Abnormal higher-order network interactions in Parkinson's disease visual hallucinations.

Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby dysfunctional communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between-functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques-diffusion-map embedding and t-distributed stochastic neighbour embedding (t-SNE)-to resting state functional MRI data, in order to characterize the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy control subjects. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions, suggesting an additional layer of complexity in the functional brain network abnormalities implicated in hallucinations, which was not apparent in traditional functional connectivity analyses. Together, the results confirm abnormal brain organization associated with the hallucinating phenotype in Parkinson's disease and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.

A multicentre study on grey matter morphometric biomarkers for classifying early schizophrenia and parkinson's disease psychosis.

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson's disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Dementia in long-term Parkinson's disease patients: a multicentre retrospective study.

While several studies have investigated the clinical progression of cognitive decline in Parkinson's disease (PD) patients, there has been a paucity of data on specifically evaluating PD patients with a disease duration of over 20 years. This study retrospectively investigated the frequency of dementia in PD (PDD) patients with a disease duration of over 20 years assessed in research clinics across the UK and Australia. Data from 2327 PD patients meeting the United Kingdom Parkinson's Disease Society Brain Bank Criteria was pooled. A diagnosis of probable PDD was made according to the Movement Disorder Society Level 1 criteria. Thirty-six participants had a disease duration of at least 20 years. Of the 36 patients, only 7 (19%) were classified as probable PDD. Compared to PD patients without dementia, those with dementia had lower levels of educational attainment and exhibited more severe motor features. Additionally, 34 out of the 36 patients (94%) exhibited a non-tremor dominant phenotype. No significant differences in age, age onset, disease duration, dopaminergic medication use, and sex distribution were observed between PD patients with and without dementia. Findings from the present study suggest that the prevalence of dementia in long-term PD patients may be lower than anticipated and suggest that the trajectory of cognitive decline in PD patients can be different. These findings highlight the need to investigate factors that might affect the outcome of cognitive decline in long-term PD patients, which may lead to the determination of potential modulating factors in the development of dementia in these patients.

Subtle gait and balance impairments occur in idiopathic rapid eye movement sleep behavior disorder.

BACKGROUND: Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. METHODS: A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. RESULTS: Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. CONCLUSIONS: This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.

Evidence for subtypes of freezing of gait in Parkinson's disease.

BACKGROUND: The purpose of this study is to identify and characterize subtypes of freezing of gait by using a novel questionnaire designed to delineate freezing patterns based on self-reported and behavioral gait assessment. METHODS: A total of 41 Parkinson's patients with freezing completed the Characterizing Freezing of Gait questionnaire that identifies situations that exacerbate freezing. This instrument underwent examination for construct validity and internal consistency, after which a data-driven clustering approach was employed to identify distinct patterns amongst individual responses. Behavioral freezing assessments in both dopaminergic states were compared across 3 identified subgroups. RESULTS: This novel questionnaire demonstrated construct validity (severity scores correlated with percentage of time frozen; r = 0.54) and internal consistency (Cronbach's α = .937), and thus demonstrated promising utility for identifying patterns of freezing that are independently related to motor, anxiety, and attentional impairments. CONCLUSIONS: Patients with freezing may be dissociable based on underlying neurobiological underpinnings that would have significant implications for targeting future treatments. © 2018 International Parkinson and Movement Disorder Society.

Cognitive training for freezing of gait in Parkinson's disease: a randomized controlled trial.

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson's disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required.

Alterations in white matter network topology contribute to freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a common symptom in advanced Parkinson's disease (PD). Despite current advances, the neural mechanisms underpinning this disturbance remain poorly understood. To this end, we investigated the structural organisation of the white matter connectome in PD freezers and PD non-freezers. We hypothesized that freezers would show an altered network architecture, which could hinder the effective information processing that characterizes the disorder. Twenty-six freezers and twenty-four well-matched non-freezers were included in this study. Using diffusion tensor imaging, we investigated the modularity and integration of the regional connectome by calculating the module degree z score and the participation coefficient, respectively. Compared to non-freezers, freezers demonstrated lower participation coefficients in the right caudate, thalamus, and hippocampus, as well as within superior frontal and parietal cortical regions. Importantly, several of these nodes were found within the brain's 'rich club'. Furthermore, group differences in module degree z scores within cortical frontal and sensory processing areas were found. Together, our results suggest that changes in the structural network topology contribute to the manifestation of FOG in PD, specifically due to a lack of structural integration between key information processing hubs of the brain.

