Caregiver Burden in Parkinson Disease: A Scoping Review of the Literature from 2017-2022.

Caregiver burden is a term that refers to the adverse effect of caregiving on the physical, emotional, social, spiritual, and financial well-being of the caregiver. Caregiver burden is associated with providing care to an individual with a chronic illness or disability, and the unique symptoms of Parkinson disease (PD) can amplify a patient's needs and reliance on others, leading to adverse outcomes for patients and their caregivers. In this scoping review of the literature from January 2017 through April 2022 that included 114 studies, we provide an updated, evidence-based summary of patient and caregiver-related factors that contribute to caregiver burden in PD. We also describe the impact of caregiver stress and burden on caregivers based on qualitative research studies and review recent interventions to mitigate burden. By providing clinical updates for practitioners, this review is designed to improve recognition of caregiver burden in the post-pandemic era and foster the development of targeted interventions to reduce caregiver burden in PD.

Hippocampal, basal ganglia and olfactory connectivity contribute to cognitive impairments in Parkinson's disease.

Cognitive impairment is increasingly recognized as a characteristic feature of Parkinson's disease (PD), yet relatively little is known about its underlying neurobiology. Previous investigations suggest that dementia in PD is associated with subcortical atrophy, but similar studies in PD with mild cognitive impairment have been mixed. Variability in cognitive phenotypes and diversity of PD symptoms suggest that a common neuropathological origin results in a multitude of impacts within the brain. These direct and indirect impacts of disease pathology can be investigated using network analysis. Functional connectivity, for instance, may be more sensitive than atrophy to decline in specific cognitive domains in the PD population. Fifty-eight participants with PD underwent a neuropsychological test battery and scanning with structural and resting state functional MRI in a comprehensive whole-brain association analysis. To investigate atrophy as a potential marker of impairment, structural gray matter atrophy was associated with cognitive scores in each cognitive domain using voxel-based morphometry. To investigate connectivity, large-scale networks were correlated with voxel time series and associated with cognitive scores using distance covariance. Structural atrophy was not associated with any cognitive domain, with the exception of visuospatial measures in primary sensory and motor cortices. In contrast, functional connectivity was associated with attention, executive function, language, learning and memory, visuospatial, and global cognition in the bilateral hippocampus, left putamen, olfactory cortex, and bilateral anterior temporal poles. These preliminary results suggest that cognitive domain-specific networks in PD are distinct from each other and could provide a network signature for different cognitive phenotypes.

Spirituality and Spiritual Distress in Parkinson's Disease Caregivers: A Scoping Review.

Despite recognition that spiritual concerns contribute to caregiver burden, little is known about spirituality, spiritual well-being, and spiritual distress in Parkinson's disease caregivers. In this scoping review of the literature through October 2022, we searched PubMed, PsychINFO, Embase, and CINAHL. From an initial pool of 328 studies, 14 were included. Caregiver factors (e.g., depression, age) and patient factors (e.g., faith, motor function) affected caregiver spirituality and spiritual well-being. Caregivers experienced loss of meaning, existential guilt, and loneliness, and coped through acquiescence, cultural beliefs, prayer, and gratitude. Future research should focus on the specific spiritual needs of Parkinson's disease caregivers and interventions to address them.

Profiling Parkinson's disease cognitive phenotypes via resting-state magnetoencephalography.

Aberrant brain oscillations are a hallmark of Parkinson's disease (PD) pathophysiology and may be related to both motor and nonmotor symptoms. Mild cognitive impairment (MCI) affects many people with PD even at the time of diagnosis and conversion risks to PD dementia (PDD) are very high. Unfortunately, pharmacotherapies are not addressing cognitive symptoms in PD. Profiling PD cognitive phenotypes (e.g., MCI, PDD, etc.) may therefore help inform future treatments. Neurophysiological methods, such as magnetoencephalography (MEG), offer the advantage of observing oscillatory patterns, whose regional and temporal profiles may elucidate how cognitive changes relate to neural mechanisms. We conducted a resting-state MEG cross-sectional study of 89 persons with PD stratified into three phenotypic groups: normal cognition, MCI, and PDD, to identify brain regions and frequencies most associated with each cognitive profile. In addition, a neuropsychological battery was administered to assess each domain of cognition. Our data showed higher power in lower frequency bands (delta and theta) observed along with more severe cognitive impairment and associated with memory, language, attention, and global cognition. Of the total 119 brain parcels assessed during source analysis, widespread group differences were found in the beta band, with significant changes mostly occurring between the normal cognition and MCI groups. Moreover, bilateral frontal and left-hemispheric regions were particularly affected in the other frequencies as cognitive decline becomes more pronounced. Our results suggest that MCI and PDD may be qualitatively distinct cognitive phenotypes, and most dramatic changes seem to have happened when the PD brain shows mild cognitive decline.NEW & NOTEWORTHY Can we better stage cognitive decline in patients with Parkinson's disease (PD)? Here, we provide evidence that mild cognitive impairment, rather than being simply a milder form of dementia, may be a qualitatively distinct phase in its development. We suggest that the most dramatic neurophysiological changes may occur during the time the PD brain transitions from normal cognition to MCI, then compensatory changes further occur as the brain "switches" to a dementia state.

