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Background: There are no evidence-based guidelines for data cleaning of electronic health record (EHR) databases in Parkinson's disease (PD). Previous filtering criteria have primarily used the 9th International Statistical Classification of Diseases and Related Health Problems (ICD) with variable accuracy for true PD cases. Prior studies have not excluded atypical or drug-induced parkinsonism, and little is known about differences in accuracy by race., Objective: To determine if excluding parkinsonism diagnoses improves accuracy of ICD-9 and -10 PD diagnosis codes., Methods: We included ≥2 instances of an ICD-9 and/or -10 code for PD. We removed any records with at least one code indicating atypical or drug-induced parkinsonism first in all races, and then in Non-Hispanic White and Black patients. We manually reviewed 100 randomly selected charts per group before and after filtering, and performed a test of proportion (null hypothesis 0.5) for confirmed PD., Results: 5633 records had ≥2 instances of a PD code. 2833 remained after filtering. The rate of true PD cases was low before and after filtering to remove parkinsonism codes (0.55 vs. 0.51, p = 0.84). Accuracy was lowest in Black patients before filtering (0.48, p = 0.69), but filtering had a greater (though modest) impact on accuracy (0.68, p < 0.001)., Conclusions: There was inadequate accuracy of PD diagnosis codes in the largest study of ICD-9 and -10 codes. Accuracy was lowest in Black patients but improved the most with removing other parkinsonism codes. This highlights the limitations of using current real-world EHR data in PD research and need for further study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Acknowledgements and Financial Disclosures: Dr. Hill was supported by the CT2 scholarship through the CCTST at the University of Cincinnati. The CCTST is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, grant UL1TR001425. The CTSA program is led by the NIH’s National Center for Advancing Translational Sciences (NCATS). The content of this website is solely the responsibility of the CCTST and does not necessarily represent the official views of the NIH. Dr. Sawyer was supported by institutional grants from the University of Cincinnati (Center for Environmental Genetics, Clinical Research Feasibility Fund/Schubert Research Clinic, University of Cincinnati College of Medicine Institute Pilot Program). Dr. Kissela has received research support from NIH/NINDS and NCATS. Dr. Espay has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Bexion, Kyowa Kirin, Sunovion, Supernus (formerly, USWorldMeds), Avion Pharmaceuticals, and Herantis Pharma. He is co-owner of a patent that covers synthetic soluble nonaggregating peptide analogs as replacement treatments in proteinopathies. Dr. Marsili has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support. Drs. Sharma, Wissel, Duque, Botsford, and Wood as well as Ms. Delano, Ms. Sun, and Ms. Jiang report no disclosures., (Copyright © 2023. Published by Elsevier Ltd.)

Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus - SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction : Multiple system atrophy (MSA) is a progressive degenerative disorder of the central and autonomic nervous systems characterized by parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal signs. The confirmatory diagnosis is pathological, but clinical-diagnostic criteria have been developed to help clinicians. To date, the early diagnosis of MSA is challenging due to the lack of reliable diagnostic biomarkers. Areas covered : The authors reappraised the main clinical, neurophysiological, imaging, genetic, and laboratory evidence to help in the early diagnosis of MSA in the clinical and in the research settings. They also addressed the practical clinical issues in the differential diagnosis between MSA and other parkinsonian and cerebellar syndromes. Finally, the authors summarized the unmet needs in the early diagnosis of MSA and proposed the next steps for future research efforts in this field. Expert opinion : In the last decade, many advances have been achieved to help the correct MSA diagnosis since early stages. In the next future, the early diagnosis and correct classification of MSA, together with a better knowledge of the causative mechanisms of the disease, will hopefully allow the identification of suitable candidates to enroll in clinical trials and select the most appropriate disease-modifying strategies to slow down disease progression.

