Localizing apraxia in corticobasal syndrome: a morphometric MRI study.

Apraxia localization has relied on voxel-based, lesion-symptom mapping studies in left hemisphere stroke patients. Studies on the neural substrates of different manifestations of apraxia in neurodegenerative disorders are scarce. The primary aim of this study was to look into the neural substrates of different manifestations of apraxia in a cohort of corticobasal syndrome patients (CBS) by use of cortical thickness. Twenty-six CBS patients were included in this cross-sectional study. The Goldenberg apraxia test (GAT) was applied. 3D-T1-weighted images were analyzed via the automated recon-all Freesurfer version 6.0 pipeline. Vertex-based multivariate General Linear Model analysis was applied to correlate GAT scores with cortical thickness. Deficits in imitation of meaningless gestures correlated with bilateral superior parietal atrophy, extending to the angular and supramarginal gyri, particularly on the left. Finger imitation relied predominantly on superior parietal lobes, whereas the left angular and supramarginal gyri, in addition to superior parietal lobes, were critical for hand imitation. The widespread bilateral clusters of atrophy in CBS related to apraxia indicate different pathophysiological mechanisms mediating praxis in neurodegenerative disorders compared to vascular lesions, with implications both for our understanding of praxis and for the rehabilitation approaches of patients with apraxia.

Blood Pressure Variability in Acute Stroke: A Narrative Review.

The management of blood pressure variability (BPV) in acute stroke presents a complex challenge with profound implications for patient outcomes. This narrative review examines the role of BPV across various stages of acute stroke care, highlighting its impact on treatment strategies and prognostic considerations. In the prehospital setting, while guidelines lack specific recommendations for BP management, emerging evidence suggests a potential link between BPV and outcomes. Among ischaemic stroke patients who are ineligible for reperfusion therapies, BPV independently influences functional outcomes, emphasising the need for individualised approaches to BP control. During intravenous thrombolysis and endovascular therapy, the intricate interplay between BP levels, recanalisation status, and BPV is evident. Striking a balance between aggressive BP lowering and avoiding hypoperfusion-related complications is essential. Intracerebral haemorrhage management is further complicated by BPV, which emerges as a predictor of mortality and disability, necessitating nuanced BP management strategies. Finally, among patients with acute subarachnoid haemorrhage, increased BPV may be correlated with a rebleeding risk and worse outcomes, emphasizing the need for BPV monitoring in this population. Integration of BPV assessment into clinical practice and research protocols is crucial for refining treatment strategies that are tailored to individual patient needs. Future studies should explore novel interventions targeting BPV modulation to optimise stroke care outcomes.

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer's Disease.

The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer's disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.

Parkin mRNA Expression Levels in Peripheral Blood Mononuclear Cells in Parkin-Related Parkinson's Disease.

INTRODUCTION: Pathogenic variants in parkin (PRKN gene) are the second most prevalent known monogenic cause of Parkinson's disease (PD). How monoallelic or biallelic pathogenic variants in the PRKN gene may affect its transcription in patient-derived biological material has not been systematically studied. METHODS: PRKN mRNA expression levels were measured with real-time polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs). PBMCs were derived from PRKN-mutated PD patients (PRKN-PD) (n = 12), sporadic PD (sPD) (n = 21) and healthy controls (n = 21). Six of the PRKN-PD patients were heterozygous, four were compound heterozygous, and two were homozygous for PRKN variants. RESULTS: A statistically significant decrease in PRKN expression levels was present, compared to healthy controls and sPD, in heterozygous (P = 0.019 and 0.031 respectively) and biallelic (P < 0.001 for both) PRKN-PD. PRKN expression levels in biallelic PD patients were uniformly very low and were reduced, albeit not significantly, compared to heterozygotes. Based on receiver operating characteristic analysis, low PRKN expression levels were a sensitive and extremely specific indicator for the presence of PRKN pathogenic variants. CONCLUSIONS: Assessment of PRKN mRNA levels in PBMCs may be a useful way to screen for biallelic pathogenic variants in the PRKN gene. Suspicion for certain variants in a heterozygous state may also be raised based on low PRKN mRNA levels. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations.

