The functional brain connectome in isolated rapid eye movement sleep behavior disorder and Parkinson's disease.

BACKGROUND: Isolated rapid-eye-movement behavior disorder (iRBD) often precedes the development of alpha-synucleinopathies such as Parkinson's disease (PD). Magnetic resonance imaging (MRI) studies have revealed structural brain alterations in iRBD partially resembling those observed in PD. However, relatively little is known about whole-brain functional brain alterations in iRBD. Here, we characterize the functional brain connectome of iRBD compared with PD patients and healthy controls (HC) using resting-state functional MRI (rs-fMRI). METHODS: Eighteen iRBD subjects (67.3 ± 6.6 years), 18 subjects with PD (65.4 ± 5.8 years), and 39 age- and sex-matched HC (64.4 ± 9.2 years) underwent rs-fMRI at 3 T. We applied a graph theoretical approach to analyze the brain functional connectome at the global and regional levels. Data were analyzed using both frequentist and Bayesian statistics. RESULTS: Global connectivity was largely preserved in iRBD and PD individuals. In contrast, both disease groups displayed altered local connectivity mainly in the motor network, temporal cortical regions including the limbic system, and the visual system. There were some group specific alterations, and connectivity changes were pronounced in PD individuals. Overall, however, there was a good agreement of the connectome changes observed in both disease groups. CONCLUSIONS: This study provides evidence for widespread functional brain connectivity alterations in iRBD, including motor circuitry, despite normal motor function. Connectome alterations showed substantial resemblance with those observed in PD, underlining a close pathophysiological relationship of iRBD and PD.

Dopaminergic treatment strategies for people with Parkinson's disease in Europe: a retrospective analysis of PRISM trial data.

BACKGROUND: Levodopa (LD) is the most effective drug to treat Parkinson's disease (PD). The recently concluded multinational Parkinson's Real-World Impact Assessment (PRISM) trial revealed highly variable prescription patterns of LD monotherapy across six European countries. The reasons remain unclear. METHODS: In this post hoc analysis of PRISM trial data, we used multivariate logistic regression analysis to identify socio-economic factors affecting prescription practice. We applied receiver-operated characteristics and split sample validation to test model accuracy to predict treatment class (LD monotherapy vs. all other treatments). RESULTS: Subject age, disease duration, and country of residence were significant predictors of treatment class. The chance of receiving LD monotherapy increased by 6.9% per year of age. In contrast, longer disease duration reduced the likelihood of receiving LD monotherapy by 9.7% per year. Compared to the other countries, PD patients in Germany were 67.1% less likely and their counterparts in the UK 86.8% more likely to receive an LD monotherapy. The model classification accuracy of treatment class assignment was 80.1%. The area under the curve to predict treatment condition was 0.758 (95% CI [0.715, 0.802]). Split sample validation revealed poor sensitivity (36.6%), but excellent specificity (92.7%) to predict treatment class. CONCLUSION: The relative lack of socio-economic variables affecting prescription practice in the study sample and limited model accuracy to predict treatment class suggest the presence of additional, country-specific factors affecting prescription patterns that were not assessed in the PRISM trial. Our findings indicate that physicians still avoid prescribing LD monotherapy to younger PD patients.

Anti-SEZ6L2 antibodies in paraneoplastic cerebellar syndrome: case report and review of the literature.

Seizure Related 6 Homolog Like 2 (SEZ6L2) protein has been shown to have implications in neuronal and especially motor function development. In oncology, overexpression of SEZ6L2 serves as a negative prognostic marker in several tumor entities. Recently, few cases of anti-SEZ6L2 antibody mediated cerebellar syndromes were reported. In this article, we present a case of a 70-year-old woman with subacute onset of gait disturbance, dysarthria and limb ataxia. Serum anti-SEZ6L2 antibodies were markedly increased, and further diagnostic workup revealed left sided breast cancer. Neurological symptoms and SEZ6L2 titer significantly improved after curative tumor therapy. This is a very rare and educationally important report of anti-SEZ6L2 autoimmune cerebellar syndrome with a paraneoplastic etiology. Additionally, we performed a review of the current literature for SEZ6L2, focusing on comparing the published cases on autoimmune cerebellar syndrome.

Effective treatment of advanced Hodgkin lymphoma with a modified BEACOPP regimen for a patient with demyelinating hereditary motor and sensory neuropathy type 1 (HMSN1).

Treatment for Hodgkin lymphoma (HL) in adults comprises substantial risk of chemotherapy-induced peripheral neurotoxicity. Here, we describe the case of patient with Charcot-Marie-Tooth disease or HSMN1 and advanced Hodgkin lymphoma undergoing treatment with modified BEACOPP achieving complete remission without major aggravation of neurological symptoms.

Imaging the Pathophysiology of Essential Tremor-A Systematic Review.

