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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. • Secondary parkinsonism has multiple etiologies. • Infectious, autoimmune, and paraneoplastic etiologies are rare but of increasing interest. • Awareness of rare parkinsonian syndromes is crucial for diagnosis and treatment. • Research efforts are needed to clarify the molecular underpinnings of parkinsonism. [ABSTRACT FROM AUTHOR]

• Disease milestones represent clinically relevant measures of disease progression. • A score of 3 or more on Hoehn and Yahr scale is the most common motor milestone. • Clinical milestones have expanded to include motor and non-motor manifestations, and functionality. • Milestones should be periodically assessed in the care of every affected individual. • Milestones could inform on disease-modifying interventions. [ABSTRACT FROM AUTHOR]

Background: the study of movement disorders associated with oncological diseases and anticancer treatments highlights the wide range of differential diagnoses that need to be considered. In this context, the role of immune-mediated conditions is increasingly recognized and relevant, as they represent treatable disorders. Methods: we reappraise the phenomenology, pathophysiology, diagnostic testing, and treatment of movement disorders observed in the context of brain tumors, paraneoplastic conditions, and cancer immunotherapy, such as immune-checkpoint inhibitors (ICIs). Results: movement disorders secondary to brain tumors are rare and may manifest with both hyper-/hypokinetic conditions. Paraneoplastic movement disorders are caused by antineuronal antibodies targeting intracellular or neuronal surface antigens, with variable prognosis and response to treatment. ICIs promote antitumor response by the inhibition of the immune checkpoints. They are effective treatments for several malignancies, but they may cause movement disorders through an unchecked immune response. Conclusions: movement disorders due to focal neoplastic brain lesions are rare but should not be missed. Paraneoplastic movement disorders are even rarer, and their clinical-laboratory findings require focused expertise. In addition to their desired effects in cancer treatment, ICIs can induce specific neurological adverse events, sometimes manifesting with movement disorders, which often require a case-by-case, multidisciplinary, approach. [ABSTRACT FROM AUTHOR]

Objective: We sought to test the hypothesis that technology could predict the risk of falls in Parkinson's disease (PD) patients with orthostatic hypotension (OH) with greater accuracy than in-clinic assessment. Methods: Twenty-six consecutive PD patients with OH underwent clinical (including home-like assessments of activities of daily living) and kinematic evaluations of balance and gait as well as beat-to-beat blood pressure (BP) monitoring to estimate their association with the risk of falls. Fall frequency was captured by a diary collected prospectively over 6 months. When applicable, the sensitivity, specificity, and diagnostic accuracy were measured using the area under the receiver operating characteristics curve (AUC). Additional in-clinic assessments included the OH Symptom Assessment (OHSA), the OH Daily Activity Score (OHDAS), and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Results: The prevalence of falls was 53.8% over six months. There was no association between the risk of falls and test of gait and postural stability (p ≥ 0.22) or home-like activities of daily living (p > 0.08). Conversely, kinematic data (waist sway during time-up-and-go, jerkiness, and centroidal frequency during postural sway with eyes-opened) predicted the risk of falls with high sensitivity and specificity (> 80%; AUC ≥ 0.81). There was a trend for higher risk of falls in patients with orthostatic mean arterial pressure ≤ 75 mmHg. Conclusions: Kinematic but not clinical measures predicted falls in PD patients with OH. Orthostatic mean arterial pressure ≤ 75 mmHg may represent a hemodynamic threshold below which falls become more prevalent, supporting the aggressive deployment of corrective measures. [ABSTRACT FROM AUTHOR]

Animal models have been used to gain pathophysiologic insights into Parkinson's disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom. [ABSTRACT FROM AUTHOR]

