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Background: Functional neurological movement disorders are common and disabling. Little is known about their coexistence with other non-functional movement disorders and their impact on the general disease burden., Objectives: Investigating frequency and characteristics of functional movement disorders in GCH1-positive dopa-responsive dystonia patients., Methods: Twenty-one patients underwent a detailed clinical motor examination and completed self-questionnaires evaluating non-motor characteristics., Results: Seven patients (33 %) had comorbid functional movement symptoms, including functional gait disorders (n = 7), balance disturbances (n = 7), and weakness (n = 5), dominating the clinical phenotype and resulting in disability with immobilization. None of them was previously diagnosed with or treated for the functional symptoms. Functional movement symptoms appeared suddenly (on average 18 years after the first dopa-responsive dystonia symptoms) and were unresponsive to L-Dopa. These patients showed significantly higher disability and received unnecessary treatments., Conclusion: Functional neurological movement disorders are common in patients with dopa-responsive dystonia and impact the clinical picture and the degree of disability. Diagnosing both disorders in an individual patient has substantial therapeutical implications because increases in L-Dopa dosages to treat functional symptoms should be avoided, and physiotherapy should relocate attention away from the affected body region so that movements in the affected body part can be executed without external control to facilitates automatic movements. Physiotherapy should be complemented by psychoeducation and psychotherapeutic approaches., Competing Interests: Declaration of competing interest The study was supported by the German Research Foundation (DFG, WE 5919/4-1 to Anne Weissbach and FOR2698 to Anne Weissbach, Alexander Münchau, and Tobias Bäumer, and FOR2488 to Katja Lohmann, Christine Klein, and Norbert Brüggemann). The other authors declare that they did not receive specific funding for this work. All the authors declare that there are no conflicts of interest relevant to this work. All authors approved the final version of the manuscript for submission., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Four-pool Voigt (FPV) machine learning (ML)-based fitting for Z-spectra was developed to reduce fitting times for clinical feasibility in terms of on-scanner analysis and to promote larger cohort studies. The approach was compared to four-pool Lorentzian (FPL)-ML-based modeling to empirically verify the advantage of Voigt models for Z-spectra., Methods: Voigt and Lorentzian models were fitted to human 3 T Z-spectral data using least squares (LS) to generate training data for the corresponding ML versions. Gradient boosting decision trees were trained, resulting in one Voigt and one Lorentzian ML model. Modeling accuracy was tested, and the fitting times of the ML models and LS versions were evaluated. The goodness of fits of Voigt and Lorentzian ML models were compared., Results: The training time for each ML model (Voigt and Lorentzian) was less than 1 min, and the modeling accuracy compared to the corresponding LS versions was excellent, as indicated by a nonsignificant difference between the parameters obtained by LS and corresponding ML versions. The average fitting time was 20 μs/spectrum for both ML models compared to 0.27 and 0.82 s/spectrum for LS with FPL and FPV, respectively. The goodness of fits of FPV-ML and FPL-ML differed significantly (p < 0.005), with FPV-ML showing an improvement for all tested data., Conclusion: Gradient boosting decision trees fitting of multi-pool Z-spectra significantly reduces fitting times compared to traditional LS approaches, allowing fast data processing while upholding fitting quality. Along with the short training times, this makes the method suitable for clinical settings and for large cohort research applications. The FPV-ML approach provides a significant improvement of goodness of fit compared to FPL-ML., (© 2025 International Society for Magnetic Resonance in Medicine.)

Pathogenic variants in PRKN cause early-onset Parkinson's disease (PD), while the role of alpha-synuclein in PRKN-PD remains uncertain. One study performed a blood-based alpha-synuclein seed amplification assay (SAA) in PRKN-PD, not detecting seed amplification in 17 PRKN-PD patients. By applying a methodologically different SAA focusing on neuron-derived extracellular vesicles, we demonstrated alpha-synuclein seed amplification in 8 of 13 PRKN-PD patients, challenging the view of PRKN-PD as a non-synucleinopathy. Moreover, we performed blinded replication of the neuron-derived extracellular vesicles-dependent SAA in idiopathic PD patients and healthy controls. In conclusion, blood-based neuron-derived extracellular vesicles-dependent SAA represents a promising biomarker to elucidate the underpinnings of (monogenic) PD. ANN NEUROL 2024;95:1173-1177., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored., Objectives: To investigate the bioenergetic state in male patients with XDP and female carriers using 31 phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations., Methods: We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls., Results: HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers., Conclusions: Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers., (© 2024 International Parkinson and Movement Disorder Society.)

