Structural and metabolic correlates of neuropsychological profiles in multiple system atrophy and Parkinson's disease.

BACKGROUND: Despite increased recognition of cognitive impairment in Multiple System Atrophy (MSA), its neuroanatomical correlates are not well defined. We aimed to explore cognitive profiles in MSA with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) and their relationship to frontostriatal structural and metabolic changes. METHODS: Detailed clinical and neuropsychological evaluation was performed together with diffusion tensor imaging (DTI) and [18F]-fluoro-deoxyglucose positron emission tomography ([18F]-FDG-PET) in patients with MSA-P (n = 11) and PD (n = 11). We compared clinical and neuropsychological data to healthy controls (n = 9) and correlated neuropsychological data with imaging findings in MSA-P and PD. RESULTS: Patients with MSA-P showed deficits in executive function (Trail Making Test B-A) and scored higher in measures of depression and anxiety compared to those with PD and healthy controls. Widespread frontostriatal white matter tract reduction in fractional anisotropy was seen in MSA-P and PD compared to an imaging control group. Stroop Test interference performance correlated with [18F]-FDG uptake in the bilateral dorsolateral prefrontal cortex (DLPFC) and with white matter integrity between the striatum and left inferior frontal gyrus (IFG) in PD. Trail Making Test performance correlated with corticostriatal white matter integrity along tracts from the bilateral IFG in MSA-P and from the right DLPFC in both groups. CONCLUSION: Executive dysfunction was more prominent in patients with MSA-P compared to PD. DLPFC metabolism and frontostriatal white matter integrity seem to be a driver of executive function in PD, whereas alterations in corticostriatal white matter integrity may contribute more to executive dysfunction in MSA-P.

A brief psychometric and clinimetric evaluation of self-report burden and mental health measures completed by care partners of people with Parkinson's-related dementia.

This report describes the evaluation of the psychometric and clinimetric properties of nine self-report measures completed by informal care partners of individuals with mild cognitive impairment or dementia in Parkinson's disease and dementia with Lewy bodies. One hundred thirty-six care partners completed measures on relationship satisfaction, burden, stress, mood, resilience, health, quality of life, and feelings related to care provision. Psychometric properties, such as internal consistency, convergent validity, floor and ceiling effects, completion rate and data missingness, as well as clinimetric properties, such as time to administer, ease of scoring, readability and availability of the scales, were examined. Additionally, the design of the measure development studies was assessed with the 2018 COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) Risk of Bias checklist. Participants were mostly married women (>85%) with a mean age of 69.4 years. The methodological quality of the design of all measure development studies was "inadequate." Five widely applied measures (Zarit Burden Interview, Hospital Anxiety and Depression Scale, Short Form 12 Health Survey, Relatives' Stress Scale, and EuroQoL-5D) and two less researched instruments (Brief Resilience Scale and Relationship Satisfaction Scale) had high internal consistency and completion rates, moderate to strong convergent validity, low missingness and floor effects, and excellent clinical utility ratings. Two scales (Dyadic Relationship Scale and Family Caregiving Role) received poor psychometric ratings, and their usage among informal care partners is not recommended. In conclusion, well-validated and widely used measures received strong psychometric and clinimetric ratings. Future studies are required to determine the most reliable, valid and robust caregiver-reported measures.

Cognitive training interventions for dementia and mild cognitive impairment in Parkinson's disease.