Palliative Care in Movement Disorders: an Evolving Field.

PURPOSE OF REVIEW: This review summarizes the current state of evidence for palliative care (PC) in movement disorders, describes the application of PC to clinical practice, and suggests future research directions. RECENT FINDINGS: PC needs are common in persons living with movement disorders and their families from the time of diagnosis through end-of-life and contribute to quality of life. Early advance care planning is preferred by patients, impacts outcomes and is promoted by PC frameworks. Systematic assessment of non-motor symptoms, psychosocial needs and spiritual/existential distress may address gaps in current models of care. Several complementary and emerging models of PC may be utilized to meet the needs of this population. A PC approach may identify and improve important patient and caregiver-centered outcomes. As a relatively new application of PC, there is a need for research to adapt, develop and implement approaches to meet the unique needs of this population.

Would people living with epilepsy benefit from palliative care?

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

Lessons from the COVID-19 pandemic for improving outpatient neuropalliative care: A qualitative study of patient and caregiver perspectives.

BACKGROUND: COVID-19 has impacted persons with serious illness, including those with chronic, neurodegenerative conditions. While there are several reports on COVID-19's impact on inpatient palliative care, literature is limited about the impact on outpatient care which may be more relevant for these patients. AIM: To generate a person-centered description of the impact of COVID-19 from the perspectives of patients living with neurodegenerative disease and caregivers to improve outpatient palliative care delivery. DESIGN: This qualitative study used rapid analysis via matrix design to identify emergent themes related to participant perspectives on the challenges of COVID-19. Data sources included semi-structured interviews, open-ended survey responses, medical record documentation and participant-researcher communications. SETTING/PARTICIPANTS: Data was collected from 108 patients with Parkinson's disease, Alzheimer's disease or related disorders and 90 caregivers enrolled in a multicenter, clinical trial of community-based, outpatient palliative care between March 20, 2020 and August 8, 2020 (NCT03076671). RESULTS: Four main themes emerged: (1) disruptions to delivery of healthcare and other supportive services; (2) increased symptomatic and psychosocial needs; (3) increased caregiver burden; (4) limitations of telecommunications when compared to in-person contact. We observed that these themes interacted and intersected. CONCLUSIONS: Patients and caregivers have unmet care needs because of the pandemic, exacerbated by social isolation. While telemedicine has helped improve access to healthcare, patients and caregivers perceive clear limitations compared to in-person services. Changes in society and healthcare delivery in response to COVID-19 highlight ongoing and novel gaps that must be addressed to optimize future outpatient palliative care for neurologic illness.

Progressive Supranuclear Palsy and Statin Use.

INTRODUCTION: Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy. METHODS: Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed. RESULTS: Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale. CONCLUSION: Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society.

Transcranial Magnetic Stimulation as Treatment for Mal de Debarquement Syndrome: Case Report and Literature Review.

This manuscript presents the case of an adult, male patient with mal de debarquement syndrome (MdDS); results from his experimental treatment with repetitive transcranial magnetic stimulation (rTMS) are also provided. Additionally, we included a review of literature related to the neurophysiology of MdDS and its treatment with rTMS. A 41-year-old man had been experiencing symptoms of MdDS, which initially emerged following a car ride, for 11 to 12 years. Pharmacologic approaches had failed to provide symptom relief; thus, we investigated an intervention using low-frequency (1 Hz) rTMS unilaterally for 2 consecutive weeks. The outcome measures included a standardized, computerized dynamic posturography test to quantify the patient's balance and identify abnormalities in his use of the sensory systems contributing to postural control, as well as the Hospital Anxiety and Depression Scale (HADS) to measure his anxiety and depression. An rTMS treatment log was created to document any adverse events. Following rTMS, the patient's balance scores improved significantly; these improvements were mostly related to the patient's increased reliance on the visual and vestibular systems. Our patient's HADS Anxiety and Depression subscores also showed improvement post-rTMS. The presented case study provides preliminary evidence that rTMS may be a noninvasive treatment option for improving balance, specifically in individuals with MdDS. This evidence can be used to further therapeutic research on, and provide strategies for treating, MdDS.

