GiOPARK Project: The Genetic Study of Parkinson's Disease in the Croatian Population.

Parkinson's disease is a neurological disorder that affects motor function, autonomic functions, and cognitive abilities. It is likely that both genetic and environmental factors, along with age, contribute to the cause. However, there is no comprehensive guideline for genetic testing for Parkinson's disease, and more research is needed to understand genetic variations in different populations. There has been no research on the genetic background of Parkinson's disease in Croatia so far. Therefore, with the GiOPARK project, we aimed to investigate the genetic variants responsible for Parkinson's disease in 153 Croatian patients with early onset, familial onset, and sporadic late-onset using whole-exome sequencing, along with multiplex ligation-dependent probe amplification and Sanger sequencing in select patients. We found causative variants in 7.84% of the patients, with GBA being the most common gene (4.58%), followed by PRKN (1.96%), ITM2B (0.65%), and MAPT (0.65%). Moreover, variants of uncertain significance were identified in 26.14% of the patients. The causative variants were found in all three subgroups, indicating that genetic factors play a role in all the analyzed Parkinson's disease subtypes. This study emphasizes the need for more inclusive research and improved guidelines to better understand the genetic basis of Parkinson's disease and facilitate more effective clinical management.

Applicability of clinical genetic testing for deep brain stimulation treatment in monogenic Parkinson's disease and monogenic dystonia: a multidisciplinary team perspective.

In this perspective article, we highlight the possible applicability of genetic testing in Parkinson's disease and dystonia patients treated with deep brain stimulation (DBS). DBS, a neuromodulatory technique employing electrical stimulation, has historically targeted motor symptoms in advanced PD and dystonia, yet its precise mechanisms remain elusive. Genetic insights have emerged as potential determinants of DBS efficacy. Known PD genes such as GBA, SNCA, LRRK2, and PRKN are most studied, even though further studies are required to make firm conclusions. Variable outcomes depending on genotype is present in genetic dystonia, as DYT-TOR1A, NBIA/DYTPANK2, DYT-SCGE and X-linked dystonia-parkinsonism have demonstrated promising outcomes following GPi-DBS, while varying outcomes have been documented in DYT-THAP1. We present two clinical vignettes that illustrate the applicability of genetics in clinical practice, with one PD patient with compound GBA mutations and one GNAL dystonia patient. Integrating genetic testing into clinical practice is pivotal, particularly with advancements in next-generation sequencing. However, there is a clear need for further research, especially in rarer monogenic forms. Our perspective is that applying genetics in PD and dystonia is possible today, and despite challenges, it has the potential to refine patient selection and enhance treatment outcomes.

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

Post-COVID-19 Syndrome in Neurology Patients: A Single Center Experience.

Our aim was to determine the frequency and characteristics of neurological post-COVID-19 syndrome and the diagnostic and therapeutic measures that were used for the treatment of these patients. Data were collected for 243 patients examined during the period of 11 May 2021 to 22 June 2022. The inclusion criteria were COVID-19 illness and neurological symptoms associated with COVID-19. The exclusion criteria were non-neurological symptoms, patients who did not suffer from COVID-19, and symptoms that occurred after vaccination against the SARS-CoV-2 virus. Data for 227 patients with neurological post-COVID-19 symptoms were analyzed. Most patients presented with multiple symptoms, most often headache, cognitive impairment, loss of smell, paresthesia, fatigue, dizziness, and insomnia. Patients were most often referred for consultative examinations, neuroradiological imaging, and EEG. The therapy was mostly symptomatic. Most patients had no change in their symptoms on follow-up visits (53.21%), while positive outcome was found in 44.95% of patients. This study found that neurological post-COVID-19 syndrome appears to be more common in women, and generally, the most common symptoms are headache and cognitive impairment. The gender distribution of symptoms was clearly visible and should be further investigated. There is a need for longitudinal follow-up studies to better understand the disease dynamic.

GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature.

Introduction: Dystonia is the third most common pediatric movement disorder and is often difficult to treat. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been demonstrated as a safe and effective treatment for genetic dystonia in adolescents and adults. The results of DBS in children are limited to individual cases or case series, although it has been proven to be an effective procedure in carefully selected pediatric cohorts. The aim of our study was to present the treatment outcome for 7- to 9-year-old pediatric patients with disabling monogenic isolated generalized DYT-THAP1 and DYT-KMT2B dystonia after bilateral GPi-DBS. Patients and results: We present three boys aged <10 years; two siblings with disabling generalized DYT-THAP1 dystonia and a boy with monogenic-complex DYT-KMT2B. Dystonia onset occurred between the ages of 3 and 6. Significantly disabled children were mostly dependent on their parents. Pharmacotherapy was inefficient and patients underwent bilateral GPi-DBS. Clinical signs of dystonia improved significantly in the first month after the implantation and continued to maintain improved motor functions, which were found to have improved further at follow-up. These patients were ambulant without support and included in everyday activities. All patients had significantly lower Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) values, indicating >25% improvement over the first 15 months. However, there was a decline in speech and upper limb function, manifesting with bradylalia, bradykinesia, and dysphonia, which decreased after treatment with trihexyphenidyl. Conclusion: Although reports of patients with monogenic dystonia, particularly DYT-THAP1, treated with DBS are still scarce, DBS should be considered as an efficient treatment approach in children with pharmacoresistent dystonia, especially with generalized monogenic dystonia and to prevent severe and disabling symptoms that reduce the quality of life, including emotional and social aspects. Patients require an individual approach and parents should be properly informed about expectations and possible outcomes, including relapses and impairments, in addition to DBS responsiveness and related improvements. Furthermore, early genetic diagnosis and the provision of appropriate treatments, including DBS, are mandatory for preventing severe neurologic impairments.

