPECT.

BACKGROUND: Quantitative measures of dopamine transporter (DaT) uptake in caudate, putamen, and globus pallidus (GP) derived from dopamine transporter-single-photon emission computed tomography (DaT-SPECT) images have potential as biomarkers for measuring the severity of Parkinson's disease. Reliable quantification of this uptake requires accurate segmentation of the considered regions. However, segmentation of these regions from DaT-SPECT images is challenging, a major reason being partial-volume effects (PVEs) in SPECT. The PVEs arise from two sources, namely the limited system resolution and reconstruction of images over finite-sized voxel grids. The limited system resolution results in blurred boundaries of the different regions. The finite voxel size leads to TFEs, that is, voxels contain a mixture of regions. Thus, there is an important need for methods that can account for the PVEs, including the TFEs, and accurately segment the caudate, putamen, and GP, from DaT-SPECT images. PURPOSE: Design and objectively evaluate a fully automated tissue-fraction estimation-based segmentation method that segments the caudate, putamen, and GP from DaT-SPECT images. METHODS: The proposed method estimates the posterior mean of the fractional volumes occupied by the caudate, putamen, and GP within each voxel of a three-dimensional DaT-SPECT image. The estimate is obtained by minimizing a cost function based on the binary cross-entropy loss between the true and estimated fractional volumes over a population of SPECT images, where the distribution of true fractional volumes is obtained from existing populations of clinical magnetic resonance images. The method is implemented using a supervised deep-learning-based approach. RESULTS: Evaluations using clinically guided highly realistic simulation studies show that the proposed method accurately segmented the caudate, putamen, and GP with high mean Dice similarity coefficients of ∼ 0.80 and significantly outperformed ( p < 0.01 $p < 0.01$ ) all other considered segmentation methods. Further, an objective evaluation of the proposed method on the task of quantifying regional uptake shows that the method yielded reliable quantification with low ensemble normalized root mean square error (NRMSE) < 20% for all the considered regions. In particular, the method yielded an even lower ensemble NRMSE of ∼ 10% for the caudate and putamen. CONCLUSIONS: The proposed tissue-fraction estimation-based segmentation method for DaT-SPECT images demonstrated the ability to accurately segment the caudate, putamen, and GP, and reliably quantify the uptake within these regions. The results motivate further evaluation of the method with physical-phantom and patient studies.

Current Guidelines for Classifying and Diagnosing Cervical Dystonia: Empirical Evidence and Recommendations.

BACKGROUND: The dystonias are phenotypically and etiologically heterogenous disorders. Many proposals and a consensus recommendation have been provided for the diagnosis and classification of the dystonias, but these recommendations serve only as general guidelines. Current diagnosis and classification may still depend on clinical judgment causing different opinions. OBJECTIVE: To delineate clinical features used by movement disorder specialists in the diagnosis and classification of isolated focal cervical dystonia, and to develop recommendations for a more consistent approach to classification according to anatomical regions involved. METHODS: Cross-sectional data for subjects diagnosed with isolated dystonia were acquired from the Dystonia Coalition, an international, multicenter collaborative research network. Data from many movement disorder specialists were evaluated to determine how diagnoses of cervical dystonia related to their recorded examinations. Cases were included if they were given a diagnosis of focal cervical dystonia. Cases were also included if they had dystonia of the neck on exam, but were given an alternative diagnosis such as segmental dystonia. RESULTS: Among 2916 subjects with isolated dystonia, 1258 were diagnosed with focal cervical dystonia. Among these 1258 cases, 28.3% had dystonia outside of the neck region. Regions involved outside of the neck included the shoulder, larynx, and sometimes other regions. Analysis of the results pointed to several factors that may influence specialists' use of current diagnostic guidelines for making a diagnosis of isolated focal cervical dystonia including varied interpretations of involvement of nearby regions (shoulder, larynx, platysma), severity of dystonia across different regions, and occurrence of tremor in different regions. CONCLUSIONS: Although focal cervical dystonia is the most common type of dystonia, a high percentage of subjects given this diagnosis had dystonia outside of the neck region. This observation points to the need for more specific guidelines for defining this common disorder. Such guidelines are proposed here.

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

Managing Advanced Parkinson Disease.

Advanced Parkinson disease (PD) is associated with treatment-related motor fluctuations and reduced ability to perform activities of daily living. Progression of non-motor symptoms and medication-induced adverse effects complicate focused approach to motor symptom management, frequently accelerating reduced quality of life. It is thus critical for clinicians to consider disease progression versus therapeutic contributions when balancing management decisions. Such an approach requires careful recognition of inflection points resulting from therapeutic decisions and should prompt consideration of reduced pharmacologic burden and increased reliance on non-pharmacologic strategies in advanced disease. The successful approach to advanced PD requires a multidisciplinary effort focused on improving the patient's and family's quality of life, sometimes requiring sacrifice of motor symptom benefit. Here, we emphasize management strategies in advanced PD, focusing on the need to balance the therapeutic approach across advancing motor symptoms, progressive non-motor features, and potential pharmacologic adverse effects.

Is Levodopa Response a Valid Indicator of Parkinson's Disease?

BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. METHODS: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. RESULTS: There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. CONCLUSION: A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Resting-State Functional Connectivity Predicts STN DBS Clinical Response.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. METHODS: We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. RESULTS: Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. DISCUSSION: Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Regional, not global, functional connectivity contributes to isolated focal dystonia.

OBJECTIVE: To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls. METHODS: Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences. RESULTS: Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups. CONCLUSION: Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants.

Clinical and Demographic Characteristics of Upper Limb Dystonia.

