Prodromal Parkinson's Disease Research Articles

Cognition and Other Non-Motor Symptoms in an At-Risk Cohort for Parkinson's Disease Defined by REM-Sleep Behavior Disorder and Hyposmia.

REM-sleep behavior disorder (RBD) and other non-motor symptoms such as hyposmia were proposed by the Movement Disorder Society as research criteria for prodromal Parkinson's disease (P-PD). Global cognitive deficit was later added. To compare non-motor symptoms, focusing on cognition, between a P-PD group and a matched control group. In this cross-sectional, case-control study, in a first set of analyses, we performed extensive cognitive testing on people with (n = 76) and a control group without (n = 195) probable RBD and hyposmia. Furthermore, we assessed motor and non-motor symptoms related to Parkinson's Disease (PD). After propensity score matching, we compared 62 P-PD with 62 age- and sex-matched controls. In addition, we performed regression analyses on the total sample (n = 271). In a second set of analyses, we used, a.o., the CUPRO to evaluate retrograde procedural memory and visuo-constructive functions. People with P-PD showed significantly poorer performances in global cognition, visuo-constructive and executive functions, mainly in mental flexibility (p < 0.001; p = 0.004; p = 0.003), despite similar educational levels (p = 0.415). We observed significantly more motor and non-motor symptoms (p < 0.001; p = 0.004), higher scores for depression (p = 0.004) and apathy (p < 0.001) as well as lower quality of life (p < 0.001) in P-PD. Our findings confirm that global cognitive, executive, and visuo-constructive deficits define the P-PD group. In addition, depression, apathy, and lower quality of life were more prevalent in P-PD. If replicated in other samples, executive and visuo-constructive deficits should be considered in non-motor P-PD. Determining specific patterns will support early recognition of PD, secondary prevention of complications and the development of neuroprotective treatments.

Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson's Disease.

Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease-modifying therapies. The aim was to evaluate a blood-based α-synuclein seed amplification assay (α-syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase. In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α-syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α-syn-SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed. All individuals with PD showed positive immunoblots and a positive α-syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α-syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α-syn SAA. All healthy controls had a negative SAA. We here demonstrate the possibility to detect and amplify pathological α-syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood-based α-syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurocognitive Impairment and Social Cognition in Parkinson's Disease Patients.

In addition to motor symptoms, neurocognitive impairment (NCI) affects patients with prodromal Parkinson's disease (PD). NCI in PD ranges from subjective cognitive complaints to dementia. The purpose of this review is to present the available evidence of NCI in PD and highlight the heterogeneity of NCI phenotypes as well as the range of factors that contribute to NCI onset and progression. A review of publications related to NCI in PD up to March 2023 was performed using PubMed/Medline. There is an interconnection between the neurocognitive and motor symptoms of the disease, suggesting a common underlying pathophysiology as well as an interconnection between NCI and non-motor symptoms, such as mood disorders, which may contribute to confounding NCI. Motor and non-motor symptom evaluation could be used prognostically for NCI onset and progression in combination with imaging, laboratory, and genetic data. Additionally, the implications of NCI on the social cognition of afflicted patients warrant its prompt management. The etiology of NCI onset and its progression in PD is multifactorial and its effects are equally grave as the motor effects. This review highlights the importance of the prompt identification of subjective cognitive complaints in PD patients and NCI management.

