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Family studies have linked several rare genetic variants to hereditary forms of Parkinson's disease (PD). In addition to these monogenic forms, many PD cases are associated with genetic risk factors. Asymptomatic individuals carrying pathogenic variants linked to PD are at risk of developing the disease later in life, thereby providing a unique opportunity for the detection of the earliest pathophysiological and later clinical changes and, importantly, also of protective and compensatory features and mechanisms. However, the rarity of monogenic PD-causing variants is a major challenge of this approach. In this review, we discuss recent advances in the search for biomarkers in the prodromal/earliest phase of genetically linked PD. Plain Language Summary: While the cause of most cases of Parkinson's disease (PD) is still unknown, and age is considered the greatest risk factor, a combination of environmental influences and genetics are thought to affect disease risk and progression. The identification of carriers of pathogenic genetic changes, who have not yet developed motor symptoms of PD, offers the chance to closely monitor developing signs of PD. Some of these signs may be suitable biomarkers and could be used to predict early stages of the disease. In this review, we discuss recent advances in the search for biomarkers in the prodromal/earliest phase of genetically linked PD. [ABSTRACT FROM AUTHOR]

The recent development of new methods to detect misfolded α-synuclein (αSyn) aggregates in biofluids and tissue biopsies in the earliest Parkinson's disease (PD) phases is dramatically challenging the biological definition of PD. The αSyn seed amplification methods in cerebrospinal fluid (CSF) showed high sensitivity and specificity for early diagnosis of PD and Lewy bodies disorders. Several studies in isolated REM sleep behavior disorders and other at-risk populations also demonstrated a high prevalence of CSF αSyn positivity and its potential value in predicting the phenoconversion to clinically manifested diseases. Growing evidence exists for αSyn aggregates in olfactory mucosa, skin, and other tissues in subjects with PD or at-risk subjects. DOPA decarboxylase and numerous other candidates have been additionally proposed for either diagnostic or prognostic purposes in earliest PD phases. The newly described αSyn detection in blood, through its quantification in neuronally-derived exosome vesicles, represents a technical challenge that could open a new scenario for the biological diagnosis of PD. Despite this growing evidence in the field, most of method of αSyn detection and markers still need to be validated in ongoing longitudinal studies through an accurate assessment of different prodromal disease subtypes and scenarios before being definitively implemented in clinical settings. [ABSTRACT FROM AUTHOR]

The ability to identify individuals in the prodromal phase of Parkinson's disease has improved in recent years, raising the question of whether and how those affected should be informed about the risk of future disease. Several studies investigated prognostic counselling for individuals with isolated REM sleep behavior disorder and have shown that most patients want to receive information about prognosis, but autonomy and individual preferences must be respected. However, there are still many unanswered questions about risk disclosure or early diagnosis of PD, including the impact on personal circumstances, cultural preferences and specific challenges associated with different profiles of prodromal symptoms, genetic testing or biomarker assessments. This narrative review aims to summarize the current literature on prognostic counselling and risk disclosure in PD, as well as highlight future perspectives that may emerge with the development of new biomarkers and their anticipated impact on the definition of PD. Plain Language Summary: An important goal of Parkinson's disease research is to diagnose the disease at an earlier stage, even before the typical motor symptoms appear, in the so-called 'prodromal phase'. Currently, there are no treatments available that can slow down or prevent disease progression in this early phase, even though many of the early symptoms are treatable. This raises ethical questions about whether people want to know their future risk of Parkinson's and, if so, how this information should be given. This article summarizes the current state of knowledge, but also open questions about risk disclosure in the prodromal phase of Parkinson's. Previous studies have shown that many people with early symptoms of Parkinson's would like to know their risk, but that the individual's wish to know (or not to know) must first be ascertained and respected. Future studies need to find out whether very early diagnosis of Parkinson's might have an impact on people affected, for example in terms of psychological stress or anxiety, and whether cultural background might influence attitudes to risk disclosure. Furthermore, it is expected that in the future it will be possible to make an early diagnosis of Parkinson's using specific new techniques, e.g., by testing spinal fluid. It is of utmost importance to find out if and how test results of these new techniques should be communicated to patients, even if they do not lead to direct medical treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Motor deficits typical of Parkinson's disease (PD), such as gait and balance disturbances, tremor, reduced arm swing and finger movement, and voice and breathing changes, are believed to manifest several years prior to clinical diagnosis. Here we describe the evidence for the presence and progression of motor deficits in this pre-diagnostic phase in order to provide suggestions for the design of future observational studies for an effective, quantitatively oriented investigation. On the one hand, these future studies must detect these motor deficits in as large (potentially, population-based) cohorts as possible with high sensitivity and specificity. On the other hand, they must describe the progression of these motor deficits in the pre-diagnostic phase as accurately as possible, to support the testing of the effect of pharmacological and non-pharmacological interventions. Digital technologies and artificial intelligence can substantially accelerate this process. [ABSTRACT FROM AUTHOR]

Background: The association of lung function with the risk of developing prodromal and clinical-diagnosed Parkinson's disease (PD) and with the risk of mortality among individuals with PD remains unknown. Objective: To prospectively examine the associations of lung function with the risk of prodromal, clinical-diagnosed PD, and PD-related mortality in participants of the UK Biobank. Methods: Included were 452,518 participants free of PD at baseline. Baseline lung function, including forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and FEV1/FVC ratio, was assessed. Eight prodromal features were measured using self-reported diagnoses, hospital admission, and primary care data. Incident PD cases were identified using linkages with hospital admission, death register, and self-report. Vital status and date of death were provided by the UK National Health Service (NHS) and the NHS Central Register. We used Cox proportional hazard models to evaluate these associations. Results: Poor lung function was associated with higher risk of PD in a dose-response relationship: the adjusted hazard ratio comparing the lowest vs. the highest lung function quintile was 1.18 (95% CI, 1.02– 1.37) for FEV1, 1.14 (95% CI, 0.99– 1.29) for FVC, and 1.23 (95% CI, 1.08– 1.41) for PEF (p-trend <0.05 for all). Similar results were obtained for risk of prodromal PD and mortality among individuals with PD. Conclusions: The current study showed that individuals with poor lung function had a high future risk of prodromal and clinical PD and a higher rate of PD-related mortality. [ABSTRACT FROM AUTHOR]