Rhythmic auditory cues shape neural network recruitment in Parkinson's disease during repetitive motor behavior.

It is well established clinically that rhythmic auditory cues can improve gait and other motor behaviors in Parkinson's disease (PD) and other disorders. However, the neural systems underlying this therapeutic effect are largely unknown. To investigate this question we scanned people with PD and age-matched healthy controls using functional magnetic resonance imaging (fMRI). All subjects performed a rhythmic motor behavior (right hand finger tapping) with and without simultaneous auditory rhythmic cues at two different speeds (1 and 4 Hz). We used spatial independent component analysis (ICA) and regression to identify task-related functional connectivity networks and assessed differences between groups in intra- and inter-network connectivity. Overall, the control group showed greater intra-network connectivity in perceptual and motor related networks during motor tapping both with and without rhythmic cues. The PD group showed greater inter-network connectivity between the auditory network and the executive control network, and between the executive control network and the motor/cerebellar network associated with the motor task performance. We interpret our results as indicating that the temporal rhythmic auditory information may assist compensatory mechanisms through network-level effects, reflected in increased interaction between auditory and executive networks that in turn modulate activity in cortico-cerebellar networks.

Validation of a performance-based assessment of cognitive functional ability in Parkinson's disease.

BACKGROUND: Outcome measures that capture functional abilities related to cognition offer the potential to demonstrate real-world effectiveness of cognitive-enhancing treatments. However, distinguishing functional disability related to cognition from that attributed to motor symptoms can be difficult in PD. A performance-based functional assessment allows for direct observation of activity of daily living skills and separation of cognitive from motoric disabilities. OBJECTIVES: Validate the University of California San Diego Performance-Based Skills Assessment in PD. METHODS: One hundred PD participants, ranging from normal cognition to dementia, completed the University of California San Diego Performance-Based Skills Assessment, a performance-based measure of cognitively demanding activities of daily living, as well as a neuropsychological battery and motor examination. Cognitive classification was determined by consensus conference, blinded to University of California San Diego Performance-Based Skills Assessment scores. Psychometric properties of the University of California San Diego Performance-Based Skills Assessment, including internal consistency, test-retest and inter-rater reliability, and discriminant validity for dementia, were examined. RESULTS: The University of California San Diego Performance-Based Skills Assessment demonstrated strong internal consistency (Cronbach's α = 0.82) and test-retest reliability (r = 0.89) and correlated strongly with global cognition (Mattis Dementia Rating Scale: r = 0.80; P < 0.001). University of California San Diego Performance-Based Skills Assessment regression models indicated greater contribution from cognitive explanatory variables (marginal partial: R2 = 0.33) than motor variables (marginal partial: R2 = 0.05), controlling for age, education, disease duration, and l-dopa equivalent dose. Additionally, the University of California San Diego Performance-Based Skills Assessment exhibited strong discriminant validity for dementia (area under the curve = 0.91). CONCLUSIONS: The University of California San Diego Performance-Based Skills Assessment is a valid measure of functional abilities related to cognition rather than motor symptoms in PD. Furthermore, it reliably distinguishes demented from nondemented participants. The University of California San Diego Performance-Based Skills Assessment may be considered as an outcome measure that combines cognitive and functional abilities in treatment trials for cognitive impairment in PD. © 2018 International Parkinson and Movement Disorder Society.

Assessing the validity of proxy caregiver reporting for potential palliative care outcome measures in Parkinson's disease.

