In recent years, several studies have investigated the potential of immunohistochemical detection of α-synuclein in the gastrointestinal tract to diagnose Parkinson's disease (PD). Although ...methodological heterogeneity has hindered comparability between studies, it has become increasingly apparent that the high sensitivity and specificity reported in preliminary studies has not been sustained in subsequent large-scale studies. What constitutes pathological α-synuclein in the alimentary canal that could distinguish between PD patients and controls and how this can be reliably detected represent key outstanding questions in the field. In this review, we will comment on and compare the variable technical aspects from previous studies, and by highlighting some advantages and shortcomings we hope to delineate a standardized approach to facilitate the consensus criteria urgently needed in the field. Furthermore, we will describe alternative detection techniques to conventional immunohistochemistry that have recently emerged and may facilitate ease of interpretation and reliability of gastrointestinal α-synuclein detection. Such techniques have the potential to detect the presence of pathological α-synuclein and include the paraffin-embedded tissue blot, the proximity ligation assay, the protein misfolding cyclic amplification technique, and the real-time quaking-induced conversion assay. Finally, we will review 2 nonsynonymous theories that have driven enteric α-synuclein research, namely, (1) that α-synuclein propagates in a prion-like fashion from the peripheral nervous system to the brain via vagal connections and (2) that gastrointestinal α-synuclein deposition may be used as a clinically useful biomarker in PD.
Objective
We recently demonstrated that 998 features derived from a simple 7‐minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye ...Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6‐91.9%. Here, we investigate whether the same smartphone features can be used to predict future clinically relevant outcomes in early Parkinson's.
Methods
A total of 237 participants with Parkinson's (mean (SD) disease duration 3.5 (2.2) years) in the Oxford Discovery cohort performed smartphone tests in clinic and at home. Each test assessed voice, balance, gait, reaction time, dexterity, rest, and postural tremor. In addition, standard motor, cognitive and functional assessments and questionnaires were administered in clinic. Machine learning algorithms were trained to predict the onset of clinical outcomes provided at the next 18‐month follow‐up visit using baseline smartphone recordings alone. The accuracy of model predictions was assessed using 10‐fold and subject‐wise cross validation schemes.
Results
Baseline smartphone tests predicted the new onset of falls, freezing, postural instability, cognitive impairment, and functional impairment at 18 months. For all outcome predictions AUC values were greater than 0.90 for 10‐fold cross validation using all smartphone features. Using only the 30 most salient features, AUC values greater than 0.75 were obtained.
Interpretation
We demonstrate the ability to predict key future clinical outcomes using a simple smartphone test. This work has the potential to introduce individualized predictions to routine care, helping to target interventions to those most likely to benefit, with the aim of improving their outcome.
OBJECTIVEWe sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson ...disease (PD) using a customized smartphone application.
METHODSA total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, rest tremor, and postural tremor. Smartphone recordings were collected both in clinic and at home under noncontrolled conditions over several days. All participants underwent detailed parallel in-clinic assessments. Using only the smartphone sensor recordings, we sought to (1) discriminate whether the participant had iRBD or PD and (2) identify which of the above 7 motor tasks were most salient in distinguishing groups.
RESULTSStatistically significant differences based on these 7 tasks were observed between the 3 groups. For the 3 pairwise discriminatory comparisons, (1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the mean sensitivity and specificity values ranged from 84.6% to 91.9%. Postural tremor, rest tremor, and voice were the most discriminatory tasks overall, whereas the reaction time was least discriminatory.
CONCLUSIONSProdromal forms of PD include the sleep disorder iRBD, where subtle motor impairment can be detected using clinician-based rating scales (e.g., Unified Parkinsonʼs Disease Rating Scale), which may lack the sensitivity to detect and track granular change. Consumer grade smartphones can be used to accurately separate not only iRBD from controls but also iRBD from PD participants, providing a growing consensus for the utility of digital biomarkers in early and prodromal PD.
OBJECTIVETo describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and ...controls.
METHODSParticipants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinsonʼs Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinsonʼs Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations.
RESULTSData from 921 cases of PD at baseline, 768 cases at 18 months, and 531 cases at 36 months were included, with 21% to 25% screening positive for ICBs at each visit. Interviews of ICB screen–positive individuals revealed that 10% met formal criteria for impulse control disorders (ICD), while 33% had subsyndromal ICD (ICB symptoms without reaching the formal diagnostic criteria for ICD). When these data were combined through the use of multiple imputation, the prevalence of PD-ICB was estimated at 19.1% (95% confidence interval 10.1–28.2). On follow-up, 24% of cases of subsyndromal ICD had developed full symptoms of an ICD. PD-ICD was associated with dopamine agonist use, motor complications, and apathy but not PD-RBD. ICD prevalence in the RBD group (1%) was similar to that in controls (0.7%).
CONCLUSIONSICBs occur in 19.1% of patients with early PD, many persisting or worsening over time. RBD is not associated with increased ICD risk. Psychosocial drivers, including mood and support networks, affect severity.
We have developed a novel real‐time quaking‐induced conversion RT‐QuIC‐based assay to detect alpha‐synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and ...Parkinson's disease patients. This assay can detect alpha‐synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT‐QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha‐synucleinopathies.
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