Prodromal Stage Of Parkinson's Disease Research Articles

Novel Variants Linked to the Prodromal Stage of Parkinson's Disease (PD) Patients.

The symptoms of most neurodegenerative diseases, including Parkinson's disease (PD), usually do not occur until substantial neuronal loss occurs. This makes the process of early diagnosis very challenging. Hence, this research used variant call format (VCF) analysis to detect variants and novel genes that could be used as prognostic indicators in the early diagnosis of prodromal PD. Data were obtained from the Parkinson's Progression Markers Initiative (PPMI), and we analyzed prodromal patients with gVCF data collected in the 2021 cohort. A total of 304 participants were included, including 100 healthy controls, 146 prodromal genetic individuals, 21 prodromal hyposmia individuals, and 37 prodromal individuals with RBD. A pipeline was developed to process the samples from gVCF to reach variant annotation and pathway and disease association analysis. Novel variant percentages were detected in the analyzed prodromal subgroups. The prodromal subgroup analysis revealed novel variations of 1.0%, 1.2%, 0.6%, 0.3%, 0.5%, and 0.4% for the genetic male, genetic female, hyposmia male, hyposmia female, RBD male, and RBD female groups, respectively. Interestingly, 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300, and PPP6R2) that were recently detected in PD patients were detected in the prodromal stage of PD. Genetic biomarkers are crucial for the early detection of Parkinson's disease and its prodromal stage. The novel PD genes detected in prodromal patients could aid in the use of gene biomarkers for early diagnosis of the prodromal stage without relying only on phenotypic traits.

Mood disturbances in Parkinson's disease: From prodromal origins to application of animal models

Parkinson's disease (PD) is a complex illness with a constellation of environmental insults and genetic vulnerabilities being implicated. Strikingly, many studies only focus on the cardinal motor symptoms of the disease and fail to appreciate the major non-motor features which typically occur early in the disease process and are debilitating. Common comorbid psychiatric features, notably clinical depression, as well as anxiety and sleep disorders are thought to emerge before the onset of prominent motor deficits. In this review, we will delve into the prodromal stage of PD and how early neuropsychiatric pathology might unfold, followed by later motor disturbances. It is also of interest to discuss how animal models of PD capture the complexity of the illness, including depressive-like characteristics along with motor impairment. It remains to be determined how the underlying PD disease processes contributes to such comorbidity. But some of the environmental toxicants and microbial pathogens implicated in PD might instigate pro-inflammatory effects favoring α-synuclein accumulation and damage to brainstem neurons fueling the evolution of mood disturbances. We posit that comprehensive animal-based research approaches are needed to capture the complexity and time-dependent nature of the primary and co-morbid symptoms. This will allow for the possibility of early intervention with more novel and targeted treatments that fit with not only individual patient variability, but also with changes that occur over time with the evolution of the disease.

Evaluation of iron overload in nigrosome 1 via quantitative susceptibility mapping as a progression biomarker in prodromal stages of synucleinopathies

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.

Characterizing mild cognitive impairment in prodromal Parkinson's disease: A community-based study in China.

ObjectiveThe International Parkinson and Movement Disorder Society (MDS) has published research criteria for prodromal Parkinson's disease (pPD), which includes cognitive impairment as a prodromal marker. However, the clinical features of mild cognitive impairment (MCI) in pPD remain unknown. Our study aimed to evaluate the frequency and clinical features of mild cognitive impairment of pPD in the elderly in China.MethodsThe cross‐sectional community‐based study recruited 2688 participants aged ≥50 years. Subjects were diagnosed with pPD according to the MDS criteria. Overall, 39 pPD and 22 healthy controls underwent comprehensive clinical and neuropsychological assessment. MCI was also diagnosed by the MDS criteria. Next, we investigated the relationship between clinical factors and cognition.ResultsAmong the 2,663 dementia‐free and Parkinson disease (PD)‐free participants, 55 met the criteria for pPD (2.1%) and 23 pPD met the criteria for MCI. Memory, attention/working memory, and executive function were the most frequent impaired domains, and amnestic MCI multidomain phenotype was the most frequent MCI subtype (69.57%) in pPD. Additionally, correlation analysis revealed that the global cognitive performance was negatively related to UPDRS‐III score (r = −0.456, p = 0.004).ConclusionMCI, specifically impairment in memory, attention/working memory, and executive domain, is present at the prodromal stage of PD. In addition, cognitive performance is correlated with motor symptoms in pPD. Our results reflect that cognitive profile, combined with motor symptoms, can help clinicians to identify individuals with pPD early, as those would be the optimal candidates for neuroprotective therapy.