Objective: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown., Methods: We performed a double-blinded, cross-over, placebo-controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31 phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain., Results: In total, 20 (6 female) patients with Parkinson's disease and 22 sex- and age-matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high-energy phosphorus-containing metabolites in the basal ganglia (patients with Parkinson's disease: -40%; healthy controls: -39%) but not in the midbrain. There were no differences in high-energy phosphorus-containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response., Interpretation: Exogenously administered levodopa/benserazide strongly interferes with basal ganglia high-energy phosphorus-containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024;95:849-857., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo . These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Prasuhn, Xu, Hua, van Zijl and Knutsson.)

Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment of depressive symptoms both in PD and DC should be improved., (© 2023. The Author(s).)

There is a pressing need for disease-modifying therapies in patients suffering from neurodegenerative diseases, including Parkinson's disease (PD). However, these disorders face unique challenges in clinical trial designs to assess the neuroprotective properties of potential drug candidates. One of these challenges relates to the often unknown individual disease mechanisms that would, however, be relevant for targeted treatment strategies. Neuroinflammation and mitochondrial dysfunction are two proposed pathophysiological hallmarks and are considered to be highly interconnected in PD. Innovative neuroimaging methods can potentially help to gain deeper insights into one's predominant disease mechanisms, can facilitate patient stratification in clinical trials, and could potentially map treatment responses. This review aims to highlight the role of neuroinflammation and mitochondrial dysfunction in patients with PD (PwPD). We will specifically introduce different neuroimaging modalities, their respective technical hurdles and challenges, and their implementation into clinical practice. We will gather preliminary evidence for their potential use in PD research and discuss opportunities for future clinical trials.

Coenzyme Q 10 (CoQ 10 ) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ 10 supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ 10 biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ 10 biosynthesis enzymes have been identified. Thus far, 11 disease genes are known ( PDSS1 , PDSS2 , COQ2 , COQ4 , COQ5 , COQ6 , COQ7 , COQ8A , COQ8B , COQ9 and HPDL ). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ 10 deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ 10 deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ 10 biosynthesis disorders and to highlight disease-specific findings.

Background and Objective: Bioenergetic disturbance, mainly caused by mitochondrial dysfunction, is an established pathophysiologic phenomenon in neurodegenerative movement disorders. The in vivo assessment of brain energy metabolism by 31 phosphorus magnetic resonance spectroscopy imaging could provide pathophysiologic insights and serve in the differential diagnosis of parkinsonian disorders. In this study, we investigated such aspects of the underlying pathophysiology in patients with idiopathic Parkinson disease (PwPD) and progressive supranuclear palsy (PwPSP)., Methods: In total, 30 PwPD, 16 PwPSP, and 25 healthy control subjects (HCs) underwent a clinical examination, structural magnetic resonance imaging, and 31 phosphorus magnetic resonance spectroscopy imaging of the forebrain and basal ganglia in a cross-sectional study., Results: High-energy phosphate metabolites were remarkably decreased in PwPD, particularly in the basal ganglia (-42% compared with HCs and -43% compared with PwPSP, p < 0.0001). This result was not confounded by morphometric brain differences. By contrast, PwPSP had normal levels of high-energy energy metabolites. Thus, the combination of morphometric and metabolic neuroimaging was able to discriminate PwPD from PwPSP with an accuracy of up to 0.93 [95%-CI: 0.91-0.94]., Discussion: Our study shows that mitochondrial dysfunction and bioenergetic depletion contribute to idiopathic Parkinson disease pathophysiology but not to progressive supranuclear palsy. Combined morphometric and metabolic imaging could serve as an accompanying diagnostic biomarker in the neuroimaging-guided differential diagnosis of these parkinsonian disorders., Classification of Evidence: This study provides Class III evidence that 31 phosphorus magnetic resonance spectroscopy imaging combined with morphometric MRI can differentiate PwPD from PwPSP., (© 2022 American Academy of Neurology.)