Predictors of the Rapid Progression in Prodromal Parkinson’s Disease: A Longitudinal Follow-Up Study

Introduction: Parkinson’s disease (PD) is characterized by a prodromal phase preceding the onset of classic motor symptoms. The duration and clinical manifestations of prodromal PD vary widely, indicating underlying heterogeneity within this stage. This discrepancy prompts the question of whether specific factors contribute to the divergent rates of progression in prodromal PD. Methods: This study included prodromal PD patients from the Parkinson’s progression marker initiative. They were followed up to assess the disease progression. The data collected during the follow-up period were analyzed to identify potential predictors of rapid disease progression in prodromal PD. Results: In this study, 61 individuals with prodromal PD were enrolled. Among them, 43 patients presented with both RBD and hyposmia, 17 had hyposmia alone, and 1 had RBD alone at baseline. 13 (21.3%) prodromal PD participants exhibited rapid disease progression, with two of these cases advancing to non-neurological diseases. Significant differences were observed between the rapid progression group and no rapid progression group in terms of MDS-UPDRS II score and UPSIT score. Longitudinal analysis showed a significant increase in the MDS-UPDRS III score and MDS-UPDRS total score in the rapid progression group. Regression analyses identified the MDS-UPDRS II score and UPSIT score as predictors of rapid disease progression in prodromal PD. Conclusion: Our study findings suggest that the MDS-UPDRS II score and UPSIT score may serve as clinical markers associated with rapid disease progression. Further research and development of precise biomarkers and advanced assessment methods are needed to enhance our understanding of prodromal PD and its progression patterns.

Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Opportunities and Pitfalls of REM Sleep Behavior Disorder and Olfactory Dysfunction as Early Markers in Parkinson's Disease.

During its pre-motor stage, Parkinson's disease (PD) presents itself with a multitude of non-motor symptoms with different degrees of specificity and sensitivity. The most important among them are REM sleep behavior disorder (RBD) and olfactory dysfunction. RBD is a parasomnia characterized by the loss of REM sleep muscle atonia and dream-enacting behaviors. Olfactory dysfunction in individuals with prodromal PD is usually described as hyposmia (reduced sense of smell) or anosmia (complete loss of olfactory function). These symptoms can precede the full expression of motor symptoms by decades. A close comprehension of these symptoms and the underlying mechanisms may enable early screening as well as interventions to improve patients' quality of life. Therefore, these symptoms have unmatched potential for identifying PD patients in prodromal stages, not only allowing early diagnosis but potentially opening a window for early, possibly disease-modifying intervention. However, they come with certain challenges. This review addresses some of the key opportunities and pitfalls of both RBD and olfactory dysfunction as early markers of PD.

Turning alterations detected by mobile health technology in idiopathic REM sleep behavior disorder

Idiopathic REM sleep Behavior Disorder (iRBD) is a condition at high risk of developing Parkinson’s disease (PD) and other alpha-synucleinopathies. The aim of the study was to evaluate subtle turning alterations by using Mobile health technology in iRBD individuals without subthreshold parkinsonism. A total of 148 participants (23 persons with polysomnography-confirmed iRBD without subthreshold parkinsonism, 60 drug-naïve PD patients, and 65 age-matched controls were included in this prospective cross-sectional study. All underwent a multidimensional assessment including cognitive and non-motor symptoms assessment. Then a Timed-Up-and-Go test (TUG) at normal and fast speed was performed using mobile health technology on the lower back (Rehagait®, Hasomed, Germany). Duration, mean, and peak angular velocities of the turns were compared using a multivariate model correcting for age and sex. Compared to controls, PD patients showed longer turn durations and lower mean and peak angular velocities of the turns in both TUGs (all p ≤ 0.001). iRBD participants also showed a longer turn duration and lower mean (p = 0.006) and peak angular velocities (p < 0.001) compared to controls, but only in the TUG at normal speed. Mobile health technology assessment identified subtle alterations of turning in subjects with iRBD in usual, but not fast speed. Longitudinal studies are warranted to evaluate the value of objective turning parameters in defining the risk of conversion to PD in iRBD and in tracking motor progression in prodromal PD.

