Asymmetry in Atypical Parkinsonian Syndromes-A Review.

Background/Objectives: Atypical parkinsonian syndromes (APSs) are a group of neurodegenerative disorders that differ from idiopathic Parkinson's disease (IPD) in their clinical presentation, underlying pathology, and response to treatment. APSs include conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). These disorders are characterized by a combination of parkinsonian features and additional symptoms, such as autonomic dysfunction, supranuclear gaze palsy, and asymmetric motor symptoms. Many hypotheses attempt to explain the causes of neurodegeneration in APSs, including interactions between environmental toxins, tau or α-synuclein pathology, oxidative stress, microglial activation, and vascular factors. While extensive research has been conducted on APSs, there is a limited understanding of the symmetry in these diseases, particularly in MSA. Neuroimaging studies have revealed metabolic, structural, and functional abnormalities that contribute to the asymmetry in APSs. The asymmetry in CBS is possibly caused by a variable reduction in striatal D2 receptor binding, as demonstrated in single-photon emission computed tomography (SPECT) examinations, which may explain the disease's asymmetric manifestation and poor response to dopaminergic therapy. In PSP, clinical dysfunction correlates with white matter tract degeneration in the superior cerebellar peduncles and corpus callosum. MSA often involves atrophy in the pons, putamen, and cerebellum, with clinical symmetry potentially depending on the symmetry of the atrophy. The aim of this review is to present the study findings on potential symmetry as a tool for determining potential neuropsychological disturbances and properly diagnosing APSs to lessen the misdiagnosis rate. Methods: A comprehensive review of the academic literature was conducted using the medical literature available in PubMed. Appropriate studies were evaluated and examined based on patient characteristics and clinical and imaging examination outcomes in the context of potential asymmetry. Results: Among over 1000 patients whose data were collected, PSP-RS was symmetrical in approximately 84% ± 3% of cases, with S-CBD showing similar results. PSP-P was symmetrical in about 53-55% of cases, while PSP-CBS was symmetrical in fewer than half of the cases. MSA-C was symmetrical in around 40% of cases. It appears that MSA-P exhibits symmetry in about 15-35% of cases. CBS, according to the criteria, is a disease with an asymmetrical clinical presentation in 90-99% of cases. Similar results were obtained via imaging methods, but transcranial sonography produced different results. Conclusions: Determining neurodegeneration symmetry may help identify functional deficits and improve diagnostic accuracy. Patients with significant asymmetry in neurodegeneration may exhibit different neuropsychological symptoms based on their individual brain lateralization, impacting their cognitive functioning and quality of life.

Current Perspectives on Olfactory Loss in Atypical Parkinsonisms-A Review Article.

INTRODUCTION: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. STATE OF THE ART: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. CLINICAL SIGNIFICANCE: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. FUTURE DIRECTIONS: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies.

The possible connection between neutrophil-to-high-density lipoprotein ratio and cerebral perfusion in clinically established corticobasal syndrome: a pilot study.

Introduction: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are tauopathic atypical parkinsonisms. Given their overlap in terms of clinical manifestation, there is growing interest in the mechanisms leading to these entities. Materials and methods: In total, 71 patients were included in the study, 19 of whom were clinically diagnosed with CBS, 37 with PSP, and 15 with Parkinson's disease (PD). The mean ages of the participants were 72.8, 72.9, and 64.0 years, respectively, and the disease duration varied from 3 to 6 years. Each individual underwent blood collection. Morphological and biochemical evaluation of blood samples was performed to analyze the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-high-density lipoprotein ratio (NHR). A single-photon emission computed tomography (SPECT) with technetium-99m hexamethylpropyleneamine oxime (99Tc-HMPAO) tracer was used to assess perfusion in two regions of interest (ROI): the thalamus and insula. Using Pearson correlation to assess the linear relationship between NHR and perfusion in the insula and thalamus for CBS, PSP, and PD patients, the authors intended to verify possible correlations between NLR, PLR, and NHR and perfusion in the indicated ROIs. Results: The study revealed a negative linear correlation between NHR and perfusion of both the left (Insula L; R = -0.59) and right (Insula R; R = -0.58) insula regions. Similar to the insula, a linear correlation between NHR and activity in both the left (Thalamus L) and right (Thalamus R) thalamus regions in CBS subjects with a relatively stronger correlation in the right thalamus (R = -0.64 vs. R = -0.58) was found. These observations were not confirmed in PSP and PD patients. Conclusion: Simultaneously using non-specific parameters for peripheral inflammation (NLR, PLR, and NHR) and perfusion, SPECT may be an interesting beginning point for further analysis of inflammatory disease mechanisms. To the best of our knowledge, this is the first study to address the potential correlation between the peripheral neuroinflammatory markers NLR, PLR, and NHR and perfusion disturbances in particular ROIs.