Blood Cholesterol Decreases as Parkinson's Disease Develops and Progresses.

Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson's disease (PD); this finding has important ramifications, but its interpretation has been debated. To longitudinally examine how blood total cholesterol changes during the development of PD. In the Health, Aging and Body Composition study (n = 3,053, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. Compared to the lowest tertile of baseline total cholesterol, the cumulative incidence ratio of PD and 95% confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values ∼4 years before disease diagnosis (observed-expected difference, -6.68 mg/dL (95% confidence interval: -13.14, -0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to -13.59 mg/dL (95% confidence interval: -22.12, -5.06), although the linear trend did not reach statistical significance (p = 0.10). Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD.

Future Perspectives on the Relevance of Auditory Markers in Prodromal Parkinson's Disease.

Research on auditory processing in Parkinson's disease (PD) has recently made substantial progress. At present, evidence has been found for altered auditory processing in the clinical stage of PD. The auditory alterations in PD have been demonstrated with low-cost and non-invasive assessments that are already used in routine clinical practice. Since auditory alterations have been reported early in disease progression, it would be highly relevant to investigate whether auditory markers could be provided in the prodromal stage of PD. In addition, auditory alterations in early stage PD might be modulated by dopaminergic medication. Therefore, the aim of this review is (1) to summarize the literature on auditory processing in PD with a specific focus on the early disease stages, (2) to give future perspectives on which audiological and electrophysiological measurements could be useful in the prodromal stage of PD and (3) to assess the effect of dopaminergic medication on potential auditory markers in the prodromal stage of PD.

Prodromal Parkinson disease in patients with idiopathic hyposmia.

Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification of individuals with IH at prodromal stage of PD would serve to select them to implement neuroprotective agents, when available. To identify prodromal PD in IH patients using the Movement Disorders Society (MDS) research criteria for prodromal PD. We applied the MDS research criteria for prodromal PD to 25 consecutive patients older than 50years who were self-referred for smell loss and had IH, and to 18 controls. A number of risk and prodromal PD markers were assessed in all participants including REM sleep behavior disorder (RBD) by video-polysomnography and nigrostriatal dopaminergic dysfunction by DAT-SPECT. After follow-up of 4.7 ± 2.2years, participants were re-assessed to look for incident PD. Prodromal PD probability was higher in patients than in controls (19.45 ± 34.9% versus 1.74 ± 4.48%; p = 0.019). Four (16%) patients met the criteria of prodromal PD surpassing 80% probability (99.8%, 99.5%, 88.3%, 86.4%). Three (12%) patients had RBD and four (16%) abnormal DAT-SPECT. At the end of follow-up, one (4%) IH patient who had RBD and baseline prodromal PD probability of 86.4% developed PD, while all controls remained disease free. Prodromal PD is infrequent among IH patients. MDS research criteria for prodromal PD are useful to identify a subgroup of IH patients at high risk of PD when RBD is assessed by video-polysomnography and nigrostriatal dopamine deficiency with DAT-SPECT.

Protein trapping leads to altered synaptic proteostasis in synucleinopathies.

Parkinson's disease (PD) is associated with the accumulation of alpha-synuclein (aSyn) in intracellular inclusions known as Lewy bodies and Lewy neurites. Under physiological conditions, aSyn is found at the presynaptic terminal and exists in a dynamic equilibrium between soluble, membrane-associated and aggregated forms. Emerging evidence suggests that, under pathological conditions, aSyn begins to accumulate and acquire a toxic function at the synapse, impairing their normal function and connectivity. However, the precise molecular mechanisms linking aSyn accumulation and synaptic dysfunction are still elusive. Here, we provide an overview of our current findings and discuss the hypothesis that certain aSyn aggregates may interact with proteins with whom aSyn normally does not interact with, thereby trapping them and preventing them from performing their normal functions in the cell. We posit that such abnormal interactions start to occur during the prodromal stages of PD, eventually resulting in the overt manifestation of clinical features. Therefore, understanding the nature and behaviour of toxic aSyn species and their contribution to aSyn-mediated toxicity is crucial for the development of therapeutic strategies capable of modifying disease progression in PD and other synucleinopathies.

