Decreased brain volume may be associated with the occurrence of peri-lead edema in Parkinson's disease patients with deep brain stimulation.

BACKGROUND: Peri-lead edema (PLE) is a poorly understood complication of deep brain stimulation (DBS), which has been described in patients presenting occasionally with profound and often delayed symptoms with an incidence ranging from 0.4% up to even 100%. Therefore, our study aims to investigate the association of brain and brain compartment volumes on magnetic resonance imaging (MRI) with the occurrence of PLE in Parkinson's disease (PD) patients after DBS implantation in subthalamic nuclei (STN). METHODS: This retrospective study included 125 consecutive PD patients who underwent STN DBS at the Department of Neurosurgery, Dubrava University Hospital from 2010 to 2022. Qualitative analysis was done on postoperative MRI T2-weighted sequence by two independent observers, marking PLE on midbrain, thalamus, and subcortical levels as mild, moderate, or severe. Quantitative volumetric analysis of brain and brain compartment volumes was conducted using an automated CIVET processing pipeline on preoperative MRI T1 MPRAGE sequences. In addition, observed PLE on individual hemispheres was delineated manually and measured using Analyze 14.0 software. RESULTS: In our cohort, PLE was observed in 32.17%, mostly bilaterally. Mild PLE was observed in the majority of patients, regardless of the level observed. Age, sex, diabetes, hypertension, vascular disease, and the use of anticoagulant/antiplatelet therapy showed no significant association with the occurrence of PLE. Total grey matter volume showed a significant association with the PLE occurrence (r = -0.22, p = 0.04), as well as cortex volume (r = -0.32, p = 0.0005). Cortical volumes of hemispheres, overall hemisphere volumes, as well as hemisphere/total intracranial volume ratio showed significant association with the PLE occurrence. Furthermore, the volume of the cortex and total grey volume represent moderate indicators, while hemisphere volumes, cortical volumes of hemispheres, and hemisphere/total intracranial volume ratio represent mild to moderate indicators of possible PLE occurrence. CONCLUSION: The results of our study suggest that the morphometric MRI measurements, as a useful tool, can provide relevant information about the structural status of the brain in patients with PD and represent moderate indicators of possible PLE occurrence. Identifying patients with greater brain atrophy, especially regarding grey matter before DBS implantation, will allow us to estimate the possible postoperative symptoms and intervene in a timely manner. Further studies are needed to confirm our findings and to investigate other potential predictors and risk factors of PLE occurrence.

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.

Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells.

Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn's disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. METHODS: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 µM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. RESULTS: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOShighCD206low) to quiescent anti-inflammatory M2 phenotype (iNOSlowCD206high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. CONCLUSION: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions.

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.

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells.

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.

Potential pathophysiological mechanisms leading to increased COVID-19 susceptibility and severity in obesity.

As we are facing worldwide pandemic of COVID-19, we aimed to identify potential pathophysiological mechanisms leading to increased COVID-19 susceptibility and severity in obesity. Special emphasis will be given on increased susceptibility to infections due to obesity-related low-grade chronic inflammation, higher expression of angiotensin converting enzyme-2 and pathway-associated components, as well as decreased vitamin D bioavailability, since all of them provide easier ways for the virus to enter into host cells, replicate and stunt adequate immune responses.

Immunometabolic phenotype of BV-2 microglia cells upon murine cytomegalovirus infection.

Microglia are resident brain macrophages with key roles in development and brain homeostasis. Cytomegalovirus (CMV) readily infects microglia cells, even as a possible primary target of infection in development. Effects of CMV infection on a cellular level in microglia are still unclear; therefore, the aim of this research was to assess the immunometabolic changes of BV-2 microglia cells following the murine cytomegalovirus (MCMV) infection. In light of that aim, we established an in vitro model of ramified BV-2 microglia (BV-2∅FCS, inducible nitric oxide synthase (iNOSlow), arginase-1 (Arg-1high), mannose receptor CD206high, and hypoxia-inducible factor 1α (HIF-1αlow)) to better replicate the in vivo conditions by removing FCS from the cultivation media, while the cells cultivated in 10% FCS DMEM displayed an ameboid morphology (BV-2FCS high, iNOShigh, Arg-1low, CD206low, and HIF-1αhigh). Experiments were performed using both ramified and ameboid microglia, and both of them were permissive to productive viral infection. Our results indicate that MCMV significantly alters the immunometabolic phenotypic properties of BV-2 microglia cells through the manipulation of iNOS and Arg-1 expression patterns, along with an induction of a glycolytic shift in the infected cell cultures.

Retrospective Analysis of the Effectiveness and Tolerability of Long-Acting Paliperidone Palmitate Antipsychotic in Adolescent First-Episode Schizophrenia Patients.

OBJECTIVE: The aim of this study was to explore the effectiveness and tolerability of long-acting paliperidone palmitate antipsychotic in adolescent first-episode schizophrenia patients while comparing the results with the oral antipsychotic risperidone. METHODS: This study is a retrospective, noninterventional study to assess the effectiveness and tolerability of long-acting injectable antipsychotic paliperidone palmitate in first-episode adolescent patients during the first 12 months of treatment compared with the oral antipsychotic risperidone. The data include general sociodemographic characteristics, number of hospitalizations, side effects, and the following clinical scales: Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), Clinical Global Impression Improvement and Severity (CGI-I and CGI-S), and Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: During the 12-month study period significant improvement was registered in patients receiving both paliperidone palmitate and risperidone in the following scales: PANSS, PSP, CGI-I, and CGI-S. Patients receiving paliperidone palmitate had significantly greater improvement in PANSS, CGI-S, and PSP compared with the risperidone group. Patients receiving risperidone had significantly higher number of hospitalizations than the patients receiving paliperidone palmitate. The TSQM revealed that the patients who were receiving paliperidone palmitate achieved significantly higher scores on the convenience scale, global satisfaction, and on the overall result, whereas no difference was observed on the effectiveness scale. There were several side effects reported for paliperidone (5.5% hyperprolactinemia, 5.5% weight gain) and risperidone (5.5% hyperprolactinemia, 16.7% weight gain). CONCLUSIONS: In conclusion, paliperidone palmitate seems to be safe and effective in adolescent patients. Furthermore, it compared favorably with risperidone in the clinical response, side effects, and hospitalizations.

Values of vanillylmandelic acid and homovanillic acid in the urine as potential prognostic biomarkers in ischaemic stroke patients.

BACKGROUND: Suitable biomarkers that have prognostic values are one of the key points of interest in ischaemic stroke. Increased sympathetic nervous system activity in ischaemic stroke causes multiple local and systemic effects that can be detrimental to the outcome. The mechanism of action is increased secretion and activity of catecholamines, whose end metabolic products are vanillylmandelic acid and homovanilic acid. Aim of our study was to determine whether these compounds can be used as potential prognostic biomarkers in ischaemic stroke, as a unique insight into the activity of the sympathetic nervous system. METHODS: Urine samples of 96 patients with ischaemic stroke and transitory ischaemic attacks were analysed. Values of vanillylmandelic and homovanillic acids in urine were tested using liquid chromatography on the first and third day post-stroke. Severity of stroke was determined using the NIHSS scale, while functional outcome was determined using the Modified Rankin Scale. RESULTS: Values of vanillylmandelic and homovanillic acids positively correlated with functional outcome of ischaemic stroke. Favorable outcomes correlated with decreased values, on contrary to increased values, which were associated with unfavourable outcomes. CONCLUSION: Determining the values of these compounds in the urine is an easily available prognostic tool for the ischaemic stroke outcome, while also influencing potential therapeutic changes.