The Possible Associations between Tauopathies and Atherosclerosis, Diabetes Mellitus, Dyslipidemias, Metabolic Syndrome and Niemann-Pick Disease.

Clinical evaluation and treatment of tauopathic syndromes remain a challenge. There is a growing interest in theories concerning their possible associations with metabolic diseases. The possible connection between those diseases might be linked with cerebrovascular dysfunction. The endothelial cell damage and impairment of the blood-brain barrier observed in atherosclerosis or diabetes may play a role in contributing to tauopathic syndrome development. Additionally, the inflammation evoked by pathological metabolic changes may also be involved in this process. Multiple cases indicate the coexistence of metabolic disorders and tauopathic syndromes. These findings suggest that modifying the evolution of metabolic and cerebrovascular diseases may impact the course of neurodegenerative diseases. Obtained data could indicate the possible benefits of introducing routine carotid artery sonography, revascularization operation or antihypertensive medications among patients at high risk for tauopathies. This review has identified this understudied area, which is currently associated with several diseases for which there is no treatment. Due to the pathomechanisms linking metabolic diseases and tauopathies, further investigation of this area of research, including cohort studies, is recommended and may provide new pharmacological perspectives for treatment.

The associations between common neuroimaging parameters of Progressive Supranuclear Palsy in magnetic resonance imaging and non-specific inflammatory factors - pilot study.

Progressive Supranuclear Palsy is an atypical parkinsonism based on tauopathic pathology. Growing interest is associated with the pathomechanism of this disease. Among theories analyzing this issue can be mentioned the one highlighting the significance of inflammation. In this study authors examined 14 patients with PSP-Richardson syndrome (PSP-RS) and 13 healthy volunteers using laboratory testing based on the analysis of interleukins 1 and 6 (IL-1 and IL-6), tau in the cerebrospinal fluid (CSF) and non-specific parameters of peripheral inflammation in the serum (IL-1, IL-6, neutrophils, lymphocytes, monocytes, platelets and the ratios based on the factors). All of the patients underwent neuroimaging using magnetic resonance imaging using 3 Tesla. The serum levels of IL-1 were positively correlated with the area of the mesencephalon, suggesting that higher levels of IL-1 are not linked with atrophic changes in this region, whereas serum levels IL-6 was positively correlated with frontal horn width and negatively correlated with superior cerebellar area. Additionally IL-6 in the serum was found to be correlated with neutrophil-to-high density lipoprotein ratio. The observations were not confirmed in the analysis of the levels of interleukins in the CSF. To the best of our knowledge this work is one of the first analyzing this issue. The outcome of the work shows that the role of interleukins associated with microglial activation may possibly differ in the context of neurodegenerative changes, moreover the role of peripheral inflammation in PSP requires further analysis.

The potential significance of hepcidin evaluation in progressive supranuclear palsy.

