Current Concepts and Controversies in the Management of REM Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment and the loss of muscle atonia during REM sleep, known as REM sleep without atonia (RSWA). RBD can result in significant injuries, prompting patients to seek medical attention. However, in others, it may present only as non-violent behaviors noted as an incidental finding during polysomnography (PSG). RBD typically occurs in the context of synuclein-based neurodegenerative disorders but can also be seen accompanying brain lesions and be exacerbated by medications, particularly antidepressants. There is also an increasing appreciation regarding isolated or idiopathic RBD (iRBD). Symptomatic treatment of RBD is a priority to prevent injurious complications, with usual choices being melatonin or clonazepam. The discovery that iRBD represents a prodromal stage of incurable synucleinopathies has galvanized the research community into delineating the pathophysiology of RBD and defining biomarkers of neurodegeneration that will facilitate future disease-modifying trials in iRBD. Despite many advances, there has been no progress in available symptomatic or neuroprotective therapies for RBD, with recent negative trials highlighting several challenges that need to be addressed to prepare for definitive therapeutic trials for patients with this disorder. These challenges relate to i) the diagnostic and screening strategies applied to RBD, ii) the limited evidence base for symptomatic therapies, (iii) the existence of possible subtypes of RBD, (iv) the relevance of triggering medications, (v) the absence of objective markers of severity, (vi) the optimal design of disease-modifying trials, and vii) the implications around disclosing the risk of future neurodegeneration in otherwise healthy individuals. Here, we review the current concepts in the therapeutics of RBD as it relates to the above challenges and identify pertinent research questions to be addressed by future work.

Cognitive Function in Parkinson's Disease Patients with and without Anxiety.

Research on the implications of anxiety in Parkinson's disease (PD) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life. Previous reports have noted that neuropsychiatric symptoms impair cognitive performance in PD patients; however, to date, no study has directly compared PD patients with and without anxiety to examine the impact of anxiety on cognitive impairments in PD. This study compared cognitive performance across 50 PD participants with and without anxiety (17 PDA+; 33 PDA-), who underwent neurological and neuropsychological assessment. Group performance was compared across the following cognitive domains: simple attention/visuomotor processing speed, executive function (e.g., set-shifting), working memory, language, and memory/new verbal learning. Results showed that PDA+ performed significantly worse on the Digit Span forward and backward test and Part B of the Trail Making Task (TMT-B) compared to the PDA- group. There were no group differences in verbal fluency, logical memory, or TMT-A performance. In conclusion, anxiety in PD has a measurable impact on working memory and attentional set-shifting.

Anxiety is associated with freezing of gait and attentional set-shifting in Parkinson's disease: A new perspective for early intervention.

Previous research has shown that anxiety in Parkinson's disease (PD) is associated with freezing of gait (FOG), and may even contribute to the underlying mechanism. However, limited research has investigated whether PD patients with FOG (PD+FOG) have higher anxiety levels when compared directly to non-freezing PD patients (PD-NF) and moreover, how anxiety might contribute to FOG. The current study evaluated whether: (i) PD+FOG have greater anxiety compared to PD-NF, and (ii) anxiety in PD is related to attentional set-shifting, in order to better understand how anxiety might be contributing to FOG. In addition, we explored whether anxiety levels differed between those PD patients with mild FOG (PD+MildFOG) compared to PD-NF. Four hundred and sixty-one patients with PD (231 PD-NF, 180 PD+FOG, 50 PD+MildFOG) were assessed using the Freezing of Gait Questionnaire item 3 (FOG-Q3), Hospital Anxiety and Depression Scale (HADS), Digit Span Test, Logical Memory Retention Test and Trail Making Tests. Compared to PD-NF, PD+FOG had significantly greater anxiety (p<0.001). PD+MildFOG, however, demonstrated similar levels of anxiety as the PD+FOG. In all patients, the severity of anxiety symptoms was significantly correlated to their degree of self-reported FOG on FOG-Q3 (p<0.001) and TMT B-A (p=0.039). Similar results were found for depression. In conclusion, these results confirm the key role played by anxiety in FOG and also suggest that anxiety might be a promising biomarker for FOG. Future research should consider whether treating anxiety with pharmacological and/or cognitive behavioural therapies at early stages of gait impairment in PD may alleviate troublesome FOG.

