Ronald B. Postuma

Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Objective: Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. Methods: We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. Results: Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. Conclusions: Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

MDS clinical diagnostic criteria for Parkinson's disease

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinsons disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder

Background: Idiopathic REM sleep behavior disorder (RBD) is characterized by loss of atonia during REM sleep, resulting in motor activity during dreams. Studies estimate that approximately half of patients with RBD will eventually develop Parkinson disease (PD), so RBD may be an indicator of presymptomatic PD. Several potential early diagnostic markers of PD have been proposed, but they have generally not been tested in presymptomatic PD. The authors hypothesized that these markers may be abnormal in idiopathic RBD. Methods: The authors compared 25 patients with polysomnography-confirmed RBD without PD with age- and sex-matched controls. Color vision, olfaction, quantitative motor testing, and indices of depression, personality, and autonomic function were examined. Results: Patients demonstrated significant impairment in color discrimination and olfactory function. Patients had subtle abnormalities on quantitative testing of motor and gait speed. Autonomic symptoms were more common in patients than controls. Abnormalities were heterogeneous, with some patients scoring normally on all domains, whereas others were severely impaired on multiple domains. Dysfunction on tests of olfactory function, color vision, and motor speed were highly correlated, such that patients who performed poorly on one test tended to perform poorly on the others. Conclusions: Many potential early markers of Parkinson disease are significantly abnormal in idiopathic REM sleep behavior disorder. These abnormalities are present in approximately half of the patients, suggesting a heterogenous pathophysiology.

Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases

Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is characterised by loss of muscular atonia and prominent motor behaviours during REM sleep. RBD can cause sleep disruption and severe injuries for the patient or bed partner. The disorder is strongly associated with neurodegenerative diseases, such as multiple-system atrophy, Parkinsons disease, dementia with Lewy bodies, and progressive supranuclear palsy. In many cases, the symptoms of RBD precede other symptoms of these neurodegenerative disorders by several years. Furthermore, several recent studies have shown that RBD is associated with abnormalities of electroencephalographic activity, cerebral blood flow, and cognitive, perceptual, and autonomic functions. RBD might be a stage in the development of neurodegenerative disorders and increased awareness of this could lead to substantial advances in knowledge of mechanisms, diagnosis, and treatment of neurodegenerative disorders.

MDS research criteria for prodromal Parkinson's disease

This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease‐modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individuals risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available.

Neural Bases of Set-Shifting Deficits in Parkinson's Disease

Patients with Parkinsons disease (PD) exhibit impairments in several cognitive functions similar to those observed in patients with prefrontal cortex (PFC) lesions. The physiological origins of these cognitive deficits are not well documented. Two mechanisms have been proposed: disruptions in corticostriatal circuits or a deficiency in frontal dopamine. We previously used functional magnetic resonance imaging (fMRI) in young healthy subjects to separate patterns of PFC and striatum activity during distinct phases of performance of the Wisconsin Card Sorting Task, a set-shifting task that reveals deficits in patients with PD. Here, the same fMRI protocol was used in PD patients and matched controls. Decreased activation was observed in the PD group compared with the matched control group in the ventrolateral PFC when receiving negative feedback and the posterior PFC when matching after negative feedback. In controls, these prefrontal regions specifically coactivated with the striatum during those stages of task performance. In contrast, greater activation was found in the PD group compared with the matched control group in prefrontal regions, such as the posterior and the dorsolateral PFC when receiving positive or negative feedback, that were not coactivated with the striatum in controls. These results suggest that both nigrostriatal dopamine depletion and intracortical dopamine deficiency may play a role in cognitive deficits in PD, depending on the involvement of the striatum in the task at hand.

Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease.

Increasing recognition that Parkinsons 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.

Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease

With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinsons disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early‐stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease.

To investigate the frequency and subtypes of mild cognitive impairment (MCI) in idiopathic rapid eye movement sleep behavior disorder (RBD) and Parkinsons disease (PD) in association with RBD.