INTRODUCTION: Hepcidin is a peptide associated with controlling the distribution of iron in tissues. Growing interest is linked with its impact on neurodegenerative diseases, as disruption of the iron regulation may be considered an initiatory element of pathological protein accumulation. The possible impact of hepcidin was not previously sufficiently explored in progressive supranuclear palsy (PSP). METHODS: Twelve patients with PSP-Richardson's syndrome (PSP-RS), 12 with PSP-Parkinsonism Predominant (PSP-P), and 12 controls were examined using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III) in OFF stage and analyzed in the context of hepcidin levels in the serum. RESULTS: The work revealed increased levels of hepcidin in PSP-RS when compared to PSP-P and controls. Moreover, hepcidin was found to be negatively correlated with UPDRS-III results in PSP-RS, whereas positively in PSP-P. CONCLUSION: The work may suggest a possible impact of hepcidin in PSP, possibly differing depending on its subtype.

The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson's Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.

Glucose Metabolism and Cognitive Decline in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Preliminary Study.

Multiple studies have analyzed the possible correlations between diabetes and Alzheimer's disease. Less is known about the context of cognitive deterioration among patients with atypical Parkinsonian syndromes and glucose metabolism impairment. The aim of this study was to evaluate the association between the impaired glucose metabolism and cognitive decline among patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The study included 22 patients with PSP and CBS with disease durations varying from 3 to 6 years. The levels of glycated hemoglobin (HbA1C), fasting blood glucose, fasting C-peptide and the presence of microalbuminuria were evaluated, and oral glucose tolerance tests (OGTT) were performed. Based on the OGTT results, the glycemic variability, mean glycemia, glycemia standard deviation (SD) and coefficient of variation (%CV) were calculated. All patients underwent a three-Tesla brain magnetic resonance (MRI) examination and neuropsychological cognitive assessment with the use of standardized scales: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). A statistical analysis revealed that poor control of glycemia with high glycemic variability and increased atrophy of the medial temporal lobe among patients with PSP and CBS correlated with worse cognitive performance independent of age or sex, even among patients who did not fulfill the criteria for diabetes. The study results indicate the importance of glucose metabolism control and optimal treatment in the context of cognition maintenance among patients with PSP and CBS. Due to the relatively small number of analyzed patients, the issue requires further assessment. To the best of our knowledge, this is the first study discussing the role of glycemic variability in atypical Parkinsonian syndromes.

Clinical Phenotypes of Progressive Supranuclear Palsy-The Differences in Interleukin Patterns.

Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome based on tau pathology; its clinical phenotype differs, but PSP with Richardson's syndrome (PSP-RS) and the PSP parkinsonism predominant (PSP-P) variant remain the two most common manifestations. Neuroinflammation is involved in the course of the disease and may cause neurodegeneration. However, an up-to-date cytokine profile has not been assessed in different PSP phenotypes. This study aimed to evaluate possible differences in neuroinflammatory patterns between the two most common PSP phenotypes. Serum and cerebrospinal fluid (CSF) concentrations of interleukin-1 beta (IL-1ß) and IL-6 were analyzed using enzyme-linked immunosorbent assay (ELISA) kits in 36 study participants-12 healthy controls and 24 patients with a clinical diagnosis of PSP-12 PSP-RS and 12 PSP-P. Disease duration among PSP patients ranged from three to six years. All participants underwent basic biochemical testing, and neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values were calculated. Due to a lack of neuropathological examinations, as all patients remain alive, total tau levels were assessed in the CSF. Tau levels were significantly higher in the PSP-P and PSP-RS groups compared to the healthy controls. The lowest concentrations of serum and CSF interleukins were observed in PSP-RS patients, whereas PSP-P patients and healthy controls had significantly higher interleukin concentrations. Furthermore, there was a significant correlation between serum IL-6 levels and PLR in PSP-RS patients. The results indicate the existence of distinct neuroinflammatory patterns or a neuroprotective role of increased inflammatory activity, which could cause the differences between PSPS phenotypes and clinical course. The causality of the correlations described requires further studies to be confirmed.

The Role of the Evans Index and the Maximal Width of the Frontal Horns of the Lateral Ventricles in the Diagnostic Imaging of Progressive Supranuclear Palsy and Multiple-System Atrophy.