BACKGROUND: Approximately 60% to 80% of people with Parkinson's disease (PD) experience cognitive impairment that impacts on their quality of life. Cognitive decline is a core feature of the disease and can often present before the onset of motor symptoms. Cognitive training may be a useful non-pharmacological intervention that could help to maintain or improve cognition and quality of life for people with PD dementia (PDD) or PD-related mild cognitive impairment (PD-MCI). OBJECTIVES: To determine whether cognitive training (targeting single or multiple domains) improves cognition in people with PDD and PD-MCI or other clearly defined forms of cognitive impairment in people with PD. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group Trials Register (8 August 2019), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and PsycINFO. We searched reference lists and trial registers, searched relevant reviews in the area and conference proceedings. We also contacted experts for clarifications on data and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials where the participants had PDD or PD-MCI, and where the intervention was intended to train general or specific areas of cognitive function, targeting either a single domain or multiple domains of cognition, and was compared to a control condition. Multicomponent interventions that also included motor or other elements were considered eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts, and full-text articles for inclusion in the review. Two review authors also independently undertook extraction of data and assessment of methodological quality. We used GRADE methods to assess the overall quality of the evidence. MAIN RESULTS: Seven studies with a total of 225 participants met the inclusion criteria for this review. All seven studies compared the effects of a cognitive training intervention to a control intervention at the end of treatment periods lasting four to eight weeks. Six studies included people with PD living in the community. These six studies recruited people with single-domain (executive) or multiple-domain mild cognitive impairment in PD. Four of these studies identified participants with MCI using established diagnostic criteria, and two included both people with PD-MCI and people with PD who were not cognitively impaired. One study recruited people with a diagnosis of PD dementia who were living in long-term care settings. The cognitive training intervention in three studies targeted a single cognitive domain, whilst in four studies multiple domains of cognitive function were targeted. The comparison groups either received no intervention or took part in recreational activities (sports, music, arts), speech or language exercises, computerised motor therapy, or motor rehabilitation combined with recreational activity. We found no clear evidence that cognitive training improved global cognition. Although cognitive training was associated with higher scores on global cognition at the end of treatment, the result was imprecise and not statistically significant (6 trials, 178 participants, standardised mean difference (SMD) 0.28, 95% confidence interval (CI) -0.03 to 0.59; low-certainty evidence). There was no evidence of a difference at the end of treatment between cognitive training and control interventions on executive function (5 trials, 112 participants; SMD 0.10, 95% CI -0.28 to 0.48; low-certainty evidence) or visual processing (3 trials, 64 participants; SMD 0.30, 95% CI -0.21 to 0.81; low-certainty evidence). The evidence favoured the cognitive training group on attention (5 trials, 160 participants; SMD 0.36, 95% CI 0.03 to 0.68; low-certainty evidence) and verbal memory (5 trials, 160 participants; SMD 0.37, 95% CI 0.04 to 0.69; low-certainty evidence), but these effects were less certain in sensitivity analyses that excluded a study in which only a minority of the sample were cognitively impaired. There was no evidence of differences between treatment and control groups in activities of daily living (3 trials, 67 participants; SMD 0.03, 95% CI -0.47 to 0.53; low-certainty evidence) or quality of life (5 trials, 147 participants; SMD -0.01, 95% CI -0.35 to 0.33; low-certainty evidence). There was very little information on adverse events. We considered the certainty of the evidence for all outcomes to be low due to risk of bias in the included studies and imprecision of the results. We identified six ongoing trials recruiting participants with PD-MCI, but no ongoing trials of cognitive training for people with PDD. AUTHORS' CONCLUSIONS: This review found no evidence that people with PD-MCI or PDD who receive cognitive training for four to eight weeks experience any important cognitive improvements at the end of training. However, this conclusion was based on a small number of studies with few participants, limitations of study design and execution, and imprecise results. There is a need for more robust, adequately powered studies of cognitive training before conclusions can be drawn about the effectiveness of cognitive training for people with PDD and PD-MCI. Studies should use formal criteria to diagnose cognitive impairments, and there is a particular need for more studies testing the efficacy of cognitive training in people with PDD.

Care Burden and Mental Ill Health in Spouses of People With Parkinson Disease Dementia and Lewy Body Dementia.

