Autonomic Dysfunction in Parkinson’s Disease

Recognition of the importance of nonmotor dysfunction as a component of Parkinson’s disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson’s disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson’s disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00897-4) contains supplementary material, which is available to authorized users.Key Words: Autonomic, gastrointestinal, orthostatic hypotension, urinary, erectile dysfunction, thermoregulatory     

Approach to Cognitive Impairment in Parkinson’s Disease

Cognitive dysfunction is common in Parkinson’s disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00963-x.Key Words: Parkinson’s disease, dementia, mild cognitive impairment, neuropsychology, cholinesterase inhibitors, deep brain stimulation, neuromodulation, neurorehabilitation.     

Regional Metabolic Changes Influencing Three-Dimensional Perception in Parkinson’s Disease

Background and PurposeStereopsis refers to the perception of depth and awareness of the distance of an object from the observer that results from the brain receiving visual stimuli from both eyes in combination. Patients with idiopathic Parkinson’s disease (PD patients) typically experience problems with vision, eyeball movements, and visual perception due to degeneration of the cells that generate dopamine in the brain. We therefore hypothesized that stereopsis is affected more by visual cortical dysfunction in idiopathic PD than by retina and subcortical structural dysfunction.MethodsWe analyzed stereopsis in 12 PD patients and 7 healthy controls using a three-dimensional (3D) television (TV). Before allowing patients to watch TV, we examined their visual acuity and strabismus using the Titmus Stereo Fly Test, and evaluated their cognitive function using cognitive tests. The patients watched 3D and two-dimensional (2D) versions of a movie with an approximate duration of 17 minutes, and then completed a questionnaire about stereopsis. All subjects underwent brain F-18 fluorodeoxyglucose (FDG) positron-emission tomography after watching the 3D version of the movie. One week later, subjects watched the 2D version of the same movie under the same conditions. Each scan was analyzed using statistical parametric mapping (version 8) software.ResultsThe visual cortex was activated less in the PD patients than in the healthy controls when watching the 2D or 3D movie. However, there was no significant difference between watching 2D and 3D movies in the PD patients or healthy controls.ConclusionsThe lower activation of the primary visual cortex in PD patients suggests the presence of dysfunction of the visual cortex. In addition, there was less activation of the visual association cortex in PD patients when watching a 3D movie than in controls under the same conditions. This might be one reason why PD patients do not recognize real and dynamic stereopsis. These findings have clinical significance since they suggest that safety needs to be considered when making devices or programs using 3D or virtual reality for use by patients with various cerebral degenerative diseases.     

Current approaches to the treatment of Parkinson’s disease

Enormous progress has been made in the treatment of Parkinson’s disease (PD). As a result of advances in experimental therapeutics, many promising therapies for PD are emerging. Levodopa remains the most potent drug for controlling PD symptoms, yet is associated with significant complications such as the “wearing off” effect, levodopa-induced dyskinesias and other motor complications. Catechol-o-methyl-transferase inhibitors, dopamine agonists and nondopaminergic therapy are alternative modalities in the management of PD and may be used concomitantly with levodopa or one another. The neurosurgical treatment, focusing on deep brain stimulation, is reviewed briefly. Although this review has attempted to highlight the most recent advances in the treatment of PD, it is important to note that new treatments are not necessarily better than the established conventional therapy and that the treatment options must be individualized and tailored to the needs of each individual patient.     

Seborrheic Dermatitis Is Related to Motor Symptoms in Parkinson’s Disease

Background and PurposeParkinson’s disease (PD) patients present with numerous motor and nonmotor symptoms. Seborrheic dermatitis (SD) is reported in 18.6%–59% of PD patients. However, the etiology of SD in PD patients remains unknown. The aim of this study was to determine how motor and nonmotor symptoms, age, sex, and levodopa-equivalent daily dose (LEDD) influence the appearance and severity of SD in PD patients, and then discuss about SD possible etiology based on the obtained results.MethodsMotor symptoms were evaluated using the Unified Parkinson’s Disease Rating Scale part III and nonmotor symptoms were evaluated using the Parkinson’s Disease Sleep Scale, Scales for Outcomes in Parkinson’s Disease–Autonomic Dysfunction, and Non-Motor Symptoms Questionnaire. LEDD was calculated and demographic data on age, sex, disease duration, and symptoms of SD prior to a PD diagnosis were collected. A dermatologist evaluated the skin for SD using the Seborrhea Area and Severity Index.ResultsSD was present in 36.1% of the PD patients. There were positive correlations between age, motor-symptoms severity, and SD. After adjusting for age, disease duration, and sex, there remained a positive correlation between the severity of motor symptoms and SD. Patients with moderate-to-severe motor symptoms had more-severe SD symptoms, and their risk of developing SD was 1.8-fold higher. There was no correlation between SD and autonomic dysfunction, sleep disturbances, or other nonmotor symptoms, and no sex difference.ConclusionsIn PD, SD is related to motor symptoms.     