Daytime sleepiness, reported in about 50 % of patients with Parkinson's disease (PD), is associated with high morbidity, poor quality of life and increased risk for accidents. While an association between dysautonomia and daytime sleepiness in early, de-novo PD has been reported, our understanding of the role of medications, cognitive status and co-morbidites on this relationship is inadequate. Data were analyzed from the prospective Cincinnati Cohort Biomarkers Program. The primary outcome of interest was excessive daytime sleepiness (EDS), as measured by the Epworth Sleepiness Scale (ESS; ESS score > 10). The primary exposure variable was orthostatic hypotension (OH). Linear and logistic regression analyses followed by moderated graphical network analyses were conducted to explore the complex association between OH and ESS. Edge weight from graphical network analysis indicates the strength of the association. Data on 453 subjects with PD were analyzed. Median disease duration was 5.8 years and nearly 90 % were H&Y stage <3. OH was not associated with EDS. OH was associated with depression (edge weight, 0.22) in cognitively impaired patients but not in cognitively normal patients. In addition, depression was associated with ESS (edge weight, 0.37; moderation weight, 0.22) in cognitively impaired patients to a greater extent than in cognitively normal patients (edge weight, 0.22). OH is not directly associated with daytime sleepiness in early, treated PD. However, OH seems to be associated with ESS via depression in cognitively impaired patients. This complex relationship deserves additional study. • Daytime sleepiness is associated with high morbidity in Parkinson's disease (PD). • Our understanding of the association between orthostatic hypotension (OH) and daytime sleepiness in PD is inadequate. • OH was not associated with daytime sleepiness in early, treated PD. • OH seems to be associated with daytime sleepiness via depression in cognitively impaired PD patients. [ABSTRACT FROM AUTHOR]

Background: Patients with essential tremor (ET), Parkinson's disease (PD) and dystonic tremor (DT) can be difficult to classify and often share similar characteristics. Objectives: To use ubiquitous smartphone accelerometers with and without clinical features to automate tremor classification using supervised machine learning, and to use unsupervised learning to evaluate if natural clusterings of patients correspond to assigned clinical diagnoses. Methods: A supervised machine learning classifier was trained to classify 78 tremor patients using leave-one-out cross-validation to estimate performance on unseen accelerometer data. An independent cohort of 27 patients were also studied. Next, we focused on a subset of 48 patients with both smartphone-based tremor measurements and detailed clinical assessment metrics and compared two separate machine learning classifiers trained on these data. Results: The classifier yielded a total accuracy of 74.4% and F1-score of 0.74 for a trinary classification with an area under the curve of 0.904, average F1-score of 0.94, specificity of 97% and sensitivity of 84% in classifying PD from ET or DT. The algorithm classified ET from non-ET with 88% accuracy, but only classified DT from non-DT with 29% accuracy. A poorer performance was found in the independent cohort. Classifiers trained on accelerometer and clinical data respectively obtained similar results. Conclusions: Machine learning classifiers achieved a high accuracy of PD, however moderate accuracy of ET, and poor accuracy of DT classification. This underscores the difficulty of using AI to classify some tremors due to lack of specificity in clinical and neuropathological features, reinforcing that they may represent overlapping syndromes. [ABSTRACT FROM AUTHOR]

Introduction: We sought to examine whether levels of soluble alpha-synuclein (α-syn), amyloid-beta (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease.Methods: We assessed the 4-year change in total brain volume (n = 99) and baseline CSF α-syn, Aβ42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied.Results: The 4-year change in total brain volume was -21.2 mm3 (95% confidence interval, -26.1, -16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aβ42 was linearly associated with total brain volume at baseline (R2 = 0.60, p = 0.0004) and at year 2 (R2 = 0.66, p < 0.0001), with CSF Aβ42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α-syn was linearly associated with total brain volume at baseline (R2 = 0.58, p = 0.0044) but not at year 2 (R2 = 0.58, p = 0.1342).Conclusion: Reduction in soluble Aβ42 is associated with lower total brain volume in Parkinson's disease. [ABSTRACT FROM AUTHOR]

We examined the role of the cerebellum in patients with tremor-dominant cervical dystonia by measuring the adaptive capacity of rapid reflexive eye movements (saccades). We chose the saccade adaptation paradigm because, unlike other motor learning paradigms, the real-time modification of saccades cannot "wait" for the sensory (visual) feedback. Instead, saccades rely primarily on the internal reafference modulated by the cerebellum. The saccade adaptation happens over fast and slow timescales. The fast timescale has poor retention of learned response, while the slow timescale has strong retention. Cerebellar defects resulting in loss of function affect the fast timescale but the slow timescale of saccade adaptation is retained. In contrast, maladaptive cerebellar disorders feature the absence of both fast and slow timescales. We were able to measure both timescales using noninvasive oculography in 6 normal individuals. In contrast, both timescales were absent in 12 patients with tremor-dominant cervical dystonia. These findings are consistent with maladaptive cerebellar outflow as a putative pathophysiological basis for tremor-dominant cervical dystonia. [ABSTRACT FROM AUTHOR]