OBJECTIVES: To explore and compare levels of mental health, care burden, and relationship satisfaction among caregiving spouses of people with mild cognitive impairment or dementia in Parkinson disease (PD-MCI or PDD) or dementia with Lewy bodies (DLB). METHODS: Spouses (n = 136) completed measures of mood, stress, resilience, general health, quality of life, care burden, and relationship satisfaction, as well as sociodemographic factors. Additionally, data on motor and neuropsychiatric symptom severity of people with PD-MCI, PDD, or DLB were obtained in a subsample. RESULTS: Most spouses were married women (>85%) who provided a median of 4 years of care and 84 hours of weekly care. Among these, relationship dissatisfaction, stress, anxiety, care burden, and feelings of resentment were common. Spouses of people with PDD and DLB had significantly higher rates of burden, resentment, and depression compared to spouses of people with PD-MCI. Furthermore, unique group differences emerged whereby spouses of people with PDD had significantly longer duration of care provision, higher stress, more relationship dissatisfaction, and fewer positive interactions, compared to PD-MCI group, whereas anxiety and lower levels of mental health were prominent in spouses of people with DLB, compared to PD-MCI group. Despite this, the majority of spouses reported good quality of life, resilience, and satisfaction with the caring role. CONCLUSION: Both PDD and DLB significantly contribute to poorer mental health and higher levels of care burden in spouses. Clinicians should actively screen the risk of burden, stress, depression, and anxiety among caregiving spouses of people with these conditions.

Apathy as a behavioural marker of cognitive impairment in Parkinson's disease: a longitudinal analysis.

BACKGROUND: Understanding the longitudinal course of non-motor symptoms, and finding markers to predict cognitive decline in Parkinson's disease (PD), are priorities. Previous work has demonstrated that apathy is one of the only behavioural symptoms that differentiates people with PD and intact cognition from those with mild cognitive impairment (MCI-PD). Other psychiatric symptoms emerge as dementia in PD develops. OBJECTIVE: We explored statistical models of longitudinal change to detect apathy as a behavioural predictor of cognitive decline in PD. METHODS: We followed 104 people with PD intermittently over 2 years, undertaking a variety of motor, behavioural and cognitive measures. We applied a linear mixed effects model to explore behavioural factors associated with cognitive change over time. Our approach goes beyond conventional modelling based on a random-intercept and slope approach, and can be used to examine the variability in measures within individuals over time. RESULTS: Global cognitive scores worsened during the two-year follow-up, whereas the longitudinal evolution of self-rated apathy scores and other behavioural measures was negligible. Level of apathy was negatively (- 0.598) correlated with level of cognitive impairment and participants with higher than average apathy scores at baseline also had poorer cognition. The model indicated that departure from the mean apathy score at any point in time was mirrored by a corresponding departure from average global cognitive score. CONCLUSION: High levels of apathy are predictive of negative cognitive and behavioural outcomes over time, suggesting that apathy may be a behavioural indicator of early cognitive decline. This has clinical and prognostic implications.

Which computer-use behaviours are most indicative of cognitive decline? Insights from an expert reference group.

Computer use is becoming ubiquitous among older adults. As computer use depends on complex cognitive functions, measuring individuals' computer-use behaviours over time may provide a way to detect changes in their cognitive functioning. However, it is uncertain which computer-use behaviour changes are most likely to be associated with declines of particular cognitive functions. To address this, we convened six experts from clinical and cognitive neurosciences to take part in two workshops and a follow-up survey to gain consensus on which computer-use behaviours would likely be the strongest indicators of cognitive decline. This resulted in a list of 21 computer-use behaviours that the majority of experts agreed would offer a 'strong indication' of decline in a specific cognitive function, across Memory, Executive function, Language and Perception and Action domains. This list enables a hypothesis-driven approach to analysing computer-use behaviours predicted to be markers of cognitive decline.

Multidimensional Care Burden in Parkinson-Related Dementia.

