Glycosphingolipid Changes in Plasma in Parkinson's Disease Independent of Glucosylceramide Levels.

BACKGROUND: Alteration in glycosphingolipids (GSLs) in Parkinson's disease (PD) still needs to be determined. OBJECTIVES: We evaluated if PD subjects show abnormal GSLs levels compared to healthy controls (HC) and if GSLs correlate with clinical features. METHODS: We analyzed GSLs and glucosylceramide (GlcCer) in plasma using two normal-phase high-performance liquid chromatography assays; clinico-demographic data were extracted. RESULTS: Eighty PD subjects and 25 HCs were analyzed. Levels of GlcCer, GD1b, Gb4, GalNAcGA1, and b-series were higher in PD patients than in HCs; total GSLs, GT1b, GM1a, GM3, GM2, and a-series levels were lower in PD patients than in HCs. Changes in GSLs were present in PD subjects, with GlcCer levels similar to those in HCs. The results were similar after excluding certain GBA1 mutation carriers. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III, correlated with Gb4 and Montreal Cognitive Assessment with GD1b levels. CONCLUSIONS: Multiple GSL abnormalities in plasma were detected in patients with and without GlcCer changes, indicating a broader shift in lipid homeostasis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Novel targeted therapies for Parkinson's disease.

Parkinson's disease (PD) is the second more common neurodegenerative disease with increasing incidence worldwide associated to the population ageing. Despite increasing awareness and significant research advancements, treatment options comprise dopamine repleting, symptomatic therapies that have significantly increased quality of life and life expectancy, but no therapies that halt or reverse disease progression, which remain a great, unmet goal in PD research. Large biomarker development programs are undertaken to identify disease signatures that will improve patient selection and outcome measures in clinical trials. In this review, we summarize PD-related mechanisms that can serve as targets of therapeutic interventions aiming to slow or modify disease progression, as well as previous and ongoing clinical trials in each field, and discuss future perspectives.

Euglycemia Indicates Favorable Motor Outcome in Parkinson's Disease.

BACKGROUND: The interplay between glycemic control and Parkinson's disease (PD) has long been recognized but not fully understood. OBJECTIVES: To investigate the association of glycated hemoglobin (HbA1c) levels with motor and cognitive symptom progression in a prospective PD cohort. METHODS: Of 244 PD patients, 17 had low HbA1c (≤30 mmol/mol), 184 were euglycemic (HbA1c 31-41 mmol/mol), 18 had high HbA1c (HbA1 ≥42 mmol/mol), and 25 had diabetes mellitus (DM). Survival analysis was applied on time until Hoehn and Yahr stage ≥3 (motor outcome) and until mild cognitive impairment. RESULTS: Low HbA1c (HR 2.7; 95% CI 1.3-6; P = 0.01) as well as high HbA1c (HR 3.6; 95% CI 1.5-8.9; P = 0.005) but not DM were independent predictors of unfavorable motor outcome. CONCLUSIONS: Both high and low HbA1c levels may be associated with motor symptom progression in PD; however, further studies are needed to confirm these findings and increase understanding regarding causality. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dietary patterns and food insecurity of students participating in a food aid programme: the Mediterranean perspective.

BACKGROUND: To explore the effect of household food insecurity on dietary patterns of children and adolescents participating in a school food-aid programme in regions of Greece with low socioeconomic status. METHODS: A cross-sectional study was conducted during the school year 2013-14, among 406 schools in low socioeconomic status regions of Greece. Dietary habits and sociodemographic characteristics of students and their families were recorded. Factor analysis was used in order to derive children's and adolescents' dietary patterns and analysis of covariance was performed to examine the effect of households' food insecurity level on those patterns. A total of 31 399 students participated in the study; 16 652 children (5-11 years) and 14 747 adolescents (12-18 years). RESULTS: Factor analysis identified five dietary patterns in both age groups, explaining the 49.1% (children) and 53.0% (adolescents) of the total variation in intake. After adjusting for various factors, the household's food insecurity was significantly associated with the majority of the derived patterns in both age groups, with most pronounced differences being observed for the consumption of red meat, poultry and fish, fruits, as well as red processed meat, cereals and dairy products, which was lower among children and adolescents with food insecurity. Children with food insecurity consumed significantly more unhealthy food, such as chips, fast food, sugared drinks, sweets, French fries and mayonnaise sauce. CONCLUSIONS: Promotion of healthy eating to households facing food insecurity is of crucial importance, giving emphasis in the design of low cost, yet highly nutritious programmes.