A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 gene (FGF14) has been recently identified as the cause of spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late-onset cerebellar ataxia (LOCA) for FGF14 repeat expansions using a combination of long-range PCR and bidirectional repeat-primed PCRs. We identified 19 index cases (12%) carrying a pathogenic FGF14 GAA expansion, a diagnostic yield higher than that of previously screened repeat-expansion ataxias in Greek LOCA patients. The age at onset of SCA27B patients was 60.5 ± 12.3 years (range, 34-80). Episodic onset (37%), downbeat nystagmus (32%) and vertigo (26%) were significantly more frequent in FGF14 expansion-positive cases compared to expansion-negative cases. Beyond typical cerebellar signs, SCA27B patients often displayed hyperreflexia (47%) and reduced vibration sense in the lower extremities (42%). The frequency and phenotypic profile of SCA27B in Greek patients was similar to most other previously studied populations. We conclude that FGF14 GAA repeat expansions are the commonest known genetic cause of LOCA in the Greek population and recommend prioritizing testing for FGF14 expansions in the diagnostic algorithm of patients with LOCA.

Mild Behavioral Impairment in Parkinson's Disease: An Updated Review on the Clinical, Genetic, Neuroanatomical, and Pathophysiological Aspects.

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, visual hallucinations, and impulse control disorders, are very common during the course of Parkinson's disease (PD), occurring even at the prodromal and premotor stages. Mild behavioral impairment (MBI) represents a recently described neurobehavioral syndrome, characterized by the emergence of persistent and impactful NPS in later life, reflecting arisk of dementia. Accumulating evidence suggests that MBI is highly prevalent in non-demented patients with PD, also being associated with an advanced disease stage, more severe motor deficits, as well as global and multiple-domain cognitive impairment. Neuroimaging studies have revealed that MBI in patients with PD may be related todistinct patterns of brain atrophy, altered neuronal connectivity, and distribution of dopamine transporter (DAT) depletion, shedding more light on its pathophysiological background. Genetic studies in PD patients have also shown that specific single-nucleotide polymorphisms (SNPs) may be associated with MBI, paving the way for future research in this field. In this review, we summarize and critically discuss the emerging evidence on the frequency, associated clinical and genetic factors, as well as neuroanatomical and neurophysiological correlates of MBI in PD, aiming to elucidate the underlying pathophysiology and its potential role as an early "marker" of cognitive decline, particularly in this population. In addition, we aim to identify research gaps, and propose novel relative areas of interest that could aid in our better understanding of the relationship of this newly defined diagnostic entity with PD.

Parkinson's Disease and Driving Fitness: A Systematic Review of the Existing Guidelines.

BACKGROUND: Motor/nonmotor symptomatology and antiparkinsonian drugs deteriorate the driving ability of Parkinson's disease (PD) patients. OBJECTIVES: Treating neurologists are frequently asked to evaluate driving fitness of their patients and provide evidence-based consultation. Although several guidelines have been published, the exact procedure along with the neurologist's role in this procedure remains obscure. METHODS: We systematically reviewed the existing guidelines, regarding driving fitness evaluation of PD patients. We searched MEDLINE and Google Scholar and identified 109 articles. After specified inclusion criteria were applied, 15 articles were included (nine national guidelines, five recommendation papers, and one consensus statement). RESULTS: The treating physician is proposed as the initial evaluator in 8 of 15 articles (neurologist in 2 articles) and may refer patients for a second-line evaluation. The evaluation should include motor, cognitive, and visual assessment (proposed in 15, 13, and 8 articles, respectively). Specific motor tests are proposed in eight articles (cutoff values in four), whereas specific neuropsychological and visual tests are proposed in seven articles each (cutoff values in four and three articles, respectively). Conditional licenses are proposed in 11 of 15 articles, to facilitate driving for PD patients. We summarized our findings on a graphic of the procedure for driving fitness evaluation of PD patients. CONCLUSIONS: Neurological aspects of driving fitness evaluation of PD patients are recognized in most of the guidelines. Motor, neuropsychological, visual, and sleep assessment and medication review are key components. Clear-cut instructions regarding motor, neuropsychological, and visual tests and relative cutoff values are lacking. Conditional licenses and periodical reevaluation of driving fitness are important safety measures.