Background: In this case series, results from daily visual exposure to intense polychromatic light of 2000 to 4000 LUX is presented. Bright light treatment is a standard procedure for treating seasonal affective disorder and prodromal Parkinson's disease with high success. With the post-encephalitic symptoms of long-COVID closely approximating those of prodromal Parkinson's disease, we treated insomnia and sleep-related parameters in these patients, including total sleep, number of awakenings, tendency to fall back to sleep, and fatigue, to determine whether mending sleep could improve quality of life. Case presentation: We present three female and two male Caucasian patients aged 42–70 years with long-COVID that persisted from 12 weeks to 139 weeks after contracting coronavirus disease. Conclusion: A light presentation protocol was adapted for long-COVID that not only restored sleep in all patients, but also unexpectedly repaired the depression, anxiety, and cognitive changes (brain fog) as well. A robust pattern of recovery commencing 4–5 days after treatment and was maintained for weeks to months without relapse. These preliminary findings represent a novel, minimally invasive approach for managing the most debilitating symptoms of long-COVID, making it an ideal candidate for the drug hypersensitive, post-encephalitic brain. That a compromised circadian mechanism seen in Parkinson's disease may also underlie post-encephalitic long-COVID implicates a compromised role of the circadian system in these disorders. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurological degradation disease involving inflammation and oxidative stress. Although increasing attention has been paid to PD recently, the importance of prodromal PD (pPD) has not gotten enough attention. The expression and significance of miR-590-5p were evaluated in pPD and PD to reveal its function in disease development and disclose its potential regulatory mechanism. Serum miR-590-5p in healthy individuals (n = 55), pPD patients (n = 62), and PD patients (n = 68) was analyzed by PCR. The PD mice models were established by 30 mg/kg/day 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the microglia were stimulated by 1 μg/mL LPS. The pro-inflammation cytokines were measured by ELISA, and the oxidative stress was evaluated by the activity of LDH, SOD, and ROS. Reduced miR-590-5p was observed in pPD and PD patients compared to the healthy and showed significant discriminating significance in both pPD and PD patients. A significant correlation of miR-590-5p with the increasing levels of IL-6, IL-8, and TNF-α of pPD and PD patients was observed. In PD mice, miR-590-5p was also downregulated and its overexpression could alleviate the increasing pro-inflammation cytokines, LDH, ROS, and decreasing SOD. Consistently in microglia, LPS induced significant inflammatory response and oxidative stress, which were reversed by miR-590-5p overexpression. Conclusion: miR-590-5p could act as a diagnostic indicator of both pPD and PD patients. miR-590-5p could regulate neurological inflammation and oxidative stress in PD, implying its potential in regulating PD development. [ABSTRACT FROM AUTHOR]

Abstract Background In this case series, results from daily visual exposure to intense polychromatic light of 2000 to 4000 LUX is presented. Bright light treatment is a standard procedure for treating seasonal affective disorder and prodromal Parkinson’s disease with high success. With the post-encephalitic symptoms of long-COVID closely approximating those of prodromal Parkinson’s disease, we treated insomnia and sleep-related parameters in these patients, including total sleep, number of awakenings, tendency to fall back to sleep, and fatigue, to determine whether mending sleep could improve quality of life. Case presentation We present three female and two male Caucasian patients aged 42–70 years with long-COVID that persisted from 12 weeks to 139 weeks after contracting coronavirus disease. Conclusion A light presentation protocol was adapted for long-COVID that not only restored sleep in all patients, but also unexpectedly repaired the depression, anxiety, and cognitive changes (brain fog) as well. A robust pattern of recovery commencing 4–5 days after treatment and was maintained for weeks to months without relapse. These preliminary findings represent a novel, minimally invasive approach for managing the most debilitating symptoms of long-COVID, making it an ideal candidate for the drug hypersensitive, post-encephalitic brain. That a compromised circadian mechanism seen in Parkinson’s disease may also underlie post-encephalitic long-COVID implicates a compromised role of the circadian system in these disorders.

Cheng-Jie Mao,1,&ast; Hao Peng,2,&ast; Sheng Zhuang,1,&ast; Ying-Chun Zhang,3 Wei-Ye Xie,1 Jia-Hui Yan,1 Hui-Hui Liu,1 Jing Chen,1 Jun-Yi Liu,4 Jianan Zhang,5 Hai Jiang,5 Yonghong Zhang,2 Mingzhi Zhang,2 Chun-Feng Liu1,6 1Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Epidemiology, School of Public Health, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 3Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Department of Neurology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 5Department of Chronic Disease, Taicang Center of Disease Prevention and Control, Suzhou, People’s Republic of China; 6Institute of Neuroscience, Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Feng Liu, Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, People’s Republic of China, Email liuchunfeng@suda.edu.cn Mingzhi Zhang, Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou, 215123, People’s Republic of China, Email zhangmingzhi@suda.edu.cnBackground: 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.Methods: 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.Results: 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.Conclusion: Poor sleep quality was associated with a high probability of prodromal PD. Sleep may be helpful for understanding and intervention of prodromal PD.Keywords: prodromal Parkinson’s disease, sleep, Parkinson’s disease

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. [ABSTRACT FROM AUTHOR]

Introduction: Prodromal Parkinson's disease (PD) carriers of dual leucine‐rich repeat kinase 2 (LRRK2) and glucosylceramidase β (GBA) variants are rare, and their biomarkers are less well developed. Objective: This study aimed to investigate the biomarkers for diagnosing the prodromal phase of LRRK2‐GBA‐PD (LRRK2‐GBA‐prodromal). Methods: We assessed the clinical and whole‐brain white matter microstructural characteristics of 54 prodromal PD carriers of dual LRRK2 (100% M239T) and GBA (95% N409S) variants, along with 76 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort. Results: By analyzing the four values of 100 nodes on 20 fiber bundles, totaling 8000 data points, we identified the smallest p value in the fractional anisotropy (FA) value of the 38th segment of left corticospinal tract (L‐CST) with differences between LRRK2‐GBA‐prodromal and HCs (p = 8.94 × 10−9). The FA value of the 38th node of the L‐CST was significantly lower in LRRK2‐GBA‐prodromal (FA value, 0.65) compared with HCs (FA value, 0.71). The receiver‐operating characteristic curve showed a cut‐off value of 0.218 for the FA value of L‐CST, providing sufficient sensitivity (79.2%) and specificity (72.2%) to distinguish double mutation prodromal PD from the healthy population. Conclusion: L‐CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population. [ABSTRACT FROM AUTHOR]

Several studies suggested the presence of non-motor symptoms in Essential Tremor (ET), including REM sleep behavioral disorder (RBD). RBD is an essential criterion for Prodromal Parkinson's Disease (PPD), suggesting a link between ET and PD. Our objective was to assess the prevalence and features of ET patients with RBD and PDD.RBD was diagnosed by questionnaire screening, followed by polysomnography. PPD risk factors and prodromic markers were assessed with a structured protocol. Patients were characterized regarding tremor features. ET patients with RBD (ET-RBD) and PPD (ET-PPD) were compared to patients without RBD (ET-nonRBD) and without PPD (ET-nonPPD), respectively. ET-RBD patients were also compared with a group of isolated RBD (iRBD) regarding PPD features.We assessed a total of 64 ET patients. Five (8.3 %) and 4 (6.3 %) had criteria for RBD and PPD, respectively. ET-RBD patients did not differ from ET-nonRBD except for a higher prevalence of PPD. There were no significant differences between ET-RBD and iRBD (n = 12) groups. ET-PPD had a higher prevalence of positive DaT-Scans and RBD compared to ET-nonPPD. Three ET-RBD patients had PPD and 3 ET-PPD had RBD.Both RBD and PPD are more frequent in ET patients than in general aged population but not related with specific tremor features. ET-RBD patients did not differ significantly from iRBD patients, a group prone to develop PD. These data suggest a link between ET and PD and are in accordance with studies showing an increase incidence of lewy-body pathology and PD in ET populations.