Introduction: Adductor-type spasmodic dysphonia is a task-specific focal dystonia characterized by involuntary laryngeal muscle spasms. Due to the lack of quantitative instrumental tools, voice assessment in patients with adductor-type spasmodic dysphonia is mainly based on qualitative neurologic examination. We evaluated patients with cepstral analysis and specific machine-learning algorithms and compared the results with those collected in healthy subjects. In patients, we also used cepstral analysis and machine-learning algorithms to investigate the effect of botulinum neurotoxin type A.Methods: We investigated 60 patients affected by adductor-type spasmodic dysphonia before botulinum neurotoxin type A therapy and 60 age and gender-matched healthy subjects. A subgroup of 35 patients was also evaluated after botulinum neurotoxin type A therapy. We recorded the sustained emission of a vowel and a sentence by means of a high-definition audio recorder. Voice samples underwent cepstral analysis as well as machine-learning algorithm classification techniques.Results: Cepstral analysis was able to differentiate between healthy subjects and patients, but receiver operating characteristic curve analysis demonstrated that machine-learning algorithms achieved better results than cepstral analysis in differentiating healthy subjects and patients affected by adductor-type spasmodic dysphonia. Similar results were obtained when differentiating patients before and after botulinum neurotoxin type A therapy. Cepstral analysis and machine-learning measures correlated with the severity of voice impairment in patients before and after botulinum neurotoxin type A therapy.Conclusions: Cepstral analysis and machine-learning algorithms are new tools that offer meaningful support to clinicians in the diagnosis and treatment of adductor-type spasmodic dysphonia. [ABSTRACT FROM AUTHOR]

Background: Cervical dystonia (CD) can present with head tremor. It is unclear whether ataxic features are differentially associated with this phenotype at onset of CD. Objectives: We sought to evaluate: (1) the demographic features of CD patients with (Tr-CD) and without head tremor (nTr-CD) at onset, and (2) the differential ataxic features between these CD subtypes. Methods: For the first objective, we compared demographic data in Tr-CD versus nTr-CD subtypes in the entire cohort of CD subjects enrolled in the Dystonia Coalition Natural History and Biorepository studies (n = 1608). For the second objective, we rated the standardized videos from consecutively enrolled Tr-CD subjects (n = 50) and age-, gender-, and disease duration-matched nTr-CD subjects (n = 50) for ataxia severity scoring using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS); and for dystonia severity using the Toronto Western Spasmodic Torticollis Rating Scale section-I (TWSTRS) and the Global Dystonia Rating Scale (GDRS). Results: Of 1,608 subjects, 18.1% (n = 291) were classified as Tr-CD and 81.9% (n = 1317) as nTr-CD. The Tr-CD cohort was older, predominantly female, and had longer disease duration than the nTr-CD cohort (p = 0.01). Compared to nTr-CD, Tr-CD subjects had worse generalized ataxia, speech, and gait and posture scores. High ataxia severity with low dystonia severity distinguished Tr-CD from nTr-CD with high accuracy (area under the curve, 0.91 (95% CI 0.85–0.97). Conclusions: Head tremor at disease onset represents a clinically distinguishable subtype of cervical dystonia affecting predominantly older women, with worse ataxia and milder dystonia than the non-tremulous dystonic phenotype. [ABSTRACT FROM AUTHOR]