A Clinically Applicable Interactive Micro and Macro-Sleep Staging Algorithm for Elderly and Patients with Neurodegeneration.

Elderly and patients with neurodegenerative diseases (NDD) often complain about sleep problems and show altered sleep structure. Automated algorithms for efficient and specific sleep staging are needed. We propose a new algorithm using only one electroencephalographic and two electrooculographic channels to score wakefulness, rapid eye movement (REM) sleep and non-REM sleep in a cohort of elderly healthy controls (HC), patients with Parkinson's disease (PD), isolated REM sleep behavior disorder (iRBD), considered the prodromal stage of PD, and patients with PD and RBD (PD+RBD). The proposed method scores both standard 30-s epochs (macro-staging) and 5-s mini-epochs (micro-staging), whose evaluation may help to better understand sleep micro-structure. Moreover, the algorithm is interactive, as it labels the classified sleep epochs as either certain or uncertain, so that experts can manually review the uncertain ones. The algorithm performances were evaluated for macro-sleep staging, where it achieved overall accuracies of 0.87±0.05 in 41 HC, 0.86±0.10 in 57 PD, 0.76±0.10 in 31 iRBD and 0.77±0.10 in 30 PD+RBD patients when all 30-s epochs were considered. The accuracies increased to 0.91±0.05, 0.90±0.08, 0.85±0.09, 0.88±0.08 respectively when considering only the certain ones. The epochs labeled as uncertain were 9.95±4.15%, 11.13±7.86%, 18.39±7.38% and 18.90±8.00% in HC, PD, iRBD and PD+RBD respectively. The proposed interactive micro and macro sleep staging algorithm can be used in clinics to reduce the burden of manual sleep staging in elderly and patients with NDD.

Alpha-synuclein aggregates in the parotid gland of idiopathic REM sleep behavior disorder

BackgroundThe neuropathological hallmark of Parkinson's disease (PD) is the presence of aggregates of phosphorylated alpha-synuclein (pAS) in the nervous system. MethodWe report a patient with video-polysomnography-confirmed idiopathic REM sleep behavior disorder that underwent parotidectomy because of parotid gland cancer. Immunohistochemistry of the gland tissue revealed abundant pAS deposits. One year after surgery the patient was diagnosed with PD. Prompted by this observation we examined the parotid gland in 10 consecutive individuals that underwent elective parotidectomy irrespective of their clinical condition. ResultsOne had PD and another had mild parkinsonian signs plus reduced dopamine transporter uptake in the striatum. Both had pAS deposits in the parotid gland. The remaining eight subjects had no neurological signs and pAS was found in one of them. ConclusionOur study shows that the parotid gland may contain pAS pathology in the prodromal stage of PD and in manifested PD.

The Metabolic Pattern of Idiopathic REM Sleep Behavior Disorder Reflects Early-Stage Parkinson Disease.

Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson disease (PD) and other Lewy body disorders. Spatial covariance analysis of 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 with the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we studied the expression of the iRBD pattern in de novo PD patients. Methods: The iRBD-related pattern was identified in 18F-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 in 18F-FDG PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable REM sleep behavior disorder (RBD) according to the Mayo Sleep Questionnaire. Neuropsychologic evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom 16 also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms. Results: The iRBD-related pattern was characterized by relative hypermetabolism in the cerebellum, brain stem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in the 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 with controls (P < 0.0001). iRBD-related pattern expression was not significantly different between PD patients with and without probable RBD, or between PD patients with unilateral or bilateral parkinsonism. iRBD-related pattern (iRBDRP) expression was higher in PD-MCI patients than in PD patients with preserved cognition (P = 0.001). Subject scores on the iRBD-related pattern were highly correlated to subject scores on the PDRP (r = 0.94, P < 0.0001). Conclusion: Our results show that the iRBDRP is an early manifestation of the PDRP. Expression of both PDRP and iRBDRP was higher in patients with a more severe form of PD (PD-MCI), which indicates that expression of the 2 patterns increases with disease severity.

The Changing Landscape of Parkinson Epidemiologic Research.

