Effect of dopamine on limbic network connectivity at rest in Parkinson's disease patients with freezing of gait.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine "OFF" state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear. Objective: To evaluate how dopamine therapy alters resting state functional connectivity (rsFC) of the fronto-striato-limbic circuitry in PD freezers, and whether the degree of connectivity change is related to freezing severity and anxiety. Methods: Twenty-three PD FOG patients underwent MRI at rest (rsfMRI) in their clinically defined "OFF" and "ON" dopaminergic medication states. A seed-to-seed based analysis was performed between a priori defined limbic circuitry ROIs. Functional connectivity was compared between OFF and ON states. A secondary correlation analyses evaluated the relationship between Hospital Anxiety and Depression Scale (HADS)-Anxiety) and FOG Questionnaire with changes in rsFC from OFF to ON. Results: PD freezers' OFF compared to ON showed increased functional coupling between the right hippocampus and right caudate nucleus, and between the left putamen and left posterior parietal cortex (PPC). A negative association was found between HADS-Anxiety and the rsFC change from OFF to ON between the left amygdala and left prefrontal cortex, and left putamen and left PPC. Conclusion: These findings suggest that dopaminergic medication partially modulates the frontoparietal-limbic-striatal circuitry in PD freezers, and that the influence of medication on the amygdala, may be related to clinical anxiety in freezer.

Emotional states affect steady state walking performance.

Gait is a large component and indicator of health. Many factors affect gait including age, disease, and even mood disorders. Few studies have looked at the influence of emotional states on gait. This study aimed to investigate the influence of emotional states on walking performance to understand whether an emotional state may be an important factor to consider when evaluating gait. Thirty-six young adults were recruited (23F, 13M) and performed a neutral baseline condition of walking which included six passes of walking across an 8m walkway (a total of 48m of walking). Participants then completed 6 pseudo-randomized emotional state induction conditions while immersive 360-degree videos were used to induce the following emotional conditions: happiness, excitement, sadness, fear, and anger. Participants viewed the emotion elicitation videos using a virtual reality head-mounted display (HMD), then rated their emotional state using self-assessment manikins and walked (without the HMD) over a pressure sensor walkway. One-way repeated measures ANOVA and pairwise comparisons were used to examine differences in gait parameters across the emotional conditions. Participants walked with significantly reduced step length and speed during the sadness condition compared to the other emotional conditions and the neutral condition. Furthermore, participants adjusted the timing of their walking during the sadness condition and walked with significantly increased step, stance, and swing times compared to other emotional conditions, but not the neutral condition. Step time was significantly reduced during the conditions of excitement and fear compared to the neutral condition. Emotions may impact variety of gait parameters involving pace and rhythm, however have little influence on gait variability and postural control. These results indicate that perhaps the emotions of sadness and excitement should be taken into account as potential confounds for future gait analysis.

Modulating arousal to overcome gait impairments in Parkinson's disease: how the noradrenergic system may act as a double-edged sword.

In stressful or anxiety-provoking situations, most people with Parkinson's disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal-some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic 'cross-talk' between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Exploring the Sensitivity of Prodromal Dementia with Lewy Bodies Research Criteria.

Dementia with Lewy bodies (DLB) is an insidious neurodegenerative disease characterised by a precipitous decline in cognition, sleep disturbances, motor impairment and psychiatric features. Recently, criteria for prodromal DLB (pDLB) including clinical features and biomarkers have been put forward to aid the classification and research of this ambiguous cohort of patients. Researchers can use these criteria to classify patients with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) as either possible (either one core clinical feature or one biomarker are present) or probable pDLB (at least two core clinical features, or one core clinical feature and at least one biomarker present). However, as isolated REM sleep behaviour disorder (iRBD) confirmed with polysomnography (PSG) can be included as both a clinical and a biomarker feature, potentially reducing the specificity of these diagnostic criteria. To address this issue, the current study classified a cohort of 47 PSG-confirmed iRBD patients as probable prodromal DLB only in the presence of an additional core feature or if there was an additional non-PSG biomarker. Thirteen iRBD patients demonstrated MCI (iRBD-MCI). In the iRBD-MCI group, one presented with parkinsonism and was thus classified as probable pDLB, whilst the remaining 12 were classified as only possible pDLB. All patients performed three tasks designed to measure attentional deficits, visual hallucinations and visuospatial impairment. Patients also attended clinical follow-ups to monitor for transition to DLB or another synucleinopathy. Findings indicated that the only patient categorised by virtue of having two core clinical features as probable pDLB transitioned over 28 months to a diagnosis of DLB. The performance of this probable pDLB patient was also ranked second-highest for their hallucinatory behaviours and had comparatively lower visuospatial accuracy. These findings highlight the need for more stringent diagnostic research criteria for pDLB, given that only one of the 13 patients who would have satisfied the current guidelines for probable pDLB transitioned to DLB after two years and was indeed the patient with two orthogonal core clinical features.