BACKGROUND: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies. OBJECTIVE: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource. METHODS: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset. RESULTS: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately. CONCLUSIONS: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.

Bilateral Subthalamic Nucleus Deep Brain Stimulation in Elderly Patients With Parkinson Disease: A Case-Control Study.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective adjunctive therapy for Parkinson disease. Studies have shown improvement of motor function but often exclude patients older than 75 yr. OBJECTIVE: To determine the safety and effectiveness of STN DBS in patients 75 yr and older. METHODS: A total of 104 patients (52 patients >75 yr old, 52 patients <75 yr old) with STN DBS were paired and retrospectively analyzed. The primary outcome was change in Unified Parkinson Disease Rating Scale (UPDRS) subscale III at 1 yr postoperatively, OFF medication. Secondary outcomes were changes in UPDRS I, II, and IV subscales and levodopa equivalents. Complications and all-cause mortality were assessed at 30 d and 1 yr. RESULTS: Both cohorts had significant improvements in UPDRS III at 6 mo and 1 yr with no difference between cohorts. Change in UPDRS III was noninferior to the younger cohort. The cohorts had similar worsening in UPDRS I at 1 yr, no change in UPDRS II, similar improvement in UPDRS IV, and similar levodopa equivalent reduction. There were similar numbers of postoperative intracerebral hemorrhages (2/52 in each cohort, more severe in the older cohort) and surgical complications (4/52 in each cohort), and mortality in the older cohort was similar to an additional matched cohort not receiving DBS. CONCLUSION: STN DBS provides substantial motor benefit and reduction in levodopa equivalents with a low rate of complications in older patients, which is also noninferior to the benefit in younger patients. STN DBS remains an effective therapy for those over 75 yr.

Integrative and Network-Specific Connectivity of the Basal Ganglia and Thalamus Defined in Individuals.

The basal ganglia, thalamus, and cerebral cortex form an interconnected network implicated in many neurological and psychiatric illnesses. A better understanding of cortico-subcortical circuits in individuals will aid in development of personalized treatments. Using precision functional mapping-individual-specific analysis of highly sampled human participants-we investigated individual-specific functional connectivity between subcortical structures and cortical functional networks. This approach revealed distinct subcortical zones of network specificity and multi-network integration. Integration zones were systematic, with convergence of cingulo-opercular control and somatomotor networks in the ventral intermediate thalamus (motor integration zones), dorsal attention and visual networks in the pulvinar, and default mode and multiple control networks in the caudate nucleus. The motor integration zones were present in every individual and correspond to consistently successful sites of deep brain stimulation (DBS; essential tremor). Individually variable subcortical zones correspond to DBS sites with less consistent treatment effects, highlighting the importance of PFM for neurosurgery, neurology, and psychiatry.

Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study.

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.

Cognitive correlates of cerebellar resting-state functional connectivity in Parkinson disease.

OBJECTIVE: To investigate in a cross-sectional study the contributions of altered cerebellar resting-state functional connectivity (FC) to cognitive impairment in Parkinson disease (PD). METHODS: We conducted morphometric and resting-state FC-MRI analyses contrasting 81 participants with PD and 43 age-matched healthy controls using rigorous quality assurance measures. To investigate the relationship of cerebellar FC to cognitive status, we compared participants with PD without cognitive impairment (Clinical Dementia Rating [CDR] scale score 0, n = 47) to participants with PD with impaired cognition (CDR score ≥0.5, n = 34). Comprehensive measures of cognition across the 5 cognitive domains were assessed for behavioral correlations. RESULTS: The participants with PD had significantly weaker FC between the vermis and peristriate visual association cortex compared to controls, and the strength of this FC correlated with visuospatial function and global cognition. In contrast, weaker FC between the vermis and dorsolateral prefrontal cortex was found in the cognitively impaired PD group compared to participants with PD without cognitive impairment. This effect correlated with deficits in attention, executive functions, and global cognition. No group differences in cerebellar lobular volumes or regional cortical thickness of the significant cortical clusters were observed. CONCLUSION: These results demonstrate a correlation between cerebellar vermal FC and cognitive impairment in PD. The absence of significant atrophy in cerebellum or relevant cortical areas suggests that this could be related to local pathophysiology such as neurotransmitter dysfunction.

Thalamic and ventricular volumes predict motor response to deep brain stimulation for Parkinson's disease.

BACKGROUND: Brain atrophy frequently occurs with Parkinson's disease (PD) and relates to increased motor symptoms of PD. The predictive value of neuroimaging-based measures of global and regional brain volume on motor outcomes in deep brain stimulation (DBS) remains unclear but potentially could improve patient selection and targeting. OBJECTIVES: To determine the predictive value of preoperative volumetric MRI measures of cortical and subcortical brain volume on motor outcomes of subthalamic nucleus (STN) DBS in PD. METHODS: Preoperative T1 3D MP-RAGE structural brain MRI images were analyzed for each participant to determine subcortical, ventricular, and cortical volume and thickness. Change in Unified Parkinson's Disease Rating Scale (UPDRS) scores for subsection 3, representing motor outcomes, was computed preoperatively and postoperatively following DBS programming in 86 participants. A multiple linear regression analysis was performed to investigate the relationship between volumetric data and the effect of DBS on UPDRS 3 scores. RESULTS: Larger ventricular and smaller thalamic volumes predicted significantly less improvement of UPDRS 3 scores after STN DBS. CONCLUSIONS: Our findings demonstrate in PD that regional brain volumes, in particular thalamic and ventricular volumes, predict motor outcomes after DBS. Differences in regional brain volumes may alter electrode targeting, reflect a specific disease trait such as postoperative progression of subclinical dementia, or directly interfere with the action of DBS.