Multiple faces of multiple sclerosis in the era of highly efficient treatment modalities: Lymphopenia and switching treatment options challenges daily practice.

The expanded treatment landscape in relapsing-remitting multiple sclerosis (MS) has resulted in highly effective treatment options and complexity in managing disease- or drug-related events during disease progression. Proper decision-making requires thorough knowledge of the immunobiology of MS itself and an understanding of the main principles behind the mechanisms that lead to secondary autoimmunity affecting organs other than the central nervous system as well as opportunistic infections. The immune system is highly adapted to both environmental and disease-modifying agents. Immune reconstitution following cell depletion or cell entrapment therapies eliminates pathogenic aspects of the disease but can also lead to distorted immune responses with harmful effects. Atypical relapses occur with second-line treatments or after their discontinuation and require appropriate clinical decisions. Lymphopenia is a result of the mechanism of action of many drugs used to treat MS. However, persistent lymphopenia and cell-specific lymphopenia could result in disease exacerbation, secondary autoimmunity, or the emergence of opportunistic infections. Clinicians treating patients with MS should be aware of the multiple faces of MS under novel, efficient treatment modalities and understand the intricate brain-immune cell interactions in the context of an altered immune system. MS relapses and disease progression still occur despite the current treatment modalities and are mediated either by failure to control effector mechanisms inherent to MS pathophysiology or by new drug-related mechanisms. The multiple faces of MS due to the highly adapted immune system of patients impose the need for appropriate switching therapies that safeguard disease remission and further clinical improvement.

Alzheimer's Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus.

The aim of the present study is the evaluation of established Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in patients with idiopathic normal-pressure hydrocephalus (iNPH), both individually and as a total profile, and the investigation of their use as potential predictors of Tap-test responsiveness. Fifty-three patients with iNPH participated in the study. Aß42, Aß40, total Tau and phospho-Tau proteins were measured in duplicate with double-sandwich ELISA assays. Clinical evaluation involved a 10 m timed walk test before an evacuative lumbar puncture (LP) and every 24 h for three consecutive days afterwards. Neuropsychological assessment involved a mini-mental state examination, frontal assessment battery, 5-word test and CLOX drawing test 1 and 2, which were also performed before and 48 h after LP. Response in the Tap-test was defined as a 20% improvement in gait and/or a 10% improvement in neuropsychological tests. The Aß42/Aß40 ratio was found to be significantly higher in Tap-test responders than non-responders. Total Tau and phospho-Tau CSF levels also differed significantly between these two groups, with Tap-test responders presenting with lower levels compared to non-responders. Regarding the AD CSF biomarker profile (decreased amyloid and increased Tau proteins levels), patients with a non-AD profile were more likely to have a positive response in the Tap-test than patients with an AD profile.

The Landscape of Monogenic Parkinson's Disease in Populations of Non-European Ancestry: A Narrative Review.