The Ziegler Test Is Reliable and Valid for Measuring Freezing of Gait in People With Parkinson Disease.

OBJECTIVE: The purpose of this study was to determine interrater and test-retest reliability of the Ziegler test to measure freezing of gait (FOG) severity in people with Parkinson disease. Secondary aims were to evaluate test validity and explore Ziegler test duration as a proxy FOG severity measure. METHODS: Physical therapists watched 36 videos of people with Parkinson disease and FOG perform the Ziegler test and rated FOG severity using the rating scale in real time. Two researchers rated 12 additional videos and repeated the ratings at least 1 week later. Interrater and test-retest reliability were calculated using intraclass correlation coefficients (ICCs). Bland-Altman plots were used to visualize agreement between the researchers for test-retest reliability. Correlations between the Ziegler scores, Ziegler test duration, and percentage of time frozen (based on video annotations) were determined using Pearson r. RESULTS: Twenty-four physical therapists participated. Overall, the Ziegler test showed good interrater (ICC2,1 = 0.80; 95% CI = 0.65-0.92) and excellent test-retest (ICC3,1 = 0.91; 95% CI = 0.82-0.96) reliability when used to measure FOG. It was also a valid measure, with a high correlation (r = 0.72) between the scores and percentage of time frozen. Ziegler test duration was moderately correlated (r = 0.67) with percentage of time frozen and may be considered a proxy FOG severity measure. CONCLUSION: The Ziegler test is a reliable and valid tool to measure FOG when used by physical therapists in real time. Ziegler test duration may be used as a proxy for measuring FOG severity. IMPACT: Despite FOG being a significant contributor to falls and poor mobility in people with Parkinson disease, current tools to assess FOG are either not suitably responsive or too resource intensive for use in clinical settings. The Ziegler test is a reliable and valid measure of FOG, suitable for clinical use, and may be used by physical therapists regardless of their level of clinical experience.

An Adaptive Measure of Visuospatial Impairment in Dementia with Lewy Bodies.

Background: Dementia with Lewy bodies (DLB) is a common cause of dementia with poor prognosis and high hospitalization rates. DLB is frequently misdiagnosed, with clinical features that overlap significantly with other diseases including Parkinson's disease (PD). Clinical instruments that discriminate and track the progression of cognitive impairment in DLB are needed. Objectives: The current study was designed to assess the utility of a mental rotation (MR) task for assessing visuospatial impairments in early DLB. Methods: Accuracy of 22 DLB patients, 22 PD patients and 22 age-matched healthy controls in the MR task were compared at comparing shapes with 0°, 45° and 90° rotations. Results: Healthy controls and PD patients performed at similar levels while the DLB group were significantly impaired. Further, impairment in the visuospatial and executive function measures correlated with MR poor outcomes. Conclusion: These findings support the MR task as an objective measure of visuospatial impairment with the ability to adjust difficulty to suit impairments in a DLB population. This would be a useful tool within clinical trials.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

The influence of visual feedback on alleviating freezing of gait in Parkinson's disease is reduced by anxiety.

BACKGROUND: Previous research has established that anxiety is associated with freezing of gait (FOG) in Parkinson's disease (PD). Although providing body-related visual feedback has been previously suggested to improve FOG, it remains unclear whether anxiety-induced FOG might be improved. RESEARCH QUESTION: The current study aimed to evaluate whether body-related visual feedback (VF) improves FOG consistently across low and high threat conditions. METHODS: Sixteen PD patients with FOG were instructed to walk across a plank in a virtual environment that was either located on the ground (low threat) or elevated above a deep pit (high threat). Additionally, visual feedback (VF) was either provided (+) or omitted (-) using an avatar that was synchronised in real-time with the participants movements. RESULTS: revealed that in the low threat condition (i.e., ground), %FOG was significantly reduced when VF was provided (VF+) compared to when VF was absent (VF-). In contrast, during the elevated high threat condition, there were no differences in %FOG regardless of whether VF was provided or not. SIGNIFICANCE: These findings confirm that although VF can aid in the reduction of FOG, anxiety may interfere with freezers' ability to use sensory feedback to improve FOG and hence, in high threat conditions, VF was unable to aid in the reduction of FOG. Future studies should direct efforts towards the treatment of anxiety to determine whether better management of anxiety may improve FOG.