The underlying causes of Parkinson's disease are complex, and besides recent advances in elucidating relevant disease mechanisms, no disease-modifying treatments are currently available. One proposed pathophysiological hallmark is mitochondrial dysfunction, and a plethora of evidence points toward the interconnected nature of mitochondria in neuronal homeostasis. This also extends to iron and neuromelanin metabolism, two biochemical processes highly relevant to individual disease manifestation and progression. Modern neuroimaging methods help to gain in vivo insights into these intertwined pathways and may pave the road to individualized medicine in this debilitating disorder. In this narrative review, we will highlight the biological rationale for studying these pathways, how distinct neuroimaging methods can be applied in patients, their respective limitations, and which challenges need to be overcome for successful implementation in clinical studies.

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q 10 (CoQ 10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ 10 deficiency leads to an early-onset mitochondrial multi-organ disorder., Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines., Results: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ 10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone., Conclusion: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disease characterized by an aggressive disease course. Total and intracellular-weighted sodium imaging ( 23 Na-MRI) is a promising method for investigating neurodegeneration in vivo. We enrolled 10 patients with PSP and 20 age- and gender-matched healthy control subjects; all study subjects underwent a neurological examination, whole-brain structural, and (total and intracellular-weighted) 23 Na-MRI. Voxel-wise analyses revealed increased brainstem total sodium content in PSP that correlated with disease severity. The ROI-wise analysis highlighted additional sodium level changes in other regions implicated in the pathophysiology of PSP. 23 Na-MRI yields substantial benefits for the diagnostic workup of patients with PSP and adds complementary information on the underlying neurodegenerative tissue changes in PSP.

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., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders.

Background: The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson's disease., Methods: Thirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31 phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios., Results: Subcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects., Conclusions: Our study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease., (© 2021. The Author(s).)

Background: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson's disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD. Further, postmortem studies suggest involvement of neuromelanin (NM) loss and iron deposition in nigral neurodegeneration and HE+ emergence. However, the associations between HE+ and signs of nigral NM loss and iron deposition revealed by magnetic resonance imaging (MRI) have not been examined., Objective: To elucidate the magnetic resonance- (MR-) morphological representation of the HE+ by NM-weighted (NMI) and susceptibility-weighted MRI (SWI)., Methods: Thirty-four PD patients and 29 healthy controls (HCs) received TCS followed by NMI and SWI. From MR images, two independent raters manually identified the SN, placed seeds in non-SN midbrain areas, and performed semi-automated SN segmentation with different thresholds based on seed mean values and standard deviations. Masks of the SN were then used to extract mean area, mean signal intensity, maximal signal area, maximum signal (for NMI), and minimum signal (for SWI)., Results: There were no significant differences in NMI- and SWI-based parameters between patients and HCs, and no significant associations between HE+ extent and NMI- or SWI-based parameters., Conclusion: HE+ on TCS appears unrelated to PD pathology revealed by NMI and SWI. Thus, TCS and MRI parameters should be considered complementary, and the pathophysiological correlates of the HE+ require further study.

Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches., Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson's disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome., Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future., Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

