Jennifer Y. Y. Szeto

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.

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

Alzheimers disease (AD) and Parkinsons 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.

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 Parkinsons 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 Parkinsons 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 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.

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

BACKGROUND Recent attempts to standardise the definition of Mild Cognitive Impairment (MCI) in Parkinsons 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.

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.

Cognitive Function in Parkinson’s Disease Patients with and without Anxiety

Research on the implications of anxiety in Parkinsons 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.

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.Freezing of gait: a non-pharmacological approachCognitive training can reduce the severity of gait freezing in Parkinson’s disease (PD) patients on dopaminergic medication. The inability to move forwards despite the intention to walk is one of the most debilitating symptoms in patients with PD and has been linked to cognitive dysfunction. Simon Lewis at the University of Sydney, Australia, and colleagues examined the effects of cognitive training in patients with self-reported freezing of gait and without dementia. Patients receiving cognitive therapy twice a week for seven weeks showed a significant reduction in gait freezing compared to the control group. Interestingly, the effect was observed when patients had maximum benefit from their PD medication (on-state) but not in the off-state. Cognitive training also improved patients’ processing speed and reduced their daytime sleepiness highlighting the usefulness of non-pharmacological interventions in the treatment of PD.

Evidence for subtypes of freezing of gait in Parkinson's disease: Investigating Subtypes Of Freezing

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.

A double-blind randomized controlled trial of cognitive training for freezing of gait in Parkinson's disease

This free journal suppl. entitled: Supplement: Abstracts of the Twentieth International Congress of Parkinsons Disease and Movement DisordersObjective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype. (Less)Objective: The aim of this study is to develop and evaluate methods for quantifying motor symptoms in Parkinson’s disease (PD) using combined upper limb motor test data collected during tapping and ...20th International Congress of Parkinson’s disease and Movement Disorders, Berlin, Germany, 19-23 June, 2016Upper limb motor tests are related to clinical ratings of motor function in advanced Parkinsons disease