Progressive Supranuclear Palsy and Multiple-System Atrophy are entities within the spectrum of atypical parkinsonism. The role of imaging methods in the diagnosis and differentiation between PSP and MSA is limited and Magnetic Resonance Imaging (MRI) is currently used as a reference modality. In this study, the authors examined a group of patients with atypical parkinsonism using a 1.5 T MRI system and aimed to find simple and repeatable measurements that may be useful to distinguish between these diseases. The results of the study indicate that the maximal width of the frontal horns of the lateral ventricles and Evans' Index may, to some extent, be useful as basic and simple measurements in the diagnostic imaging of patients with atypical parkinsonism.

Role of orexin in pathogenesis of neurodegenerative parkinsonisms.

INTRODUCTION: The pathogenesis of parkinsonisms is not fully understood. Among possible factors which may influence the course of neurodegenerative diseases, endocrine abnormalities may be interpreted as having been underevaluated. STATE OF THE ART: Growing interest is associated with the role of neuropeptides such as orexin. Orexin is a neuropeptide produced by orexigenic neurons in the lateral parts of the hypothalamus and is linked with excitement, wakefulness and appetite. An extended analysis of this neuropeptide might answer whether changes in the metabolism of orexin is more likely to be a cause or a consequence of neurodegeneration. CLINICAL SIGNIFICANCE: Orexin is a neuropeptide produced by orexigenic neurons in the lateral parts of the hypothalamus and is linked with excitement, wakefulness and appetite. The aim of this study was to discuss the role of this factor and its abnormalities in the pathogenesis and course of parkinsonian syndrome. FUTURE DIRECTIONS: Understanding the role of orexin in these diseases may be interpreted as an important feature in evolving therapeutical methods. Further evaluation based on larger groups of patients is required.

Inflammation in multiple system atrophy.

Misfolding protein aggregation inside or outside cells is the major pathological hallmark of several neurodegenerative diseases. Among proteinopathies are neurodegenerative diseases with atypical Parkinsonism and an accumulation of insoluble fibrillary alpha-synuclein (synucleinopathies) or hyperphosphorylated tau protein fragments (tauopathies). As there are no therapies available to slow or halt the progression of these disea ses, targeting the inflammatory process is a promising approach. The inflammatory biomarkers could also help in the differential diagnosis of Parkinsonian syndromes. Here, we review inflammation's role in multiple systems atrophy pathogenesis, diagnosis, and treatment.

Sleep disturbances in progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS).

INTRODUCTION: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are clinical manifestations of tauopathies. They are commonly associated with rapid motor and cognitive deterioration. Sleep disturbances are less frequently described as a feature of these diseases, though they are reported among 50-75% of PSP patients. STATE OF THE ART: Apart from various clinical manifestations, sleep abnormalities in PSP and CBS seem to be a factor enhancing pathogenesis as well its consequences. Multiple researchers have looked into the issue of whether the complexity of sleep disturbances in PSP and CBS could be linked to atrophic changes within structures crucial for daytime regulation, coexisting pathologies, or other less explored mechanisms. CLINICAL SIGNIFICANCE: Among sleep abnormalities in PSP and CBS have been reported excessive daytime sleepiness, night-time insomnia, reduction of total sleep time, more pronounced sleep fragmentation, restless leg syndrome (RLS), agrypnia excitata, periodic limb movements, sleep respiratory disturbances, rapid-eye movement behaviour disorder, and others. FUTURE DIRECTIONS: The aim of this review was to elaborate upon the significance of sleep abnormalities in tauopathic parkinsonian syndromes, and to determine their usefulness in differential diagnosis with synucleinopathic parkinsonian syndromes. Extended analyses of sleep disturbances may provide a different perspective on atypical parkinsonisms.

Could hyperlipidemia be a risk factor for corticobasal syndrome? - a pilot study.