Background: In uncommon tremor disorders, clinical efficacy and optimal anatomical targets for deep brain stimulation (DBS) remain inadequately studied and insufficiently quantified.Methods: We performed a systematic review of PubMed.gov and ClinicalTrials.gov. Relevant articles were identified using the following keywords: “tremor”, “Holmes tremor”, “orthostatic tremor”, “multiple sclerosis”, “multiple sclerosis tremor”, “neuropathy”, “neuropathic tremor”, “fragile X-associated tremor/ataxia syndrome”, and “fragile X.”Results: We identified a total of 263 cases treated with DBS for uncommon tremor disorders. Of these, 44 had Holmes tremor (HT), 18 orthostatic tremor (OT), 177 multiple sclerosis (MS)-associated tremor, 14 neuropathy-associated tremor, and 10 fragile X-associated tremor/ataxia syndrome (FXTAS). DBS resulted in favorable, albeit partial, clinical improvements in HT cases receiving Vim-DBS alone or in combination with additional targets. A sustained improvement was reported in OT cases treated with bilateral Vim-DBS, while the two cases treated with unilateral Vim-DBS demonstrated only a transient effect. MS-associated tremor responded to dual-target Vim-/VO-DBS, but the inability to account for the progression of MS-associated disability impeded the assessment of its long-term clinical efficacy. Neuropathy-associated tremor substantially improved with Vim-DBS. In FXTAS patients, while Vim-DBS was effective in improving tremor, equivocal results were observed in those with ataxia.Conclusions: DBS of select targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is currently in its incipient form and based on single cases or limited case series. An international registry is, therefore, warranted to clarify selection criteria, long-term results, and optimal surgical targets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. To determine if excluding parkinsonism diagnoses improves accuracy of ICD-9 and -10 PD diagnosis codes. 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. 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). 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. • PD diagnosis codes are often inaccurate in EHR. • Reasons for low rates of PD in Black vs. White Americans are unknown. • Removing parkinsonism codes improved accuracy in Black but not White patients. • Accuracy of PD codes was low after filtering in all groups. • EHR databases for PD are insufficiently accurate for real-world data research. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's Disease (PD) is a highly heterogeneous entity in terms of clinical manifestations, progression, and treatment response. This variability has given rise to the hypothesis that different clinical subtypes of the disease exist., State of the Art: To date, several clinical subtypes have been described, mostly based on different clinical features, and sometimes with the support of biomarkers, either fluid, neuroimaging, or neurophysiological. The most homogeneous subtypes detected are a 'benign subtype', characterised by younger age at onset, mild non-motor symptoms, and a slower rate of disease progression, and a 'malignant subtype', which features an older age at onset, a higher burden of non-motor symptoms, and faster disease progression., Clinical Implications: Despite extensive research, none of the subtypes identified so far seem to be biologically supported, so clinical subtyping does not elucidate PD aetiology and does not allow for the prediction of prognosis or treatment response. This study was aimed to review the literature on this topic and to examine the studies on PD subtyping. We also reviewed the proposed biomarkers for a biological classification of PD, and outlined the role of genetics and pathology within this context., Future Directions: In light of the recent proposal of a biological classification of PD, which might overcome the limits of the clinical diagnosis, PD subtyping should hopefully shepherd researchers towards a biological approach, also aided by recent advances in the field of biomarkers.

Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing-WES; whole-genome sequencing-WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.

Pathogenic variants in the LRRK2 gene represent the most common cause of autosomal dominant Parkinson's disease (PD) worldwide. We identified the LRRK2 p.L1795F variant in 14 White/European ancestry PD patients, including two families with multiple affected carriers and seven additional affected individuals with familial PD using genotyping and sequencing data from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and CENTOGENE. All variant carriers were of White/European ancestry, and those with available genotyping data shared a common haplotype. The clinical presentation of p.L1795F carriers resembles that of other LRRK2 pathogenic variant carriers. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide conclusive evidence that the LRRK2 p.L1795F variant is pathogenic. It represents a rare cause of PD in the European population but needs to be included in genetic testing efforts and considered for ongoing gene-specific clinical trials., Competing Interests: Competing interests L.M.L., N.A., K. Lo., and L.A.H. declare no competing interests.