BACKGROUND: There is increasing interest in applying palliative care approaches for patients with Parkinson's disease. Methodological studies are needed to validate palliative care outcome measures for Parkinson's disease to build this evidence base. As many patients with Parkinson's disease have cognitive and/or communication issues, proxy outcome measures may improve the inclusivity and relevance of research. AIM: To assess the validity of proxy caregiver reports for several potential palliative care outcome measures. DESIGN: A cross-sectional study of Parkinson's disease patients and caregivers completed a battery of outcome measures relevant to palliative care including the Memorial Symptom Assessment Scale, Hospital Anxiety and Depression Scale, Prolonged Grief Questionnaire 12, Parkinson Disease Questionnaire 39, Functional Assessment of Chronic Illness Therapy-Spiritual Wellbeing, and Schwab and England. Intraclass correlation coefficients were used to assess agreement. SETTING/PARTICIPANTS: A total of 50 Parkinson's disease patient and caregiver dyads recruited at an academic medical center, Veterans Affairs Medical Center, and community support groups. RESULTS: There was moderate to good agreement for Schwab and England, Parkinson Disease Questionnaire 39 total, and majority of Parkinson Disease Questionnaire 39 subscales; moderate to good agreement for the Hospital Anxiety and Depression Scale, Functional Assessment of Chronic Illness Therapy-Spiritual Wellbeing, Prolonged Grief Questionnaire 12, and Memorial Symptom Assessment Scale; and poor to moderate agreement for the Parkinson Disease Questionnaire 39 stigma, social support, and bodily pain subscales. Caregivers tended to attribute higher symptom severity than patients. We did not detect differences in intraclass correlation coefficient based on cognitive status but patients with advanced illness had significantly lower intraclass correlation coefficients for several outcomes. CONCLUSIONS: Caution is indicated when considering caregiver proxy reporting for most outcomes assessed, particularly in Parkinson's disease patients with advanced disease.

Compensatory Neural Activity in Response to Cognitive Fatigue.

Prolonged continuous performance of a cognitively demanding task induces cognitive fatigue and is associated with a time-related deterioration of objective performance, the degree of which is referred to cognitive fatigability. Although the neural underpinnings of cognitive fatigue are poorly understood, prior studies report changes in neural activity consistent with deterioration of task-related networks over time. While compensatory brain activity is reported to maintain motor task performance in the face of motor fatigue and cognitive performance in the face of other stressors (e.g., aging) and structural changes, there are no studies to date demonstrating compensatory activity for cognitive fatigue. High-density electroencephalography was recorded from human subjects during a 160 min continuous performance of a cognitive control task. While most time-varying neural activity showed a linear decline over time, we identified an evoked potential over the anterior frontal region which demonstrated an inverted U-shaped time-on-task profile. This evoked brain activity peaked between 60 and 100 min into the task and was positively associated with better behavioral performance only during this interval. Following the peak and during subsequent decline of this anterior frontal activity, the rate of performance decline also accelerated. These findings demonstrate that this anterior frontal brain activity, which is not part of the primary task-related activity at baseline, is recruited to compensate for fatigue-induced impairments in the primary task-related network, and that this compensation terminates as cognitive fatigue further progresses. These findings may be relevant to understanding individual differences in cognitive fatigability and developing interventions for clinical conditions afflicted by fatigue. SIGNIFICANCE STATEMENT: Fatigue refers to changes in objective performance and subjective effort induced by continuous task performance. We examined the neural underpinnings of cognitive fatigue in humans using a prolonged continuous performance task and high-density electroencephalography with the goal of determining whether compensatory processes exist to maintain performance in the face of fatigue. We identified brain activity demonstrating an inverted U-shaped time-on-task profile. This brain activity showed features consistent with a compensatory role including: peaking between 60 and 100 min into the task, a positive association with behavioral performance only during this interval, and accelerated performance decline following its peak. These findings may be relevant to understanding individual differences in cognitive fatigue and developing interventions for clinical conditions afflicted by fatigue.

Genetic influences on cognition in progressive supranuclear palsy.

BACKGROUND: Cognitive dysfunction is common in progressive supranuclear palsy, but the influence of genetics on cognition in this disorder has not been well studied. The objective of this study was to investigate the effect of genes previously identified as risk alleles, including microtubule-associated protein tau, myelin-associated oligodendrocyte basic protein, eukaryotic translation initiation factor 2-alpha kinase 3, and syntaxin 6, as well as apolipoprotein E, on cognitive function in progressive supranuclear palsy. METHODS: The sample was composed of 305 participants who met criteria for possible or probable progressive supranuclear palsy. Genetic information was determined by TaqMan genotyping assays. A neuropsychological battery was administered to all study participants. Measures included in the battery evaluated for general cognition, executive function, memory, attention, language, and visuospatial ability. RESULTS: Cognition did not vary significantly between individuals homozygous or heterozygous for the microtubule-associated protein tau H1 haplotype. However, cognition varied significantly at the subhaplotype level, with carriers of the microtubule-associated protein tau rs242557/A allele, which marks the H1c subhaplotype, performing better than noncarriers on measures of general cognitive function, executive function, and attention. No associations were found for other genes. CONCLUSIONS: The results of the current study indicate that variations in microtubule-associated protein tau influence cognition in progressive supranuclear palsy. Although the H1c-specific rs242557/A allele is a risk factor for progressive supranuclear palsy, carriers of this allele may exhibit better cognition than non-carriers in patients with the atypical parkinsonian syndrome. Further studies are needed. © 2017 International Parkinson and Movement Disorder Society.