INTRODUCTION: There has been a bias in the existing literature on Parkinson's disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD patients of non-European or mixed ancestry. METHODS: We reviewed articles published during the 2000-2023 period, focusing on the genetic status of PD patients of non-European origin (Indian, East and Central Asian, Latin American, sub-Saharan African and Pacific islands). RESULTS: There were substantial differences regarding monogenic PD forms between patients of European and non-European ancestry. The G2019S Leucine Rich Repeat Kinase 2 (LRRK2) mutation was rather scarce in non-European populations. In contrast, East Asian patients carried different mutations like p.I2020T, which is common in Japan. Parkin (PRKN) variants had a global distribution, being common in early-onset PD in Indians, in East Asians, and in early-onset Mexicans. Furthermore, they were occasionally present in Black African PD patients. PTEN-induced kinase 1 (PINK1) and PD protein 7 (DJ-1) variants were described in Indian, East Asian and Pacific Islands populations. Glucocerebrosidase gene variants (GBA1), which represent an important predisposing factor for PD, were found in East and Southeast Asian and Indian populations. Different GBA1 variants have been reported in Black African populations and Latin Americans. CONCLUSIONS: Existing data reveal a pronounced heterogeneity in the genetic background of PD. A number of common variants in populations of European ancestry appeared to be absent or scarce in patients of diverse ethnic backgrounds. Large-scale studies that include genetic screening in African, Asian or Latin American populations are underway. The outcomes of such efforts will facilitate further clinical studies and will possibly contribute to the identification of either new pathogenic mutations in already described genes or novel PD-related genes.

Frequency of Impulsive-Compulsive Behavior and Associated Psychological Factors in Parkinson's Disease: Lack of Control or Too Much of It?

Background and Objectives: Impulse Control Disorders (ICDs) including pathological gambling, hypersexuality, compulsive eating, compulsive buying, and other related behaviors are well-known distinct non-motor symptoms in Parkinson's Disease (PD). Some large-scale studies present a prevalence of at least 10%, however, there are other reports providing much higher rates. The majority of the conducted studies investigating ICDs focus mainly on pharmacological factors, however, from a psychological perspective, there is yet enough room for investigation. In order to address the above issues, we designed a two-part study. Materials and Methods: First, we aimed to identify the incidence of ICD and related behaviors in a cohort of 892 Greek PD patients. Second, we administered a comprehensive battery of psychometric tools to assess psychological factors such as personality dimensions, quality of life, defenses, coherence, and resilience as well as to screen general cognitive capacity in PD patients with ICD manifestations. Results: With regard to the first part, we identified ICD manifestations in 12.4% of the patients. Preliminary findings from the second part indicate elevated activity, rather than impulsivity, as well as interrelations between several variables, including measures of activity, coping mechanisms, and quality of life. Conclusions: We present a working hypothesis for the contribution of high activity channeled to specific behavioral patterns through specific coping mechanisms, concerning the emergence of ICDs and related behaviors in PD, and further stress the importance of compulsivity rather than impulsivity in this process.

Comprehensive Evaluation of Psychotic Features and Their Clinical Correlates in Early Parkinson's Disease.

BACKGROUND: Some reports suggest that psychotic features may occur in the early stages of Parkinson's disease (PD), but sensitive tools have not been utilized. OBJECTIVE: The aim was to evaluate the presence of psychotic symptoms using detailed scales and to assess the association with clinical characteristics. METHODS: Healthy controls and patients within three years of PD onset were recruited. Participants were examined for psychotic symptoms using two different instruments: the Comprehensive Assessment of At-Risk Mental States (CAARMS) and a 10 question PD specific psychosis severity scale (10PDQ). In the PD group, medication use, motor and non-motor symptoms were documented. RESULTS: Based on CAARMS and 10PDQ scales, psychotic features were present in 39% (27/70) of patients and 4% (3/74) of controls. The prevalence of passage hallucinations and illusions was significantly higher in PD compared to the control group. The presence of PD-associated psychotic features was not significantly affected by medication, motor severity or global cognitive status. Higher prevalence of overall non-motor manifestations, REM sleep behavior disorder (RBD) and depressive symptoms was significantly associated with the manifestation of psychotic features in PD [(adjusted OR:1.3; 95% CI:1.1-1.6; p = 0.003), (adjusted OR:1.3; 95% CI:1.0-1.6; p = 0.023), and (adjusted OR:1.2; 95% CI:1.0-1.4;p = 0.026)]. CONCLUSIONS: Psychotic phenomena mainly of minor nature are highly common in early PD. Cumulative non-motor symptoms, RBD and depressive features are associated with the presence of psychotic symptoms in this non-demented, early-stage PD population. More studies are needed to clarify the mechanisms that contribute to the onset of psychotic features in early PD.