The Contribution of Noradrenergic Activity to Anxiety-Induced Freezing of Gait.

BACKGROUND: Freezing of gait is a complex paroxysmal phenomenon that is associated with a variety of sensorimotor, cognitive and affective deficits, and significantly impacts quality of life in patients with Parkinson's disease (PD). Despite a growing body of evidence that suggests anxiety may be a crucial contributor to freezing of gait, no research study to date has investigated neural underpinnings of anxiety-induced freezing of gait. OBJECTIVE: Here, we aimed to investigate how anxiety-inducing contexts might "set the stage for freezing," through the ascending arousal system, by examining an anxiety-inducing virtual reality gait paradigm inside functional magnetic resonance imaging (fMRI). METHODS: We used a virtual reality gait paradigm that has been validated to elicit anxiety by having participants navigate a virtual plank, while simultaneously collecting task-based fMRI from individuals with idiopathic PD with confirmed freezing of gait. RESULTS: First, we established that the threatening condition provoked more freezing when compared to the non-threatening condition. By using a dynamic connectivity analysis, we identified patterns of increased "cross-talk" within and between motor, limbic, and cognitive networks in the threatening conditions. We established that the threatening condition was associated with heightened network integration. We confirmed the sympathetic nature of this phenomenon by demonstrating an increase in pupil dilation during the anxiety-inducing condition of the virtual reality gait paradigm in a secondary experiment. CONCLUSIONS: In conclusion, our findings represent a neurobiological mechanistic pathway through which heightened sympathetic arousal related to anxiety could foster increased "cross-talk" between distributed cortical networks that ultimately manifest as paroxysmal episodes of freezing of gait. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Narrow doorways alter brain connectivity and step patterns in isolated REM sleep behaviour disorder.

BACKGROUND: Motor impairments in those with isolated REM sleep behaviour disorder (iRBD) significantly increases the likelihood of developing Lewy body disease (e.g. Parkinson's disease and Dementia with Lewy Bodies). OBJECTIVE: This study sought to explore the prodromal process of neurodegeneration by examining the neural signature underlying motor deficits in iRBD patients. METHODS: A virtual reality (VR) gait paradigm (which has previously been shown to elicit adaptive changes in gait performance whilst navigating doorways in Parkinson's Disease - PD) was paired with fMRI to investigate whether iRBD patients demonstrated worsened motor performance and altered connectivity across frontoparietal, motor and basal ganglia networks compared to healthy controls. Forty participants (23 iRBD and 17 healthy controls) completed the virtual reality gait task whilst in the MRI scanner, and an additional cohort of 19 Early PD patients completed the behavioural virtual reality gait task. RESULTS: As predicted, iRBD patients demonstrated slower and more variable stepping compared to healthy control participants and demonstrated an exaggerated response when navigating narrow compared to wide doorways, a phenomenon characteristically seen in PD. The iRBD patients also demonstrated less BOLD signal change in the left posterior putamen and right mesencephalic locomotor region, as well as reduced functional connectivity between the frontoparietal network and the motor network, when navigating narrow versus wide doorways compared to healthy control participants. CONCLUSIONS: Taken together, this study demonstrates that iRBD patients have altered task-related brain connectivity, which may represent the neural underpinnings of early motor impairments that are evident in iRBD.

Dynamic network impairments underlie cognitive fluctuations in Lewy body dementia.

Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson's disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB (n = 25) and age-matched controls (n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.

A Video Self-Modeling Intervention Using Virtual Reality Plus Physical Practice for Freezing of Gait in Parkinson Disease: Feasibility and Acceptability Study.

