Impulse control disorders in Parkinson and RBD:a longitudinal study of severity.

Objective To 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. Methods Participants 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 Parkinson's Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinson's Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations. Results Data 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%). Conclusions ICBs 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

Personality and addictive behaviours in early Parkinson's disease and REM sleep behaviour disorder

INTRODUCTION: Changes in personality have been described in Parkinson's disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction. METHODS: 941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory. RESULTS: Patients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more. CONCLUSIONS: A similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality

Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies

We have developed a novel real-time quaking-induced conversion RT-QuICbased 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

Smartphone motor testing to distinguish idiopathic REM sleep behavior disorder, controls, and PD

OBJECTIVE: We 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. METHODS: A 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. RESULTS: Statistically 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. CONCLUSIONS: Prodromal forms of PD include the sleep disorder iRBD, where subtle motor impairment can be detected using clinician-based rating scales (e.g., Unified Parkinson's 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

Equating scores of the University of Pennsylvania smell identification test and sniffin' sticks test in patients with Parkinson's disease

Background Impaired olfaction is an important feature in Parkinson's disease (PD) and other neurological diseases. A variety of smell identification tests exist such as “Sniffin’ Sticks” and the University of Pennsylvania Smell Identification Test (UPSIT). An important part of research is being able to replicate findings or combining studies in a meta-analysis. This is difficult if olfaction has been measured using different metrics. We present conversion methods between the: UPSIT, Sniffin’ 16, and Brief-SIT (B-SIT); and Sniffin’ 12 and Sniffin’ 16 odour identification tests. Methods We used two incident cohorts of patients with PD who were tested with either the Sniffin’ 16 (n = 1131) or UPSIT (n = 980) and a validation dataset of 128 individuals who took both tests. We used the equipercentile and Item Response Theory (IRT) methods to equate the olfaction scales. Results The equipercentile conversion suggested some bias between UPSIT and Sniffin’ 16 tests across the two groups. The IRT method shows very good characteristics between the true and converted Sniffin’ 16 (delta mean = 0.14, median = 0) based on UPSIT. The equipercentile conversion between the Sniffin’ 12 and 16 item worked well (delta mean = 0.01, median = 0). The UPSIT to B-SIT conversion showed evidence of bias but amongst PD cases worked well (mean delta = −0.08, median = 0). Conclusion We have demonstrated that one can convert UPSIT to B-SIT or Sniffin’ 16, and Sniffin’ 12 to 16 scores in a valid way. This can facilitate direct comparison between tests aiding future collaborative analyses and evidence synthesis

Detection of alpha-synuclein conformational variants from gastro-intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Gastrointestinal (GI) alpha-synuclein (ASN) detection may represent a clinically useful biomarker of Parkinson’s disease (PD), but this has been challenged by conflicting results of recent studies employing different immunohistochemical (IHC) methods and reporting diverse morphological patterns with variable biological interpretation. To increase sensitivity and specificity, we applied three different techniques to detect different possible conformations of ASN in GI tissue derived from biopsies of the GI tract, which were obtained from a longitudinally followed, clinically well-characterized cohort of PD subjects and healthy controls (HC) (Oxford Discovery study). With IHC, we used antibodies reactive for total (T-ASN-Abs), phosphorylated (P-ASN-Abs) and oligomeric (O-ASN-Abs) ASN; with the ASN Proximity Ligation Assay (AS-PLA), we targeted oligomeric ASN species specifically; finally, with the Paraffin-Embedded Tissue Blot (PET-Blot) we aimed to detect fibrillary conformations of ASN specifically. Optimisation and validation of the PET-Blot and PLA techniques was carried out with studies on brain tissue from subjects with ASN pathology, and these experiments were used to gain insight into morphology and distribution of different conformational variants of ASN in the brain of subjects with Lewy pathology. We specified all the detected morphological staining patterns with each technique interpreting them as pathologic or non-specific. Correlation to clinical symptoms was assessed to investigate the potential predictive or diagnostic value of specific staining patterns as biomarkers. A total of 163 GI tissue blocks were collected from 51 PD patients (113 blocks) and 21 healthy controls (50 blocks). In 31 PD patients, GI biopsies had been taken before PD diagnosis (Prodromal PD group); while in 20 PD patients biopsies were obtained after PD diagnosis (Manifest PD group). The majority of these tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four ASN staining patterns were detected in GI tissue (Neuritic, Ganglionic, Epithelial, and Cellular), while two distinct staining patterns were detected with AS-PLA (cellular and diffuse signal) and with AS-PET-Blot (ASN-localised and peri-crypt signal). The level of agreement between different techniques was generally low, and no single technique or staining pattern was able to reliably distinguish PD patients (Prodromal or Manifest) from HC. Overall, our study suggests that even specific detection of ASN conformational variants currently considered pathologic was not adequate for the prediction of PD. Future studies with these or other novel techniques focusing on the upper part of the GI tract could overcome current limitations in sensitivity and specificity.</p

Detection of alpha-synuclein conformational variants from gastro-intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Gastrointestinal (GI) alpha-synuclein (ASN) detection may represent a clinically useful biomarker of Parkinsonâs disease (PD), but this has been challenged by conflicting results of recent studies employing different immunohistochemical (IHC) methods and reporting diverse morphological patterns with variable biological interpretation. To increase sensitivity and specificity, we applied three different techniques to detect different possible conformations of ASN in GI tissue derived from biopsies of the GI tract, which were obtained from a longitudinally followed, clinically well-characterized cohort of PD subjects and healthy controls (HC) (Oxford Discovery study). With IHC, we used antibodies reactive for total (T-ASN-Abs), phosphorylated (P-ASN-Abs) and oligomeric (O-ASN-Abs) ASN; with the ASN Proximity Ligation Assay (AS-PLA), we targeted oligomeric ASN species specifically; finally, with the Paraffin-Embedded Tissue Blot (PET-Blot) we aimed to detect fibrillary conformations of ASN specifically. Optimisation and validation of the PET-Blot and PLA techniques was carried out with studies on brain tissue from subjects with ASN pathology, and these experiments were used to gain insight into morphology and distribution of different conformational variants of ASN in the brain of subjects with Lewy pathology. We specified all the detected morphological staining patterns with each technique interpreting them as pathologic or non-specific. Correlation to clinical symptoms was assessed to investigate the potential predictive or diagnostic value of specific staining patterns as biomarkers. A total of 163 GI tissue blocks were collected from 51 PD patients (113 blocks) and 21 healthy controls (50 blocks). In 31 PD patients, GI biopsies had been taken before PD diagnosis (Prodromal PD group); while in 20 PD patients biopsies were obtained after PD diagnosis (Manifest PD group). The majority of these tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four ASN staining patterns were detected in GI tissue (Neuritic, Ganglionic, Epithelial, and Cellular), while two distinct staining patterns were detected with AS-PLA (cellular and diffuse signal) and with AS-PET-Blot (ASN-localised and peri-crypt signal). The level of agreement between different techniques was generally low, and no single technique or staining pattern was able to reliably distinguish PD patients (Prodromal or Manifest) from HC. Overall, our study suggests that even specific detection of ASN conformational variants currently considered pathologic was not adequate for the prediction of PD. Future studies with these or other novel techniques focusing on the upper part of the GI tract could overcome current limitations in sensitivity and specificity.</p

Predictors of motor complications in early Parkinson's disease::A prospective cohort study

The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] 6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Supplementary Figure 2

Supplementary text figure