microRNA and circRNA in Parkinson's Disease and atypical parkinsonian syndromes.

Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are atypical parkinsonian syndromes (APS) with various clinical phenotypes and considerable clinical overlap with idiopathic Parkinson's disease (iPD). This disease heterogeneity makes ante-mortem diagnosis extremely challenging with up to 24% of patients misdiagnosed. Because diagnosis is predominantly clinical, there is great interest in identifying biomarkers for early diagnosis and differentiation of the different types of parkinsonism. Compared to protein biomarkers, microRNAs (miRNAs) and circularRNAs (circRNAs) are stable tissue-specific molecules that can be accurately measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This chapter critically reviews miRNAs and circRNAs as diagnostic biomarkers and therapeutics to differentiate atypical parkinsonian disorders and their role in disease pathogenesis.

Jumping to conclusions bias, psychosis and impulsivity in early stages of Parkinson's disease.

OBJECTIVES: The aim was to explore the correlations between Jumping to Conclusions (JtC) tendency and neuropsychiatric features in patients with early Parkinson's disease (PD). BACKGROUND: According to few reports, PD patients with impulsive-compulsive behaviors (ICBs) are prone to working memory difficulties including JtC bias. The correlation of psychotic features and JtC tendency remains still unclear. METHODS: Healthy controls and patients within 3 years of PD onset were recruited. Participants were examined for psychotic symptoms using a 10 question PD-specific psychosis severity scale. JtC was measured by a probalistic reasoning scenario (beads task). In PD group, medication use, motor and non-motor symptoms were documented. Impulsivity was evaluated using the Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP). RESULTS: The prevalence of JtC bias was 9% (6/70) in healthy individuals, compared to 32% (22/68) of PD group [p = 0.001]. No association was detected between the presence of JtC tendency and PD-associated psychosis (p = 0.216). Patients with JtC had shorter duration of PD, more tremor-dominant PD subtype and higher QUIP scores, regardless of the dopaminergic therapy (p = 0.043, p = 0.015, p = 0.007, respectively). A trend towards attention and inhibition control deficit was noticed in JtC patients. CONCLUSIONS: We found a high prevalence of JtC bias in early, cognitively intact PD population and a potential link between subthreshold ICBs and poor performance on beads task. Additional studies are needed to confirm our results and elaborate on the mechanisms that correlate impulsivity with JtC tendency, which are likely to be different from those mediating psychotic features in early PD.

Flame (v2.0): advanced integration and interpretation of functional enrichment results from multiple sources.

Functional enrichment is the process of identifying implicated functional terms from a given input list of genes or proteins. In this article, we present Flame (v2.0), a web tool which offers a combinatorial approach through merging and visualizing results from widely used functional enrichment applications while also allowing various flexible input options. In this version, Flame utilizes the aGOtool, g: Profiler, WebGestalt, and Enrichr pipelines and presents their outputs separately or in combination following a visual analytics approach. For intuitive representations and easier interpretation, it uses interactive plots such as parameterizable networks, heatmaps, barcharts, and scatter plots. Users can also: (i) handle multiple protein/gene lists and analyse union and intersection sets simultaneously through interactive UpSet plots, (ii) automatically extract genes and proteins from free text through text-mining and Named Entity Recognition (NER) techniques, (iii) upload single nucleotide polymorphisms (SNPs) and extract their relative genes, or (iv) analyse multiple lists of differentially expressed proteins/genes after selecting them interactively from a parameterizable volcano plot. Compared to the previous version of 197 supported organisms, Flame (v2.0) currently allows enrichment for 14 436 organisms. AVAILABILITY AND IMPLEMENTATION: Web Application: http://flame.pavlopouloslab.info. Code: https://github.com/PavlopoulosLab/Flame. Docker: https://hub.docker.com/r/pavlopouloslab/flame.

