A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5\u00d710(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n\u200a=\u200a399) and methylation (n\u200a=\u200a292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.
\n \n\n \n \nA 22-year-old immunocompetent woman who presented with a 3-week history of fever, headache, and visual loss and was found to have subnormal visual acuity and bilateral optic disc swelling. Serum cytomegalovirus (CMV) IgM and IgG and polymerase chain reaction results were positive, indicating an acute CMV infection. No cause of immunocompromise was found. After treatment with intravenous ganciclovir, the papillitis and systemic CMV illness resolved with no residual deficit. This is the first reported case of primary CMV papillitis to be successfully treated with ganciclovir alone.
\n \n\n \n \nBackground: Hyposmia is an early feature in neurodegenerative diseases, most notably Parkinson's disease (PD). Using abbreviated smell tests could provide a cost-effective means for large-scale hyposmia screening. It is unclear whether short smell tests can effectively detect hyposmia in patient populations. Objectives: To test the ability of short smell combinations to \"prescreen\" for probable hyposmia in people with PD and target administration of more extensive tests, such as the University of Pennsylvania Smell Identification Test. Methods: We assessed the screening performance of a short 4-smell combination previously derived from use of the 40-item University of Pennsylvania Smell Identification Test in healthy older people and its ability to detect hyposmia in a large cohort of PD patients. Results: The novel 4-smell combination included menthol, clove, onion, and orange and had a sensitivity of 87.1% (95% confidence interval, 84.9%-89.2%) and specificity of 69.7% (63.3%-75.5%) for detecting hyposmia in patients with PD. A different (also novel) 4-item combination developed using a data-driven approach in PD patients only achieved 81.3% (78.2%-84.4%) sensitivity for equivalent specificity. Conclusions: A short 4-smell combination derived from a healthy population demonstrated high sensitivity to detect those with hyposmia and PD.
\n \n\n \n \nBACKGROUND: Cognitive impairment is well recognized in Parkinson's disease (PD), but when it begins to develop is unclear. The aim of this study was to identify early signs of cognitive impairment along with abnormalities in saccadic behavior in newly diagnosed unmedicated PD patients. METHODS: Nineteen drug-naive PD patients and 20 controls were examined using a battery of tests, including an antisaccade task, phonemic and semantic verbal fluencies, and a switching and rule finding task. RESULTS: With simple tasks, no differences were found between the two groups. However, cognitive performance of the two groups diverged with more complex tasks, occurring independently of PD-related motor impairment. Patients exhibited higher antisaccadic error rates and switch costs in the task switching test, and performed significantly worse in the rule finding task. CONCLUSIONS: Certain cognitive domains and saccadic parameters are already significantly impoverished in newly diagnosed Parkinson's patients, even before the initiation of medication.
\n \n\n \n \nBACKGROUND: Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. METHODS: The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. RESULTS: The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). CONCLUSIONS: pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.
\n \n\n \n \nOBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p =\u20091.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p =\u20094.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p =\u20092E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.
\n \n\n \n \nOBJECTIVE: Evidence suggests Rapid-Eye-Movement (REM) Sleep Behaviour Disorder (RBD) is an early predictor of Parkinson's disease. This study proposes a fully-automated framework for RBD detection consisting of automated sleep staging followed by RBD identification. METHODS: Analysis was assessed using a limited polysomnography montage from 53 participants with RBD and 53 age-matched healthy controls. Sleep stage classification was achieved using a Random Forest (RF) classifier and 156 features extracted from electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) channels. For RBD detection, a RF classifier was trained combining established techniques to quantify muscle atonia with additional features that incorporate sleep architecture and the EMG fractal exponent. RESULTS: Automated multi-state sleep staging achieved a 0.62 Cohen's Kappa score. RBD detection accuracy improved from 86% to 96% (compared to individual established metrics) when using manually annotated sleep staging. Accuracy remained high (92%) when using automated sleep staging. CONCLUSIONS: This study outperforms established metrics and demonstrates that incorporating sleep architecture and sleep stage transitions can benefit RBD detection. This study also achieved automated sleep staging with a level of accuracy comparable to manual annotation. SIGNIFICANCE: This study validates a tractable, fully-automated, and sensitive pipeline for RBD identification that could be translated to wearable take-home technology.
\n \n\n \n \nMagnetic resonance imaging (MRI) studies in early Parkinson's disease (PD) have shown promise in the detection of disease-related brain changes in the white and deep grey matter. We set out to establish whether intrinsic cortical involvement in early PD can be detected with quantitative MRI. We collected a rich, multi-modal dataset, including diffusion MRI, T1 relaxometry and cortical morphometry, in 20 patients with early PD (disease duration, 1.9 \u00b1 0.97\u00a0years, Hoehn & Yahr 1-2) and in 19 matched controls. The cortex was reconstructed using FreeSurfer. Data analysis employed linked independent component analysis (ICA), a novel data-driven technique that allows for data fusion and extraction of multi-modal components before further analysis. For comparison, we performed standard uni-modal analysis with a general linear model (GLM). Linked ICA detected multi-modal cortical changes in early PD (p = 0.015). These comprised fractional anisotropy reduction in dorsolateral prefrontal, cingulate and premotor cortex and the superior parietal lobule, mean diffusivity increase in the mesolimbic, somatosensory and superior parietal cortex, sparse diffusivity decrease in lateral parietal and right prefrontal cortex, and sparse changes to the cortex area. In PD, the amount of cortical dysintegrity correlated with diminished cognitive performance. Importantly, uni-modal analysis detected no significant group difference on any imaging modality. We detected microstructural cortical pathology in early PD using a data-driven, multi-modal approach. This pathology is correlated with diminished cognitive performance. Our results indicate that early degenerative processes leave an MRI signature in the cortex of patients with early PD. The cortical imaging findings are behaviourally meaningful and provide a link between cognitive status and microstructural cortical pathology in patients with early PD.