BACKGROUND AND OBJECTIVE: Providing care to people with Parkinson-related dementia (PwPRD) may result in significant stress, strain, and burden for life partners. A common measurement of life partner burden is the Zarit Burden Interview (ZBI), which considers "burden" as a unitary concept; however, burden is highly complex and most likely comprises several dimensions. This study aimed to explore the factor structure of the ZBI in life partners of PwPRD and to examine the relationships among the emerging factors and the demographic and clinical features. METHODS: Life partners of PwPRD participated in home-based quantitative assessments and self-completed postal questionnaires. The assessment battery included ZBI, measures of relationship satisfaction, mood, stress, resilience, health, quality of life, feelings related to care provision, and sociodemographic questions. Data on PwPRDs' motor and neuropsychiatric symptom severity were also elicited in home-based assessments. RESULTS: An exploratory factor analysis (principal axis factoring) of ZBI, conducted with 127 life partners, revealed five burden dimensions: social and psychological constraints, personal strain, interference with personal life, concerns about future, and guilt. These burden factors were associated with lower relationship satisfaction, mental health, and resilience, and higher stress, anxiety, depression, resentment, negative strain, and PwPRD motor severity. In multiple linear regression analyses, where each factor score was the dependent variable, stress, negative strain, and resentment emerged as significant predictors of specific burden dimensions. CONCLUSIONS: Burden is a complex and multidimensional construct. Interventions should address specific types of burden among life partners of PwPRD to support couples' relationships and maintain quality of life.

A qualitative study of female caregiving spouses' experiences of intimate relationships as cognition declines in Parkinson's disease.

BACKGROUND: the complex and progressive nature of Parkinson's disease (PD) and cognitive impairment may necessitate a care provider, a role which is frequently undertaken by a spouse. Providing and receiving care related to dementia impacts on a couple's partnership and may result in decreased intimacy and relationship satisfaction. OBJECTIVE: to explore the changes in long-term intimate relationships in Parkinson's-related dementia, as perceived by spouses providing care to their partners. METHODS: participants were identified using purposive sampling. Twelve female spouses whose partners had PD and mild cognitive impairment (PD-MCI), PD dementia (PDD) or dementia with Lewy bodies (DLB) completed semi-structured face-to-face interviews. Transcribed data were analysed using inductive thematic analysis. The consolidated criteria for reporting qualitative research (COREQ) were applied. RESULTS: couples' relationship satisfaction, intimacy and communication had already reduced in the mild cognitive impairment stage of PD, but the decline in these domains was markedly greater with the emergence of dementia. Increased spousal care responsibilities resulted in partners spending more time together, but feeling emotionally more distanced. Several participants' roles transitioned from spouse to caregiver and they reported feelings of frustration, resentment, anger, sadness and a worry for the future. Cognitive impairment was significantly harder to accept, manage and cope with than the motor symptoms of PD. Spouses acknowledged their marital commitments and exhibited acceptance, adjustment, resilience and various coping strategies. CONCLUSION: this is the first study exploring relationship satisfaction in Parkinson's-related dementia and has provided valuable insight into the changing patterns of intimate relationships.

Psychosocial therapy for Parkinson's-related dementia: intervention development.

BACKGROUND: Group-based psychosocial therapy, such as group Cognitive Stimulation Therapy, improves cognition and quality of life in people living with dementia. Neuropsychiatric symptoms and restricted mobility are common complications for people with Parkinson's-related dementia (PRD) and may limit access to, and participation in, group activities. This study describes the development of a condition-specific, home-based psychosocial therapy for people with PRD ready to be trialled in a clinical population. METHODS: By means of a multistage process, a draft therapy manual was developed in an iterative manner through collaboration with medical experts, researchers and Patient and Public Involvement (PPI) representatives. In stage 1, an extensive literature search of psychosocial therapies for dementia with potential relevance for Parkinson's disease (PD) was undertaken to select a candidate therapy for adaptation. In stage 2, qualitative feedback from stakeholders and intelligence regarding existing nonpharmacological therapies for cognitive impairment in PD was combined to produce a prototype therapy manual. In stage 3, the manual was field tested in: 1) a home-setting using a 25-item assessment tool; and 2) at a local PD support group with PPI representatives. Based on the feedback from this phase, final design modifications were implemented and a draft therapy manual produced. RESULTS: The manual was developed in an iterative manner. Interview and focus group transcripts identified three enduring themes: manual form and content, therapy acceptability by people with PRD, and companion guidance and support. Major adaptations included: removal of discrete levels of task complexity, removal of images that were potentially hallucinogenic or lacked clarity, and updating of the content. CONCLUSION: We have successfully developed a Cognitive Stimulation Therapy-based psychosocial therapy specifically adapted for people with PRD. The therapy is ready to trial in a pilot randomized controlled study.

