Identifying prodromal Parkinson's disease: Pre-Motor disorders in Parkinson's disease

Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada.
Movement Disorders (Impact Factor: 5.68). 04/2012; 27(5):617-26. DOI: 10.1002/mds.24996
Source: PubMed


Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

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    • "autonomic and cognitive deficits as well as sleep and affective disorders such as depression and anxiety , which may even precede the characteristic motor deficits [1] [2]. Related to the cognitive deficits, though different in nature, impairments in advanced Theory of Mind (ToM), refer to the ability to infer other people's thoughts, intentions, or emotions. "
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    ABSTRACT: Background: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ability to read others' mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. Objective: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli. Methods: We have submitted Thy1-aSyn mice to tests adapted from autism models. Results: At 7-8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3-4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. Conclusion: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alpha-synuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.
    Journal of Parkinson's Disease 01/2015; 5(3). DOI:10.3233/JPD-140503 · 1.91 Impact Factor
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    • "In line with the hypothesis that PD pathology first starts in extranigral sites, many studies have highlighted the fact that nonmotor symptoms such as hyposmia may antedate the clinical manifestation of cardinal motor PD features by several years [2] [6]. Table 1 Baseline characteristics of subjects according to the group at follow-up. "
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    ABSTRACT: Mild parkinsonian signs (MPS) are common in the elderly population and are associated with a wide range of adverse health outcomes, including incident Parkinson's disease (PD). We aimed to prospectively evaluate potential risk factors for incident MPS. Participants of the population-based Bruneck Study representative for the general elderly community underwent a baseline assessment of substantia nigra (SN)-echogenicity with transcranial sonography, olfactory function with the Sniffin' Sticks identification test and vascular risk according to the Framingham risk score as well as a baseline and 5-year follow-up neurological examination. MPS were defined according to established criteria based on the entire motor section of the Unified PD Rating Scale. Participants with PD at baseline or follow-up and subjects with MPS at baseline were excluded. A logistic regression analysis adjusted for age and sex was used to detect risk factors for incident MPS in the remaining 393 participants. SN-hyperechogenicity and hyposmia were related to the development of MPS with odds ratios of 2.0 (95%CI, 1.1-3.7) and 1.6 (95%CI, 1.0-2.7), respectively, while increased vascular risk was not. Having both, SN-hyperechogenicity and hyposmia, was associated with an odds ratio of 3.0 (95%CI, 1.2-7.7) for incident MPS. Among the various motor domains, increased SN-echogenicity predicted the development of bradykinesia and rigidity, whereas diminished olfactory function predicted the development of impaired axial motor function. In addition to their established roles as risk factors for PD, SN-hyperechogenicity and hyposmia are associated with an increased risk for MPS in the general elderly community. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 12/2014; 21(3). DOI:10.1016/j.parkreldis.2014.12.021 · 3.97 Impact Factor
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    • "While the nature and extent of autonomic involvement in PD is still poorly understood [4], post-mortem neuropathological and biochemical studies in PD patients showed the concomitant occurrence of nigrostriatal degeneration and a-synuclein agglomeration in enteric nervous system [5]. In accordance with Braak theory [6] and consistently with several clinical findings [7], the neuropathologic involvement of the autonomic nervous system is a crucial characteristic of the early stage of the disease. It is postulated that the PD pathogenetic process might actually start in the enteric nervous system [8] and spread from there via the vagus nerve to reach the central nervous system [9]. "
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    ABSTRACT: Constipation is one of most frequent non-motor symptoms of Parkinson's disease (PD) and it may precede the clinical diagnosis of PD by years, with negative effects on quality of life. In contrast to motor features, levodopa is ineffective and possibly detrimental on constipation. Treatment of constipation in PD is non-specific and frequently unsuccessful. Stemming from a clinical observation of unexpected relief of bothersome constipation, abdominal bloating and pain after treatment with the beta-blocker carvedilol in one patient, we have evaluated the association between the use of beta-blockers and the presence of constipation in a large, unselected PD cohort. Retrospective review of the medical records of every patient with a diagnosis of PD seen in the Movement Disorders clinic at Cedars-Sinai Medical Center from October 2010 to April 2014. 341 medical records with a primary diagnosis of PD were reviewed, 336 of which contained information about constipation. Overall, 205/336 patients (61%) reported constipation. Among the 66 subjects treated with beta-blockers at the time of the encounter of record, only 28 (42.4%) reported constipation. By comparison, among the 270 subjects not treated with beta-blockers, 177 (65.5%) had constipation (χ(2) test p value = 0.001). Multivariate logistic analysis showed an odds ratio (OR) of 0.293 for beta-blockers (95% C.I. 0.161-0.535, p = 0.0001), 2.287 for levodopa (95% C.I. 1.271-4.117, p = 0.006) and 1.805 for dopamine agonists (95% C.I. 1.039-3.136, p = 0.036). Beta-blockers are associated with a lower risk of constipation, while dopaminergic treatments appear to increase risk of constipation. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 11/2014; 21(2). DOI:10.1016/j.parkreldis.2014.11.015 · 3.97 Impact Factor
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