Defining Parkinson's Disease: Past and Future.

Parkinson's disease (PD) is the second most common still relentlessly progressive neurodegenerative disorder with a long period in which the pathophysiological process is already spreading but cardinal motor symptoms are not present. This review outlines the major developments and milestones in our understanding of PD that have shaped the way we define this disorder. Past criteria and definitions of PD have been based on clinical motor manifestations enabling diagnosis of the disease only in later symptomatic stages. Nevertheless, with advancing knowledge of disease pathophysiology and aim of early disease detection, a major shift of the diagnostic paradigm is being advocated towards a biological definition similar to other neurodegenerative disorders including Alzheimer's disease and Huntington's disease, with the ultimate goal of an earlier, disease course modifying therapy. We summarize the major pillars of this possible approach including in vivo detection of neuronal α-synuclein aggregation, neurodegeneration and genetics and outline their possible application in different contexts of use in the frame of biological PD definition.

Endoscopic Complications Are More Frequent in Levodopa-Carbidopa Intestinal Gel Treatment via JET-PEG in Parkinson's Disease Patients Compared to Nutritional PEG in Non-Parkinson's Disease Patients.

Background: To date, no studies comparing complication rates between patients with nutritional percutaneous endoscopic gastrostomy (N-PEG) and Parkinson's disease (PD) patients with percutaneous endoscopic gastro-jejunostomy (JET-PEG) for treatment administration have been published. Our study aimed to compare complication rates and the number of re-endoscopies between N-PEG and JET-PEG patients. Methods: Individuals requiring N-PEG or JET-PEG insertion between 2014 and 2021 were included in this single-center retrospective observational study. Complications were divided into time-related medical and technical complications. Reasons for post-insertion re-endoscopies and their number were also analyzed. Results: Eighty-seven subjects, 47 (54.02%) in JET-PEG group and 40 (45.98%) in the N-PEG group, were included. Early and technical complications were more frequent in JET-PEG vs. N-PEG subjects (70% vs. 10% [p < 0.001], and 54.5% vs. 5.1% [p < 0.001], respectively). The presence of psychiatric disease was associated with a higher number of early complications (p < 0.002). All three types of complications were significantly more frequent in subjects where a healthcare professional did not handle PEG (p < 0.001). Subjects with JET-PEG required a higher number of re-endoscopies compared to the N-PEG group (57.1% vs. 35%, p = 0.05). Conclusions: Complications are significantly more common in individuals with JET-PEG than those with N-PEG, which can be attributed to higher mobility in PD patients.

α-synuclein antibody 5G4 identifies idiopathic REM-sleep behavior disorder in abdominal skin biopsies.

INTRODUCTION: Idiopathic REM-sleep behavior disorder (iRBD) is considered the most specific prodromal marker of Parkinson's disease (PD). With the need to improve early detection of prodromal α-synucleinopathies, several methods to identify peripheral α-synuclein (α-syn) pathology have been exploited in manifest and prodromal PD with varying diagnostic accuracy. Recently, a disease specific 5G4 antibody has been evaluated in skin biopsies of manifest PD patients. The aim of our study was to analyze the 5G4 α-syn immunoreactivity in skin biopsies of deeply phenotyped subjects with iRBD and controls. METHODS: The study cohort consisted of 28 patients with PD, 24 subjects with iRBD and 27 healthy controls, recruited from the CEGEMOD, PDBIOM and PARCAS cohorts. All subjects were deeply phenotyped and assessed for prodromal PD (pPD) probability based on MDS research criteria. Abdominal skin punch biopsies were processed and stained using a conformation specific 5G4 α-syn antibody as well as axonal markers SMI-31 and S100. RESULTS: 5G4-positivity was identified in 23/28 PD patients, 20/24 iRBD subjects and 8/27 healthy controls. Compared to healthy controls, sensitivity and specificity reached 83.33 % and 70.37 % for iRBD; and 82.14 % and 70.37 % for PD, respectively. 5G4-positivity rate in our study was irrespective of the calculated pPD probability of iRBD subjects. CONCLUSIONS: This work establishes the diagnostic yield of conformation specific 5G4 α-syn antibody testing in skin biopsies of subjects with pPD, specifically iRBD. The diagnostic accuracy for this method seems to be similar for both manifest and prodromal PD and is not dependent on the pPD probability ratios.

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction.

BACKGROUND: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. OBJECTIVE: We sought to characterize the role of EIF4A2 variants in dystonic conditions. METHODS: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts. RESULTS: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees. CONCLUSIONS: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Scales for Antipsychotic-Associated Movement Disorders: Systematic Review, Critique, and Recommendations.