The effects of microbiota abundance on symptom severity in Parkinson's disease: A systematic review.

Introduction: Parkinson's disease (PD) is neurodegenerative disease with a multifactorial etiopathogenesis with accumulating evidence identifying microbiota as a potential factor in the earliest, prodromal phases of the disease. Previous research has already shown a significant difference between gut microbiota composition in PD patients as opposed to healthy controls, with a growing number of studies correlating gut microbiota changes with the clinical presentation of the disease in later stages, through various motor and non-motor symptoms. Our aim in this systematic review is to compose and assess current knowledge in the field and determine if the findings could influence future clinical practice as well as therapy in PD. Methods: We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria. Results: 20 studies were included in this systematic review according to the selected inclusion and exclusion criteria. The search yielded 18 case control studies, 1 case study, and 1 prospective case study with no controls. The total number of PD patients encompassed in the studies cited in this review is 1,511. Conclusion: The link between gut microbiota and neurodegeneration is a complex one and it depends on various factors. The relative abundance of various microbiota taxa in the gut has been consistently shown to have a correlation with motor and non-motor symptom severity. The answer could lie in the products of gut microbiota metabolism which have also been linked to PD. Further research is thus warranted in the field, with a focus on the metabolic function of gut microbiota in relation to motor and non-motor symptoms.

A multicenter study of genetic testing for Parkinson's disease in the clinical setting.

Parkinson's disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected.

Cognitive Impact of Deep Brain Stimulation in Parkinson's Disease Patients: A Systematic Review.

Introduction: Parkinson's disease (PD) patients have a significantly higher risk of developing dementia in later disease stages, leading to severe impairments in quality of life and self-functioning. Questions remain on how deep brain stimulation (DBS) affects cognition, and whether we can individualize therapy and reduce the risk for adverse cognitive effects. Our aim in this systematic review is to assess the current knowledge in the field and determine if the findings could influence clinical practice. Methods: We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria. Results: Sixty-seven studies were included in this systematic review according to the selected criteria. This includes 6 meta-analyses, 18 randomized controlled trials, 17 controlled clinical trials, and 26 observational studies with no control arms. The total number of PD patients encompassed in the studies cited in this review is 3677, not including the meta-analyses. Conclusion: Cognitive function in PD patients can deteriorate, in most cases mildly, but still impactful to the quality of life. The strongest evidence is present for deterioration in verbal fluency, while inconclusive evidence is still present for executive function, memory, attention and processing speed. Global cognition does not appear to be significantly impacted by DBS, especially if cognitive screening is performed prior to the procedure, as lower baseline cognitive function is connected to poor outcomes. Further randomized controlled studies are required to increase the level of evidence, especially in the case of globus pallidus internus DBS, pedunculopontine nucleus DBS, and the ventral intermediate nucleus of thalamus DBS, and more long-term studies are required for all respective targets.

Effect of the coronavirus disease 2019 pandemic on people with Parkinson's disease: experience from a Croatian regional center.

AIM: To assess the effect of social isolation due to the coronavirus disease 2019 (COVID-19) pandemic on physical and mental health of Parkinson's disease patients treated at the University Hospital Center Rijeka. METHODS: This cross-sectional telephone study involved Parkinson's disease patients who had at least one control examination at University Hospital Center Rijeka in 2020 and were Croatian citizens. A questionnaire was used to obtain data on the socio-demographic characteristics and the severity of motor, anxiety, depression, and non-motor symptoms. RESULTS: The final sample included 87 patients. Most patients reported subjective worsening of motor symptoms. Patients who lived alone had worse motor scores than those not living alone. The majority of patients reported worsening of anxiety symptoms. Significant worsening of anxiety symptoms was found in patients who lived alone, had a longer disease duration, and had avoided check-ups. Fewer patients had depression symptoms than motor and anxiety symptoms. Significantly higher Hamilton Depression Rating Scale scores were observed in patients with a longer disease duration. Significant worsening of non-motor symptoms was identified in patients who lived alone, were less educated, had a longer disease duration, and had a higher Charlson comorbidity index. CONCLUSION: Patients who live alone, have longer disease duration, are less educated, avoid check-ups, and have more comorbidities are more vulnerable to the negative effects of social isolation.

A Systematic Review of Parkinson's Disease Pharmacogenomics: Is There Time for Translation into the Clinics?

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.