Courtney C. Walton

Cognitive training in Parkinson disease A systematic review and meta-analysis

Objective: To quantify the effects of cognitive training (CT) on cognitive and behavioral outcome measures in patients with Parkinson disease (PD). Methods: We systematically searched 5 databases for randomized controlled trials (RCTs) of CT in patients with PD reporting cognitive or behavioral outcomes. Efficacy was measured as standardized mean difference (Hedges g) of post-training change. Results: Seven studies encompassing 272 patients with Hoehn & Yahr Stages 1–3 were included. The overall effect of CT over and above control conditions was small but statistically significant (7 studies: g = 0.23, 95% confidence interval [CI] 0.014–0.44, p = 0.037). True heterogeneity across studies was low (I2 = 0%) and there was no evidence of publication bias. Larger effect sizes were noted on working memory (4 studies: g = 0.74, CI 0.32–1.17, p = 0.001), processing speed (4 studies: g = 0.31, CI 0.01–0.61, p = 0.04), and executive function (5 studies: g = 0.30, CI 0.01–0.58, p = 0.042), while effects on measures of global cognition (4 studies), memory (5 studies), visuospatial skills (4 studies), and depression (5 studies), as well as attention, quality of life, and instrumental activities of daily living (3 studies each), were not statistically significant. No adverse events were reported. Conclusions: Though still small, the current body of RCT evidence indicates that CT is safe and modestly effective on cognition in patients with mild to moderate PD. Larger RCTs are necessary to examine the utility of CT for secondary prevention of cognitive decline in this population.

The range and nature of non-motor symptoms in drug-naive Parkinson’s disease patients: a state-of-the-art systematic review

Non-motor symptoms (NMS) are a key component of Parkinson’s disease (PD). A range of NMS, most notably impaired sense of smell, sleep dysfunction, and dysautonomia are present from the ‘pre-motor’ phase to the final palliative stage. Theories as to the pathogenesis of PD such as those proposed by Braak and others also support the occurrence of NMS in PD years before motor symptoms start. However, research addressing the range and nature of NMS in PD has been confounded by the fact that many NMS arise as part of drug-related side effects. Thus, drug-naive PD (DNPD) patients provide an ideal population to study the differences in the presentation of NMS. The aim of this paper is therefore to systematically review all the available studies of NMS in DNPD patients. We believe this is the first review of its kind. The current review confirms the increasing research being conducted into NMS in DNPD patients as well as the necessity for further investigation into less-studied NMS, such as pain. Moreover, the data confirms non-motor heterogeneity among PD patients, and, therefore, further research into the concept of non-motor subtyping is encouraged. The review suggests that the clinical assessment of NMS should be integral to any assessment of PD in clinical and research settings.

Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature

Parkinsons disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.

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.

Freezing of gait in Parkinson's disease: current treatments and the potential role for cognitive training.

Freezing of gait (FOG) is a complex motor symptom of Parkinsons disease that manifests as an inability to generate effective gait, leading to a significant falls risk and a severe impact on quality of life. Research into effective treatment options has provided relatively limited benefits and is often hindered by substantial limitations. In this article, current treatment and research options are briefly discussed and a proposal for the further exploration of non-invasive therapeutic approaches is given. Recent advances in the literature continue to identify a pattern of selective executive dysfunction in patients with freezing of gait and such findings highlight a possible common underlying pathophysiology. Therefore, cognitive training is of particular interest as it may be able to improve executive processes thus reducing the manifestation of FOG. This article focuses on the existing evidence for such intervention strategies and proposes that targeted cognitive training may offer a novel treatment option for FOG that is worthy of an increased research focus.

Impaired cognitive control in Parkinson's disease patients with freezing of gait in response to cognitive load.

Freezing of gait is a frequent and disabling symptom experienced by many patients with Parkinson’s disease. A number of executive deficits have been shown to be associated with the phenomenon suggesting a common underlying pathophysiology, which as of yet remains unclear. Neuroimaging studies have also implicated the role of the cognitive control network in patients with freezing. To explore this concept, the current study examined error-monitoring as a measure of cognitive control. Thirty-four patients with and 38 without freezing of gait, who were otherwise well matched on disease severity, completed a colour-word interference task that allowed the specific assessment of error monitoring during conflict. Whilst both groups performed colour-naming and word-reading tasks equally well, those patients with freezing showed a pattern between conditions whereby they were better able to monitor performance and self-correct errors in the pure inhibition task but not after a switching rule was introduced. The novel results shown here provide insight into possible pathophysiological mechanisms involved in cognitive load and error monitoring in patients with freezing of gait. These results provide further evidence for the role of functional frontostriatal circuitry impairments in patients with freezing of gait and have implications for future studies and possible therapeutic interventions.

Stuck in the mud: time for change in the implementation of cognitive training research in ageing?

Over the past two decades, within the field of healthy ageing and dementia prevention there has been a substantial growth of interest in the potential of cognitive training (CT) interventions (see Figure 1). Whilst various studies have employed different methodologies, generally the term refers to programs which provide theoretically driven skills and strategies, involving guided practice on tasks reflecting specific cognitive functions (Mowszowski et al., 2010). The focus of such interventions is to improve functioning of particular cognitive skills such as memory, working memory, attention, and executive functions, as decline in these or other cognitive domains may lead to functional impairment in day-to-day activities as well as contribute to reduced quality of life and disability (Salthouse, 2004). Improvements in these cognitive abilities may lead to more effective or independent functioning and may be instigated through various CT approaches including repetitive computerized exercise, pen and paper tasks, and clinically-driven strategy learning.

Brain activation underlying turning in Parkinson’s disease patients with and without freezing of gait: a virtual reality fMRI study

Background:Freezing of gait is a debilitating symptom affecting many patients with Parkinson’s disease (PD), causing severe immobility and decreased quality of life. Turning is known to be the most common trigger for freezing and also causes the highest rates of falls. However, the pathophysiological basis for these effects is not well understood.Methods:This study used a virtual reality paradigm in combination with functional magnetic resonance imaging to explore the neural correlates underlying turning in 17 PD patients with freezing of gait (FOG) and 10 PD patients without FOG while off their dopaminergic medication. Participants used foot pedals to navigate a virtual environment, which allowed for blood oxygen level-dependent (BOLD) responses and footstep latencies to be compared between periods of straight “walking” and periods of turning through 90°. BOLD data were then analyzed using a mixed effects analysis.Results:Within group similarities revealed that overall, PD patients with freezing relied heavily on cortical control to enable effective stepping with increased visual cortex activation during turning. Between groups differences showed that when turning, patients with freezing preferentially activated inferior frontal regions that have been implicated in the recruitment of a putative stopping network. In addition, freezers failed to activate premotor and superior parietal cortices. Finally, increased task-based functional connectivity was found in subcortical regions associated with gait and stopping within the freezers group during turning.Conclusions:These findings suggest that an increased propensity towards stopping in combination with reduced sensorimotor integration may underlie the neurobiology of freezing of gait during turning.

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.

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

BACKGROUND Previous studies have associated freezing of gait in Parkinsons 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 Parkinsons 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 Parkinsons disease are likely to be related to specific changes in the frontostriatal pathways rather than being due to brainstem or more diffuse neuropathology.