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson’s Disease

Disease outcomes are heterogeneous in Parkinson’s disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the “NIH Exploratory Trials in PD Long-term Study 1” (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson’s Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00965-9.     

Medical Management and Prevention of Motor Complications in Parkinson’s Disease

Levodopa is the most effective medication for the treatment of the motor symptoms of Parkinson’s disease. However, over time, the clinical response to levodopa becomes complicated by a reduction in the duration and reliability of motor improvement (motor fluctuations) and the emergence of involuntary movements (levodopa-induced dyskinesia). Strategies that have been attempted in an effort to delay the development of these motor complications include levodopa sparing and continuous dopaminergic therapy. Once motor complications occur, a wide array of medical treatments is available to maximize motor function through the day while limiting dyskinesia. Here, we review the clinical features, epidemiology, and risk factors for the development of motor complications, as well as strategies for their prevention and medical management.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00889-4) contains supplementary material, which is available to authorized users.     

Surgical Treatment of Parkinson’s Disease: Devices and Lesion Approaches

Surgical treatments have transformed the management of Parkinson’s disease (PD). Therapeutic options available for the management of PD motor complications include deep brain stimulation (DBS), ablative or lesioning procedures (pallidotomy, thalamotomy, subthalamotomy), and dopaminergic medication infusion devices. The decision to pursue these advanced treatment options is typically done by a multidisciplinary team by considering factors such as the patient’s clinical characteristics, efficacy, ease of use, and risks of therapy with a goal to improve PD symptoms and quality of life. DBS has become the most widely used surgical therapy, although there is a re-emergence of interest in ablative procedures with the introduction of MR-guided focused ultrasound. In this article, we review DBS and lesioning procedures for PD, including indications, selection process, and management strategies.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00939-x) contains supplementary material, which is available to authorized users.Key Words: Deep brain stimulation, ablation, RF ablation, stereotactic radiosurgery, focused ultrasound     

Sensorimotor integration training in Parkinson’s disease

Objectives:To determine the effects of sensorimotor integration training on postural control in Parkinson’s disease.Methods:This prospective, randomized controlled trial was conducted at Hacettepe University (Ankara, Turkey). The study was carried out from August 2012 until March 2015 and included 24 Parkinson’s patients with stage 2–3 according to the Modified Hoehn&Yahr Rating Scale. The patients were divided into 2 groups (control and study). The control group received conventional physiotherapy; the study group received sensorimotor integration training combined with conventional physiotherapy, 2 times per week for 6 weeks. We assessed the patients with clinical balance tests and computerized dynamic posturography. Assessments were performed at baseline, 7- and 12-weeks follow-up.Results:Computerized dynamic posturography posturography values (5th and 6th positions, composite balance, and vestibular system scores) were higher in the study group than in the control group. The improvements were maintained at the 12-week follow up except 6th positions scores (p<0.05).Conclusions:Sensorimotor integration training combined with conventional physiotherapy approach ameliorated postural control by improving vestibular system in patients with Parkinson’s disease by improving sensory processes.

Postural instability is a symptom of Parkinson’s disease (PD) that causes severe disability.1 It involves a loss of postural control. The pathophysiology of postural instability in PD is complex and multi-factorial. Poor and slow anticipatory postural responses, inadequately organized automatic postural reactions, defective somatosensory integration and modulation of afferent sensory information, orthostatic hypotension, age-related sensory and postural changes, rigidity, and other Parkinsonian signs can occur in postural instability, resulting in an increase in its severity.2-3 Postural instability is poorly responsive to medications containing L-dopa. Therefore, other therapies, such as physiotherapy, have come into prominence.4 Many different modes of physiotherapy intervention can be used to decrease postural instability. This includes classical balance training, external cueing training, and movement strategy training.5 The most commonly used treatment is balance training.3,6 However, the pathophysiology of postural instability suggests that the therapeutic program for postural instability should be complex and multifaceted.The sensory integration training approach was devised by Jean Ayres to “take in, interpret, and integrate the spatial temporal aspect of sensory information from the body and the environment to plan and produce organized motor behaviors”.7 The approach usually used in children emphasizes the use of sensory and perceptual components to produce motor responses.8-9 The multi-sensory aspect of this approach could contribute to a decrease in postural instability in PD patients when considering the pathophysiology of postural instability. Sensorimotor integration training (SMIT) was created to keep in mind the principles of sensory integration training and the mechanisms of postural instability in PD. A pioneering study that we previously completed with fewer participants and no follow-up results has shown that SMIT has improved some parameters in Parkinson’s patients.10 Therefore, we planned this study was to investigate the short and long time effects of SMIT on postural instability in PD patients.     

Oxidative stress factors in Parkinson’s disease

Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.     

Recent Progress in Non-motor Features of Parkinson’s Disease with a Focus on Circadian Rhythm Dysregulation

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.     