Background: Reduced gastric motility in Parkinson's disease (PD) has been reported, but hardly any study exists in subjects with isolated rapid‐eye‐movement (REM) sleep behavior disorder (iRBD), a specific prodrome of α‐synucleinopathies. Objectives: We compared the gastric motility of 17 iRBD subjects with that of 18 PD subjects (15 drug naive, 3 early treated in defined off) and 15 healthy controls (HC) with real‐time magnetic resonance imaging (rtMRI). Methods: After overnight fasting, participants consumed a standardized breakfast and underwent a 3‐T rtMRI of the stomach. Amplitude and velocity of the peristaltic waves were analyzed under blinded conditions. Gastric motility index (GMI) was calculated. The procedure was repeated in 12 of 17 iRBD subjects ~2.5 years later. Nine of these 12 iRBD subjects were hyposmic. Results: In iRBD and PD subjects the amplitude of the peristaltic waves was significantly reduced compared with HCs (iRBD vs. HC: 8.7 ± 3.7 vs. 11.9 ± 4.1 mm, P = 0.0097; PD vs. HC: 6.8 ± 2.2 vs. 11.9 ± 4.1 mm, P = 0.0001). The amplitude in iRBD and PD subjects was decreased to the same extent. The GMI was reduced in only PD subjects (PD vs. HC: P = 0.0027; PD vs. iRBD: P = 0.0203). After ~2.5 years the amplitude in iRBD subjects did not significantly decrease further. Conclusion: The amplitude of the peristaltic waves was markedly reduced in iRBD, a prodrome of α‐synucleinopathies. This reduction was similar to the extent observed already in manifest early PD. This finding implies that the α‐synuclein pathology affects the innervation of the stomach already in the prodromal stage. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, visual hallucinations, and impulse control disorders, are very common during the course of Parkinson's disease (PD), occurring even at the prodromal and premotor stages. Mild behavioral impairment (MBI) represents a recently described neurobehavioral syndrome, characterized by the emergence of persistent and impactful NPS in later life, reflecting arisk of dementia. Accumulating evidence suggests that MBI is highly prevalent in non-demented patients with PD, also being associated with an advanced disease stage, more severe motor deficits, as well as global and multiple-domain cognitive impairment. Neuroimaging studies have revealed that MBI in patients with PD may be related todistinct patterns of brain atrophy, altered neuronal connectivity, and distribution of dopamine transporter (DAT) depletion, shedding more light on its pathophysiological background. Genetic studies in PD patients have also shown that specific single-nucleotide polymorphisms (SNPs) may be associated with MBI, paving the way for future research in this field. In this review, we summarize and critically discuss the emerging evidence on the frequency, associated clinical and genetic factors, as well as neuroanatomical and neurophysiological correlates of MBI in PD, aiming to elucidate the underlying pathophysiology and its potential role as an early "marker" of cognitive decline, particularly in this population. In addition, we aim to identify research gaps, and propose novel relative areas of interest that could aid in our better understanding of the relationship of this newly defined diagnostic entity with PD. [ABSTRACT FROM AUTHOR]

Background: REM Behavior Disorder (RBD) is considered one of most powerful prodromal condition in different neurodegenerative disorders, mainly alpha-synucleinopathies. A large amount of research recently explored this relationship. Objective and Design: The present critically appraised review undertakes this topic, from the perspective of the pathogenetic interplay between clinical manifestations in RBD patients and the misfolding processes that characterize neurodegeneration. In particular, evidence in favor and against the role of RBD as a biomarker of neurodegeneration is discussed. Results and Conclusion: The selected papers were functional to structure the review into three main sections: 1) Protein misfolding in neurodegenerative disorders with focus on alpha-synuclein; 2) Clinical features, diagnosis, and pathophysiology of RBD; 3) RBD as a clinical biomarker of protein misfolding. Data herein highlights the current knowledge and the areas of uncertainties in the relationship between RBD and neurodegenerative disorders; we went through preclinical, prodromal and clinical stages of neurodegenerative processes as a useful reference for clinicians involved in brain pathological aging and future research in this field.

Purpose: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that occurs during REM sleep, characterized by REM sleep without atonia (RSWA) and dream enactment behavior (DEB). RBD is associated with several diseases and medications but most notably is a prodromal feature of synucleinopathies, including Parkinson's disease (PD). This article reviews RBD, its treatments, and implications for PD therapeutics. Recent Findings: Recent research recognizes RBD as a prodromal marker of PD, resulting in expansion of basic science and clinical investigations of RBD. Current basic science research investigates the pathophysiology of RBD and explores animal models to allow therapeutic development. Clinical research has focused on natural history observation, as well as potential RBD treatments and their impact on sleep and phenoconversion to neurodegenerative disease. Summary: RBD serves as a fresh access point to develop both neuroprotective and symptomatic therapies in PD. These types of investigations are novel and will benefit from the more established basic science infrastructure to develop new interventions. [ABSTRACT FROM AUTHOR]

Degeneration of the nucleus basalis of Meynert (NBM) has been implicated in cognitive impairments in Parkinson's disease. The role of the NBM volumes in the cognitive function in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has not been explored. We investigated changes in NBM volumes and their associations with cognitive deficits in iRBD. Baseline NBM volumes were compared between 29 iRBD patients and 29 healthy controls by using structural MRI data from the Parkinson Progression Marker Initiative database. Partial correlation analyses were used to evaluate cross-sectional relationships between baseline NBM volumes and cognitive performance in iRBD. Linear mixed models were applied to assess between-group differences in longitudinal cognitive changes, and whether baseline NBM volumes could predict longitudinal changes of cognition in iRBD. Compared with controls, NBM volumes were significantly reduced in iRBD patients. In patients with iRBD, higher NBM volumes were significantly associated with greater performance in global cognition function. In the longitudinal analyses, iRBD patients showed more severe and rapid decline on tests of global cognition compared to healthy controls. Furthermore, greater baseline NBM volumes were significantly associated with greater follow-up Montreal Cognitive Assessment (MoCA) scores, thus predicting less longitudinal cognitive changes in iRBD. This study provides important in vivo evidence for an association between the NBM degeneration and cognitive impairments in iRBD. • iRBD patients demonstrated significantly reduced NBM volumes. • NBM volumes were positively correlated with scores of global cognition in iRBD. • iRBD patients showed significant decline in global cognition over time. • Baseline NBM volumes of iRBD predict longitudinal changes in global cognition. [ABSTRACT FROM AUTHOR]

