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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.

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

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 a-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 to be effective.

The field of prodromal PD is still in its infancy, and at the cusp of major advances. This article summarizes where we are, and most importantly where we need to go in order for the promise of prodromal PD to be realized. In the immediate future, the criteria need to be updated with additional markers and disseminated broadly. In the near future, they need to better incorporate changes in likelihood ratio with age and sex, combine markers in novel ways using big data approaches, identify subtypes, and incorporate better higher-specificity markers as they are discovered. Integration of smartphone/wearable markers and biomarkers of progression from the prodromal phase will allow development of neuroprotective trials in early stages. By 2040, it is hoped that prodromal criteria will be incorporated into active neuroprotective treatment programs, allowing a program of population-based screening followed by early treatment and ultimately the prevention of clinical PD from ever becoming manifest.

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.

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.

For people with Parkinson&rsquo, s disease (PD), considered the most common neurodegenerative disease behind Alzheimer&rsquo, s disease, accurate diagnosis is dependent on many factors, however, misdiagnosis is extremely common in the prodromal phases of the disease, when treatment is thought to be most effective. Currently, there are no robust biomarkers that aid in the early diagnosis of PD. Following previously reported work by our group, we accurately measured the concentrations of 18 bile acids in the serum of a prodromal mouse model of PD. We identified three bile acids at significantly different concentrations (p &lt, 0.05) when mice representing a prodromal PD model were compared with controls. These include &omega, murichoclic acid (MCAo), tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA). All were down-regulated in prodromal PD mice with TUDCA and UDCA at significantly lower levels (17-fold and 14-fold decrease, respectively). Using the concentration of three bile acids combined with logistic regression, we can discriminate between prodromal PD mice from control mice with high accuracy (AUC (95% CI) = 0.906 (0.777&ndash, 1.000)) following cross validation. Our study highlights the need to investigate bile acids as potential biomarkers that predict PD and possibly reflect the progression of manifest PD.

Rationale: Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson's disease (PD) and other Lewy-body disorders. Spatial covariance analysis of [18F]-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET) data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it to the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we study the expression of the iRBD pattern in de novo PD patients.Methods:The iRBD-related pattern was identified in18F-FDG-PET scans of 21 patients with polysomnographically-confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in18F-FDG-PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable RBD according to the Mayo Sleep Questionnaire. Neuropsychological evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom sixteen also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms.Results:The iRBD-related pattern was characterized by relative hypermetabolism in cerebellum, brainstem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in middle cingulate, temporal, occipital and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared to controls (P

The diagnosis of Parkinson’s disease (PD) is based on clinical features and differently to the common opinion that detecting this condition is easy, seminal clinico-pathological studies have shown that up one-fourth of patients diagnosed as PD during life has an alternative diagnosis at post-mortem. The misdiagnosis is even higher when only the initial diagnosis is considered, since the diagnostic accuracy improves by time, during follow-up visits. Given that the confirmation of the diagnosis of PD can be only obtained through neuropathology, to improve and facilitate the diagnostic-therapeutic workup in PD, a number of criteria and guidelines have been introduced in the last three decades. In the present paper, we will critically re-appraise the main diagnostic criteria proposed for PD, with particular attention to the recently published revised criteria by the International Parkinson and Movement Disorder Society (MDS) task force, underlying their novelty and focusing on the diagnostic issues still open. We also emphasize that the MDS-PD criteria encompass the two main previous sets of diagnostic criteria (United Kingdom Parkinson’s Disease Society Brain Bank and Gelb’s criteria), introducing at the same time new aspects as the use of non-motor symptoms as additional diagnostic features, and the adoption of the concept of prodromal PD, crucial to enroll in clinical trials PD patients in the very early phase of the disease. To better understand the real diffusion of the new MDS-PD diagnostic criteria among neurologists, we have also collected selective opinions of sixteen movement disorder experts from various world regions on their practical approach for the clinical diagnosis of PD. Results from this brief survey showed that, although innovative and complete, the revised diagnostic criteria produced by MDS task force are still scarcely employed among clinicians. We believe that both national and international scientific societies should operate in the future for a broader diffusion of these criteria with specific initiatives, including dedicated events and teaching courses.

Introduction: Sarcopenia and Parkinson's disease (PD) are both common age-related syndromes, and there is preliminary evidence that the probability of the co-occurrence of these syndromes within one individual is higher than expected. However, it is unclear to date whether one of the syndromes induces the other, or whether there may be common underlying causes. This pilot study thus aimed at investigating the association of the features of increased risk for PD with early stage sarcopenia (ESS). Method: Two hundred and fifty-five community-dwelling individuals were recruited from the Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study. The following features that are associated with an increased risk for future PD were evaluated: the motor part of the Unified PD Rating Scale (UPDRS-III), hyperechogenicity of the substantia nigra, prevalence of lifetime depression, hyposmia, REM sleep behavior disorder and the recently introduced probability score for prodromal PD. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People, which was adapted to this cohort of healthy adults. Multiple linear regression analysis was used to identify associations of PD-related features with ESS. Results: The UPDRS-III score was significantly associated with ESS. The result remained significant after the adjustment for age, gender and physical activity. No association was found between the other PD-related features and ESS. Conclusion: The significant association of the UPDRS-III score with ESS in this cohort might indicate a common and early pathway in both diseases and supports the existence of an "extended neurodegenerative overlap syndrome." Moreover, the potential of EES to serve as a prodromal marker of PD should be evaluated in future studies.

BackgroundThe search for disease-modifying treatments for Parkinson's disease advances, however necessary markers for early detection of the disease are still lacking. There is compelling evidence that changes of postural stability occur at very early clinical stages of Parkinson's disease, making it tempting to speculate that changes in sway performance may even occur at a prodromal stage, and may have the potential to serve as a prodromal marker for the disease.Methodology/principal findingsBalance performance was tested in 20 individuals with an increased risk of Parkinson's disease, 12 Parkinson's disease patients and 14 controls using a cross-sectional approach. All individuals were 50 years or older. Investigated groups were similar with respect to age, gender, and height. An accelerometer at the centre of mass at the lower spine quantified sway during quiet semitandem stance with eyes open and closed, as well as with and without foam. With increasing task difficulty, individuals with an increased risk of Parkinson's disease showed an increased variability of trunk acceleration and a decrease of smoothness of sway, compared to both other groups. These differences reached significance in the most challenging condition, i.e. the eyes closed with foam condition.Conclusions/significanceIndividuals with an increased risk of Parkinson's disease have subtle signs of a balance deficit under most challenging conditions. This preliminary finding should motivate further studies on sway performance in individuals with an increased risk of Parkinson's disease, to evaluate the potential of this symptom to serve as a biological marker for prodromal Parkinson's disease.