INTRODUCTION: Corticobasal syndrome (CBS) is a specific clinical manifestation shared by multiple pathologies. The exact mechanism of this phenomenon remains unclear. Differential diagnosis of CBS in everyday clinical practice is challenging, as this syndrome can overlap with other entities, especially progressive supranuclear palsy Richardson-Steele phenotype (PSP-RS). Several papers have suggested a possible role of vascular pathology as a linking factor in the pathogenesis of CBS based on different neuropathologies. This paper analyses differences in the occurrence of the most common vascular risk factors such as hypertension and lipid profile with respect to dietary habits among patients who fulfill the diagnostic criteria for probable/possible CBS and PSP-RS. MATERIAL AND METHODS: Seventy (70) patients in total were included in the study. Exclusion criteria comprised hydrocephalus, stroke in the past, the presence of marked vascular changes in white matter defined as the presence of vascular change ≥ 1 mm in 3T MRI, medical history of hyperlipidemia or the use of drugs that could impact upon lipid metabolism before the initiation of the neurodegenerative disease, and neoplastic focuses in the central nervous system. Patients with diabetes, or with BMI exceeding 18-25, or who were smokers, or who were affected by chronic stress were also excluded. Data was analysed statistically using the Shapiro-Wilk test, the U Mann-Whitney test for group comparison, and a Bonferroni correction to control the false discovery rate (FDR). RESULTS: Our obtained results indicated a statistically significantly higher level of total cholesterol in the CBS group (p = 0.0039) without a correlation with dietary habits. CONCLUSIONS AND CLINICAL IMPLICATIONS: The results obtained in our study may suggest a possible role of vascular pathology in CBS development. This issue requires further research.

The Use of Cerebellar Hypoperfusion Assessment in the Differential Diagnosis of Multiple System Atrophy with Parkinsonism and Progressive Supranuclear Palsy-Parkinsonism Predominant.

The differential diagnosis of MSA-P and PSP-P remains a difficult issue in clinical practice due to their overlapping clinical manifestation and the lack of tools enabling a definite diagnosis ante-mortem. This paper describes the usefulness of SPECT HMPAO in MSA-P and PSP-P differentiation through the analysis of cerebellar perfusion of small ROIs. Thirty-one patients were included in the study­20 with MSA-P and 11 with PSP-P; the analysis performed indicated that the most significant difference in perfusion was observed in the anterior quadrangular lobule (H IV and V) on the left side (p < 0.0026). High differences in the median perfusion between the groups were also observed in a few other regions, with p < 0.05, but higher than premised p = 0.0026 (the Bonferroni correction was used in the statistical analysis). The assessment of the perfusion may be interpreted as a promising method of additional examination of atypical parkinsonisms with overlapping clinical manifestation, as in the case of PSP-P and MSA-P. The results obtained suggest that the interpretation of the differences in perfusion of the cerebellum should be made by evaluating the subregions of the cerebellum rather than the hemispheres. Further research is required.

The Assessment of Subregions in the Frontal Lobe May Be Feasible in the Differential Diagnosis of Progressive Supranuclear Palsy-Parkinsonism Predominant (PSP-P) and Multiple System Atrophy (MSA).

Progressive Supranuclear Palsy-Parkinsonism Predominant (PSP-P) is associated with moderate responsiveness to levodopa treatment and a possible lack of typical PSP milestones. The clinical manifestation of PSP-P poses difficulties in neurological examination. In the early stages it is often misdiagnosed as Parkinson's Disease, and in the more advanced stages PSP-P shows more symptoms in common with Multiple System Atrophy-Parkinsonian type (MSA-P). The small number of tools enabling differential diagnosis of PSP-P and MSA leads to the necessity of searching for parameters facilitating in vivo diagnosis. In this study, 14 patients with PSP-P and 21 patients with MSA-P were evaluated using Single Photon Emission Computed Tomography. Considering the fact that PSP is linked with frontal deficits, regions of the frontal lobe were assessed in the context of hypoperfusion and their possible usefulness in the differential diagnosis with MSA-P. The outcome of the work revealed that the right middle frontal gyrus was the region most significantly affected in PSP-P.