Double Trouble: Association of Malignant Melanoma with Sporadic and Genetic Forms of Parkinson's Disease and Asymptomatic Carriers of Related Genes: A Brief Report.

Introduction: Previous epidemiological evidence has established the co-occurrence of malignant melanoma (MM) and Parkinson's disease (PD). Shared molecular mechanisms have been proposed to be implicated in this relationship. The aim of the present study was to assess the prevalence of MM in patients with sporadic and genetic types of PD, as well as in asymptomatic carriers of PD-related genes. Methods: Data regarding past medical history and concomitant disease of 1416 patients with PD (including 20 participants with prodromal disease who phenoconverted to PD), 275 healthy controls (HCs) and 670 asymptomatic carriers of PD-related genes were obtained from the database of the Parkinson's Progression Markers Initiative (PPMI). Focus was placed on information about a medical record of MM. We also retrieved data regarding the genetic status of selected PPMI participants with a positive MM history. Results: In total, 46 patients with PD reported a positive MM history. Concerning the genetic forms of PD, nine of these PD patients (2.47%) carried a Leucine Rich Repeat Kinase 2 (LRRK2) gene mutation (mainly the G2019S), while eight (4.49%) harbored a Glucocerebrosidase (GBA) gene mutation (mainly the N370S). No alpha-synuclein (SNCA) gene mutation was identified in patients with an MM history. The remaining 29 PD patients (3.5%) were genetically undetermined. In total, 18 asymptomatic carriers of PD-related genes had a positive medical history for MM: among them, 10 carried an LRRK2 gene mutation (2.69%) and 10 a GBA gene mutation (3.51%) (2 were dual carriers). MM history was identified for seven HCs (2.5%). Conclusions: We replicated the previously reported association between genetically undetermined PD (GU-PD) and MM. A correlation of LRRK2 mutations with the development of MM could not be verified in either symptomatic PD patients or asymptomatic carriers, implicating distinct pathogenetic mechanisms as compared to GU-PD. Importantly, despite the limited literature evidence on Gaucher disease, this study highlights for the first time the relatively high prevalence of MM among asymptomatic and symptomatic PD GBA mutation carriers, with potential clinical implications.

Serum Uric Acid as a Putative Biomarker in Prodromal Parkinson's Disease: Longitudinal Data from the PPMI Study.

BACKGROUND: The role of blood uric acid as a biomarker in symptomatic motor PD has been increasingly established in the literature. OBJECTIVE: Our present study assessed the role of serum uric acid as a putative biomarker in a prodromal PD cohort [REM Sleep Behavior disorder (RBD) and Hyposmia] followed longitudinally. METHODS: Longitudinal 5-year serum uric acid measurement data of 39 RBD patients and 26 Hyposmia patients with an abnormal DATSCAN imaging were downloaded from the Parkinson's Progression Markers Initiative database. These cohorts were compared with 423 de novo PD patients and 196 healthy controls enrolled in the same study. RESULTS: After adjusting for age, sex, body mass index, and concomitant disorders (hypertension/gout), baseline and longitudinal serum uric acid levels were higher in the RBD subgroup as compared to the established PD cohort (p = 0.004 and p = 0.001). (Baseline RBD 6.07±1.6 vs. Baseline PD 5.35±1.3 mg/dL and Year-5 RBD 5.7±1.3 vs. Year-5 PD 5.26±1.33). This was also true for longitudinal measurements in the Hyposmic subgroup (p = 0.008) (Baseline Hyposmic 5.7±1.6 vs. PD 5.35±1.3 mg/dL and Year-5 Hyposmic 5.58±1.6 vs. PD 5.26±1.33). CONCLUSION: Our results indicate that serum uric acid levels are higher in prodromal PD subjects with ongoing dopaminergic degeneration compared to those with manifest PD. These data indicate that the well-established decrease in the levels of serum uric acid occurs with the transition from prodromal to clinical PD. Whether the higher levels of serum uric acid observed in prodromal PD may provide protection against conversion to full-blown clinical PD will require further study.