Background: The role of blood uric acid as a biomarker in symptomatic motor PD has been increasingly established in the literature. Objective: Our present study assessed the role of serum uric acid as a putative biomarker in a prodromal PD cohort [REM Sleep Behavior disorder (RBD) and Hyposmia] followed longitudinally. Methods: Longitudinal 5-year serum uric acid measurement data of 39 RBD patients and 26 Hyposmia patients with an abnormal DATSCAN imaging were downloaded from the Parkinson's Progression Markers Initiative database. These cohorts were compared with 423 de novo PD patients and 196 healthy controls enrolled in the same study. Results: After adjusting for age, sex, body mass index, and concomitant disorders (hypertension/gout), baseline and longitudinal serum uric acid levels were higher in the RBD subgroup as compared to the established PD cohort (p = 0.004 and p = 0.001). (Baseline RBD 6.07±1.6 vs. Baseline PD 5.35±1.3 mg/dL and Year-5 RBD 5.7±1.3 vs. Year-5 PD 5.26±1.33). This was also true for longitudinal measurements in the Hyposmic subgroup (p = 0.008) (Baseline Hyposmic 5.7±1.6 vs. PD 5.35±1.3 mg/dL and Year-5 Hyposmic 5.58±1.6 vs. PD 5.26±1.33). Conclusion: Our results indicate that serum uric acid levels are higher in prodromal PD subjects with ongoing dopaminergic degeneration compared to those with manifest PD. These data indicate that the well-established decrease in the levels of serum uric acid occurs with the transition from prodromal to clinical PD. Whether the higher levels of serum uric acid observed in prodromal PD may provide protection against conversion to full-blown clinical PD will require further study. [ABSTRACT FROM AUTHOR]

BackgroundChina is witnessing an accelerated aging process and an increasingly serious situation of Parkinson's disease. Research on the pre-disease stage and its related influencing factors has gained more and more attention.ObjectiveTo analyze the current situation of prodromal Parkinson's disease (pPD) of people aged 55 years and above in four provinces of China, and to explore its influencing demographic and socio-economic characteristics.MethodsUsing the data of Community-based Cohort Study on Nervous System Disease in 2020, a total of 10724 participants with complete data on demographic and socio-economic factors and risk factors on Parkinson's disease were selected. Based on the criteria recommended by the International Parkinson and Movement Disorder Society (MDS), we evaluated risk level (i.e., post-test probability) of pPd, prevalence of possible or probable pPD, and number of pPD-related risk/prodromal markers in the participants. Multiple linear regression and multiple logistic regression models were used to analyze the influencing socio-demographic factors of risk level of pPd and prevalence of possible or probable pPD, and Poisson regression and multinomial logit regression models were used to analyze the influencing socio-demographic factors of the number of pPD-related risk/prodromal markers in the total sample, men, and women, respectively.ResultsThe median (P25, P75) of post-test probability of pPD in 2020 was 0.78% (0.42%, 1.66%), the prevalence rate of possible or probable pPD was 0.34%, and 69.03% of the participants reported 3-5 pPD-related risk/prodromal markers. The post-test probabilities of men, those with older age, lower education level, per capita monthly household income < 1000 yuan, urban residency, or without active employment were higher (P

BackgroundChanges in cognitive function exist before the onset of clinical Parkinson's disease. However, studies on association between cognitive function and prodromal Parkinson's disease (pPD) are limited.ObjectiveTo estimate probability of pPD and assess its association with global and domain cognitive function in Chinese elders.MethodsData were drawn from the Community-based Cohort Study on Nervous System Disease 2018 (baseline) and 2020 (follow-up). We selected 3911 residents aged 55 and above who participated the two waves, without Alzheimer's disease and Parkinson's disease, and with completed information on demographics, disease history, cognitive function test, and risk factors of Parkinson's disease. Cognitive function was assessed using the Chinese version of Montreal Cognitive Assessment Scale. Calculation of probability of pPD and assessment of possible (probability between 30% and

With the expansion of aging population in China, the increasingly serious situation of Parkinson's disease (PD) threatens the physical and mental health and quality of life of middle-aged and elderly people, posing a great challenge to increase healthy life expectancy and realize the Healthy China Strategy. Previous studies showed some connections between dietary and lifestyle factors and PD and suggested that excessive intake of red meat might increase the risk of PD; however, coffee and tea, dietary antioxidants, n-3 polyunsaturated fatty acids, vitamin D, and vitamin B were associated with reducing the risk of PD or delaying the progression of PD, and dietary patterns with high intakes of fresh vegetables and fruits, legumes, whole grains, fish, and poultry meat were also associated with a reduced risk of PD. In addition, physical activity was a protective factor for PD, and smoking was also associated with a reduced risk of PD, but the related mechanisms were still unclear. This paper evaluated the relationships of factors like foods, nutrients, dietary patterns, and lifestyle with PD based on published literature, summarized the limitations of relevant studies, and provided useful enlightenment for PD prevention and control.

BackgroundIt has been reported that a high intake of dairy products might be associated with an increased risk of Parkinson's disease (PD) in foreign studies, but no such study has yet been conducted on prodromal Parkinson's disease (pPD) and the Chinese population. ObjectiveTo investigate the prospective relationship between the intake of dairy products and pPD among people aged 55 and above in four provinces of China. MethodsThe research data were obtained from the baseline 2018 and follow-up 2020 surveys of Community-based Cohort Study on Nervous System Disease. A total of 9984 residents were selected who participated in both waves of surveys and had complete data on demographics, dietary products intake, and risk factors for PD. We evaluated the risk level and the numbers of related risk/prodromal markers of pPD in the participants based on a criteria recommended by the International Parkinson and Movement Disorder Society (MDS). Food Frequency Questionnaire was used to obtain food consumption data in the past 12 months, and the intake of dairy products was calculated and divided into non-consumption and tertiles of consumption (T1, T2, and T3 from low to high). Multiple linear regression was used to analyze the association between baseline dairy intake and risk level of follow-up pPD. Poisson regression and multinomial logit regression models were used to analyze the relationship of baseline dairy products and the number of risk/prodromal markers of follow-up pPD in the population, and multiple logistic regression was used to analyze each risk/prodromal marker of follow-up pPD according to baseline levels of dairy products intake. ResultsThe percentage of residents without dairy products consumption was 58.02% in 2018, and the dairy products intakes were relatively high among residents being female, aged 55 to 74 years, with an education level of middle school and above, with a per capita monthly household income ≥ 1000 yuan, living in urban areas, and without active employment (P