Virtual reality walking and dopamine: opening new doorways to understanding freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a disabling form of gait disturbance that is common in the advanced stages of Parkinson's disease (PD). Despite its prevalence, methods of studying and assessing FOG are limited. We have previously shown that a virtual reality paradigm was able to distinguish between those who report FOG ("freezers") and those who do not report FOG ("non-freezers"). In this paradigm, 'freezers' were found to have prolonged footstep latency in response to known triggers of FOG including doorways, sliding doors and dual-tasking. In this study, we employed the same paradigm to assess performance of 27 freezers and 14 non-freezers in their clinical 'on' and 'off' medication states. In this study, only participants in the freezing group demonstrated statistically significant increases in latencies experienced in the 'off' state compared to the 'on' state in response to wide and narrow doorways and the opening of a sliding door. By contrast, these behavioral differences were not apparent in non-freezers. Furthermore the delay was specific to environmental cues and was not due to generalized slowing in the 'off' state. The findings suggest that this motor delay when processing environmentally salient cues is specific to freezers and is partially mediated by dopamine-dependent neurocircuitry.

Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.

BACKGROUND: Neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) have been mostly attributed to neurotransmitter imbalances. However, recent findings suggest that gray matter atrophy also contributes to NPS in PD. We contrast PD patients with different levels of NPS, who are well-matched for dopaminergic medication levels and disease stage, to identify the fronto-striatal gray matter atrophy areas associated with NPS in PD. METHODS: Fifty mild, non-demented PD patients were included. We median-split the group via a neuropsychiatric screening tool (Cambridge Behavioural Inventory-Revised), which resulted in higher vs. lower NPS groups (n = 25 in each group). Using T1 brain scans acquired on a 3 Tesla MRI scanner, voxel-based morphometry analysis was applied to characterize the pattern of fronto-striatal gray matter atrophy associated with elevated NPS. RESULTS: We found that the higher NPS group was characterized by greater atrophy in the prefrontal cortex, but not striatal areas. This was further corroborated by a post-hoc analysis cross-correlating the severity of NPS with gray matter loss across the whole PD group, which revealed that atrophy in the orbitofrontal cortex and frontal pole was specifically associated with elevated NPS. CONCLUSIONS: Prefrontal cortex atrophy in PD has an additional effect to dopamine replacement therapy on the generation of NPS in these patients. These findings are an important step towards the delineation of atrophy vs. neurochemical imbalance in PD, and the results emphasize the importance of considering interactions between prefrontal atrophy and neurochemical dysfunction in the genesis of neuropsychiatric symptoms in PD.

Early phenotypic differences between Parkinson's disease patients with and without freezing of gait.

BACKGROUND: Previous studies have associated freezing of gait in Parkinson's disease with the presence of specific phenotypic features such as mood disturbances, REM sleep behavior disorder and selective cognitive impairments. However, it is not clear whether these features are present in the earlier stages of disease or simply represent a more general pattern of progression. To investigate this issue, the current study evaluated motor, cognitive, affective and autonomic features as well as REM sleep behavior disorder in Parkinson's disease patients in the early stages of the condition. METHODS: Thirty-eight freezers and fifty-three non-freezers with disease duration of less than five years and a Hoehn and Yahr stage of less than three were included in this study. The groups were matched on a number of key disease features including age, disease duration, motor severity and dopamine dose equivalence. Furthermore, patients were assessed on measures of motor, cognitive, affective and autonomic features, as well as REM sleep behavior disorder. RESULTS: Compared to non-freezers, patients with freezing of gait had significantly more non-tremor symptoms and a selective impairment on executive functions, such as set-shifting ability and working memory. Freezers and non-freezers did not differ on measures of tremor, autonomic function, REM sleep behavior disorder, mood or more general cognition. CONCLUSION: These results suggest the pathophysiological mechanisms underlying freezing of gait in the early clinical stages of Parkinson's disease are likely to be related to specific changes in the frontostriatal pathways rather than being due to brainstem or more diffuse neuropathology.

Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease.

OBJECTIVE: Using salivary dim light melatonin onset (DLMO) and actigraphy, our study sought to determine if Parkinson disease (PD) patients demonstrate circadian disturbance compared to healthy controls. Additionally, our study investigated if circadian disturbances represent a disease-related process or may be attributed to dopaminergic therapy. METHODS: Twenty-nine patients with PD were divided into unmedicated and medicated groups and were compared to 27 healthy controls. All participants underwent neurologic assessment and 14 days of actigraphy to establish habitual sleep-onset time (HSO). DLMO time and area under the melatonin curve (AUC) were calculated from salivary melatonin sampling. The phase angle of entrainment was calculated by subtracting DLMO from HSO. Overnight polysomnography (PSG) was performed to determine sleep architecture. RESULTS: DLMO and HSO were not different across the groups. However, the phase angle of entrainment was more than twice as long in the medicated PD group compared to the unmedicated PD group (U = 35.5; P = .002) and was more than 50% longer than controls (U = 130.0; P = .021). The medicated PD group showed more than double the melatonin AUC compared to the unmedicated group (U = 31; P = 0.001) and controls (U = 87; P = .001). There was no difference in these measures comparing unmedicated PD and controls. CONCLUSIONS: In PD dopaminergic treatment profoundly increases the secretion of melatonin. Our study reported no difference in circadian phase and HSO between groups. However, PD patients treated with dopaminergic therapy unexpectedly showed a delayed sleep onset relative to DLMO, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation.

Abnormal patterns of theta frequency oscillations during the temporal evolution of freezing of gait in Parkinson's disease.

OBJECTIVE: We sought to characterize the electrophysiological signature of Freezing of gait in Parkinson's disease. METHODS: We examined 24 patients with idiopathic Parkinson's disease and significant freezing of gait as they performed a series of timed up-and-go tasks in their 'off' state while electroencephalographic data was collected from four scalp leads. Fast Fourier Transformation was utilized to explore the power spectral density between periods of normal walking and periods of freezing, as well as during the transition between the two states. In addition, Cross Spectrum and Cross Frequency analyses were used to explore the role of impaired temporal and spatial connectivity. RESULTS: When compared to walking, episodes of freezing were associated with a significant increase in theta band power within the central and frontal leads. The transition from normal walking to freezing of gait was also associated with increased theta frequency coupling between the central and frontal leads, along with an increase in cross-frequency coupling in the central lead. CONCLUSIONS: Episodes of freezing of gait in Parkinson's disease are associated with abnormal oscillatory activity in the brain. SIGNIFICANCE: These results provide novel insights into the pattern of spatiotemporal dynamics underlying freezing of gait and may provide a potential means for therapeutic prediction and alleviation of freezing episodes in susceptible patients.

A novel bedside task to tap inhibitory dysfunction and fronto-striatal atrophy in Parkinson's disease.