Approaches to Disease Modification for Parkinson’s Disease: Clinical Trials and Lessons Learned

Despite many clinical trials over the last three decades, the goal of demonstrating that a treatment slows the progression of Parkinson’s disease (PD) remains elusive. Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. Here we review recent and ongoing clinical trials employing novel strategies toward disease modification, including those targeting alpha-synuclein and those repurposing drugs approved for other indications. Active and passive immunotherapy approaches are being studied with the goal to modify the spread of alpha-synuclein pathology in the brain. Classes of currently available drugs that have been proposed to have potential disease-modifying effects for PD include calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and cAbl tyrosine kinase inhibitors. The mechanistic diversity of these treatments offers hope, but to date, results from these trials have been disappointing. Nevertheless, they provide useful lessons in guiding future therapeutic development.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00964-w.Key Words: Alpha-synuclein, clinical trial, immunotherapy, neuroprotection, repurposing     

Clinical Aspects of the Differential Diagnosis of Parkinson’s Disease and Parkinsonism

Parkinsonism is a clinical syndrome presenting with bradykinesia, tremor, rigidity, and postural instability. Nonmotor symptoms have recently been included in the parkinsonian syndrome, which was traditionally associated with motor symptoms only. Various pathologically distinct and unrelated diseases have the same clinical manifestations as parkinsonism or parkinsonian syndrome. The etiologies of parkinsonism are classified as neurodegenerative diseases related to the accumulation of toxic protein molecules or diseases that are not neurodegenerative. The former class includes Parkinson’s disease (PD), multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Over the past decade, clinical diagnostic criteria have been validated and updated to improve the accuracy of diagnosing these diseases. The latter class of disorders unrelated to neurodegenerative diseases are classified as secondary parkinsonism, and include drug-induced parkinsonism (DIP), vascular parkinsonism, and idiopathic normal-pressure hydrocephalus (iNPH). DIP and iNPH are regarded as reversible and treatable forms of parkinsonism. However, studies have suggested that the absence of protein accumulation in the nervous system as well as managing the underlying causes do not guarantee recovery. Here we review the differential diagnosis of PD and parkinsonism, mainly focusing on the clinical aspects. In addition, we describe recent updates to the clinical criteria of various disorders sharing clinical symptoms with parkinsonism.     

Prodromal non-motor symptoms of Parkinson’s disease

The motor symptoms of Parkinson’s disease (PD), bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, the intraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascending gradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported. Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder. Additionally, the neuropathological alterations outside the substantia nigra are soundly correlated with the non-motor symptoms of PD. As a result of these findings, interest is growing in the identification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest that autonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleep behavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available to detect most of these symptoms. Thus, the identification of prodromal non-motor symptoms may contribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy of neuroprotective agents.     

The under-recognition of depression in Parkinson’s disease

Depression is common in patients with Parkinson’s disease (PD) and has been identified as the main factor negatively impacting quality of life. It has been reported that depression in PD is under-recognized and under-treated. We report on 90 patients with PD who completed the Geriatric Depression Rating Scale (GDS). Thirteen subjects (14%) scored above 15, the proposed cut-off for diagnosing depression in this illness. Detailed medical record review for these subjects revealed that depression was recognized and treated in only about one-half of the cases. Comparison of mean subscale scores between subjects scoring above and below the cut-off for diagnosis of depression revealed that each of 6 proposed subscales effectively distinguished the two groups. Review of individual items demonstrated that many of the subjects endorsed low energy, regardless of whether they were depressed. This study supports the notion that efforts should be made to educate patients, caregivers and physicians about identifying depression in PD. The routine use of a depression rating scale may facilitate the recognition of depression in this illness.     

Neuroprotective effects of curcumin on the cerebellum in a rotenone‐induced Parkinson’s Disease Model

AimsParkinson''s disease (PD) is the second most prevalent age‐related neurodegenerative disorder. The cerebellum plays a role in PD pathogenesis. Curcumin has numerous medicinal uses, mostly attributed to its potent antioxidant properties. This study investigated the potential protective influence of curcumin on the cerebellum of albino rats with rotenone‐induced PD.MethodsForty adult male albino rats were randomized into four treatment groups: vehicle (group I); rotenone 3 mg/kg/day i.p. injection (group II); rotenone 3 mg/kg/day plus curcumin 30 mg/kg/day i.p. injection (group III); and curcumin 30 mg/kg/day i.p. injection (group IV).ResultsCompared to group I, group II exhibited marked degenerative changes in hematoxylin & eosin‐stained sections and a reduction in Nissl granules in the Purkinje cells of the cerebellum. In group III, the neurotoxic effects in the cerebellum were reduced. Furthermore, the degenerated Purkinje and GFAP‐positive cells increased considerably in group II and were partially reduced in group III versus group II. Compared to group I, rats in group II showed reduced rotarod motor activity, partially restored in group III. Acetylcholine esterase, glutathione, and superoxide dismutase were significantly reduced, and malondialdehyde was significantly increased in group II compared to group I and was partially increased in group III.ConclusionCurcumin attenuated neurotoxic effects and degenerative histological changes and alleviated induced oxidative stress in the cerebellar cortex of a PD rat model. Therefore, curcumin dietary supplementation may have neuroprotective effects against the development of cerebellum‐related PD symptoms.