BackgroundGastrointestinal microbiota plays an important role in the development of Parkinson's disease (PD), and dietary factors have a great impact on intestinal micro ecology. At present, few studies focus on red meat and PD, especially prodromal PD (pPD). ObjectiveTo understand the relationships of the intake of red meat and processed meat products with pPD and the number of risk/prodromal markers, and to explore the association of dietary factors with pPD. MethodsBased on the data of Community-based Cohort Study on Nervous System Disease in 2018 and 2020, adults aged 55 years and older with complete demographic information, dietary survey information, and information on risk factors related to PD were selected from four provinces of China. After excluding those reporting abnormal total energy intake or those reporting alcohol drinking or abused drugs for a long period of time, and confirmed mental diseases with prescribed drugs, a total of 10003 subjects were included. Food frequency questionnaire was used to calculate the intake of red meat and processed meat products. The pPD-related risk/prodromal markers were selected following the International Parkinson and Movement Disorder Society criteria for pPD, and the risk level and the number of markers of pPD were then calculated. The relationship between the intake of red meat and processed meat and the risk level of pPD was analyzed by multiple linear regression. The relationship between the intake of red meat and processed meat and the pPD marker number groups was analyzed by multinomial logit regression model. ResultsIn 2018, the intake of red meat and processed meat was 28.57 g·d−1 in the target population. In 2020, the median of the number of risk/prodromal markers was 3, and the median M (P25, P75) of the posterior probability of pPD was 0.74% (0.42%, 1.49%). The multiple linear regression analysis showed that the higher the intake of red meat and processed meat, the higher the risk level of pPD in follow-up (b=0.021, P

Background: Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation. Objective: The aim was to investigate SN free water values across prodromal and clinical stages of PD. Methods: Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow‐up was performed for 14 pPD patients. Results: PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time. Conclusions: The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, visual hallucinations, and impulse control disorders, are very common during the course of Parkinson’s disease (PD), occurring even at the prodromal and premotor stages. Mild behavioral impairment (MBI) represents a recently described neurobehavioral syndrome, characterized by the emergence of persistent and impactful NPS in later life, reflecting arisk of dementia. Accumulating evidence suggests that MBI is highly prevalent in non-demented patients with PD, also being associated with an advanced disease stage, more severe motor deficits, as well as global and multiple-domain cognitive impairment. Neuroimaging studies have revealed that MBI in patients with PD may be related todistinct patterns of brain atrophy, altered neuronal connectivity, and distribution of dopamine transporter (DAT) depletion, shedding more light on its pathophysiological background. Genetic studies in PD patients have also shown that specific single-nucleotide polymorphisms (SNPs) may be associated with MBI, paving the way for future research in this field. In this review, we summarize and critically discuss the emerging evidence on the frequency, associated clinical and genetic factors, as well as neuroanatomical and neurophysiological correlates of MBI in PD, aiming to elucidate the underlying pathophysiology and its potential role as an early “marker” of cognitive decline, particularly in this population. In addition, we aim to identify research gaps, and propose novel relative areas of interest that could aid in our better understanding of the relationship of this newly defined diagnostic entity with PD.

Parkinson's disease (PD) is a chronic neurodegenerative disease commonly seen in middle-aged and elderly people, and aging is the largest risk factor for PD. With acceleration of the aging process in China, the wellbeing and life quality of the elderly are expected to be disturbed by increasing prevalence of PD. The Community-based Cohort Study on Nervous System Diseases (CCSNSD) has established community population-based cohorts of epilepsy, Alzheimer's disease, and PD, respectively; baseline survey and one round of follow-up have finished so far. The CCSNSD collected data on demographics, community environment, diet, lifestyle, cognition, history of chronic diseases, and PD-related risk factors and facilitated exploration of the relationship between dietary nutrition and PD-related outcomes. This special column described status on prodromal Parkinson's disease (pPD) risk and its demographic & economic differences among people aged 55 and above in four provinces of China, and investigated the associations of red meat and processed meat products intake , dairy products intake, and cognitive function with pPD risk, respectively. Furthermore, one paper reviewed previous studies on dietary nutrition, lifestyle, and PD risks. However, the follow-up time of CCSNSD was relatively short as of the publishing of this column, longer follow-ups are required to allow studying potential factors and risk of incident PD combined with clinical examination and diagnosis of PD.

Background: The prodromal phase of Parkinson's disease (PD) is a critical window for prevention by modifying lifestyle factors. However, there is limited knowledge on how diet quality is associated with prodromal PD symptoms in Asian populations. Objective: To examine the association between overall diet quality and prodromal PD features. Methods: A total of 71,640 Chinese participants who were free of PD were included in this cross‐sectional study. Diet quality was assessed using the modified Alternative Healthy Eating Index (mAHEI) and alternate Mediterranean Diet (aMED). Five prodromal features including probable rapid eye movement sleep behavior disorder (pRBD), hyposmia, excessive daytime sleepiness, constipation, and depressive symptom were measured using validated questionnaires. Logistic regression was used to calculate the odds ratio (OR) for having a combination of prodromal PD symptoms (1 and 2+ symptoms vs. 0 symptoms), adjusting for age, sex, lifestyle factors, total energy intake, and other potential confounders. Results: In the multivariable‐adjusted model, the OR for having 2+ versus 0 prodromal PD features was 0.64 (95% confidence interval [CI]: 0.49, 0.85) comparing the highest versus the lowest mAHEI diet quality quartiles with a significant inverse trend (P‐trend = 0.003). For individual prodromal PD features, better diet quality, as assessed by the mAHEI, was associated with lower odds of having excessive daytime sleepiness and constipation (P‐trend < 0.05 for both). We observed a marginally significant association between aMED and prodromal PD features (adjusted OR comparing the extreme quartiles = 0.74; 95% CI: 0.55, 0.98; P‐trend = 0.09). Conclusion: Better diet quality, as assessed by the mAHEI and the aMED, was associated with lower probability of having prodromal PD features in Chinese adults. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy.Methods: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG.Results: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score.Conclusion: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores. [ABSTRACT FROM AUTHOR]

Background: Wearable technology research suggests that nocturnal movements are disturbed in early Parkinson's disease (PD). In this study, we investigate if patients also already experience impaired bed mobility before PD diagnosis. Furthermore, we explore its association with motor and nonmotor features and its value for phenoconversion and disease progression prediction.Methods: PPMI data were downloaded for de novo PD subjects, subjects at-risk for developing a synucleinopathy (with isolated REM sleep behavior disorder, hyposmia or a pathogenic genetic variant) and controls. Impaired bed mobility was assessed with the MDS-UPDRS part 2 item 9. A frequency analysis was performed. Multivariable logistic regression analyses were used to investigate the association with other PD variables. Cox proportional-hazards models were used to test if difficulties with turning in bed could predict phenoconversion. Linear mixed models were used to evaluate if difficulties with turning in bed could predict disease progression.Results: Of the at-risk subjects, 9.2-12.5% experienced difficulties with turning in bed vs. 25.0% of de novo PD subjects and 2.5% of controls. Impaired turning ability was associated with MDS-UPDRS motorscore (axial signs in the at-risk group, bradykinesia in the de novo PD group) and SCOPA-AUT score (gastrointestinal symptoms). In addition, difficulties with turning in bed were a significant predictor for phenoconversion in the at-risk group and for development of motor complications in the de novo PD group.Conclusion: Our findings suggest that difficulties with turning in bed can be helpful as clinical symptom for a prodromal PD screening and for motor complication prediction in early PD. [ABSTRACT FROM AUTHOR]