Objective: To investigate the contribution of substantia nigra (SN) and locus coeruleus (LC) pathology to clinical signs and symptoms in Parkinson disease (PD) by applying neuromelanin-weighted imaging., Methods: Forty-seven patients with PD and 53 matched controls underwent motor assessment, a neuropsychological test battery, and neuromelanin-weighted MRI. Patients with PD were enrolled after fulfilling the criteria for clinically established PD as defined by the Movement Disorders Society Clinical Diagnostic Criteria. Two independent raters identified SN and LC and calculated the contrast-to-noise ratio (CNR)., Results: The intrarater reliability demonstrated good reliability between raters with an intraclass correlation coefficient of 0.88 ( p < 0.001) and an interrater reliability of 0.80 ( p < 0.001). Both SN and LC CNRs were lower in patients with PD ( p ≤ 0.001) compared to controls. The CNR of SN but not of LC was strongly correlated with disease duration ( p ≤ 0.001). Neuromelanin pathology of the pars compacta-containing dorsolateral SN correlated with Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale I, II, and III but not cognitive function. In contrast, neuromelanin pathology of LC was associated with cognitive function in all tested domains but not with motor impairment or activities of daily living. No such associations were present in controls., Conclusions: Neuromelanin imaging of the SN and LC is well-suited to map neurodegeneration in PD. Neuromelanin pathology of the SN correlates with motor dysfunction whereas LC pathology is related to cognitive impairment. Neuromelanin-weighted imaging of the LC could thus serve as an imaging marker of executive and other cognitive dysfunction in PD., Classification of Evidence: This study provides Class I evidence that neuromelanin-weighted imaging was associated with the severity of various signs and symptoms in patients with PD., (© 2021 American Academy of Neurology.)

Background: With conventional MRI, no Parkinson's disease (PD)-specific abnormalities can be detected. However, there is a critical need for accompanying neuroimaging markers to guide the diagnosis. With high-resolution susceptibility-weighted MRI (SWI) sequences, the imaging of nigrosome-1 (N1) is possible. The so-called swallow tail sign (STS) has been proposed as a suitable neuroimaging marker for the diagnosis of PD., Objectives: To investigate whether the absence of the STS can be applied for distinguishing PD patients from healthy controls (HCs)., Methods: SWI images of 44 PD patients and 50 age- and gender-matched HCs were investigated using a 3T MRI scanner. Two trained neuroradiologists blind-rated the images and evaluated whether the STS was absent (1) on one side or (2) both sides of the participant's midbrain., Results: Our results confirmed good interrater reliability comparable to previously published studies. However, we did not identify any group differences between PD patients and HCs. Measures of diagnostic values revealed overall poor diagnostic performance., Conclusions: Even though previously stated, our study does not confirm the potential use of the STS as a supportive neuroimaging marker for PD in a clinical setting. In conclusion, there is a critical need for improvements in N1-targeted MRI sequences and the development of advanced segmentation algorithms., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Heterozygous carriers of Parkin mutations are suggested to be at risk of developing Parkinson's disease, while biallelic variants are associated with typical autosomal recessive early-onset PD. Investigating unaffected heterozygous mutation carriers holds the potential of a deeper understanding of monogenic PD and has implications for PD in general, in particular regarding the prodromal phase., Objectives: To discriminate healthy Parkin mutation carriers from healthy non-mutation carriers using a multimodal approach., Methods: Twenty-seven healthy heterozygous Parkin mutation carriers (13 female. age: 48 ± 13 years) and 24 healthy non-mutation carriers (14 female. age: 48 ± 15 years) from the CHRIS study (Cooperative Health Research in South Tyrol) were recalled based on their genetic profile and underwent a blinded assessment of motor and non-motor PD symptoms, transcranial sonography and sensor-based posturography and gait analyses under different conditions with increasing difficulty. For the latter, gradient-boosted trees were used to discriminate between carriers and non-carriers. The classification accuracy and the area under the curve of the receiver-operator characteristics curve were calculated., Results: We observed no differences concerning motor or non-motor symptoms and substantia nigra hyperechogenicity. The best gradient-boosted trees-based model on posturography measurements (tandem feet, eyes closed, firm surface), however, showed a classification accuracy of up to 86%. The best-performing gradient-boosted trees-based model for gait analyses showed a balanced accuracy of up to 87% (dual-tasking)., Conclusions: Sensor-based quantification of movements allows to discriminate unaffected heterozygous mutation carriers from mutation-free controls. Thereby, it is crucial to challenge the motor system with more difficult tasks to unmask subtle motor alterations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Remarkable advances have been reached in the understanding of the genetic basis of Parkinson's disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches. These genetic findings have led to an imminent progress towards pathophysiology-targeted clinical trials and potentially disease-modifying treatments in the future., Main Body of the Manuscript: In this review article we will summarize known genetic contributors to the pathophysiology of Parkinson's disease, the molecular mechanisms leading to disease development, and discuss challenges and opportunities in clinical trial designs., Conclusions: The future success of clinical trials in PD is mainly dependent on reliable biomarker development and extensive genetic testing to identify genetic cases. Whether genotype-dependent stratification of study participants will extend the potential application of new drugs will be one major challenge in conceptualizing clinical trials. However, the latest developments in genotype-driven treatments will pave the road to individualized pathophysiology-based therapies in the future.