Introduction: Smartphone applications (apps) are instruments that assist with objective measurements during the clinical assessment of patients with movement disorders. We aim to test the hypothesis that Parkinson's disease (PD) patients will exhibit an increase in tapping variability and a decrease in tapping speed over a one-year period, compared to healthy controls (HC)., Methods: Data was prospectively collected from participants enrolled in our Cincinnati Cohort Biomarker Program, in 2021-2023. Participants diagnosed with PD and age-matched HC were examined over a one-year-interval with a tapping test performed with customized smartphone app. Tapping speed (taps/s), inter-tap intervals and variability (movement regularity), and sequence effect were measured., Results: We included 295 PD patients and 62 HC. At baseline, PD subjects showed higher inter-tap variability than HC (coefficient-of-variation-CV, 37 ms [22-64] vs 26 ms [8-51]) (p = 0.007). Conversely, there was no difference in inter-tap intervals (411 ms [199-593] in PD versus 478 ms [243-618] in HC) and tapping speed (3.42[2.70-4.76] taps/s in PD versus 3.21 taps/s [2.57-4.54] in HC) (p > 0.05). Only PD subjects (n = 135), at the one-year follow-up, showed a decreased tapping speed vs baseline (3.44 taps/s [2.86-4.81] versus 3.39 taps/s [2.58,4.30]) (p = 0.036), without significant changes in inter-tap variability (CV, 32 ms [18,55] baseline versus 34 ms [22,59] follow-up) (p = 0.142). No changes were found in HC at the one-year follow up (all p values>0.05)., Conclusions: Inter-tap variability (dysrhythmia) but no inter-tap intervals or tapping speed are reliably distinctive feature of an app-based bradykinesia assessment in PD., Competing Interests: Declaration of competing interest Dr. Luca Marsili has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support, and personal compensation as a consultant/scientific advisory board member for Acadia. Dr. Marsili has received a grant (collaborative research agreement) from the International Parkinson's and Movement Disorders Society for the MDS-UTRS Validation Program (Role: PI), Non-Profit. Dr. Alberto J. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion. Dr. Espay is cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies. Drs. Abanto, Mahajan, Duque, Chinchihualpa Paredes, Deraz, and Bologna report no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024. Published by Elsevier B.V.)

Dropped head syndrome (DHS) is characterized by severe forward flexion of the cervical spine due to an imbalance in neck muscle tone. This condition can be linked to various neuromuscular diseases, including myasthenia gravis (MG). On the other hand, Parkinson's disease (PD) patients may show a clinically indistinguishable picture named antecollis, which is caused by increased axial tone, but without muscle weakness. Differentiating between DHS and antecollis is crucial due to their distinct treatment requirements. We present the case of a 71-year-old White male with a one-month history of severe neck flexion, mild dysphagia, and dysphonia. His medical history included diabetes mellitus, coronary artery disease, arterial hypertension, and mild cervical spondylosis. Neurological examination revealed features of Parkinsonism, including hypomimia, asymmetric rigidity, and reduced arm swing. There was significant weakness in his neck extensor muscles, with no signs of ptosis or diplopia. Brain/spine MRI scans were unremarkable, but electromyography showed a reduced compound muscle action potentials amplitude in repetitive nerve stimulation, consistent with MG. High-titer acetylcholine receptor antibodies confirmed the diagnosis. Treatment with pyridostigmine (60 to 120 mg/day) and plasma exchange (daily, for five consecutive days) improved the patient's general condition and neck posture. Concurrently, the patient was diagnosed with PD based on established clinical criteria and improved with carbidopa/levodopa therapy (up to 150/600 mg/daily). This case highlights the rare co-occurrence of MG and PD, emphasizing the need for thorough clinical, neurophysiological, and laboratory evaluations in complex DHS presentations. Managing MG's life-threatening aspects and addressing PD symptoms requires a tailored approach, showcasing the critical role of neurophysiology in accurate diagnosis and effective treatment., Competing Interests: The authors declare no conflicts of interest related to the present work. Dr. Luca Marsili has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support. Dr. Carlo Colosimo received grants from Ipsen and Royalties from Oxford University Press and Cambridge University Press unrelated to the present research. All other authors report no conflicts of interest.