Shoulder Dysfunction in Parkinson Disease: Review of Clinical, Imaging Findings and Contributing Factors.

This study aimed to review shoulder clinical and imaging findings in Parkinson's disease (PD), focusing on the significance of timely diagnosis and management of shoulder dysfunction in PD for the prevention of shoulder-related complications. A bibliographical search was employed, using "Parkinson's" and "Shoulder Dysfunction" as keywords. A Magnetic Resonance Imaging, twenty clinical and three US studies were selected as relevant to shoulder dysfunction in PD. Shoulder pain, frozen shoulder and arm swing asymmetry are the most prevalent clinical findings that may antedate cardinal PD symptoms. Supraspinatus tendon thickening or tearing, adhesive capsulitis, acromioclavicular changes, bursa and joint effusion are common shoulder MRI or US-detected abnormalities in mild or severe PD stages. Fractures due to falls or osteoporosis are secondary shoulder pathologies. Higher ipsilateral Unified Parkinson's Disease Rated Scale (UPDRS) scores, rigidity, tremor, and bradykinesia are associated with frozen shoulder. Disease duration, rigidity, and falls are contributing factors for tendon tears, adhesive capsulitis, and fractures respectively. When common symptoms, such as pain and frozen shoulder are unaccounted for by orthopedic or other local primary pathology, they might indicate underlying early PD. Timely diagnosis and appropriate early management of PD may, in turn, help delay or prevent shoulder-related complications.

Differential intracellular trafficking of extracellular vesicles in microglia and astrocytes.

Extracellular vesicles (EVs) have emerged as key players in cell-to-cell communication in both physiological and pathological processes in the Central Nervous System. Thus far, the intracellular pathways involved in uptake and trafficking of EVs within different cell types of the brain are poorly understood. In our study, the endocytic processes and subcellular sorting of EVs were investigated in primary glial cells, particularly linked with the EV-associated α-synuclein (α-syn) transmission. Mouse microglia and astrocytic primary cultures were incubated with DiI-stained mouse brain-derived EVs. The internalization and trafficking pathways were analyzed in cells treated with pharmacological reagents that block the major endocytic pathways. Brain-derived EVs were internalized by both glial cell types; however, uptake was more efficient in microglia than in astrocytes. Colocalization of EVs with early and late endocytic markers (Rab5, Lamp1) indicated that EVs are sorted to endo-lysosomes for subsequent processing. Blocking actin-dependent phagocytosis and/or macropinocytosis with Cytochalasin D or EIPA inhibited EV entry into glial cells, whereas treatment with inhibitors that strip cholesterol off the plasma membrane, induced uptake, however differentially altered endosomal sorting. EV-associated fibrillar α-Syn was efficiently internalized and detected in Rab5- and Lamp1-positive compartments within microglia. Our study strongly suggests that EVs enter glial cells through phagocytosis and/or macropinocytosis and are sorted to endo-lysosomes for subsequent processing. Further, brain-derived EVs serve as scavengers and mediate cell-to-glia transfer of pathological α-Syn which is also targeted to the endolysosomal pathway, suggesting a beneficial role in microglia-mediated clearance of toxic protein aggregates, present in numerous neurodegenerative diseases.

Defining the Riddle in Order to Solve It: There Is More Than One "Parkinson's Disease".

BACKGROUND: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.