Background: Postural instability is a disease milestone signaling advanced disease., Objectives: To estimate the onset of postural instability in monogenic parkinsonisms., Methods: We systematically reviewed studies (PubMed 1996-2017) in SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, FBXO7, VPS35, DNAJC6, or SYNJ1-related monogenic parkinsonisms, with documented postural instability. Genes with ≥ 15 patients were included in an individual-patient meta-analysis and compared with a retrospectively collected sporadic Parkinson's disease cohort from our center. The primary outcome measure was the progression-free survival from postural instability using Kaplan-Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR)., Results: Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, whereas a total of 871 subjects (270 from sporadic cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis. Postural instability was reported in 80% of DJ-1, 40% of PRKN, 39% of PINK1, 34% of ATP13A2, 31% of LRRK2, and 29% of SNCA patients. Progression-free survival from postural instability at 10 years after disease onset was longest in ATP13A2 (97%) and shortest in SNCA (50%). Halfway between these two extremes were PRKN (88%), PINK1 (87%), and LRRK2 (81%), similar to sporadic Parkinson's disease (72%). Higher risk of postural instability was observed in SNCA (HR = 3.2, p = 0.007) and DJ-1 (HR = 3.96, p = 0.001) compared to sporadic Parkinson's disease. Young age at onset in PINK1 and female sex in LRRK2 were associated with a decreased risk of postural instability., Conclusions: Monogenic parkinsonisms exhibit differential timelines to postural instability, informing prognostic counseling and interpretation of future genotype-specific treatment trials., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers , UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Dystonia is common in the classic atypical parkinsonian disorders such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and to a lesser extent in dementia with Lewy bodies. Its clinical phenomenology, including body distribution, timing of appearance, severity, and relationship to dopaminergic and other medications may vary considerably within and between atypical parkinsonian disorders. From a pathophysiological standpoint, the coexistence of dystonia with parkinsonism challenges the functional model of the basal ganglia. Clinical recognition of specific dystonic features may assist in the differential diagnosis of atypical parkinsonian disorders and in distinguishing them from Parkinson's disease. The presence of dystonia in atypical parkinsonian disorders informs management decisions. Reduction or withdrawal of levodopa should be considered if there is a close relationship between the onset of dystonia with periods of high dopaminergic tone. Botulinum neurotoxin may be considered in focal presentations. We here provide an updated overview of dystonia arising in the setting of atypical parkinsonian disorders, summarizing relevant clinical and clinicopathological studies, underlying pathophysiological mechanisms, diagnostic clues and potential pitfalls in the diagnosis. Finally, we suggest a tailored therapeutic approach for the management of these patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In frontotemporal dementia (FTD), the behavioral variant (bv-FTD) and nonfluent variant of primary progressive aphasia (nfv-PPA) reflect a prominent neurodegenerative involvement of the frontal lobe networks, which may include the premotor and motor areas and thus cause heterogeneous clinical symptoms including parkinsonism. With the technique of transcranial magnetic stimulation, we investigated long-term potentiation- and long-term depression-like plasticity in the primary motor cortex of bv-FTD and nfv-PPA patients, with and without parkinsonism, by using the theta-burst stimulation (TBS) protocol. We applied the intermittent TBS and continuous TBS in 20 FTD patients and 18 age-matched healthy subjects. Results were also compared with those achieved in a cohort of age-matched patients with Parkinson's disease. The responses to TBS were abnormal in FTD patients with parkinsonism. By contrast, the TBS induced normal responses in patients with both nfv-PPA and bv-FTD without parkinsonism. Finally, responses to TBS were comparable in patients with FTD with parkinsonism and patients with Parkinson's disease. We provide evidence of abnormal primary motor cortex long-term potentiation-/long-term depression-like plasticity in patients with FTD and parkinsonism suggesting neurodegenerative processes in the corticobasal ganglia-thalamo-cortical motor networks in these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Whether the primary motor cortex (M1) contributes to the pathophysiology of corticobasal syndrome (CBS) remains unclear. In this study in patients with probable CBS, we tested whether M1 plasticity contributes to the pathophysiology of symptoms in the contralateral "less affected" limb, manifesting only parkinsonism, and in the contralateral "more affected" limb, manifesting parkinsonism plus other motor and nonmotor symptoms. In Experiment 1, we applied intermittent/continuous theta-burst stimulation (iTBS/cTBS) over the M1 contralateral to the less affected limb in 17 patients. In Experiment 2, we applied iTBS/cTBS over the M1 contralateral to the more affected limb in 14 of the 17 patients. We measured iTBS/cTBS-induced plasticity as reflected by motor-evoked potential (MEP) changes. Data were compared with those obtained in 17 healthy subjects (HS). In Experiment 1, TBS over the M1 contralateral to the less affected limb disclosed reduced plasticity in patients than in HS. In Experiment 2, in 5 of 14 patients we recorded abnormally low-amplitude MEPs, preventing the evaluation of plasticity in the M1 contralateral to the more affected limb. In the remaining nine patients, TBS disclosed abnormal plasticity characterized by high intersubject variability. In these nine patients, the response to TBS correlated with specific patients' clinical features. In the present study in patients with probable CBS, we have demonstrated heterogeneous abnormalities of M1 that contribute to the pathophysiology of this condition., (Copyright © 2016 the American Physiological Society.)