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease

Parkinson’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography–mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as l-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1−/− rats

BackgroundParkinson disease (PD) is the fastest growing neurodegenerative disease. The molecular pathology of PD in the prodromal phase is poorly understood; as such, there are no specific prognostic or diagnostic tests. A validated Pink1 genetic knockout rat was used to model early-onset and progressive PD. Male Pink1−/− rats exhibit progressive declines in ultrasonic vocalizations as well as hindlimb and forelimb motor deficits by mid-to-late adulthood. Previous RNA-sequencing work identified upregulation of genes involved in disease pathways and inflammation within the brainstem and vocal fold muscle. The purpose of this study was to identify gene pathways within the whole blood of young Pink1−/− rats (3 months of age) and to link gene expression to early acoustical changes. To accomplish this, limb motor testing (open field and cylinder tests) and ultrasonic vocalization data were collected, immediately followed by the collection of whole blood and RNA extraction. Illumina® Total RNA-Seq TruSeq platform was used to profile differential expression of genes. Statistically significant genes were identified and Weighted Gene Co-expression Network Analysis was used to construct co-expression networks and modules from the whole blood gene expression dataset as well as the open field, cylinder, and USV acoustical dataset. ENRICHR was used to identify the top up-regulated biological pathways.ResultsThe data suggest that inflammation and interferon signaling upregulation in the whole blood is present during early PD. We also identified genes involved in the dysregulation of ribosomal protein and RNA processing gene expression as well as prion protein gene expression.ConclusionsThese data identified several potential blood biomarkers and pathways that may be linked to anxiety and vocalization acoustic parameters and are key candidates for future drug-repurposing work and comparison to human datasets.

Pharmacotherapy for Disease Modification in Early Parkinson's Disease: How Early Should We Be?

Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test 'disease-modifying' candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable 'preclinical' and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning 'disease-prevention' trials in subjects with biologically defined 'preclinical' or prodromal PD.

Experimental Animal Models of Prodromal Parkinson's Disease.

There is an estimated 35-45% loss of striatal dopamine at the time of diagnosis of Parkinson's disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease.

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease.

Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.

Dopamine Synthesis in the Nigrostriatal Dopaminergic System in Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms. According to our data, the majority of patients (n = 14) at risk of developing PD selected in our previous study show pronounced interhemispheric asymmetry in the incorporation of 18F-DOPA into dopamine synthesis in the striatum. This was assessed for the caudate nucleus and putamen separately using the specific binding coefficient, asymmetry index, and putamen/caudate nucleus ratio. Interhemispheric asymmetry in the incorporation of 18F-DOPA into the striatum provides strong evidence for its dopaminergic denervation and the diagnostic value of previously identified blood biomarkers. Of the 17 patients at risk of developing prodromal PD studied using PET, 3 patients developed motor symptoms within a year. Thus, our study shows the promise of using the described methodology for the development of early diagnosis of PD.

Intelligent Identification of Cerebrospinal Fluid for the Diagnosis of Parkinson's Disease.

Cerebrospinal fluid (CSF) biomarkers are more sensitive than the Movement Disorder Society (MDS) criteria for detecting prodromal Parkinson's disease (PD). Early detection of PD provides the best chance for successful implementation of disease-modifying treatments, making it crucial to effectively identify CSF extracted from PD patients or normal individuals. In this study, an intelligent sensor array was built by using three metal-organic frameworks (MOFs) that exhibited varying catalytic kinetics after reacting with potential protein markers. Machine learning algorithms were used to process fingerprint response patterns, allowing for qualitative and quantitative assessment of the proteins. The results were robust and capable of discriminating between PD and non-PD patients via CSF detection. The k-nearest neighbor regression algorithm was used to predict MDS scores with a minimum mean square error of 38.88. The intelligent MOF sensor array is expected to promote the detection of CSF biomarkers due to its ability to identify multiple targets and could be used in conjunction with MDS criteria and other techniques to diagnose PD more sensitively and selectively.