BACKGROUND: Given the heterogeneity of mild cognitive deficits in non-demented Parkinson's disease (PD), sensitive and anatomically specific behavioural measures are crucial when evaluating cognition in this patient group. Inhibitory dysfunction is one such deficit increasingly being recognised in non-demented PD; however, few clinical measures exist to detect it and its associated fronto-striatal pathology. METHODS: In 50 non-demented PD patients and 27 controls we employ a novel measure, the Excluded Letter Fluency (ELF) test, to objectively assess inhibitory dysfunction. ELF results were also contrasted with an established inhibitory measure (Hayling Test) and covaried against grey matter atrophy via voxel-based morphometry analysis in a subset of patients. RESULTS: The findings show that patients made significantly more rule-break errors than controls on the ELF and this measure was more sensitive than the Hayling in detecting inhibitory dysfunction, classifying over 76% of patients in logistic regression analysis. Importantly, ELF rule-break errors correlated with grey matter atrophy in known inhibitory-control regions (orbitofrontal cortex, inferior frontal gyrus and ventral striatum). CONCLUSIONS: The ELF is a brief bedside task that efficiently detects inhibitory dysfunction in non-demented PD. The utility of this novel behavioural measure is further substantiated by its anatomical specificity for fronto-striatal inhibitory control regions.

The differential yet concurrent contributions of motor, cognitive and affective disturbance to freezing of gait in Parkinson's disease.

OBJECTIVES: We sought to concurrently examine the specific motor, cognitive and affective contributions to self-reported FOG symptoms. PATIENTS AND METHODS: Ninety-six patients with Parkinson's disease completed the validated freezing of gait questionnaire and had their motor function scored on section three of the Unified Parkinson's Disease Rating Scale questionnaire. A 5-choice reaction time task was administered in order to measure cognitive processing speed and the Beck Depression Inventory was utilised to assess affective disturbance. RESULTS: The results showed that after controlling disease duration and dopaminergic medication dose, the triad of motor disability, cognitive processing speed and affective symptoms were all significant independent predictors of scores on the freezing of gait questionnaire. CONCLUSIONS: These findings suggest the need to consider the interplay between distinct motor, cognitive and affective domains in aetiological studies of freezing and the development of future therapies.

Modeling freezing of gait in Parkinson's disease with a virtual reality paradigm.

Freezing of gait is a paroxysmal and disabling symptom that commonly affects patients in the latter stages of Parkinson's disease, however the intermittent nature of this symptom makes it difficult to study in the clinical setting. Our research group has previously reported a correlation between self-reported freezing of gait symptoms and performance on a seated virtual reality gait task. In this study, we sought to determine whether behavioral measures recorded on this task were correlated with actual clinical measures of freezing of gait recorded in a cohort of 38 Parkinson's disease patients whilst in their clinically defined 'off' state. Firstly, patients with freezing of gait had a significantly larger frequency of spontaneous motor arrests recorded on the virtual reality gait task than 'non-freezers'. In addition, in those 24 patients with clinically proven freezing of gait, the number and percentage of time spent with freezing on the virtual reality task were both moderately correlated with the duration of freezing of gait recorded on the timed up-and-go tasks. These findings suggest that the freezing behavior observed during a virtual reality gait task may share similar neural substrates to freezing of gait. Such a relationship could offer a potential avenue for modeling the phenomenon of freezing of gait in Parkinson's disease, allowing for the exploration of the neural correlates of freezing.

Assessing the utility of Freezing of Gait Questionnaires in Parkinson's Disease.

There are currently two validated questionnaires, the Freezing of Gait Questionnaire and the New Freezing of Gait Questionnaire, that are intended to assess the degree of freezing of gait in patients with Parkinson's disease. However, to date no study has attempted to determine whether ratings on these questionnaires accurately reflect the severity (frequency and duration) of actual freezing episodes experienced by patients. We studied twenty-four patients with Parkinson's disease who self-reported significant freezing while in their practically-defined 'off' state. Prior to clinical assessment they completed both freezing of gait questionnaires before being video-recorded while performing a series of timed up-and-go tasks, which incorporated turning, rotating and passing through narrow gaps. The rating of video recordings by two independent observers identified a total of 530 freezing events. The frequency and duration of freezing episodes for each patient were calculated and correlated with questionnaire ratings. Scores on either questionnaire did not correlate with either the frequency or duration of freezing episodes experienced by patients during objective assessment. These results suggest the need to re-evaluate the utility of questionnaires in the assessment of freezing of gait. Furthermore, these results highlight the need for accurate objective methods of identifying freezing events when assessing future clinical interventions aimed at reducing this potentially disabling symptom of Parkinson's disease.