Exploring the Phenotype in Mild Cognitive Impairment to Aid the Prediction of Those at Risk of Transitioning to Parkinson Disease and Dementia With Lewy Bodies.

To date, only limited research has concurrently investigated the presence of rapid eye movement sleep behavior disorder (RBD) and other features associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB) in people presenting with mild cognitive impairment (MCI). As a first step towards a longitudinal research project, the present study explored the relationships between MCI, RBD, and depression in 108 older adults who presented with subjective memory complaints but were not known to have a neurodegenerative condition. The present study found that RBD was a frequent feature in individuals with MCI (35%). Furthermore, MCI patients with RBD were more likely to exhibit nonamnestic MCI (89%) rather than an amnestic MCI phenotype (χ2 = 4.99, P = .025). Specifically, nonamnestic MCI patients with RBD had selective deficits in executive function and verbal memory, as well as a higher level of depressive symptoms. This cognitive and psychiatric profile is aligned with PD and DLB patients at their time of initial diagnosis and suggests that targeting nonamnestic MCI patients who report RBD with additional biomarker testing including smell, color vision, and neuroimaging (eg, dopamine transporters scan and transcranial ultrasonography) may aid in early diagnosis and prediction of these α-synucleinopathies.

Mild Cognitive Impairment in Parkinson's Disease: Impact on Caregiver Outcomes.

BACKGROUND: Recent attempts to standardise the definition of Mild Cognitive Impairment (MCI) in Parkinson's disease (PD) by the Movement Disorder Society Task Force has led to a greater understanding of this entity but to date, there has been a paucity of research regarding the impact of PD-MCI on caregiver outcomes. OBJECTIVE: The aim of this study was to utilise the newly established PD-MCI diagnostic criteria to investigate caregiver outcomes in relation to four specific aspects: (1) caregiver burden, (2) quality of life (QoL), (3) caregiving experience, and (4) psychological distress. METHODS: This study included a total of 166 patient-caregiver dyads. Caregiver outcomes including quality of life, caregiver burden, mood disturbances, and caregiver experience were compared between caregivers of PD patients classified as having normal cognition (PD-NC) and PD-MCI. RESULTS: Despite the two groups being matched on demographic and clinical features, caregivers of PD-MCI patients reported a lower level of QoL with regard to physical health and more interruptions with usual activities. On the other hand, a higher impact on finances was reported in caregivers of PD-NC patients, relative to caregivers of PD-MCI patients. CONCLUSIONS: This study has shown that even at earlier stages of cognitive impairment, PD-MCI caregivers already experience elevated levels of distress in the role of providing care to their care-recipients. These findings highlight the need to include management of caregiver distress and associated sequelae alongside the management of PD-MCI patients, early on in the disease course.

Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders encountered in clinical practice. Whilst dementia has long been synonymous with AD, it is becoming more widely accepted as part of the clinical spectrum in PD (PDD). Neuropsychiatric complications, including psychosis, mood and anxiety disorders, and sleep disorders also frequently co-exist with cognitive dysfunctions in AD and PDD patients. The incidence of such symptoms is often a significant source of disability, and may aggravate pre-existing cognitive deficits. Management of AD and PDD involves both pharmacological and non-pharmacological measures. Although research on pharmacological therapies for AD and PDD has so far had some success in terms of developing symptomatic treatments, the benefits are often marginal and non-sustained. These shortcomings have led to the investigation of non-pharmacological and novel treatments for both AD and PD. Furthermore, in light of the diverse constellation of other neuropsychiatric, physical, and behavioural symptoms that often occur in AD and PD, consideration needs to be given to the potential side effects of pharmacological treatments where improving one symptom may lead to the worsening of another, rendering the clinical management of these patients challenging. Therefore, the present article will critically review the evidence for both pharmacological and non-pharmacological treatments for cognitive impairment in AD and PD patients. Treatment options for other concomitant neuropsychiatric and behavioural symptoms, as well as novel treatment strategies will also be discussed.

The relationships between mild cognitive impairment and phenotype in Parkinson's disease.