Background: The pathophysiology underlying essential tremor (ET) still is poorly understood. Recent research suggests a pivotal role of the cerebellum in tremor genesis, and an ongoing controversy remains as to whether ET constitutes a neurodegenerative disorder. In addition, mounting evidence indicates that alterations in the gamma-aminobutyric acid neurotransmitter system are involved in ET pathophysiology. Here, we systematically review structural, functional, and metabolic neuroimaging studies and discuss current concepts of ET pathophysiology from an imaging perspective. Methods: We conducted a PubMed and Scopus search from 1966 up to December 2020, entering essential tremor in combination with any of the following search terms and their corresponding abbreviations: positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and gamma-aminobutyric acid (GABA). Results: Altered functional connectivity in the cerebellum and cerebello-thalamico-cortical circuitry is a prevalent finding in functional imaging studies. Reports from structural imaging studies are less consistent, and there is no clear evidence for cerebellar neurodegeneration. However, diffusion tensor imaging robustly points toward microstructural cerebellar changes. Radiotracer imaging suggests that the dopaminergic axis is largely preserved in ET. Similarly, measurements of nigral iron content and neuromelanin are unremarkable in most studies; this is in contrast to Parkinson's disease (PD). PET and MRS studies provide limited evidence for cerebellar and thalamic GABAergic dysfunction. Conclusions: There is robust evidence indicating that the cerebellum plays a key role within a multiple oscillator tremor network which underlies tremor genesis. However, whether cerebellar dysfunction relies on a neurodegenerative process remains unclear. Dopaminergic and iron imaging do not suggest a substantial overlap of ET with PD pathophysiology. There is limited evidence for alterations of the GABAergic neurotransmitter system in ET. The clinical, demographical, and genetic heterogeneity of ET translates into neuroimaging and likely explains the various inconsistencies reported.

Putaminal y-Aminobutyric Acid Modulates Motor Response to Dopaminergic Therapy in Parkinson's Disease.

BACKGROUND: Motor response to dopaminergic therapy is a characteristic of patients with Parkinson's disease (PD). Whether nondopaminergic neurotransmitters contribute to treatment response is uncertain. OBJECTIVES: The aim of this study is to determine whether putaminal y-aminobutyric acid (GABA) levels are associated with dopaminergic motor response. METHODS: We assessed putaminal GABA levels in 19 PD patients and 13 healthy controls (HCs) utilizing ultra-high field proton magnetic resonance spectroscopy. Motor performance was evaluated using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III, in the ON and OFF states. Statistical analysis comprised group comparisons, correlation analysis, and multiple linear regression. RESULTS: In PD, GABA levels were significantly higher compared to HCs (1.50 ± 0.26 mM vs. 1.26 ± 0.31 mM, P = 0.022). Furthermore, GABA levels were independent predictors of absolute and relative dopaminergic treatment response. CONCLUSIONS: Our findings indicate that elevated putaminal GABA levels are associated with worse dopaminergic response in PD, emphasizing the essential role of nondopaminergic neurotransmitters in motor response. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Convergent patterns of structural brain changes in rapid eye movement sleep behavior disorder and Parkinson's disease on behalf of the German rapid eye movement sleep behavior disorder study group.

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is considered a prodromal state of Parkinson's disease (PD). We aimed to characterize patterns of structural brain changes in RBD and PD patients using multimodal MRI. METHODS: A total of 30 patients with isolated RBD, 29 patients with PD, and 56 age-matched healthy controls (HC) underwent MRI at 3T, including tensor-based morphometry, diffusion tensor imaging, and assessment of cortical thickness. RESULTS: RBD individuals showed increased volume of the right caudate nucleus compared with HC, and higher cerebellar volume compared with both PD subjects and HC. Similar to PD subjects, RBD patients displayed increased fractional anisotropy (FA) in the corticospinal tracts, several tracts mainly related to non-motor function, and reduced FA of the corpus callosum compared with HC. Further, RBD subjects showed higher FA in the cerebellar peduncles and brainstem compared with both, PD patients and HC. PD individuals exhibited lower than normal volume in the basal ganglia, midbrain, pedunculopontine nuclei, and cerebellum. In contrast, volume in PD subjects was increased in the thalamus compared with both HC and RBD subjects. CONCLUSIONS: We found convergent patterns of structural brain alterations in RBD and PD patients compared with HC. The changes observed suggest a co-occurrence of neurodegeneration and compensatory mechanisms that fail with emerging PD pathology. Our findings strengthen the hypothesis of RBD and PD constituting a continuous disease spectrum.

Hemispheric Network Expression in Parkinson's Disease: Relationship to Dopaminergic Asymmetries.