BACKGROUND: Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists. OBJECTIVE: An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders. METHODS: Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as "recommended," "recommended with caveats," "suggested," or "listed." RESULTS: Our review identified 23 instruments. The highest grade of recommendation reached is "recommended with caveats," assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight "suggested" instruments did not meet requirements for the "recommended" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature. CONCLUSIONS: The high number of instruments "recommended with caveats" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

Heart Rate Variability in evaluation of autonomic dysfunction in idiopathic REM-sleep behaviour disorder.

INTRODUCTION: Nearly 80% of people diagnosed with idiopathic REM sleep behaviour disorder (iRBD) via video-polysomnography (v-PSG) are expected to be in the prodromal stage of an alpha-synucleinopathy. Signs of autonomic dysfunction can appear earlier than motor or cognitive alpha-synucleinopathy symptoms. Heart Rate Variability (HRV) can potentially be an objective measurement of autonomic dysfunction, and furthermore can be obtained directly from v-PSG. OBJECTIVES: The aim of this study was to evaluate dysautonomia in iRBD subjects using HRV obtained during different sleep stages and wakefulness from v-PSG. MATERIAL AND METHODS: Subjects positively screened by an RBD screening questionnaire (RBD-SQ) underwent v-PSG to diagnose RBD. HRV obtained from v-PSG recordings was correlated to dysautonomia evaluated from a Non-Motor Symptoms Scale (NMSS) questionnaire. Optimal cut-off values of HRV parameters to predict dysautonomia were calculated using receiver operating characteristics (ROC) - area under the curve (AUC) analysis. The effect of confounder variables was predicted with binomial logistic regression and multiple regression analyses. RESULTS: Out of 72 positively screened subjects, 29 subjects were diagnosed as iRBD (mean age 66 ± 7.7 years) by v-PSG. Eighty-three per cent of the iRBD subjects in our cohort were at the time of diagnosis classified as having possible or probable prodromal Parkinson's Disease (pPD) compared to zero subjects being positively screened in the control group. The iRBD-positive subjects showed significant inverse correlations of NMSS score, particularly to log low-frequency (LF) component of HRV during wakefulness: r = -0.59 (p = 0.001). Based on ROC analysis and correlation between NMSS score, log LF during wakefulness (AUC 0.74, cut-off 4.69, sensitivity 91.7%, specificity 64.7%, p = 0.028) was considered as the most accurate predictor of dysautonomia in the iRBD group. Apnoea-hypopnoea index (AHI) negatively predicted dysautonomia in the iRBD group. None of the HRV components was able to predict the presence of iRBD in the full cohort. Age, gender, and PSG variables were significant confounders of HRV prediction. CONCLUSIONS: The presented study did not confirm the possibility of using HRV from v-PSG records of patients with iRBD to predict dysautonomia expressed by questionnaire methods. This is probably due to several confounding factors capable of influencing HRV in such a cohort.

Rating Scales for Medication Adherence in Parkinson's Disease: A Systematic Review for Critique and Recommendations.

Background: Behaviors interfering with medication adherence (MA) are common and often complex in Parkinson's disease (PD), negatively affecting quality of life and undermining the value of clinical trials. The Clinical Outcome Assessments (COA) Scientific Evaluation Committee of the International Parkinson and Movement Disorder Society (MDS) commissioned the assessment of MA rating scales to recommend the use in PD. Objective: Critically review the measurement properties of rating scales used to assess MA in PD and to issue recommendations. Methods: We conducted systematic review across seven databases to identify structured scales to assess MA in PD. Eligible studies were critically appraised for methodological quality using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) Risk of Bias checklist. Standards for good measurement properties of the selected scales were summarized narratively using the COSMIN, the MDS-COA Committee methodology, the World Health Organization concepts, and the Ascertaining Barriers to Compliance taxonomy. The certainty of the evidence was determined using the modified Grades of Recommendation, Assessment, Development and Evaluation approach with final assessments (highest to lowest) of "Recommended," "Suggested" and "Listed". Results: Of the nine reviewed scales, none met the designation "Recommended". The Morisky Medication Adherence Scale (MMAS-8); Beliefs Related to Medications Adherence questionnaire, Beliefs about Medication Questionnaire, Medication Adherence Rating Scale, and Satisfaction with Information on Medicines Scale were rated "Suggested". Conclusions: We suggest further work focusing on resolving the problems of the suggested scales or developing a new scale meeting all required criteria.