To evaluate the significance of motion artifacts in optical coherence tomography angiography (OCTA) images of patients with Parkinson's disease (PD) and healthy controls. In this prospective, cross-sectional study subjects with medicated PD (ON) and healthy, age- and gender-matched volunteers were recruited. Participants underwent specific ophthalmological examinations, including OCTA. Angiograms of the superficial retinal capillary plexus were evaluated for the type and frequency of artifacts using a validated motion artifact score (MAS). A total of 30 PD patients (60 eyes), average disease duration of 9.61 ± 5.55 years, and 30 matched, healthy controls (60 eyes) were recruited. Twenty percent of all eyes had an eye disease, unknown to the participant, with a significant impact on OCTA results. After cleansing the dataset by excluding subjects with confounding ocular comorbidities 42 eyes of 28 PD patients and 53 eyes of 29 healthy controls were further evaluated. Overall MAS and all five subtypes of motion artifacts were comparable without significant differences between groups. OCTA can be used in treated PD patients (ON) without a significant increase in motion artifacts. Nevertheless, special attention should be paid to image quality during the acquisition of OCTA data, for which an experienced OCTA operator is useful.

Background: Despite rapid advances in research on Parkinson's disease (PD), in particular in the elucidation of genetic contributions, no disease-modifying therapy has become available to date. Objectives: In the proposed project, we aim to investigate the potential effects of vitamin K2 (long-chain menaquinone 7, MK-7) in genetically determined PD with mitochondrial dysfunction. Methods: A total of 130 study participants (26 biallelic Parkin / PINK1 mutation carriers, 52 sporadic PD patients, and 52 healthy controls) will receive the trial medication (MK-7 or placebo for 1 week). 31P-Magnetic resonance spectroscopy imaging of the forebrain and basal ganglia (31P-MRSI, primary endpoint) as well as other advanced neuroimaging methods, clinical assessment, including quantitative movement analysis, and biomarker sampling will be applied pre- and post-intervention. Innovation: The proposed project is highly translational as it builds on compelling mechanistic data from animal studies as well as on a small preliminary data set in humans. Patients are selected based on their mutation-related mitochondrial dysfunction and compared to disease and a healthy control group in a personalized medicine approach. We will further investigate how neuroimaging and blood-derived biomarkers can predict individual treatment response in sporadic PD. Clinical trial registration: This study was registered at the German Clinical Trial Registry (DRKS, DRKS00019932) on the 19th of December 2019., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors CK., (Copyright © 2021 Prasuhn, Kasten, Vos, König, Schmid, Wilms, Klein and Brüggemann.)

The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prasuhn, Davis and Kumar.)

Introduction: The presence of motor signs and symptoms in Parkinson's disease (PD) is the result of a long-lasting prodromal phase with an advancing neurodegenerative process. The identification of PD patients in an early phase is, however, crucial for developing disease-modifying drugs. The objective of our study is to investigate whether Diffusion Tensor Imaging (DTI) of the Substantia nigra (SN) analyzed by machine learning algorithms (ML) can be used to identify PD patients., Methods: Our study proposes the use of computer-aided algorithms and a highly reproducible approach (in contrast to manually SN segmentation) to increase the reliability and accuracy of DTI metrics used for classification., Results: The results of our study do not confirm the feasibility of the DTI approach, neither on a whole-brain level, ROI-labelled analyses, nor when focusing on the SN only., Conclusions: Our study did not provide any evidence to support the hypothesis that DTI-based analysis, in particular of the SN, could be used to identify PD patients correctly., Competing Interests: Competing interestsThe authors have no competing or conflicting interest to report., (© The Author(s) 2020.)