Immunological shifts during early-stage Parkinson’s disease identified with DNA methylation data on longitudinally collected blood samples

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the United States. Decades before motor symptoms manifest, non-motor symptoms such as hyposmia and rapid eye movement (REM) sleep behavior disorder are highly predictive of PD. Previous immune profiling studies have identified alterations to the proportions of immune cells in the blood of clinically defined PD patients. However, it remains unclear if these phenotypes manifest before the clinical diagnosis of PD. We utilized longitudinal DNA methylation (DNAm) microarray data from the Parkinson’s Progression Marker’s Initiative (PPMI) to perform immune profiling in clinically defined PD and prodromal PD patients (Prod). We identified previously reported changes in neutrophil, monocyte, and T cell numbers in PD patients. Additionally, we noted previously unrecognized decreases in the naive B cell compartment in the defined PD and Prod patient group. Over time, we observed the proportion of innate immune cells in PD blood increased, but the proportion of adaptive immune cells decreased. We identified decreases in T and B cell subsets associated with REM sleep disturbances and early cognitive decline. Lastly, we identified increases in B memory cells associated with both genetic (LRRK2 genotype) and infectious (cytomegalovirus seropositivity) risk factors of PD. Our analysis shows that the peripheral immune system is dynamic as the disease progresses. The study provides a platform to understand how and when peripheral immune alterations occur in PD and whether intervention at particular stages may be therapeutically advantageous.

Rate of motor progression in Parkinson's disease: a systematic review and meta-analysis.

The search for neuroprotective treatments for Parkinson's disease (PD) still relies largely on motor disability scales. A limitation of these tools is the strong influence of symptomatic dopaminergic treatment effects. Drawing on a wealth of published information, we conducted a systematic review and meta-analysis of motor progression in PD and its relationships with dopaminergic therapy. We searched Medline, Embase, and Central to identify 84 publications with adequate serial motor scores to calculate progression, expressed as an increase in the percentage of maximum disability. A random-effects model showed motor progression at 2.0% p.a. (95% CI 1.7-2.4%). There were no significant differences by baseline age, sample size, or observation period. However, untreated patients, in 8 publications, progressed at 4.5% p.a. compared to 1.6% p.a. in 76 studies containing individuals on dopaminergic drugs (p = 0.0004, q = 0.003). This was supported by research on phenoconversion in prodromal PD, where motor progression exceeded 5% p.a. in the 2 years before diagnosis. Starting levodopa improved pre-treatment disability by 40.3 ± 15.2%. Practically defined off state measurements increase faster than on scores by a modest degree (p = 0.05). This survey suggests that accurate long-term measurements of motor progression to assess disease-modifying therapies can be conducted despite the sequential commencement of dopaminergic drugs and sample attrition over time. While study designs involving prodromal or untreated PD avoid confounding effects of symptomatic treatment, different assumptions about motor progression may be needed. A defined off state with the levodopa test dose method maximizes information about the medication cycle once dopaminergic therapy has begun.

Bowel movement frequency and difficult defecation using constipation assessment scale in patients with isolated REM sleep behavior disorder

IntroductionThis study evaluated constipation, including reduced bowel movement frequency and difficult defecation, in patients with isolated rapid eye movement sleep behavior disorder (IRBD), which is prodromal Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) in middle-aged and older adults. MethodsWe used a validated Japanese version of the Constipation Assessment Scale (CAS-J) to evaluate bowel habits over 1 month in 117 men aged 50–86 years and 34 women aged 56–86 years with video-polysomnography-confirmed IRBD and 22 controls. Furthermore, we performed a longitudinal assessment of outcomes at follow-up visits. ResultsThe CAS-J score was higher in the 22 IRBD patients than in 22 age- and gender-matched paired controls. In 151 IRBD patients, the CAS-J score was higher for women than for men. At baseline, the CAS-J score was similar between patients who developed PD and DLB, but the three IRBD patients who developed multiple system atrophy had a low CAS-J score. Those with constipation (CAS-J score ≥ 2) converted to PD or DLB in a significantly shorter time duration (i.e., time frame for phenoconversion) than those with CAS-J score < 2 (log-rank test, p < 0.001). When adjusted for age and gender, Cox hazards analysis revealed that the CAS-J score significantly predicted phenoconversion to PD or DLB (hazard ratio: 5.9, 95 % confidence interval: 1.8–19.1, p = 0.003). ConclusionsConstipation, i.e., reduced bowel movement frequency and difficult defecation, was common in middle-aged and elderly patients with IRBD, and CAS-J score predicted phenoconversion to PD or DLB.