Impact of advanced Parkinson's disease on caregivers: an international real-world study.

BACKGROUND: Caring for a partner or family member with Parkinson's disease (PD) negatively affects the caregiver's own physical and emotional well-being, especially those caring for people with advanced PD (APD). This study was designed to examine the impact of APD on caregiver perceived burden, quality of life (QoL), and health status. METHODS: Dyads of people with PD and their primary caregivers were identified from the Adelphi Parkinson's Disease Specific Program (DSP™) using real-world data from the United States, Japan and five European countries. Questionnaires were used to capture measures of clinical burden (people with PD) and caregiver burden (caregivers). RESULTS: Data from 721 patient-caregiver dyads in seven countries were captured. Caregivers had a mean age 62.6 years, 71.6% were female, and 70.4% were a spouse. Caregivers for people with APD had a greater perceived burden, were more likely to take medication and had lower caregiver treatment satisfaction than those caring for people with early or intermediate PD; similar findings were observed for caregivers of people with intermediate versus early PD. Caregivers for people with intermediate PD were also less likely to be employed than those with early PD (25.3% vs 42.4%) and spent more time caring (6.6 vs 3.2 h/day). CONCLUSIONS: This real-world study demonstrates that caregivers of people with APD experience a greater burden than those caring for people with early PD. This highlights the importance of including caregiver-centric measures in future studies, and emphasizes the need for implementing treatments that reduce caregiver burden in APD. TRIAL REGISTRATION: N/A.

Genetic overlap between dystonia and other neurologic disorders: A study of 1,100 exomes.

INTRODUCTION: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia. METHODS: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability. RESULTS: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia. CONCLUSIONS: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.

Skin Conditions and Movement Disorders: Hiding in Plain Sight.

Skin manifestations are well-recognized non-motor symptoms of Parkinson's disease (PD) and other hypokinetic and hyperkinetic movement disorders. Skin conditions are usually well visible during routine clinical examination and their recognition may play a major role in diagnostic work-up. In this educational review we: (1) briefly outline skin conditions related to Parkinson's disease, including therapy-related skin complications and their management; (2) discuss the role of skin biopsies in early diagnosis of PD and differential diagnosis of parkinsonian syndromes; and focus more on areas which have not been reviewed in the literature before, including (3) skin conditions related to atypical parkinsonism, and (4) skin conditions related to hyperkinetic movement disorders. In case of rare hyperkinetic movement disorders, specific dermatological manifestations, like presence of angiokeratomas, telangiectasias, Mongolian spots, lipomas, ichthyosis, progeroid skin changes and others may point to a very specific group of disorders and help guide further investigations.

Backward leaning during gait: An underrecognized sign in Niemann-Pick type C.

Niemann-Pick type C (NPC) is a rare but treatable lysosomal disorder with heterogeneous clinical presentations including cognitive impairment, movement disorders and vertical gaze palsy. We illustrate five cases of genetically confirmed NPC and highlight backward leaning during gait as a relevant clinical sign and a useful diagnostic clue.

Progressive choreodystonia in X-linked hyper-IgM immunodeficiency: a rare but recurrent presentation.

An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications.

Effect of Pillbox Organizers with Alarms on Adherence to Pharmacotherapy in Parkinson Disease Patients Taking Three and More Daily Doses of Dopaminergic Medications.

Improvement of adherence to pharmacotherapy in patients with Parkinson's disease (PD) is a challenge in routine clinical practice. Our study was aimed at the effect of pillbox organizers with alarms improving adherence to pharmacotherapy and its impact on clinical outcomes. Forty nonadherent patients with PD being treated with ≥ 3 daily doses of levodopa and/or dopamine agonists were pseudorandomized and consecutively ranked to groups A (early-start intervention) and B (delayed-start intervention). We used the following validated diagnostic instruments: MMAS-8 (adherence), PDQ-8 (quality of life, QoL), GDS (depression), NMSS (non-motor symptoms), MDS-UPDRS III (motor involvement), MDS-UPDRS IV, and WOQ-9 (motor and non-motor fluctuations and dyskinesias). We proved a significantly improved rate of adherence with the use of pillbox organizers with alarms. Moreover, after only four weeks of using the pillbox organizer, we detected an improvement in QoL scores, motor involvement, motor-, and non-motor fluctuations. Our study showed that pillbox organizers with alarms are efficient in improving adherence to pharmacotherapy in PD. It also could contribute to better motor states, less severe fluctuations, and improved QoL.