Background: A decrease in glutathione (GSH) levels is considered one of the earliest biochemical changes in Parkinson's disease (PD). Objective: The authors explored the potential role of plasma GSH as a risk/susceptibility biomarker for prodromal PD (pPD) by examining its longitudinal associations with pPD probability trajectories. Methods: A total of 405 community‐dwelling participants (median age [interquartile range] = 73.2 [7.41] years) without clinical features of parkinsonism were followed for a mean (standard deviation) of 3.0 (0.9) years. Results: A 1 μmol/L increase in plasma GSH was associated with 0.4% (95% confidence interval [CI], 0.1%–0.7%; P = 0.017) less increase in pPD probability for 1 year of follow‐up. Compared with participants in the lowest GSH tertile, participants in the highest GSH tertile had a 12.9% (95% CI, 22.4%–2.2%; P = 0.020) slower rate of increase of pPD probability for 1 year of follow‐up. Conclusion: Plasma GSH was associated with pPD probability trajectories; therefore, it might assist in the identification of individuals who are likely to reach the threshold for pPD diagnosis more rapidly. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Impressive progress in the understanding of the prodromal phase of Parkinson's disease (PD) in recent years has enabled the generation of disease prediction models. However, a remaining diagnostic uncertainty and lack of therapeutic options for affected individuals has resulted in a variety of ethical issues that have not to date been addressed sufficiently. Moreover, differences in the specificity of prodromal symptoms and possible subtypes of PD, especially the presence of rapid eye movement (REM) sleep behavior disorder (RBD), may have an important impact on prognostic counseling. Objectives: To derive a guideline for risk disclosure in prodromal PD based on the current literature and expert opinion. Methods: We performed (1) a literature review on prognostic counseling in PD and (2) consulted with international experts on prodromal PD using a semi‐structured questionnaire based on a Delphi approach to evaluate recommendations for risk disclosure in PD. Results: The literature research revealed only 11 publications addressing prognostic counseling, with only two studies directly addressing affected individuals and most studies focusing on risk disclosure in RBD. The expert survey revealed the importance of distinguishing between individuals with and without RBD in prognostic counseling. Conclusions: Based on the current literature and expert recommendations, a guideline for risk disclosure in prodromal PD for clinical care and research could be elaborated. Prognostic counseling should include differentiation between individuals with and without RBD, taking into account the high uncertainty of risk calculation in RBD‐negative prodromal PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the fastest growing neurodegeneration and has a prediagnostic phase with a lot of challenges to identify clinical and laboratory biomarkers for those in the earliest stages or those 'at risk'. Despite the current research effort, further progress in this field hinges on the more effective application of digital biomarker and artificial intelligence applications at the prediagnostic stages of PD. It is of the highest importance to stratify such prediagnostic subjects that seem to have the most neuroprotective benefit from drugs. However, current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials are still challenging due to the limited accuracy and explainability of existing prediagnostic detection and progression prediction solutions. In this brief paper, we report on a novel digital neuro signature (DNS) for prodromal-PD based on selected digital biomarkers previously discovered on preclinical Alzheimer's disease. (AD). Our preliminary results demonstrated a standard DNS signature for both preclinical AD and prodromal PD, containing a ranked selection of features. This novel DNS signature was rapidly repurposed out of 793 digital biomarker features and selected the top 20 digital biomarkers that are predictive and could detect both the biological signature of preclinical AD and the biological mechanism of a-synucleinopathy in prodromal PD. The resulting model can provide physicians with a pool of patients potentially eligible for therapy and comes along with information about the importance of the digital biomarkers that are predictive, based on SHapley Additive exPlanations (SHAP). Similar initiatives could clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of the disease.

Parkinson's disease (PD) is the fastest growing neurodegeneration and has a prediagnostic phase with a lot of challenges to identify clinical and laboratory biomarkers for those in the earliest stages or those 'at risk'. Despite the current research effort, further progress in this field hinges on the more effective application of digital biomarker and artificial intelligence applications at the prediagnostic stages of PD. It is of the highest importance to stratify such prediagnostic subjects that seem to have the most neuroprotective benefit from drugs. However, current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials are still challenging due to the limited accuracy and explainability of existing prediagnostic detection and progression prediction solutions. In this brief paper, we report on a novel digital neuro signature (DNS) for prodromal-PD based on selected digital biomarkers previously discovered on preclinical Alzheimer's disease. (AD). Our preliminary results demonstrated a standard DNS signature for both preclinical AD and prodromal PD, containing a ranked selection of features. This novel DNS signature was rapidly repurposed out of 793 digital biomarker features and selected the top 20 digital biomarkers that are predictive and could detect both the biological signature of preclinical AD and the biological mechanism of a-synucleinopathy in prodromal PD. The resulting model can provide physicians with a pool of patients potentially eligible for therapy and comes along with information about the importance of the digital biomarkers that are predictive, based on SHapley Additive exPlanations (SHAP). Similar initiatives could clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of the disease.

Several studies suggested the presence of non-motor symptoms in Essential Tremor (ET), including REM sleep behavioral disorder (RBD). RBD is an essential criterion for Prodromal Parkinson's Disease (PPD), suggesting a link between ET and PD. Our objective was to assess the prevalence and features of ET patients with RBD and PDD. RBD was diagnosed by questionnaire screening, followed by polysomnography. PPD risk factors and prodromic markers were assessed with a structured protocol. Patients were characterized regarding tremor features. ET patients with RBD (ET-RBD) and PPD (ET-PPD) were compared to patients without RBD (ET-nonRBD) and without PPD (ET-nonPPD), respectively. ET-RBD patients were also compared with a group of isolated RBD (iRBD) regarding PPD features. We assessed a total of 64 ET patients. Five (8.3 %) and 4 (6.3 %) had criteria for RBD and PPD, respectively. ET-RBD patients did not differ from ET-nonRBD except for a higher prevalence of PPD. There were no significant differences between ET-RBD and iRBD (n = 12) groups. ET-PPD had a higher prevalence of positive DaT-Scans and RBD compared to ET-nonPPD. Three ET-RBD patients had PPD and 3 ET-PPD had RBD. Both RBD and PPD are more frequent in ET patients than in general aged population but not related with specific tremor features. ET-RBD patients did not differ significantly from iRBD patients, a group prone to develop PD. These data suggest a link between ET and PD and are in accordance with studies showing an increase incidence of lewy-body pathology and PD in ET populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modification trials and the potential role of population-based studies herein. In the coming years, bridging gaps between study designs will be essential to make vital advances in elucidating the heterogeneity of pre-diagnostic Parkinson's disease.

The failure of glial cell derived neurotropic factor to be efficacious in blinded clinical trials for Parkinson's disease may be due to alterations in signaling receptors and downstream signaling molecules. To test this hypothesis, brain sections were obtained from older adults with no motor deficit (n = 6), minimal motor deficits (n = 10), and clinical diagnosis of Parkinson's disease (n = 10) who underwent motor examination proximate to death. Quantitative unbiased stereology and densitometry were performed to analyze RET and phosphorylated ribosomal protein S6 expression in nigral neurons. Individuals with no motor deficit had extensive and intense RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra. The number and staining intensity of RET-immunoreactive neurons were reduced moderately in subjects with minimal motor deficits and severely reduced in Parkinson's disease relative to no motor deficit group. The number and staining intensity of phosphorylated ribosomal protein S6 was more markedly reduced in both subjects with minimal motor deficits and Parkinson's disease. Reductions in levels of RET and phosphorylated ribosomal protein S6 were recapitulated in a non-human primate genetic Parkinson's disease model based on over-expression of human mutant α-synuclein (A53T). These data indicate that for neurotrophic factors to be effective in patients with minimal motor deficits or PD, these factors would likely have to upregulate RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra .

Background: Parkinson's disease (PD) patients exhibit deficits in saccade performance, pupil function, and blink rate. Isolated REM (rapid eye movement) Sleep Behavior Disorder (RBD) is a harbinger to PD making them candidates to investigate for early oculomotor abnormalities as PD biomarkers. Objectives: We tested whether saccade, pupillary, and blink responses in RBD were similar to PD. Methods: RBD (n = 22), PD (n = 22) patients, and healthy controls (CTRL) (n = 74) were studied with video‐based eye‐tracking. Results: RBD patients did not have significantly different saccadic behavior compared to CTRL, but PD patients differed from CTRL and RBD. Both patient groups had significantly lower blink rates, dampened pupil constriction, and dilation responses compared to CTRL. Conclusion: RBD and PD patients had altered pupil and blink behavior compared to CTRL. Because RBD saccade parameters were comparable to CTRL, pupil and blink brain areas may be impacted before saccadic control areas, making them potential prodromal PD biomarkers. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modification trials and the potential role of population-based studies herein. In the coming years, bridging gaps between study designs will be essential to make vital advances in elucidating the heterogeneity of pre-diagnostic Parkinson's disease. [ABSTRACT FROM AUTHOR]

Evidence suggests peripheral autonomic structures may contribute to autonomic dysfunction in idiopathic rapid eye movement sleep behaviour disorder (iRBD). However, whether the central autonomic network (CAN) is affected in iRBD remains unclear. Magnetic resonance imaging data were acquired from 65 participants (32 patients with iRBD and 33 matched healthy controls). We investigated the CAN in patients with iRBD using a combined voxel‐based morphometry and resting‐state functional connectivity analysis and characterised the relationships between alterations of the CAN and autonomic symptoms. Patients with iRBD had significantly reduced grey matter volume in the brainstem, anterior cingulate and insula compared with healthy controls. Functional connectivity analysis revealed reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe and anterior cingulate in patients with iRBD. In patients with iRBD, both reduced grey matter volume and decreased functional connectivity of the CAN were negatively correlated with the Scales for Outcomes in Parkinson's Disease–Autonomic scores. The present study demonstrated that both the structure and the functional connectivity of the CAN were abnormal in patients with iRBD. In addition, correlation analysis suggested that CAN abnormalities may also play a role in the development of autonomic symptoms in iRBD. [ABSTRACT FROM AUTHOR]

REM Sleep Behavior Disorder (RBD) is a chronic sleep condition characterized by dream enactment and loss of REM atonia. Individuals often present to clinic with complaints of injury to themselves or their bed-partner due to violent movements during sleep. RBD patients have a high risk of developing one of the neurodegenerative α-synucleinopathy diseases: over 70% will develop parkinsonism or dementia within 12 years of their diagnosis. RBD patients also exhibit accelerated disease progression and a more severe phenotype than α-synucleinopathy sufferers without RBD. The disease's low prevalence and the relatively limited awareness of the condition amongst medical professionals makes the diagnosis and treatment of RBD challenging. Uncertainty in patient management is further exacerbated by a lack of clinical guidelines for RBD patient care. There are no binary prognostic markers for RBD disease course and there are no clinical guidelines for neurodegeneration scaling or tracking in these patients. Both clinicians and patients are therefore forced to deal with uncertain outcomes. In this review, we summarize RBD pathology and differential diagnoses, diagnostic, and treatment guidelines as well as prognostic recommendations with a look to current research in the scientific field. We aim to raise awareness and develop a framework for best practice for RBD patient management.

Objective: The objective of this study was to validate the recently updated research criteria for prodromal Parkinson's disease (pPD) proposed by the International Parkinson's Disease and Movement Disorders Society. Methods: A total of 16 of 21 markers of pPD were ascertained in the Hellenic Longitudinal Investigation of Aging and Diet cohort composed of community‐dwelling individuals aged ≥65 years. The probability of pPD was calculated for 961 individuals without Parkinson's disease (PD) or dementia with Lewy bodies at baseline who were followed‐up for a median of 3 years. The ability of the criteria to predict conversion to PD/dementia with Lewy bodies was assessed by estimating their sensitivity and specificity, plotting receiver operating characteristics curves, and using logistic regression. These analyses were repeated using the original criteria. Results: No incident PD/dementia with Lewy bodies case had probable pPD at baseline (ie, ≥80% pPD probability). At cut‐offs of 10%, 30%, and 50% probability of pPD, the sensitivity and specificity of the criteria ranged from 4.5% to 27.3%, and 85.7% to 98.3% respectively. The area under the receiver operating characteristics curve was 0.691 (95% confidence intervals, 0.605–0.777). In logistic regression models, the criteria‐derived posttest odds of pPD were a significant predictor of conversion at follow‐up. The updated criteria performed similarly to the original but showed a slight increase in sensitivity. Conclusions: The new criteria demonstrated suboptimal sensitivity in our random sample of community‐dwelling individuals. The absence of specialized assessments with high likelihood ratios in our cohort could be hindering the demonstration of higher sensitivities. Such assessments should be a part of future validation attempts. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials.Objective: The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population.Methods: PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up.Results: A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline.Conclusions: The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

REM Sleep Behavior Disorder (RBD) is a chronic sleep condition characterized by dream enactment and loss of REM atonia. Individuals often present to clinic with complaints of injury to themselves or their bed-partner due to violent movements during sleep. RBD patients have a high risk of developing one of the neurodegenerative α-synucleinopathy diseases: over 70% will develop parkinsonism or dementia within 12 years of their diagnosis. RBD patients also exhibit accelerated disease progression and a more severe phenotype than α-synucleinopathy sufferers without RBD. The disease's low prevalence and the relatively limited awareness of the condition amongst medical professionals makes the diagnosis and treatment of RBD challenging. Uncertainty in patient management is further exacerbated by a lack of clinical guidelines for RBD patient care. There are no binary prognostic markers for RBD disease course and there are no clinical guidelines for neurodegeneration scaling or tracking in these patients. Both clinicians and patients are therefore forced to deal with uncertain outcomes. In this review, we summarize RBD pathology and differential diagnoses, diagnostic, and treatment guidelines as well as prognostic recommendations with a look to current research in the scientific field. We aim to raise awareness and develop a framework for best practice for RBD patient management. [ABSTRACT FROM AUTHOR]