We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Essential tremor (ET) may present with head tremor (HT), of presumed cerebellar nature. Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is a highly effective therapy for medication-refractory ET. However, stimulation-related side effects may include cerebellar abnormalities, such as postural instability. This retrospective cohort study evaluated the risk of post-Vim DBS postural instability (primary outcome measure) in patients with versus without head tremor (HT vs. nHT). The primary outcome measure, namely post-DBS postural instability, was assessed in both groups using a Wilcoxon rank sum t-test. The time to postural instability was determined using Cox proportional hazards regression analysis adjusted for age and sex. Out of 30 patients analyzed during the follow up period, there was similar postural instability detected in HT (9/14, 64%) and nHT patients (11/16, 69%) at 24 months post-Vim DBS (p=0.82), adjusted hazard ratio[aHR]=0.82, p=0.69). These data suggest that the presence or absence of HT does not have an impact on postural instability after bilateral Vim DBS in patients with ET., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Functional dystonia, the second most common functional movement disorder, is characterized by acute or subacute onset of fixed limb, truncal, or facial posturing, incongruent with the action-induced, position-sensitive, and task-specific manifestations of dystonia. We review neurophysiological and neuroimaging data as the basis for a dysfunctional networks in functional dystonia. Reduced intracortical and spinal inhibition contributes to abnormal muscle activation, which may be perpetuated by abnormal sensorimotor processing, impaired selection of movements, and hypoactive sense of agency in the setting of normal movement preparation but abnormal connectivity between the limbic and motor networks. Phenotypic variability may be related to as-yet undefined interactions between abnormal top-down motor regulation and overactivation of areas implicated in self-awareness, self-monitoring, and active motor inhibition such as the cingulate and insular cortices. While there remain many gaps in knowledge, further combined neurophysiological and neuroimaging assessments stand to inform the neurobiological subtypes of functional dystonia and the potential therapeutic applications., (© 2023. Springer Nature Switzerland AG.)

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.)

Objective: To evaluate 3 cases illustrating a rarely recognized phenotype of Parkinson disease (PD), namely, biphasic levodopa-induced respiratory dysfunction manifesting as dyspnea., Methods: To appreciate the nature of the fluctuations of respiratory function in response to levodopa, we measured changes in respiratory muscle control before and after the best therapeutic response to levodopa in 3 PD patients with fluctuating dyspnea., Results: Episodes of breathlessness were accompanied by shallow tachypnea and reduced respiratory muscle control, as measured by maximal expiratory pressure, peak cough flow, and forced expiratory volume in 1 second., Conclusions: The spectrum of respiratory dysfunction in PD includes a biphasic reduced respiratory muscle control accompanying periods when the effect of levodopa is subtherapeutic. This biphasic levodopa-related complication represents a rarely recognized nonmotor phenomenon in PD. Management requires increasing the levodopa dose, shortening the interdose interval, or implementing a program of continuous dopaminergic stimulation., (© 2021 American Academy of Neurology.)

Purpose: In the advanced stage of Parkinson disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). Recent evidence has underlined the general lack of randomized, blinded, head-to-head studies on device-aided therapies for advanced PD., Methods: To better clarify the real-world attitude of clinicians on this matter, we conducted an international survey of forty-four experienced movement disorder specialists regarding the management of device-aided therapies in advanced PD., Results: Our international survey showed a general agreement that nowadays, motor complications are less common compared to the past (59% agreement), that guidelines to identify candidates for device-aided therapies are currently lacking (57% agreement), and that device-aided therapies will have increased demand in the future (75% agreement)., Conclusions: We conclude that guidelines to assist clinicians and patients to choose device-aided therapies are required.

Background: Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis., Methods: This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18] F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p -tau, t -tau, and centiloids levels., Findings: Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p  < 0.001) or MCI (1.42; p  = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume., Interpretation: Normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis., Funding: Please refer to the Funding section at the end of the article., Competing Interests: None., (© 2021 The Authors.)

In advanced Parkinson's disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). We reappraised the evidence guiding the decision of appropriate device-aided therapies in advanced PD, and systematically reviewed the literature (including ongoing clinical trials) comparing CSAI, LCIG, DBS in terms of efficacy and cost-effectiveness, with particular consideration to possible conflicts of interests. Of 14,980 documents screened, sixteen were included (4 and 13 studies examining efficacy and cost-effectiveness, respectively). LCIG and DBS showed higher efficacy compared to best medical therapy (BMT). DBS was more expensive than BMT and LCIG. Lifetime costs of CSAI were lower of those of DBS, and DBS lifetime costs were lower than those of LCIG. The majority of studies (11 out of 16) showed direct or indirect sponsorship from pharmaceutical or device companies. Only one ongoing clinical trial comparing LCIG with DBS was found. Device-aided therapies address unmet needs in advanced PD. LCIG and DBS are superior to BMT in head-to-head studies; however, initial and lifetime costs should be considered when choosing those therapies. Guidelines to assist clinicians and patients to choose device-aided therapies, free from conflict of interests, are required., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM&#95;001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.