Objective: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present., Methods: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls., Results: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004)., Interpretation: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: This study focuses on genetically stratified subgroups of Parkinson's disease patients (PD) with an enrichment of risk variants in mitochondrial genes,who might benefit from treatment with the "mitochondrial enhancer" coenzyme Q10 (156 mg coenzyme Q10/d [QuinoMit Q10® Fluid] over six months). The study will be performed in a double-blind, randomized, and placebo-controlled parallel group manner., Methods: PD patients will be specifically identified and assigned to treatment groups stratified by their genetic "mitochondrial risk burden" and consequently expected mitochondrial dysfunction and treatment response to coenzyme Q10 (homozygous or compound heterozygous Parkin/PINK1 mutation carriers [P++], heterozygous Parkin/PINK1 mutation carriers [P+], "omics" positive [omics+], and "omics" negative PD patients [omics-]). The primary endpoint is the change in motor symptoms over six months (as measured by the change in the motor subscore of the MDS-UPDRS). Secondary clinical endpoints include motor fluctuations, non-motor symptoms, results of magnetic resonance imaging of brain energy metabolism (31P-magnetic resonance spectroscopy imaging), and changes in structural and functional brain anatomy (MRI)., Perspective: This study may be a first step towards a successful prediction of treatment response based on the genetic status of PD patients and translate progress in molecular genetics into personalized patient care. Further, magnetic resonance spectroscopy imaging may help quantify increased energy supply objectively and within a brief time after the start of treatment. Therefore, the potential of MRSI also for other studies addressing brain energy metabolism may will be assessed., Trial Registration: This study was registered at the German Clinical Trial Registry (DRKS, DRKS00015880) on November 15th, 2018., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

The Parkinson's disease (PD)-related ubiquitin ligase Parkin and mitochondrial kinase PINK1 function together in the clearance of damaged mitochondria. Upon mitochondrial depolarization, Parkin translocates to mitochondria in a PINK1-dependent manner to ubiquitinate outer mitochondrial membrane proteins. According to the current model, the ubiquitin- and LC3-binding adaptor protein SQSTM1 is recruited to mitochondria, followed by their selective degradation through autophagy (mitophagy). However, the role of the ubiquitin proteasome system (UPS), although essential for this process, still remains largely elusive. Here, we investigated the role of the UPS and autophagy by applying the potassium ionophore Valinomycin in PINK1-deficient human fibroblasts and isogenic neuroblastoma cell lines generated by CRISPR/Cas9. Although identical to the commonly used CCCP/FCCP in terms of dissipating the mitochondrial membrane potential and triggering complete removal of mitochondria, Valinomycin did not induce conversion of LC3 to its autophagy-related form. Moreover, FCCP-induced conversion of LC3 occurred even in mitophagy-incompetent, PINK1-deficient cell lines. While both stressors required a functional UPS, the removal of depolarized mitochondria persisted in cells depleted of LC3A and LC3B. Our study highlights the importance of the UPS in PINK1-/Parkin-mediated mitochondrial quality control. In contrast, activation of autophagy, monitored through conversion of LC3, is likely induced by depolarizing-agent-induced toxicity in a PINK1-/Parkin-independent manner.