Psychosocial therapy for Parkinson's-related dementia: study protocol for the INVEST randomised controlled trial.

INTRODUCTION: Parkinson's disease (PD) with mild cognitive impairment (MCI-PD) or dementia (PDD) and dementia with Lewy bodies (DLB) are characterised by motor and 'non-motor' symptoms which impact on quality of life. Treatment options are generally limited to pharmacological approaches. We developed a psychosocial intervention to improve cognition, quality of life and companion burden for people with MCI-PD, PDD or DLB. Here, we describe the protocol for a single-blind randomised controlled trial to assess feasibility, acceptability and tolerability of the intervention and to evaluate treatment implementation. The interaction among the intervention and selected outcome measures and the efficacy of this intervention in improving cognition for people with MCI-PD, PDD or DLB will also be explored. METHODS AND ANALYSIS: Dyads will be randomised into two treatment arms to receive either 'treatment as usual' (TAU) or cognitive stimulation therapy specifically adapted for Parkinson's-related dementias (CST-PD), involving 30 min sessions delivered at home by the study companion three times per week over 10 weeks. A mixed-methods approach will be used to collect data on the operational aspects of the trial and treatment implementation. This will involve diary keeping, telephone follow-ups, dyad checklists and researcher ratings. Analysis will include descriptive statistics summarising recruitment, acceptability and tolerance of the intervention, and treatment implementation. To pilot an outcome measure of efficacy, we will undertake an inferential analysis to test our hypothesis that compared with TAU, CST-PD improves cognition. Qualitative approaches using thematic analysis will also be applied. Our findings will inform a larger definitive trial. ETHICS AND DISSEMINATION: Ethical opinion was granted (REC reference: 15/YH/0531). Findings will be published in peer-reviewed journals and at conferences. We will prepare reports for dissemination by organisations involved with PD and dementia. TRIAL REGISTRATION NUMBER: ISRCTN (ISRCTN11455062).

Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson's disease.

BACKGROUND: Pain is a common nonmotor symptom in Parkinson's disease (PD). The pathophysiology of pain in PD is not well understood. Pain characteristics have rarely been studied in atypical parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP). AIM OF THE STUDY: We aimed to evaluate pain intensity, location, and associated symptoms in atypical parkinsonian disorders compared to PD. METHODS: Twenty-one patients with MSA, 16 patients with PSP, and 65 patients with PD were screened for pain using question 1.9 of the MDS-UPDRS. Pain intensity was quantified using the short form McGill Pain Questionnaire (SFMPQ). Pain locations were documented. Motor disability was measured using UPDRS-III. Affective symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Pain was significantly more common and more severe in PD and MSA compared to PSP (P < 0.01). Pain locations were similar with limb pain being the most common followed by neck and back pain. Pain intensity correlated with HADS scores but not motor severity. CONCLUSIONS: Pain is more common and more intense in PD and MSA than PSP. Differences in distribution of neurodegenerative pathologies may underlie these differential pain profiles.

Behavioural disorders, disability and quality of life in Parkinson's disease.