Despite recent successes in understanding the genetics of Parkinson’s disease (PD), the causes of late-onset sporadic PD remain elusive. Many of the epidemiologic findings on PD etiology have been challenged by alternative explanations such as reverse causation. This is mainly because PD often takes decades to develop before it can be diagnosed late in life. Convincing evidence shows that this prodromal stage of PD is characterized by various prodromal symptoms such as olfactory impairment and rapid-eye-movement sleep behavior disorder (RBD). As they likely reflect PD pathogenesis years, if not decades, before nigrostriatal involvement, research on these symptoms may represent an unprecedented opportunity to dissect the etiology of PD. Using PD prodromal symptoms as intermediate phenotypes, we may be able to identify factors that contribute to the development of these symptoms and factors that modify their progression to clinical PD. Further, this line of research will also enable examinations of novel etiological hypotheses of PD development such as the microbiome and prion hypotheses. In this article, the author used olfactory impairment and RBD as examples to illustrate the promises and challenges of epidemiologic research on prodromal symptoms to understand PD etiology.

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment.

Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. In addition, with the development of invasive therapies and novel disease-specific therapies, strategies for patient enrichment in trial populations are of growing importance. Imaging disease-specific patterns of regional glucose metabolism with PET and 18F-FDG allows for a highly accurate distinction between Parkinson disease (PD) and atypical parkinsonian syndromes, including multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. On the basis of a preliminary metaanalysis of currently available studies with inclusion of multiple disease groups, we estimated that the diagnostic sensitivity and specificity for visual PET readings supported by voxel-based statistical analyses for diagnosis of atypical parkinsonian syndromes are 91.4% and 90.6%, respectively. The diagnostic specificity of 18F-FDG PET for diagnosing multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration was consistently shown to be high (>90%), whereas sensitivity was more variable (>75%). It is increasingly acknowledged that cognitive impairment represents a major challenge in PD, with mild cognitive impairment being a prodromal stage of PD with dementia (PDD). In line with clinical and neuropsychologic studies, recent PET studies demonstrated that posterior cortical dysfunction in nondemented PD patients precedes cognitive decline and the development of PDD by several years. Taken together, the current literature underscores the utility of 18F-FDG PET for diagnostic evaluation of parkinsonism and the promising role of 18F-FDG PET for assessment and risk stratification of cognitive impairment in PD.

Sleep Disturbances in the Prodromal Stage of Parkinson Disease.

Decades of research on neurodegenerative diseases such as Parkinson's disease (PD) have shifted our focus from clinical symptomatic stages to one step earlier, the prodromal stage. There is convincing evidence showing that sleep disorders such as excessive daytime somnolence, insomnia, obstructive sleep apnea, and particularly REM sleep behavior disorder (RBD) are potential prodromal features starting years and decades before conversion to PD. This review aims to provide an overview on various sleep disorders as prodromal features of PD. We start with a discussion of how neuroanatomy of sleep might link to PD pathology. Afterwards, specific sleep disorders that are either known or suspected to be a prodromal symptom for PD, namely insomnia, sleep apnea, somnolence, and RBD, are discussed. Disturbances in serotonergic, cholinergic, dopaminergic, and glutamatergic neurotransmitter systems have made sleep disorders potential candidates for prodromal PD. Nevertheless, the strength of such linkage varies considerably for different entities. While RBD is by far the strongest prodromal manifestation for PD with a high likelihood of phenoconversion and there is reasonable evidence that somnolence can predict PD, data on the prodromal role of sleep apnea and insomnia is limited. Treatment options are available for symptomatic relief of prodromal sleep disorders; however, there is a dearth of knowledge on neuroprotective agents to be used on people with prodromal sleep disorders to either prevent or postpone conversion to PD.

Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease - Report of the JPND Working Group BioLoC-PD

Background: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. Methods: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. Results: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. Conclusions: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.

Brainstem pathology and non-motor symptoms in PD

Parkinson's disease (PD) is considered a multisystem disorder involving dopaminergic, noradrenergic, serotoninergic, and cholinergic systems, characterized by motor and non-motor symptoms. The causes of the non-motor symptoms in PD are multifactorial and unlikely to be explained by single lesions. However, several evidence link them to damage of specific brainstem nuclei. Numerous brainstem nuclei are engaged in fundamental homeostatic mechanisms, including gastrointestinal regulation, pain perception, mood control, and sleep–wake cycles. In addition, these nuclei are locally interconnected in a complex manner and are subject to supraspinal control. The objective of this review is to provide a better overview of the current knowledge about the consequences of the involvement of specific brainstem nuclei to the most prevalent non-motor symptoms occurring in PD. The multidisciplinary efforts of research directed to these non-nigral brainstem nuclei, in addition to the topographical and chronological spread of the disease — especially in the prodromal stages of PD, are discussed.