Psychoses in Parkinson's Disease

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD) and other degenerative parkinsonian disorders, usually but not exclusively in the context of their pharmacologic treatment. We describe the following six psychotic syndromes in PD based on existing literature: (1) hallucinations with preserved insight; (2) medication-induced psychotic disorders (in clear consciousness); (3) delirium; (4) schizophrenia-like psychotic disorders (in clear consciousness and in the absence of medication treatment); (5) schizophrenia with subsequent development of PD; and (6) other psychotic disorders. Psychosis in PD has been noted to be a marker for illness deterioration. Psychotic symptoms can profoundly affect the quality of life for PD patients and their families and may increase the economic burden of this illness. Various approaches have been used to treat psychotic symptoms in PD. We critically review this literature, which is limited, but includes studies indicating promise for "atypical" antipsychotics in these patients. Further elucidation of the phenomenology, course, pathophysiology, and treatment of the different psychotic disorders in PD is urgently needed.     

Exosomes in Parkinson's Disease

Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system(CNS). The proposed functions of these vesicles include roles in cell–cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids,and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson's disease(PD). Exosomes have been shown to spread toxic a-synuclein(asyn) between cells and induce apoptosis, which suggests a key mechanism underlying the spread of asyn aggregates in the brain and the acceleration of pathology in PD. However, potential neuroprotective roles of exosomes in PD have also been reported. On the treatment side, as drug delivery vehicles, exosomes have been used to deliver small interfering RNAs and catalase to the brain, and have shown clear therapeutic effects in a mouse model of PD. These features of exosomes in PD make them extremely interesting from the point of view of developing novel diagnostic and therapeutic approaches.     

Auditory Dysfunction in Parkinson's Disease

PD is a progressive and complex neurological disorder with heterogeneous symptomatology. PD is characterized by classical motor features of parkinsonism and nonmotor symptoms and involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates. Extensive evidence supports auditory dysfunction as an additional nonmotor feature of PD. Studies indicate a broad range of auditory impairments in PD, from the peripheral hearing system to the auditory brainstem and cortical areas. For instance, research demonstrates a higher occurrence of hearing loss in early-onset PD and evidence of abnormal auditory evoked potentials, event-related potentials, and habituation to novel stimuli. Electrophysiological data, such as auditory P3a, also is suggested as a sensitive measure of illness duration and severity. Improvement in auditory responses following dopaminergic therapies also indicates the presence of similar neurotransmitters (i.e., glutamate and dopamine) in the auditory system and basal ganglia. Nonetheless, hearing impairments in PD have received little attention in clinical practice so far. This review summarizes evidence of peripheral and central auditory impairments in PD and provides conclusions and directions for future empirical and clinical research. © 2020 International Parkinson and Movement Disorder Society     

Cell Therapy in Parkinson's Disease

Summary: The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson''s disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdraw l-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.     

Voiding Dysfunction in Parkinson's Disease

Abstract: A micturitional history of unselected 110 patients with Parkinson's disease revealed that 66 (60%) had urinary symptoms such as irritative in 28%, obstructive in 11%, and both symptoms in 21%. The frequency of urinary symptoms statistically correlated with severity of the disease, but not with the duration of illness and no sexual difference was noted. A urodynamic study was conducted in 39 patients and 7 had residual urine of 30 ml or more, 19 had detrusor hyperreflexia, 19 had a small bladder capacity and only 1 had detrusor-sphincter dyssynergia. The results indicate that the disturbed urine storage is more frequent and to a severer degree than that of urine evacuation in Parkinson's disease.     

Disease modification in Parkinson's disease

Several separate gene mutations have now been identified in familial Parkinson's disease and important environmental influences modulating risk for the idiopathic form of the disease have also been recognised. These insights have provided important clues in the development of disease modifying therapies. Some compounds have already been shown to potentially delay disease progression in early clinical trials. The most important challenge, particularly for those drugs that might have a symptomatic effect, is defining appropriate markers that will confirm a neuroprotective effect.     

New Frontiers in Parkinson's Disease

Journal of Neurology -     

Genetic Testing in Parkinson's Disease

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

PSMC1 Gene in Parkinson's Disease

Background: Impairment of the ubiquitin-proteasome system has been suggested to play an important role in the pathogenesis of Parkinson's disease (PD). The 26S proteasome regulatory subunit 1 is encoded by the gene PSMC1 in humans. PSMC1 knockout mice showed a PD-like phenotype. Our aim was to analyze the association between variations in this gene and the susceptibility to develop PD. Methods: We included 283 PD patients (165 males and 118 females) with a mean age of 63.6 ± 11.2 years (mean age at onset 55.4 ± 12.7 years), and 316 unrelated control subjects (193 males and 123 females) with a mean age of 61.5 ± 12.3 years. Four polymorphisms, providing haplotype information of PSMC1, were genotyped using TaqMan assays. Moreover, in order to identify new variations, all exons of the PSMC1 gene and their exon-intron boundaries were analyzed using high-resolution melting analysis. Results: Minor allele frequencies in PD patients and control subjects were similar. The gene coding sequence analysis showed no variation associated with the disease either. Conclusions: Our results suggest that there is no association between variations or haplotypes in the PSMC1 gene and PD, indicating that this gene is probably not involved in the pathogenesis of PD.     

Future Therapy in Idiopathic Parkinson's Disease

Journal of Neurology -