BACKGROUND: although non-motor symptoms of Parkinson's disease (PD) are known to adversely affect disability and health-related quality of life, the impact that specific disorders of reward and motivation have remains unclear. Impulse control disorders are more likely in those with a younger disease onset although there is no strong evidence to date that apathy is related to age of onset or correlated with a longer duration of disease. OBJECTIVE: to examine the effects of apathy and impulse controls disorders on disability and health-related quality of life. METHODS: a total of 99 non-demented participants with PD (35 with impulse control disorders, 26 with apathy and 38 with neither behavioural complication) were assessed using the Unified Parkinson's Disease Rating Scale (Activities of Daily Living component) and the Schwab-England scale to evaluate disability, and the PDQ (eight items) to assess quality of life. RESULTS: quality of life was reduced in both behavioural groups compared with participants without either condition. Disability was greater in the group with apathy. Variation in disability score (56%, P < 0.001) was explained by greater levels of apathy, depression, motor impairment and longer disease duration. Variation in quality of life score (54%, P < 0.001) was explained by higher levels of impulsivity, depression, dopaminergic load, motor complications, working memory problems and younger age at onset. CONCLUSION: apathy and impulsivity negatively impact on disability and health-related quality of life, emphasising the importance of effective diagnosis and management of these PD-related behavioural disturbances.

Attentional selection and action selection in the ventral and orbital prefrontal cortex.

Different accounts of the ventral and orbital prefrontal cortex (PFv+o) have emphasized either its role in learning conditional rules for action selection or the attentional selection of behaviorally relevant stimuli. Although the accounts are not mutually exclusive, it is possible that the involvement of PFv+o in conditional action selection is a consequence of its role in selecting relevant stimuli or that its involvement in attentional selection is a consequence of the conditional rules present in many attentional paradigms. Five macaques learned a conditional action-selection task in which the difficulty of identifying the stimulus relevant for guiding action selection was varied in a simple manner by either altering its distance from the action or presenting additional distracting stimuli. Simply increasing the spatial separation between the instructing stimulus led to slower responses. Experiment 1 showed that bilateral PFv+o lesions impaired conditional action selection even when attentional demands were kept to a minimum, but there was evidence that the impairment was exacerbated by manipulating stimulus selection difficulty. Experiment 2 confirmed the importance of PFv+o for conditional action selection even when stimulus selection difficulty was minimal. Experiments 3 and 4 demonstrated that the action-selection impairment was significantly increased by making identification of the behaviorally relevant stimulus difficult. PFv+o is central to the use of conditional rules when selecting courses of action, but conditional rules are also represented in premotor and striatal regions. A special contribution of PFv+o may be initial selection of behaviorally relevant stimuli.

Cortico-basal ganglia pathways are essential for the recall of well-established visuomotor associations.

Recent human neuroimaging studies, supported by lesion studies with nonhuman primates, have suggested that learning arbitrary associations between sensory cues and behavioural responses requires interactions between the infero-temporal, prefrontal and premotor cortices. We directly tested the hypothesis suggested from our neuroimaging experiments that functional links between the basal ganglia and premotor cortex are involved in the process via which task performance becomes automatic. We made unilateral excitotoxic lesions, centred on the internal pallidum, in four macaques previously given extensive experience on the associations between nonspatial visual cues and movements of a joystick. The basal ganglia lesion was later combined with a premotor cortical lesion in the opposite hemisphere so as to interrupt the connections between them. Three of the animals were subsequently found to be impaired in relearning pre-operatively acquired associations; they eventually succeeded but made three-times as many errors. A fourth animal was unimpaired but its premotor cortex lesion was later found to be incomplete. Response times were only marginally increased and the learning of novel associations appeared relatively unaffected by these lesions. As a control, the effects of a unilateral premotor cortex lesion were assessed with two additional animals but this lesion did not result in a relearning impairment. We therefore suggest that when visuomotor associations have become well established through over-training, performance depends on connections between the basal ganglia and premotor cortex.