Background: If mild parkinsonian signs can be a marker for Parkinson's disease (PD) development, an impaired Timed Up and Go test (TUG) should also be a marker for prodromal PD.Objectives: To investigate whether the Timed Up and Go test is associated with PD.Methods: We included 1,196,614 participants at 66 years of age who underwent the National Screening Program for Transitional Ages for Koreans between 2009 and 2014. Timed Up and Go test times were classified into <10 and ≥10 seconds. Incidence of PD was defined using claims data.Results: During the median follow-up period of 3.5 years, participants with slow Timed Up and Go test time had significantly increased risk of developing PD compared with those with normal Timed Up and Go test time (adjusted hazard ratio: 1.28; 95% confidence interval: 1.20-1.37). Furthermore, participants with an abnormal Timed Up and Go test result, defined as ≥20 seconds, had a significantly increased risk of PD compared with those with a normal Timed Up and Go test result (adjusted hazard ratio: 2.18; 95% confidence interval: 1.63-2.92).Conclusion: An indicator of subtle motor deficits, the Timed Up and Go test could be a prodromal marker for the risk of PD development. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Associations of substantia nigra (SN) hyperechogenicity on transcranial sonography, olfactory dysfunction, and mild parkinsonian signs (MPS) with incident Parkinson's disease (PD) have only been studied over limited periods of follow-up and their long-term predictive properties are unclear. We aimed to prospectively assess the risk for incident PD over 10 years in community-dwelling elderly individuals with these risk markers.Methods: SN-hyperechogenicity, olfactory function, and MPS were assessed in the prospective population-based Bruneck Study (2005 in-person assessment; n = 574, aged 55-94 years). Cases of incident PD were identified at 5-year and 10-year follow-up visits. We estimated relative risks of baseline markers for incident cases.Results: After excluding 35 cases with PD or secondary parkinsonism at baseline, a total of 20 cases of incident PD were identified from the remaining 539 participants (11 at 5 years and 9 at 10 years). Relative risks for incident PD over the 10-year follow-up period were 7.43 (2.71-20.39), 3.60 (1.48-8.78), and 5.52 (2.43-12.57) for baseline SN-hyperechogenicity, hyposmia, and mild parkinsonian signs, respectively. While risk of hyposmia for incident PD was similar for the two sequential 5-year periods studied, relative risks of SN-hyperechogenicity and MPS were higher for the first five years as compared to later.Conclusion: Our findings extend the established risk relationship of SN-hyperechogenicity, hyposmia, and MPS with incident PD beyond 5 years of follow-up. [ABSTRACT FROM AUTHOR]

Parkinson’s disease is the second most prevalent neurodegenerative disorder in the Western world. It is estimated that the neuronal loss related to Parkinson’s disease precedes the clinical diagnosis by more than 10 years (prodromal phase) which leads to a subtle decline that translates into non-specific clinical signs and symptoms. By leveraging diffusion magnetic resonance imaging brain (MRI) data evaluated longitudinally, at least at two different time points, we have the opportunity of detecting and measuring brain changes early on in the neurodegenerative process, thereby allowing early detection and monitoring that can enable development and testing of disease modifying therapies. In this study, we were able to define a longitudinal degenerative Parkinson’s disease progression pattern using diffusion magnetic resonance imaging connectivity information. Such pattern was discovered using a de novo early Parkinson’s disease cohort (n = 21), and a cohort of Controls (n = 30). Afterward, it was tested in a cohort at high risk of being in the Parkinson’s disease prodromal phase (n = 16). This progression pattern was numerically quantified with a longitudinal brain connectome progression score. This score is generated by an interpretable machine learning (ML) algorithm trained, with cross-validation, on the longitudinal connectivity information of Parkinson’s disease and Control groups computed on a nigrostriatal pathway-specific parcellation atlas. Experiments indicated that the longitudinal brain connectome progression score was able to discriminate between the progression of Parkinson’s disease and Control groups with an area under the receiver operating curve of 0.89 [confidence interval (CI): 0.81–0.96] and discriminate the progression of the High Risk Prodromal and Control groups with an area under the curve of 0.76 [CI: 0.66–0.92]. In these same subjects, common motor and cognitive clinical scores used in Parkinson’s disease research showed little or no discriminative ability when evaluated longitudinally. Results suggest that it is possible to quantify neurodegenerative patterns of progression in the prodromal phase with longitudinal diffusion magnetic resonance imaging connectivity data and use these image-based patterns as progression markers for neurodegeneration.

• REM sleep without atonia (RSWA) is a common finding in polysomnographic studies. • Secondary RSWA was most frequently observed in the context of antidepressant use. • Excessive daytime sleepiness was more frequently seen in isolated RSWA patients. Isolated REM sleep without atonia (iRSWA) is regarded as prodromal phase of REM sleep behavior disorder (RBD) and synucleinopathies. Other factors, however, have also been described to cause RSWA, including sleep apnea, antidepressants use and narcolepsy. We investigated the frequency of RSWA and its different etiologies. We investigated RSWA in patients that underwent a clinical video polysomnography. In iRSWA subjects, we examined polysomnography indication and two markers of prodromal Parkinson's disease: excessive daytime sleepiness and depressive symptoms, with a case-control design. Of the 864 included polysomnographies, 188 were positive for RSWA (21.8%), 17 for RBD (2.0%) and 48 for iRSWA (5.6%). Mean Epworth Sleepiness Scale scores were 9.8 ± 4.8 (iRSWA subjects) and 7.5 ± 4.9 (controls), p = 0.014. Mean Beck Depression Inventory-II scores were 11.3 ± 7.9 (iRSWA subjects) and 9.5 ± 8.4 (controls), p = 0.229. Excessive daytime sleepiness was more often the polysomnography indication in the iRSWA group (p = 0.006). RSWA is a frequent finding in the context of antidepressant use or synucleinopathies. iRSWA subjects reported increased excessive daytime sleepiness and more often had excessive daytime sleepiness as polysomnography indication. Our study provides evidence for high frequency of RSWA, underscoring the need for longitudinal studies in iRSWA patients, with interest for conversion to synucleinopathies. [ABSTRACT FROM AUTHOR]

Despite intensive effort, biomarker research for the detection of prodromal stage, diagnosis and progression of Parkinson's disease (PD) falls short of expectations. This article reviews the attempts in the last 20 years to find a biomarker, addresses challenges along the biomarker search and suggests the steps that should be taken to overcome these challenges. Although several biomarkers are currently available, none of them is specific enough for diagnosis, prediction of future PD or disease progression. The main reason for the failure finding a strong biomarker seems to be drastic heterogeneity of PD, which exhibits itself in all domains; from the clinic to pathophysiology or genetics. The diversity in patient selection, assessment methods or outcomes in biomarker studies also limit the interpretation and generalizability of the data. In search of a reliable biomarker, consideration of novel approaches encompassing individual demographic, clinical, genetic, epigenetic and environmental differences, employment of strategies enabling marker combinations, designing multicenter studies with compatible assessment methods, integration of data from preclinical domains and utilization of novel technology-based assessments are necessary. [ABSTRACT FROM AUTHOR]