BACKGROUND: Parkinson's disease (PD) is characterized by brain metabolic networks, specifically associated with motor and cognitive manifestations. Few studies have investigated network changes in cerebral hemispheres ipsilateral and contralateral to the clinically more affected body side. OBJECTIVE: We examined hemispheric network abnormalities and their relationship to striatal dopaminergic deficits in PD patients at different stages. METHODS: 45 PD patients underwent dual-tracer positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-fluorodopa (FDOPA) in a high-resolution PET scanner. In all patients, we computed expression levels for the PD-related motor/cognition metabolic patterns (PDRP/PDCP) as well as putamen/caudate FDOPA uptake values in both hemispheres. Resulting hemispheric measures in the PD group were compared with corresponding healthy control values and assessed across disease stages. RESULTS: Hemispheric PDRP and PDCP expression was significantly elevated contralateral and ipsilateral to the more affected body side in patients with unilateral symptoms (H&Y 1: p < 0.01) and in patients with bilateral limb involvement (H&Y 2-3: p < 0.001; H&Y 4: p < 0.003). Elevations in pattern expression were symmetrical at all disease stages. By contrast, FDOPA uptake in the caudate and putamen was reduced bilaterally (p < 0.002), with lower values on both sides at more advanced disease stages. Hemispheric uptake was asymmetrical in both striatal regions, with lower contralateral values at all disease stages. The magnitude of hemispheric uptake asymmetry was smaller with more advanced disease, reflecting greater change ipsilaterally. CONCLUSION: Symmetrical network expression in PD represents bilateral functional effects unrelated to nigrostriatal dopaminergic asymmetries.

Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) - A systematic review on potential biomarkers for neurodegeneration.

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of physiological atonia of skeletal muscles with abnormal behavior during dream sleep. RBD may be the initial manifestation of neurodegenerative diseases, particularly of α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, gauging the individual risk of subsequent phenoconversion and making assumptions on the type of disease that may subsequently follow RBD is challenging. Over the past years, a growing number of studies have sought to establish reliable neuroimaging markers to detect neurodegenerative brain changes in RBD subjects at the earliest possible stage. The present review summarizes recent advances in brain imaging in RBD and provides recommendations for the application of currently available structural and functional neuroimaging modalities to monitor disease progression and risk of subsequent phenoconversion. Further imaging research applying multimodal approaches is encouraged to enhance accuracy of prognoses. Additionally, more longitudinal studies are warranted to validate findings from cross-sectional studies on RBD progression and risk of subsequent phenoconversion. Aside from enabling reliable prognoses on a single-subject-level in the near future, this might give further insight into RBD pathophysiology, and finally augment the development of intervention strategies and disease-modifying therapies.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Longitudinal Changes in the Motor Learning-Related Brain Activation Response in Presymptomatic Huntington's Disease.

Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington's disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

BACKGROUND: Deterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage. METHODS: We employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed. RESULTS: MS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001). CONCLUSIONS: Changes in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Dopaminergic correlates of metabolic network activity in Parkinson's disease.

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss.

The utility of neuroimaging in the differential diagnosis of parkinsonian syndromes.

The differential diagnosis of parkinsonian syndromes can be challenging, particularly in early disease stages. However, prognosis and therapeutic regimes are not alike in Parkinson disease and atypical parkinsonism, and thus a correct diagnosis at the earliest possible stage is desirable. Over the past two decades, magnetic resonance imaging and radiotracer-based imaging techniques have proven to be helpful tools to enhance the accuracy of clinical diagnosis in these disorders. Here, we review recent advances in neuroimaging for the differential diagnosis of parkinsonian syndromes.

Abnormal metabolic network activity in REM sleep behavior disorder.

OBJECTIVE: To determine whether the Parkinson disease-related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion. METHODS: For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with (18)F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values. RESULTS: PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r(2) = 0.64, p < 0.0001). CONCLUSIONS: Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.

Functional brain networks in movement disorders: recent advances.

PURPOSE OF REVIEW: Different neuroimaging techniques have been used to identify disease-specific functional brain networks in Parkinson's disease, atypical parkinsonian syndromes, and other movement disorders. This review highlights recent advances in network imaging and its clinical applications in movement disorders. RECENT FINDINGS: Positron emission tomography and functional MRI studies have revealed distinct, abnormal metabolic brain networks and altered interregional connectivity in Parkinson's disease and related movement disorders. Network-level functional changes have been found to correlate with disease severity and progression. Moreover, network-based categorization algorithms are proving useful in enhancing the accuracy of clinical diagnosis in patients with early symptoms and in providing objective evidence of treatment response. SUMMARY: Although in most movement disorders the predominant histopathology involves the basal ganglia, including the substantia nigra, functional changes in relevant neural circuits are not limited to these structures. The current advances in functional brain imaging have contributed to a better pathophysiological understanding of movement disorders as complex alterations of widespread functional brain networks. The promising findings from recent studies may help to establish new and reliable biomarkers to monitor disease progression and treatment effects in future clinical trials.