BACKGROUND: Despite optimal medical and surgical intervention, freezing of gait commonly occurs in people with Parkinson disease. Action observation via video self-modeling, combined with physical practice, has potential as a noninvasive intervention to reduce freezing of gait. OBJECTIVE: The aim of this study is to determine the feasibility and acceptability of a home-based, personalized video self-modeling intervention delivered via a virtual reality head-mounted display (HMD) to reduce freezing of gait in people with Parkinson disease. The secondary aim is to investigate the potential effect of this intervention on freezing of gait, mobility, and anxiety. METHODS: The study was a single-group pre-post mixed methods pilot trial for which 10 participants with Parkinson disease and freezing of gait were recruited. A physiotherapist assessed the participants in their homes to identify person-specific triggers of freezing and developed individualized movement strategies to overcome freezing of gait. 180° videos of the participants successfully performing their movement strategies were created. Participants watched their videos using a virtual reality HMD, followed by physical practice of their strategies in their own homes over a 6-week intervention period. The primary outcome measures included the feasibility and acceptability of the intervention. Secondary outcome measures included freezing of gait physical tests and questionnaires, including the Timed Up and Go Test, 10-meter walk test, Goal Attainment Scale, and Parkinson Anxiety Scale. RESULTS: The recruitment rate was 24% (10/42), and the retention rate was 90% (9/10). Adherence to the intervention was high, with participants completing a mean of 84% (SD 49%) for the prescribed video viewing and a mean of 100% (SD 56%) for the prescribed physical practice. One participant used the virtual reality HMD for 1 week and completed the rest of the intervention using a flat-screen device because of a gradual worsening of his motion sickness. No other adverse events occurred during the intervention or assessment. Most of the participants found using the HMD to view their videos interesting and enjoyable and would choose to use this intervention to manage their freezing of gait in the future. Five themes were constructed from the interview data: reflections when seeing myself, my experience of using the virtual reality system, the role of the virtual reality system in supporting my learning, developing a deeper understanding of how to manage my freezing of gait, and the impact of the intervention on my daily activities. Overall, there were minimal changes to the freezing of gait, mobility, or anxiety measures from baseline to postintervention, although there was substantial variability between participants. The intervention showed potential in reducing anxiety in participants with high levels of anxiety. CONCLUSIONS: Video self-modeling using an immersive virtual reality HMD plus physical practice of personalized movement strategies is a feasible and acceptable method of addressing freezing of gait in people with Parkinson disease.

Measuring anxiety in Lewy Body Disease - Which scale to choose?

BACKGROUND: Anxiety is among the most prevalent mood disorders in Lewy Body Disease (LBD) (i.e., Parkinson's disease (PD), Dementia with Lewy bodies DLB), and those at-risk for developing LBD (e.g. isolated REM Sleep Behaviour Disorder (iRBD)). Yet, there is little consensus on which clinical scale best evaluates anxiety across synuclein-based diseases. OBJECTIVE: This study compared the convergent validity of commonly used anxiety scales across PD, DLB and iRBD patients. METHODS: Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS-A), State-Trait Anxiety Inventory (STAI), MDS-UPDRS Anxiety item, and the Parkinson Anxiety Scale (PAS) in 57 participants (17 PD, 16 DLB, and 23 iRBD). RESULTS: Across all groups, PAS total score was significantly associated with trait anxiety (STAI-Y2), whilst HADS-A was associated with PAS total score in the PD and iRBD group. In DLB patients, HADS-A was weakly associated with PAS total score, and significantly correlated with PAS episodic anxiety. Notably, the anxiety item from the MDS-UPDRS did not correlate with any of the other anxiety outcome measures in any group. CONCLUSIONS: PAS and STAI-Y2 are the most suitable scales to assess anxiety in synuclein-based diseases. HADS-A showed strong convergent validity in PD and iRBD, it had weaker convergent validity in DLB. The UPDRS anxiety item did not correlate with any of the other anxiety measures, and thus may not be sensitive at detecting anxiety symptoms. Future work should validate anxiety scales in all Lewy Body Disease groups if they are to be implemented in prospective longitudinal cohorts.

Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

Validating a Seated Virtual Reality Threat Paradigm for Inducing Anxiety and Freezing of Gait in Parkinson's Disease.