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder resulting from pathological accumulation of tau protein and is included in the spectrum of Atypical Parkinsonism. The typical clinical phenotype of CBD is characterized by the Corticobasal syndrome (CBS). In recent years it has become clear that the clinical picture of CBS may be caused by different pathological conditions, resulting in frequent misdiagnosis. CBD has high morbidity and poor prognosis with no effective therapies. In this review, we will discuss the symptomatic treatment, the palliative care and the disease modifying strategies currently in use. Symptomatic treatment in patients with CBD may sometimes be useful for improving motor (parkinsonism, dystonia and myoclonus) and non-motor (cognitive-behavioral) symptoms, but the effects are often unsatisfactory. In addition, non-pharmacological strategies and palliative care are useful integrating components of the multidisciplinary therapeutic approach for patients with CBD. Despite many efforts, a disease-modifying treatment is still unavailable for CBD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts. [ABSTRACT FROM AUTHOR]

Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967–2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration. [ABSTRACT FROM AUTHOR]

Keywords: genetic parkinsonism; sporadic Parkinson's disease; LRRK2; GBA; genotype-phenotype correlation EN genetic parkinsonism sporadic Parkinson's disease LRRK2 GBA genotype-phenotype correlation 1 3 3 08/27/21 20210823 NES 210823 With the diffusion of cost-effective genetic analyses, an increase in the spectrum of reported genetic variants associated with sporadic Parkinson's disease (sPD) (e.g., glucocerebrosidase - I GBA i ) and monogenic parkinsonisms (dominant, recessive, and atypical forms) has been achieved. Genotype-phenotype studies in genetic parkinsonisms may help in the earlier identification and in the development of disease-modifying treatments based on precision medicine strategies. Markopoulou et al., analyze single nucleotide polymorphisms (SNPs) identified in previous GWAS studies, together with low frequency and rare variants at parkinsonism-associated genes from the MDSgene database, in sPD patients. [Extracted from the article]

We describe an elderly woman meeting criteria for vascular parkinsonism/dementia associated with a likely pathogenic variant in the COL22A1 gene, supported by functional experiments in a zebrafish model. We suggest that white matter hyperintensities may not represent small-vessel ischemic disease and that, if confirmed by further observations, COL22A1 may be included among the adult-onset leukoencephalopathies mislabeled as "vascular parkinsonism." [ABSTRACT FROM AUTHOR]

The aim of this paper is to summarise the main clinical and pathophysiological features of facial bradykinesia in Parkinson's disease (PD) and in atypical parkinsonism. Clinical observation suggests that reduced spontaneous and emotional facial expressions are features of facial bradykinesia in PD and atypical parkinsonism. In atypical parkinsonism, facial bradykinesia is complicated by additional dystonic features. Experimental studies evaluating spontaneous and emotional facial movements demonstrate that PD is characterised by a reduction in spontaneous blinking and emotional facial expression. In PD, neurophysiological studies show that voluntary orofacial movements are smaller in amplitude and slower in velocity. In contrast, movements of the upper face (eg, voluntary blinking) are normal in terms of velocity and amplitude but impaired in terms of switching between the closing and opening phases. In progressive supranuclear palsy (PSP), voluntary blinking is not only characterised by a severely impaired switching between the closing and opening phases of voluntary blinking, but is also slow in comparison with PD. In conclusion, in PD, facial bradykinesia reflects abnormalities of spontaneous, emotional and voluntary facial movements. In PSP, spontaneous and voluntary facial movements are abnormal but experimental studies on emotional facial movements are lacking. Data on facial bradykinesia in other atypical parkinsonism diseases, including multiple system atrophy and corticobasal degeneration, are limited. In PD, facial bradykinesia is primarily mediated by basal ganglia dysfunction whereas in PSP, facial bradykinesia is a consequence of a widespread degeneration involving the basal ganglia, cortical and brainstem structures. [ABSTRACT FROM AUTHOR]

• Limb dystonia is an important clinical feature in progressive supranuclear palsy. • The "gunslinger" dystonia consists of the abduction and extension of the arm. • The "gunslinger" dystonia is a red flag for Richardson variant. • Clinicians should be aware of the "gunslinger" posture in Richardson variant. [ABSTRACT FROM AUTHOR]