BACKGROUND: The concept of differing clinical phenotypes within Parkinson's disease (PD) is well represented in the literature. However, there is no consensus as to whether any particular disease phenotype is associated with an increased risk of mild cognitive impairment (MCI) using the newly proposed Movement Disorders Society diagnostic criteria for this feature. AIMS: To explore the expression of PD-MCI in relation to the heterogeneity of idiopathic PD. METHODS: A cluster analysis incorporating a range of specific demographic, clinical and cognitive variables was performed on 209 patients in the early stages of PD (between Hoehn and Yahr stages I-III). Post hoc analyses exploring variables not included in the clustering solution were performed to interrogate the veracity of the subgroups generated. RESULTS: This study identified four distinct PD cohorts: a younger disease-onset subgroup, a tremor dominant subgroup, a non-tremor dominant subgroup, and a subgroup with rapid disease progression. The present study identified a differential expression of PD-MCI across these subgroups, with the highest frequency observed in the non-tremor dominant cluster. The non-tremor dominant subgroup was also associated with a higher prevalence of freezing of gait, hallucinations, daytime somnolence, and rapid eye movement sleep behavior disorder compared with other subgroups. CONCLUSIONS: This study confirms the existence of heterogeneity within the early clinical stages of PD and for the first time highlights the differential expression of PD-MCI using the newly defined diagnostic criteria for this feature. An improved understanding of PD-MCI and its clinical relationships may lead to an improved understanding of the pathophysiology underlying heterogeneity in PD.

Assessing the utility of the Movement Disorder Society Task Force Level 1 diagnostic criteria for mild cognitive impairment in Parkinson's disease.

BACKGROUND: Using the Movement Disorder Society (MDS) Task Force Level 1 criteria, this study examined the classification of mild cognitive impairment in Parkinson's Disease (PD-MCI) derived from a range of cut-off scores that have previously been suggested by the MDS Task Force. Furthermore, differences in PD-MCI frequencies were examined when comparing performance on current neuropsychological testing to the normative sample, as opposed to decline from premorbid functioning, as evidence of cognitive impairment. METHOD: Two hundred and thirty-four non-demented PD patients underwent neurological and neuropsychological assessment at the Parkinson's Disease Research Clinic at the Brain and Mind Research Institute, University of Sydney. RESULTS: When cognitive impairment was defined as 1SD and 1.5SD below premorbid intellect, 109 patients (47%) and 76 (32%) patients met criteria for PD-MCI respectively. This proportion dropped considerably to 50 patients (21%) with a 2SD cut-off score. However, when calculating impairment based on comparisons with normative data, only 68 patients (29%) and 41 patients (18%) met PD-MCI criteria when a cut-off score of 1 and 1.5SD was employed. This proportion dropped to just 22 patients (9%) with a 2SD cut-off score. CONCLUSION: Results from the present study suggest that the MDS PD-MCI criteria may be too broad, as substantial differences in frequencies of PD-MCI were observed with the application of differing criteria. We propose that a 1.5SD cut-off score below premorbid functioning may provide greater utility in characterizing PD-MCI than a 1.5SD cut-off below normative data, which has been widely applied in previous studies examining the MDS PD-MCI criteria.

The major impact of freezing of gait on quality of life in Parkinson's disease.

Freezing of gait (FOG) is a disabling motor symptom experienced by a large proportion of patients with Parkinson's disease (PD). While it is known that FOG contributes to lower health-related quality of life (HRQoL), previous studies have not accounted for other important factors when measuring the specific impact of this symptom. The aim of this study was to examine FOG and HRQoL while controlling for other factors that are known to impact patient well-being, including cognition, motor severity, sleep disturbance and mood. Two hundred and three patients with idiopathic PD (86 with FOG) were included in the study. All patients were between Hoehn and Yahr stages I-III. A forced entry multiple regression model evaluating the relative contribution of all symptoms was conducted, controlling for time since diagnosis and current dopaminergic treatment. Entering all significantly correlated variables into the regression model accounted for the majority of variance exploring HRQoL. Self-reported sleep-wake disturbances, depressive and anxious symptoms and FOG were individually significant predictors. FOG accounted for the highest amount of unique variance. While sleep-wake disturbance and mood have a significant negative impact on HRQoL in PD, the emergence of FOG represents the most substantial predictor among patients in the earlier clinical stages of disease. This finding presumably reflects the disabling loss of independence and fear of injury associated with FOG and underlines the importance of efforts to reduce this common symptom.