Background: X-linked dystonia-parkinsonism (XDP) is characterized by the unique transition of dystonia to parkinsonism and striatal degeneration. Slowing of saccades on clinical examination has been taken as suggestive of a progressive supranuclear palsy (PSP) phenotype., Objectives: To elucidate whether eye movement abnormalities in XDP patients reflect striatonigral impairment or deficits in the brainstem saccade generator as present in PSP., Methods: Eye movements of 18 male XDP patients from the Philippines and 16 ethnically and age-matched, healthy control participants were analyzed and the results related to morphometric frontostriatal changes., Results: There was moderate saccade hypometria in XDP but velocity of visually guided saccades was normal. XDP patients showed an increased antisaccade error rate which correlated with the reduction of (i) the volume of the pallidum and putamen as well as (ii) the volume and cortical thickness in dorsolateral prefrontal cortex. Amplitude of memory-guided saccades was smaller and latency prolonged. Horizontal smooth pursuit eye movements were impaired., Conclusions: Oculomotor abnormalities in XDP resemble those of patients with the Parkinsonian type of multiple system atrophy and - to a lesser degree - Parkinson's disease, but are not compatible with PSP. They indicate striatal impairment and may represent preclinical signs of the parkinsonian stage of XDP. The increasing failure of response inhibition in the antisaccade task with increasing striatal atrophy may indicate an endophenotype for striatal degeneration. Dorsolateral prefrontal degeneration can be inferred from the failure in initiating antisaccades, prolonged latency of memory-guided saccades and the reduction of dorsolateral prefrontal volume and cortical thickness., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Although the genetic load is high in early-onset Parkinson's disease, thorough investigation of the genetic diagnostic yield has yet to be established. The objectives of this study were to assess variants in known genes for PD and other movement disorders and to find new candidates in 50 patients with early-onset PD., Methods: We searched for variants either within genes listed by the International Parkinson and Movement Disorder Society Task Force on Genetic Nomenclature or rare homozygous variants in novel candidate genes. Further, exome data from 1148 European PD patients (International Parkinson Disease Genomics Consortium) were used for association testing., Results: Seven patients (14%) carried pathogenic or likely pathogenic variants in Parkin, PLA2G6, or GBA. In addition, rare missense variants in DNAJC13:p.R1830C and in PPM1K:p.Y352C were detected. SPG7:p.A510V and PPM1K:p.Y352C revealed significant association with PD risk (P < 0.05)., Conclusions: Although we identified pathogenic variants in 14% of our early-onset PD patients, the majority remain unexplained, and novel candidates need to be validated independently to better further evaluate their role in PD. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Influenza A infections are a rare cause of movement disorders. Previously described patients have suffered from acute-onset myoclonus and/or dystonia or post-viral parkinsonism., Case Report: We present the case of a 74-year-old female patient with transient generalized chorea due to influenza A-mediated encephalopathy., Discussion: We discuss whether the clinical presentation and the magnetic resonance imaging changes may be attributable to cytokine-mediated encephalopathy or to direct cytotoxic effects of the virus. Additionally, we would like to make clinicians aware of this clinical sign in the context of viral encephalopathy., Competing Interests: Funding: N.B. received funding from DFG (Deutsche Forschungsgemeinschaft), the Collaborative Center for X-linked Dystonia-Parkinsonism, and the Else-Kröner-Fresenius Foundation. T.F.M. received funding from DFG (Deutsche Forschungsgemeinschaft) and BMBF (Federal Ministry of Education and Research). Conflicts of Interest: The authors report no conflict of interest. Ethics Statement: This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The authors’ institutional ethics committee has approved this study and all patients have provided written informed consent.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.

Impairment of the dopaminergic (DA) system is a common cause of several movement disorders including Parkinson's disease (PD), however, little is known about the underlying disease mechanisms. The recent development of stem-cell-based protocols for the generation of DA neurons partially solved this issue, however, this technology is costly and time-consuming. Commonly used cell lines, i.e., neuroblastoma (SHSY5Y) and PC12 cells are still widely used to investigate PD and significantly contributed to our understanding of mechanisms involved in development of the disease. However, they either do not express DA at all or require additional, only partially efficient differentiations in order to produce DA. Here we generated and characterized transgenic SH-SY5Y cells, ectopically expressing tyrosine hydroxylase (SH TH+ ), that can be used as a homogenous, DA-producing model to study alterations in DA metabolism and oxidative stress. We demonstrated that SH TH+ produce high levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) making this model suitable to investigate not only alterations in DA synthesis but also its turnover. We also provide evidence for the presence of other enzymes involved in DA synthesis and its turnover in these cells. Finally, we showed that these cells can easily be genetically modified using CRISPR/Cas9 technology in order to study genetically defined forms of movement disorders using DJ1-linked PD as a model.