Advanced stages of PD: interventional therapies and related patient-centered care.

During the last decades, symptomatic treatment of motor symptoms of Parkinson's disease (PD) improved continuously and is reflected by long-range independency of the patient during the disease course. However, advanced stages of PD still represent an important challenge to patients, caregivers and treating physicians. In patients with advanced PD, interventional therapy strategies are increasingly applied. These device-related treatment strategies using pump-based continuous dopaminergic stimulation (CDS) or deep brain stimulation (DBS) opened new treatment options especially if motor complications predominate. Well-designed clinical studies on these interventional therapeutic approaches provided class 1 evidence for the efficacy of DBS and CDS in advanced PD and opened new perspectives for their use in earlier disease stages also. Therefore, careful selection of patients amenable to the (semi)invasive therapy options becomes more and more important and requires an interdisciplinary setting that accounts for (i) optimal patient information and awareness, (ii) selection of best individual treatment modality, (iii) training of relatives and caregivers, (iv) management of complications, and (v) follow-up care. Here, we address these topics by summarizing current state-of-the-art in patient selection, providing specificities of treatment options and troubleshooting, and defining steps towards an optimized patient-centered care. Interventional therapies pioneer in the area of individualized treatment approaches for PD, and may be complemented in the future by biomarker-based improved stratification and by closed-loop systems for adaptive therapeutic strategies. In the present review, we summarize the proceedings of an Expert Workshop on Parkinson's disease held on November 22, 2014 in Frankfurt, Germany.

Prevalidation of a human cornea construct as an alternative to animal corneas for in vitro drug absorption studies.

The use of ophthalmic drugs has increased consistently over the past few decades. Currently, most research is conducted using in vivo and ex vivo animal experiments; however, they have many disadvantages, including ethical concerns, high costs, the questionable extension of animal results to humans, and poor standardization. Although several cell culture-based cornea models have been developed, none have been validated and accepted for general use. In this study, a standardized, three-dimensional model of the human cornea (Hemicornea, HC) based on immortalized human corneal cells and cultivated in serum-free conditions was developed for drug absorption studies and prevalidated using compounds with a wide range of molecular characteristics (sodium fluorescein, rhodamine B, fluorescein isothiocyanate-labeled dextran, aciclovir, bimatoprost, dexamethasone, and timolol maleate). The HC model was independently cultured in three different laboratories, and the intralaboratory and interlaboratory reproducibility was analyzed and compared with the rabbit cornea. This analysis showed that the HC has a barrier in the same range as excised animal corneas, although with a higher reproducibility and lower variability. Because of the demonstrated transferability, the HC represents a promising in vitro alternative to the use of ex vivo tissue and offers a well-defined and standardized system for drug absorption studies.

Development of a serum-free human cornea construct for in vitro drug absorption studies: the influence of varying cultivation parameters on barrier characteristics.

The increased use of ophthalmic products in recent years has led to an increased demand for in vitro and in vivo transcorneal drug absorption studies. Cell-culture models of the human cornea can avoid several of the disadvantages of widely used animal experimental models, including ethical concerns and poor standardisation. This study describes the development of a serum-free cultivated, three-dimensional human cornea model (Hemicornea, HC) for drug absorption experiments. The impact of varying cultivation conditions on the corneal barrier function was analysed and compared with excised rabbit and porcine corneas. The HC was cultivated on permeable polycarbonate filters using immortalised human keratocytes and a corneal epithelial cell line. The equivalence to native tissue was investigated through absorption studies using model substances with a wide range of molecular characteristics, including hydrophilic sodium fluorescein, lipophilic rhodamine B and fluorescein isothiocyanate (FITC)-labelled macromolecule dextran. To study the intra-laboratory repeatability and construct cultivation, the permeation studies were performed independently by different researchers. The HC exhibited a permeation barrier in the same range as excised animal corneas, high reproducibility and a lower standard deviation. Therefore, the HC could be a promising in vitro alternative to ex vivo corneal tissues in preclinical permeation studies.

In vitro cell culture models to study the corneal drug absorption.

INTRODUCTION: Many diseases of the anterior eye segment are treated using topically applied ophthalmic drugs. For these drugs, the cornea is the main barrier to reaching the interior of the eye. In vitro studies regarding transcorneal drug absorption are commonly performed using excised corneas from experimental animals. Due to several disadvantages and limitations of these animal experiments, establishing corneal cell culture models has been attempted as an alternative. AREAS COVERED: This review summarizes the development of in vitro models based on corneal cell cultures for permeation studies during the last 20 years, starting with simple epithelial models and moving toward complex organotypical 3D corneal equivalents. EXPERT OPINION: Current human 3D corneal cell culture models have the potential to replace excised animal corneas in drug absorption studies. However, for widespread use, the contemporary validation of existent systems is required.

Lewy body dementia and Parkinson's disease with dementia.

Parkinson's disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders frequently complicate the course of the disease. In particular, psychiatric disturbances including cognitive impairment, depression and psychosis impact these patients considerably. Approximately 31 % of PD patients suffer from cognitive impairment and dementia. Currently, two different clinical presentations are distinguished in PD patients, who present with dementia: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which are two different presentations of a single underlying disease process leading to the deposition of alpha-synuclein. Clinically, PDD is distinguished from DLB alone by the different temporal manifestations of extrapyramidal motor symptoms. Dementia is characterized by a subtle onset and progressive cognitive decline with a predominant dysexecutive syndrome, which can be accompanied by different behavioral symptoms such as hallucinations, depression, anxiety and sleep disorders. Dysregulation of different neurotransmitters has been associated with cognitive decline, but reduced cholinergic transmission is currently thought to be the pivotal mechanism in the development of cognitive dysfunction. Therefore, cholinesterase inhibitors are used in the treatment of dementia and accompanying behavioral symptoms in PDD and DLB. The occurrence of dementia impacts not only the patients themselves but also their care-givers and family.This article focuses on the clinical issues related to both disorders and is based on a meeting of experts which took place in April 2008 in Dresden.

Diagnostic aspects of early Parkinson's disease.

Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i. e., visual and olfactory dysfunction, with a resulting change of personal behavior, i. e., reduced stress tolerance, precede the initially intermittently occurring motor symptoms in patients with Parkinson's disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. This underlines the clinical concept of an initial premotor phase, which starts in nondopaminergic areas in PD. Moreover a more global general understanding of chronic neurodegeneration enables the performance of clinical trials on neuroprotection, since there is increasing evidence that diagnosis of PD at the threshold of onset of motor symptoms or cognitive symptoms in Alzheimer's disease is too late. Such an earlier diagnosis of chronic neurodegeneration will allow a more convincing demonstration of the efficacy of a neuroprotective or disease modifying compound. It will also support the concept of a clinically effective pharmacological intervention on a disease process, which is also more and more demanded by the health authorities for drug approval.