Association Between Sleep Characteristics and Likelihood of Prodromal Parkinson's Disease: A Cross-Sectional Analysis in the HABIT Study.

Sleep is critical in health problems including Parkinson's disease (PD). This study examined the association between sleep characteristics and the likelihood of prodromal PD. At baseline examination of the Heart and Brain Investigation in Taicang (HABIT) study, potential PD biomarkers were obtained for 8777 participants aged over 50 years, and the probability of prodromal PD was assessed based on the Chinese expert consensus and Movement Disorder Society (MDS) criteria. General and component sleep characteristics were evaluated by the Pittsburgh Sleep Quality Index (PSQI). Median regression was applied to examine the association between sleep and the probability of prodromal PD, adjusting for age, sex, education level, physical activity, obesity, fast plasma glucose, lipids, and hypertension. Based on China criteria, a higher level of PSQI score was significantly associated with a higher probability of prodromal PD (β = 0.02, 95% CI: 0.01-0.03) and a higher risk of having an increased probability of prodromal PD (OR = 1.04, 95% CI: 1.02-1.05). Compared to participants with good quality sleep, those with poor quality sleep had a 0.07% increased probability of prodromal PD (95% CI: 0.01-0.13) and a 19% increased risk of having a high prodromal PD probability (95% CI: 1.04-1.20). Similar associations between sleep quality and the probability of prodromal PD were also observed using the MDS criteria. Subjective sleep quality, sleep latency, habitual sleep efficiency, daytime dysfunction, and use of sleep medications were also associated with the probability of prodromal PD. Poor sleep quality was associated with a high probability of prodromal PD. Sleep may be helpful for understanding and intervention of prodromal PD.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans

IntroductionThe research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants’ history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. ResultsA greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). ConclusionThese data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

Relationships Between Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease: Indication from Gut Microbiota Alterations.

Rapid eye movement sleep behavior disorder (RBD) has a close relationship with Parkinson's disease (PD) and was even regarded as the most reliable hallmark of prodromal PD. RBD might have similar changes in gut dysbiosis to PD, but the relationship between RBD and PD in gut microbial alterations is rarely studied. In this study, we aim to investigate whether there were consistent changes between RBD and PD in gut microbiota, and found some specific biomarkers in RBD that might indicate phenoconversion to PD. Alpha-diversity showed no remarkable difference and beta-diversity showed significant differences based on the unweighted (R = 0.035, P = 0.037) and weighted (R = 0.0045, P = 0.008) UniFrac analysis among idiopathic RBD (iRBD), PD with RBD, PD without RBD and normal controls (NC). Enterotype distribution indicated iRBD, PD with RBD and PD without RBD were Ruminococcus-dominant while NC were Bacteroides-dominant. 7 genera (4 increased: Aerococcus, Eubacterium, Gordonibacter and Stenotrophomonas, 3 decreased: Butyricicoccus, Faecalibacterium and Haemophilus) were consistently changed in iRBD and PD with RBD. Among them, 4 genera (Aerococcus, Eubacterium, Butyricicoccus, Faecalibacterium) remained distinctive in the comparison between PD with RBD and PD without RBD. Through clinical correlation analysis, Butyricicoccus and Faecalibacterium were found negatively correlated with the severity of RBD (RBD-HK). Functional analysis showed iRBD had similarly increased staurosporine biosynthesis to PD with RBD. Our study indicates that RBD had similar gut microbial changes to PD. Decreased Butyricicoccus and Faecalibacterium might be potential hallmarks of phenoconversion of RBD to PD.