Mild Cognitive Impairment in Parkinson’s Disease

Prospective studies conducted during the last decade have shown that the majority of patients with Parkinson’s disease (PD) develop dementia. In addition, using a variety of definitions and methods, more recent research suggests that approximately a quarter of PD patients without dementia have mild cognitive impairment (PD-MCI). Furthermore, several studies have shown that approximately 20% have MCI even at time of diagnosis of PD. The typical cognitive deficits include visuospatial, attentional, and executive deficits, but memory deficits have also been shown. The etiology of PD-MCI is not known, but it is likely that mechanisms known to contribute to dementia in PD (ie, limbic and cortical Lewy bodies, amyloid plaques, and cholinergic deficits) play a role, in addition to dysfunction of dopaminergic frontostriatal circuits. PD-MCI predicts a shorter time to dementia, and preliminary evidence suggests that this is particularly true for posterior cognitive deficits. There are currently no systematic clinical trials in PD-MCI.     

Mild Cognitive Impairment in Parkinson’s Disease—What Is It?

Purpose of Review

Mild cognitive impairment is a common feature of Parkinson’s disease, even at the earliest disease stages, but there is variation in the nature and severity of cognitive involvement and in the risk of conversion to Parkinson’s disease dementia. This review aims to summarise current understanding of mild cognitive impairment in Parkinson’s disease. We consider the presentation, rate of conversion to dementia, underlying pathophysiology and potential biomarkers of mild cognitive impairment in Parkinson’s disease. Finally, we discuss challenges and controversies of mild cognitive impairment in Parkinson’s disease.

Recent Findings

Large-scale longitudinal studies have shown that cognitive involvement is important and common in Parkinson’s disease and can present early in the disease course. Recent criteria for mild cognitive impairment in Parkinson’s provide the basis for further study of cognitive decline and for the progression of different cognitive phenotypes and risk of conversion to dementia.

Summary

Improved understanding of the underlying pathology and progression of cognitive change are likely to lead to opportunities for early intervention for this important aspect of Parkinson’s disease.

     

Urate in Parkinson’s Disease: More Than a Biomarker?

Parkinson's disease (PD) is a progressive neurodegenerative disease with characteristic motor manifestations. Although appreciation of PD as a multisystem disorder has grown, loss of dopaminergic neurons in the substantia nigra remains a pathological and neurochemical hallmark, accounting for the substantial symptomatic benefits of dopamine replacement therapies. However, currently no treatment has been shown to prevent or forestall the progression of the disease in spite of tremendous efforts. Among multiple environmental and genetic factors that have been implicated in the pathogenesis of PD, oxidative stress is proposed to play a critical role. A recent confluence of clinical, epidemiological, and laboratory evidence identified urate, an antioxidant and end product of purine metabolism, as not only a molecular predictor for both reduced risk and favorable progression of PD but also a potential neuroprotectant for the treatment of PD. This review summarizes recent findings on urate in PD and their clinical implications.     

Neuroimaging in Parkinson’s Disease

Parkinson’s disease (PD) is a common disorder in which the primary features can be related to dopamine deficiency. Changes on structural imaging are limited, but a wealth of abnormalities can be detected using positron emission tomography, single photon emission computed tomography, or functional magnetic resonance imaging to detect changes in neurochemical pathology or functional connectivity. The changes detected on these studies may reflect the disease process itself and/or compensatory responses to the disease, or they may arise in association with disease- and/or treatment-related complications. This review will focus mainly on neurochemical and metabolic studies and reviews various approaches to the assessment of dopaminergic function as well as the function of other neurotransmitters that may be affected in PD. A number of clinical applications are highlighted, including diagnostic utility, identification of preclinical disease, changes associated with motor and nonmotor complications of PD, and the effects of various therapeutic interventions.     

Nutraceuticals in Parkinson’s Disease

Current pharmacological strategies for Parkinson’s disease (PD), the most common neurological movement disorder worldwide, are predominantly symptom relieving and are often plagued with undesirable side effects after prolonged treatment. Despite this, they remain as the mainstay treatment for PD due to the lack of better alternatives. Nutraceuticals are compounds derived from natural food sources that have certain therapeutic value and the advent of which has opened doors to the use of alternative strategies to tackle neurodegenerative diseases such as PD. Notably, nutraceuticals are able to position themselves as a “safer” strategy due to the fact that they are naturally derived compounds, therefore possibly having less side effects. Significant efforts have been put into better comprehending the role of nutraceuticals in PD, and we will look at some of them in this review. Broadly speaking, these compounds execute their positive effects via modulating signalling pathways, inhibiting oxidative stress, inflammation and apoptosis, as well as regulating mitochondrial homoeostasis. Importantly, we will highlight how a component of green tea, epigallocatechin-3-gallate (EGCG), confers neuroprotection in PD via its ability to activate AMP kinase and articulate how its beneficial effects in PD are possibly due to enhancing mitochondrial quality control.     