Purpose: Teleconsultation is a consultation between two or more physicians about the diagnostic work-up and therapeutic strategy in the treatment of an individual case by means of modern telematics. 'Drip-and-ship' teleconsultation model consists of the transfer of patients, through telematics stroke networks, with large arteries occlusions from primary to comprehensive stroke centers equipped for endovascular therapy. We retrospectively investigated appropriateness, safety, and effectiveness of 'drip-and-ship' teleconsultation model in a rural area of Tuscany., Methods: Outcome measures were: door-to-ship time (including door-to-needle time), ratio of number treated/total sent patients, adverse events/mortality during transfer, and mortality and modified Rankin scale at 90 days. Analysis of non-treated patients was also done., Results: Seventy-eight patients were included; 16/78 patients were sent for endovascular therapy alone, and 62/78 for "drip-and-ship"; 12 patients were not treated. Door-to-ship, and door-to-needle times (mean ± SD) were 105 ± 29.8 and 62.5 ± 37.5 min, respectively. The ratio number of treated/total sent patients was 0.85. At 90 days, the global mortality rate was 21%, and 40% of patients showed favorable outcome. The main cause of non-treatment was spontaneous recanalization., Conclusions: The high value for treated/total sent patients' ratio underlines that "drip-and-ship" teleconsultation model is appropriate and effective, with a few untreated patients. The model is safe, without adverse events during transfer. Taken together, our outcomes are in line with the previous reports. "Drip-and-ship" teleconsultation model is safe and effective in rural areas, allowing good selections and rapid treatments for stroke patients, based on the transfer from the primary to the comprehensive stroke center.

Paraneoplastic syndromes include, by definition, any symptomatic and non-metastatic condition associated with a neoplasm. Paraneoplastic movement disorders are a heterogeneous group of syndromes encompassing both hyperkinetic and hypokinetic conditions, characterized by acute/sub-acute onset, rapidly progressive evolution, and multifocal localizations with several overlapping features. These movement disorders are immune-mediated, as shown by the rapid onset and by the presence of antineuronal antibodies in biological samples of patients, fundamental for the diagnosis. Antineuronal antibodies could be targeted against intracellular or neuronal surface antigens. Paraneoplastic movement disorders associated with anti-neuronal surface antigens antibodies respond more frequently to immunotherapy. The underlying tumors may be different, according to the clinical presentation, age, and gender of patients. Our search considered articles involving human subjects indexed in PubMed. Abstracts were independently reviewed for eligibility criteria by one author and validated by at least one additional author. In this review, we sought to critically reappraise the clinical features and the pathophysiological mechanisms of paraneoplastic movement disorders, focusing on diagnostic and therapeutic strategies. Our main aim is to make clinicians aware of paraneoplastic movement disorders, and to provide assistance in the early diagnosis and management of these rare but life-threatening conditions., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.)

Introduction: Telemedicine represents an emerging model for the assessment and management of various neurological disorders. Methods: We sought to discuss opportunities and challenges for the integration of telemedicine in the management of common and uncommon neurological disorders by reviewing and appraising studies that evaluate telemedicine as a means to facilitate the access to care, deliver highly specialized visits, diagnostic consultations, rehabilitation, and remote monitoring of neurological disorders. Results: Opportunities for telemedicine in neurological disorders include the replacement of or complement to in-office evaluations, decreased time between follow-up visits, reduction in disparities in access to healthcare, and promotion of education and training through interactions between primary care physicians and tertiary referral centers. Critical challenges include the integration of the systems for data monitoring with an easy-to-use, secure, and cost-effective platform that is both widely adopted by patients and healthcare systems and embraced by international scientific societies. Conclusions: Multiple applications may spawn from a model based on digitalized healthcare services. Integrated efforts from multiple stakeholders will be required to develop an interoperable software platform capable of providing not only a holistic approach to care but also one that reduces disparities in the access to care.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts., (© 2019 American Academy of Neurology.)