Randomized, Controlled Trial of Acupuncture for Fatigue in Parkinson's Disease.

BACKGROUND: Fatigue is a common and debilitating nonmotor symptom of PD. Because preliminary evidence suggests that acupuncture improves fatigue in other conditions, we sought to test its efficacy in PD. METHODS: Ninety-four PD patients with moderate-to-high fatigue were randomized to receive 6 weeks of biweekly real or sham acupuncture. The primary outcome was change on the Modified Fatigue Impact Scale at 6 weeks. Secondary outcomes included sleep, mood, quality of life, and maintenance of benefits at 12 weeks. RESULTS: Both groups showed significant improvements in fatigue at 6 and 12 weeks, but with no significant between-group differences. Improvements from baseline in mood, sleep, and quality of life were noted without between-group differences. Overall, 63% of patients reported noticeable improvements in their fatigue. No serious adverse events were observed. CONCLUSIONS: Acupuncture may improve PD-related fatigue, but real acupuncture offers no greater benefit than sham treatments. PD-related fatigue should be added to the growing list of conditions that acupuncture helps primarily through nonspecific or placebo effects. © 2016 International Parkinson and Movement Disorder Society.

Relationship between uric acid levels and progressive supranuclear palsy.

INTRODUCTION: The pathophysiology of both PD and PSP is characterized by a pro-oxidant state. Uric acid is an oxidative stress marker. High uric acid blood levels have been associated with a reduced risk of PD and a decreased rate of disease progression. We investigated whether a low serum concentration of uric acid is also associated with PSP. METHODS: We measured serum uric acid concentrations in a subsample of the ENGENE PSP Cohort that included 75 cases and 75 frequency-matched-by-sex healthy controls (69 spouses, 6 in-laws) from four centers willing to participate (Case Western, Rush University, University of Utah, and University of Louisville). Case severity was characterized using the total PSP-Rating Scale, UPDRS, and Mattis Dementia Rating Scale. Unconditional logistic regression, Pearson's chi-squared test, and analysis of variance were used, as appropriate. RESULTS: The mean uric acid level among cases (4.0 mg/dL) was not significantly lower than that of controls (4.1 mg/dL). When controlling for sex, there were no between-group statistical differences in uric acid levels. Uric acid levels were not correlated with disease severity. CONCLUSIONS: The results of this study do not provide evidence of uric acid having a protective role in PSP, even if oxidative injury is important in the pathophysiology of this disorder. The lack of statistical significance suggests that there is no direct association between uric acid levels and PSP. However, a small inverse association cannot be excluded. © 2016 Movement Disorder Society.

Parkinson's disease-related fatigue: A case definition and recommendations for clinical research.

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society.

Rasagiline for the symptomatic treatment of fatigue in Parkinson's disease.

BACKGROUND: Fatigue affects 40% to 50% of all PD patients and is a leading cause of disability, with no clearly established or efficacious established treatments. METHODS: In this double-blinded, placebo-controlled, pilot trial, we investigated whether rasagiline improved fatigue among PD patients. Subjects were randomized to 1 mg daily of rasagiline or placebo for 12 weeks. The primary endpoint was a change in the Modified Fatigue Impact Scale from baseline to week 12. RESULTS: Thirty PD subjects (16 men), with Modified Fatigue Impact Scale baseline score of 67 ± 15, were randomized (16 to rasagiline vs. 14 to placebo). Significant improvement was noted in the mean Modified Fatigue Impact Scale score of the rasagiline group (12 points) as compared to placebo (8.5 points) from baseline to week 12 (P = 0.003). CONCLUSION: In this pilot study, rasagiline at a dose of 1 mg per day improved fatigue. Larger randomized studies are needed to confirm this finding.