Risk factors for levodopa-induced dyskinesias in Parkinson’s disease

To identify putative risk factors for levodopa-induced dyskinesias we studied the effect of several clinical variables on the occurrence of dyskinesias in a series of 168 consecutive patients with Parkinson’s disease treated for at least 6 months with levodopa. Of these, 108 (64%) developed dyskinesias after a mean duration of levodopa treatment of 51.4 ± 43.3 months. Patients tended to suffer dyskinesias on the side of the body first affected by Parkinson’s disease. The overall probability of developing dyskinesias increased with levodopa treatment duration, about 10% per year during the first 7 years. Univariate and multivariate logistic regression analysis identified the age at onset of Parkinson’s disease (OR 0.923; 95% CI 0.883–0.964) and the initial levodopa dose (mean dose of the first 6 months of treatment; OR 1.004; 95% CI 1.002–1.006) as the main independent predictors. Survival curves showed that onset of Parkinson’s disease at age 50 years or before (logrank, P < 0.05) and initial levodopa treatment with more than 600 mg/day (logrank, P < 0.05) were associated with a higher risk for the appearance of dyskinesias. Received: 18 May 1999 Received in revised form: 7 June 1999 Accepted: 20 June 1999     

Common Variant in TREM1 Influencing Brain Amyloid Deposition in Mild Cognitive Impairment and Alzheimer’s Disease

Neurotoxicity Research - Triggering receptor expressed on myeloid cells-1 (TREM1) has been reported to associate with Alzheimer’s disease (AD) pathology. Recently, TREM1 variant rs2234246A...     

Palliative Care in Parkinson’s Disease

Palliative care for Parkinson disease (PD) is a new concept in neurodegenerative care. Abundant evidence exists supporting PD as increasing risk of death, most commonly from aspiration pneumonia despite improvements in motor and non-motor symptom management. Palliative care emphasizes an interdisciplinary and holistic approach to symptom management. In the following, the timing for considering palliative care, the communication surrounding this stage of illness, and assessing patients and caregivers will be discussed. Evaluation using the Edmonton Symptom Assessment Scale-PD can help practitioners identify symptoms requiring intervention and track their response to interventions. Adopting palliative care principles will allow neurologists to fulfill the needs of PD patients in advanced stages to the end of life.     

mTOR Signaling in Parkinson’s Disease

As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson’s disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.     

Gene-based Therapies in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurological disorder characterized primarily by the degeneration of nigrostriatal dopaminergic neurons and diminution of the neurotransmitter dopamine. Though dopamine replacement therapies such as levodopa can improve the symptoms of PD, the benefits may be overshadowed by side effects and the onset of symptoms not responsive to dopaminergic treatments (e.g., autonomic symptoms, gait and balance problems, and cognitive impairment). Furthermore, no therapies have proven to slow the neurodegenerative process. Novel approaches to address these difficult problems, and others, are being sought. Over the last decade, several innovative gene therapies for PD have entered human clinical trials in an effort to address both symptomatic and potential disease-modifying effects. Though the results of these trials have been mixed, the therapies have generally been safe and well-tolerated, suggesting gene therapy may be a viable treatment for PD in the future. This article will review past and current clinical trials of gene therapies for PD. In addition, novel preclinical approaches to gene therapy for PD will be described.     

Cell Therapeutics in Parkinson’s Disease

The main pathology underlying motor symptoms in Parkinson’s disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process long-term after implantation. Mechanisms underlying graft-induced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.     

Disturbances of Sleep and Alertness in Parkinson’s Disease

Purpose of Review

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Sleep dysfunction is one of the most common non-motor manifestations of PD that has gained significant interest over the past two decades due to its impact on the daily lives of PD patients, poorly understood mechanisms, and limited treatment options. In this review, we discuss the most common sleep disorders in PD and present recent investigations that have broadened our understanding of the epidemiology, clinical manifestations, diagnosis, and treatment of disturbed sleep and alertness in PD.

Resent Findings

The etiology of impaired sleep-wake cycles in PD is multifactorial. Sleep dysfunction in PD encompasses insomnia, REM sleep behavior disorder, sleep-disordered breathing, restless legs syndrome, and circadian dysregulation. Despite the high prevalence of sleep dysfunction in PD, evidence supporting the efficacy of treatment strategies is limited.

Summary

We are at the opportune time to advance our understanding of sleep dysfunction in PD, which will hopefully lead to mechanisms-driven interventions for better sleep and allow us to approach sleep as a modifiable therapeutic target for other non-motor and motor manifestations in PD.