The pathophysiological mechanisms underlying freezing of gait in Parkinson's Disease.

Freezing of gait is a paroxysmal phenomenon most commonly found in patients with advanced Parkinson's Disease. The pathophysiological mechanisms underlying this behaviour remain uncertain despite a well-characterised phenotype. Freezing behaviour extends beyond gait to affecting speech and upper limb function, suggesting that there is likely to be a universal mechanism underlying the phenomenon. This paper identifies the essential features required for a comprehensive model of freezing and evaluates a number of hypotheses that seek to explain the phenomenon. It appears likely that the pathophysiology of freezing involves context-dependant dysfunction across multiple levels of the neurological system, including cortical, subcortical and brainstem regions.

Parkinson's disease in general practice: assessing knowledge, confidence and the potential role of education.

In the context of an ageing population, Australian general practitioners (GPs) will be asked increasingly to manage challenging neurodegenerative conditions such as Parkinson's disease (PD). This study sought to evaluate whether Australian GPs have been provided with sufficient training to effectively diagnose and manage PD, and to determine the extent to which a brief training seminar could improve knowledge and increase confidence. A baseline assessment was completed by 168 GPs in New South Wales and the Australian Capital Territory, and was re-administered following an educational seminar to 105 GPs. Australian GPs demonstrated significant knowledge gaps on the baseline assessment, scoring only 50% (standard deviation [SD] 15.5%). Post-seminar results showed significant improvement (p<0.001) to 71.5% (SD 15%). Although following the seminar the vast majority reported increased confidence, there were some differential benefits between metropolitan and regional practitioners. These findings emphasise the need for continuing education in relation to PD in primary health care.

Tumour necrosis factor (TNF) inhibitor therapy in Susac's syndrome.

Susac's syndrome is the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss (Susac 1994) [1]. It occurs predominantly in young females and is believed to be an immune-mediated endotheliopathy of small vessels of the brain, retina and cochlea (Neumayer et al. 2009) [2]. Early, aggressive, and sustained immunosuppressive therapy has been recommended for Susac's syndrome and anecdotal evidence has suggested a therapeutic role for monoclonal antibodies (Rennebohm et al. 2008, Lee and Amezcua 2009) [3,4]. We report a case of Susac's syndrome in which the patient improved immediately after tumour necrosis factor (TNF) inhibition with the monoclonal antibody, infliximab.

Saccadic latency distributions in Parkinson's disease and the effects of L-dopa.

Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.

Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals.

RATIONALE: There is converging evidence for impairments in decision-making in chronic substance users. In the light of findings that substance abuse is associated with disruptions of the functioning of the striato-thalamo-orbitofrontal circuits, it has been suggested that decision-making impairments are linked to frontal lobe dysfunction. We sought to investigate this possibility using functional neuroimaging. METHODS: Decision-making was investigated using the Cambridge Risk Task during H2(15)O PET scans. A specific feature of the Risk Task is the decisional conflict between an unlikely high reward option and a likely low reward option. Four groups, each consisting of 15 participants, were compared: chronic amphetamine users, chronic opiate users, ex-drug users who had been long-term amphetamine/opiate users but are abstinent from all drugs of abuse for at least 1 year and healthy matched controls without a drug-taking history. RESULTS: During decision-making, control participants showed relatively greater activation in the right dorsolateral prefrontal cortex, whereas participants engaged in current or previous drug use showed relatively greater activation in the left orbitofrontal cortex. CONCLUSION: Our results indicate a disturbance in the mediation by the prefrontal cortex of a risky decision-making task associated with amphetamine and opiate abuse. Moreover, this disturbance was observed in a group of former drug users who had been abstinent for at least 1 year.