\n \n\n \n \nINTRODUCTION: 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\u00a0<\u00a00.001), less extraverted (p\u00a0<\u00a00.001) and less open than controls (p\u00a0<\u00a00.001). RBD subjects showed the same pattern of being more neurotic (p\u00a0<\u00a00.001), less extraverted (p\u00a0=\u00a00.03) and less open (p\u00a0<\u00a00.001). PD patients had smoked less (p\u00a0=\u00a00.02) and drunk less alcohol (p\u00a0=\u00a00.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p\u00a0<\u00a00.001), more open (p\u00a0<\u00a00.001), and less neurotic (p\u00a0<\u00a00.001) predicted higher alcohol use, while being more extravert (p\u00a0=\u00a00.007) and less agreeable (p\u00a0<\u00a00.001) 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.
\n \n\n \n \nINTRODUCTION: Harmonizing data across cohorts is important for validating findings or combining data in meta-analyses. We replicate and validate a previous conversion of MoCA to MMSE in PD. METHODS: We used five studies with 1,161 PD individuals and 2,091 observations measured with both the MoCA and MMSE. We compared a previously published conversion table using equipercentile equating with log-linear smoothing to our internally derived scores. RESULTS: Both conversions found good agreement within and across the studies when comparing true and converted MMSE (mean difference: 0.05; standard deviation: 1.84; median difference: 0; interquartile range: -1 to 1, using internal conversion). CONCLUSIONS: These results show that one can get a reliable and valid conversion between two commonly used measures of cognition in PD studies. These approaches need to be applied to other scales and domains to enable large-scale collaborative analyses across multiple PD cohorts.
\n \n\n \n \nPrevious imaging studies that investigated morphometric group differences of subcortical regions outside the substantia nigra between non-demented Parkinson's patients and controls either did not find any significant differences, or reported contradictory results. Here, we performed a comprehensive morphometric analysis of 20 cognitively normal, early-stage PD patients and 19 matched control subjects. In addition to relatively standard analyses of whole-brain grey matter volume and overall regional volumes, we examined subtle localized surface shape differences in striatal and limbic grey matter structures and tested their utility as a diagnostic marker. Voxel-based morphometry and volumetric comparisons did not reveal significant group differences. Shape analysis, on the other hand, demonstrated significant between-group shape differences for the right pallidum. Careful diffusion tractography analysis showed that the affected parts of the pallidum are connected subcortically with the subthalamic nucleus, the pedunculopontine nucleus, and the thalamus and cortically with the frontal lobe. Additionally, microstructural measurements along these pathways, but not along other pallidal connections, were significantly different between the two groups. Vertex-wise linear discriminant analysis, however, revealed limited accuracy of pallidal shape for the discrimination between patients and controls. We conclude that localized disease-related changes in the right pallidum in early Parkinson's disease, undetectable using standard voxel-based morphometry or volumetry, are evident using sensitive shape analysis. However, the subtle nature of these changes makes it unlikely that shape analysis alone will be useful for early diagnosis.
\n \n\n \n \nTwo weeks after starting the oral contraceptive pill, a 16-year-old girl developed increasingly violent chorea and an evolving psychosis with prominent hallucinations, ideas of reference, and paranoia. An erythematous skin rash subsequently developed and Sydenham's chorea (SC) was diagnosed. Following neuroleptic medication and steroids, her chorea and psychosis subsided. This case illustrates that severe psychotic features can occur in SC. It is recommended that antistreptolysin O titres and antibasal ganglia antibodies are checked early in patients with evolving movement disorders and prominent neuropsychiatric features, as the window for modifying the course of this immune-mediated disorder may be narrow.
\n \n\n \n \nThe anti-Hu antibody (HuAb) is directed against RNA-associated neuronal proteins and is known to cause paraneoplastic encephalomyelitis/sensory neuronopathy syndrome mostly when associated with small cell lung cancer (SCLC). Paraneoplastic encephalomyelitis/sensory neuronopathy syndrome with concurrent autonomic neuropathy has been reported to occur in paraneoplastic syndromes, although its occurrence concomitant with acute pandysautonomia is less frequent. The authors describe the clinical, neuropathologic, and serologic features of two cases with an anti-Hu-related paraneoplastic syndrome presenting with progressive autonomic neuropathy. Both patients showed features of dysautonomia, including postural dizziness, abdominal pain, and diarrhea, and symptoms of sensory neuropathy. Investigations disclosed severe sensory and autonomic neuropathy and positive HuAb titers. The disease of patient 1 had a very rapid progression, and the patient died of cardiac arrest within 2 months of the onset of symptoms. The autopsy revealed SCLC. In contrast, the disease of patient 2 had a less aggressive course. An extensive tumor search disclosed SCLC only 28 months after onset of symptoms, and the patient died 1 month later of cardiorespiratory arrest. Autopsies in both cases showed inflammation involving the intermediolateral columns and the dorsal root ganglia. These two cases illustrate the association of early dysautonomia with HuAb-related paraneoplastic syndrome and the variations of clinical, neuropathologic, and serologic findings in these types of cases.
\n \n\n \n \nBACKGROUND AND PURPOSE: Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population. METHODS: Eighty-eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated. RESULTS: A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy. CONCLUSIONS: Apathy is common in RBD and is underestimated by a single self-report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.
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