BACKGROUND: Although prior research has established that freezing of gait (FOG) in Parkinson's disease (PD) is associated with anxiety, only one study to date has directly manipulated anxiety levels to induce FOG. OBJECTIVE: The current study aimed to replicate these previous findings and evaluate whether a seated version of a 'threat' virtual reality (VR) paradigm could induce anxiety and provoke FOG. METHODS: Twenty-four PD patients with FOG were assessed across various threat conditions in both a walking VR paradigm (Experiment 1) and a seated VR paradigm (Experiment 2). Both paradigms manipulated the height (i.e., elevated vs ground) and width (wide vs narrow) of the planks participants were instructed to walk across. RESULTS: Across both experiments, the Elevated + Narrow condition provoked significantly greater number of freezing episodes compared to all other conditions. Higher levels of self-reported anxiety were reported during the Elevated+Narrow condition compared to all other conditions in Experiment 1, and compared to the Ground condition in Experiment 2. CONCLUSION: These findings confirm that anxiety contributes to FOG and validates the use of a seated VR threat paradigm for provoking anxiety-related freezing. This enables future studies to combine this paradigm with functional MRI to explore the neural correlates underlying the role of anxiety in FOG.

Prevalence and predictors of mood disturbances in idiopathic REM sleep behaviour disorder.

Depression and anxiety are commonly associated with synucleinopathies. Mood disturbances have also been reported in patients with idiopathic REM sleep behaviour disorder (iRBD) and are difficult to treat due to exacerbation of sleep symptoms with standard antidepressants. Despite this, detailed prevalence studies of mood symptomatology and contributors to mood disturbances in iRBD are limited. Mood, sleep, autonomic, cognitive and motor symptoms were assessed in 49 well-characterized patients with iRBD using a variety of clinical scales. Spearman correlations, factor analysis and multiple linear regression were used to uncover associations between mood and non-motor and motor symptoms. The prevalence of significant depression was 17.0% and that of anxiety was 14.6% in the iRBD cohort. Age and disease duration were not correlated with these affective symptoms in iRBD patients. We found depression was significantly predicted by the presence and severity of motor, sleep and cognitive symptoms. Anxiety was predicted by the severity of nocturnal and daytime sleep-related symptoms, cognitive symptoms and autonomic symptoms, with a differential effect depending on the questionnaire used. Depression and anxiety are common in iRBD patients and can be significantly explained by specific sets of non-motor and motor symptoms. These associations provide insight into the underlying pathophysiology and emphasize the importance of a holistic approach to mood disturbance in this population, which may circumvent the reliance on pharmacotherapy that can exacerbate dream enactment behaviour.

Evaluating a novel behavioral paradigm for visual hallucinations in Dementia with Lewy bodies.

The aim of this study was to evaluate the utility of the Bistable Percept Paradigm (BPP), a computerised behavioural task that has previously been utilised for the assessment of visual hallucinations in Parkinson's Disease, in a Dementia with Lewy bodies (DLB) cohort. Dementia with Lewy bodies patients demonstrated poorer performance than healthy controls (HC) on the BPP with significantly more misperceptions and a greater failure to detect bistable percepts correctly compared to HC. Further, the number of misperceptions was also correlated with the severity of hallucinations. The findings from this study demonstrate that the BPP is a viable tool to measure misperceptions in DLB patients.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Heart Rate Changes Prior to Freezing of Gait Episodes Are Related to Anxiety.

BACKGROUND: Freezing of gait (FOG) in Parkinson's disease (PD) has been shown to be more frequent in stressful situations, implicating anxiety. Heart rate (HR) has been shown to increase prior to a FOG episode supporting the notion that elevated stress levels may trigger FOG. However, no studies to date have investigated whether elevated HR precedes all subtypes of FOG or only those episodes that are driven by anxiety. OBJECTIVE: The present study sought to investigate whether 1) HR increases prior to FOG episodes in nonspecific environments (Experiment 1), and if 2) HR increases prior to FOG when provoked in high but not low threat environments using a virtual reality paradigm (Experiment 2). METHODS: In Experiment 1, 10 of 19 participants with PD and FOG (PD + FOG) experienced FOG during a series of walking trials. In Experiment 2, 12 of 23 participants with PD + FOG experienced FOG while walking across an elevated and ground level narrow plank in virtual reality. HR was collected throughout the duration of both experiments, while FOG was quantified by experts using video review and tagging. RESULTS: HR significantly increased 2-3 seconds prior to a FOG episode during Experiment 1. In Experiment 2, HR significantly increased 4-6 seconds prior to a FOG episode, specifically while navigating the elevated plank. However, there were no significant increases in HR prior to FOG episodes when participants navigated the ground plank. CONCLUSION: This study extends previous work further demonstrating that increases in HR prior to FOG episodes appear linked to elevated anxiety levels.