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. OBJECTIVES: The aim of this study was to investigate CSF markers associated with cognition in early PD. METHODS: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. RESULTS: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. CONCLUSIONS: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High cholesterol levels are associated with improved long-term survival after acute ischemic stroke.

BACKGROUND: Prior statin treatment and high admission cholesterol have been associated with favorable outcome after ischemic stroke (IS), a paradox not completely explained. The aim of this study was to investigate the effect of admission cholesterol levels and the impact of statin treatment on short- and long-term survival after IS. METHODS: Consecutive patients admitted in 2006 and 2010 were included in the study. Total cholesterol of 4.6 mmol/L or more was defined as high. Logistic regression analysis was performed to assess predictors of 1-month mortality, and Cox proportional hazard regression analysis was applied to investigate predictors of long-term mortality. RESULTS: Of 190 patients included in the final analysis, 21 (11%) died within 1 month and 61 (32%) died during 7 years of observation. Low cholesterol was associated with older age, lower blood pressure (BP), presence of angina, and higher risk of death. Three-month, 1-year, and 5-year survival rates were 100%, 98%, and 84%, respectively, in high cholesterol patients, compared with 92%, 87%, and 57% in low cholesterol group (P = .0001 with the log-rank test). Mortality risk was increased for patients with low cholesterol (hazard ratio: 1.97; 95% confidence interval [CI]: 1.05-3.69), after adjustment for age and admission National Institutes of Health Stroke Scale score. After further adjustment for angina and admission BP, the effect of cholesterol on mortality risk was still obvious, yet attenuated (hazard ratio: 1.87; 95% CI: .94-3.32). CONCLUSIONS: High admission cholesterol may be associated with increased long-term survival after IS. Future studies on the temporal profile of cholesterol levels and stroke outcome would be of interest.

Long-term survival of ischemic cerebrovascular disease in the acute inflammatory stroke study, a hospital-based cohort described by TOAST and ASCO.

BACKGROUND: Ischemic cerebrovascular disease (ICVD) comprises multiple etiological phenotypes that share common clinical characteristics. Etiological classification of patients with ICVD is of major clinical interest to achieve optimal medical treatment and predict prognosis. The TOAST classification system has been widely used to describe stroke etiology but provides restricted phenotypic homogeneity within groups. The ASCO classification system has introduced a new approach in phenotypic classification, and aims to describe clinical characteristics without merging concurrent comorbidities. Inflammatory processes have been suggested to mediate stroke etiology and pathology. The Acute Inflammatory Stroke Study (AISS), a hospital-based cohort, is here introduced and described by TOAST and ASCO classification systems. The aim of this first analysis of AISS was to investigate long-term mortality in relation to ischemic stroke subtypes, and clinical and biochemical markers. METHODS: AISS consecutively follows patients on 6 occasions up to 1 year after stroke onset. Complete workup according to ASCO comprised CT or MRI of the head, ECG, duplex of the extracranial arteries or CT/MR angiography and ultrasound of the heart. Level 2 evidence was required in each domain to obtain a comparable system to TOAST (ASCO2). Clinical and biochemical characteristics and mortality rates were documented and compared by the two classification systems. RESULTS: Of 142 patients consecutively evaluated and recruited in the study, a total of 101 ICVD patients (ischemic stroke, n = 84; transient ischemic attack, n = 17) were included in the final analysis. Agreement between ASCO2 and TOAST was very good. During the mean observation period of 28 months, 26 patients died. The 1- and 4-year mortality rates were 0 and 4% for large artery atherosclerosis (LAA); 23 and 36% for cardioembolism (CE); 0% for small artery occlusion (SAO); 63 and 100% for the subtype with unknown etiology due to incomplete workup (Unknown), and 12 and 29% for the cryptogenic subtype. As for the ASCO2 groups, the 1- and 4-year mortality rates were 0 and 6% in LAA, 25 and 36% in CE, 0% in SAO, 0 and 14% in LAA + CE, 0% in SAO + CE, 16 and 36% in the subgroup with undetermined etiology despite complete workup, and 56 and 100% in Unknown. Regression analysis showed that age, white blood cell count, fibrinogen and bilirubin, but not etiological subgroup, were independent predictors of mortality. CONCLUSION: Our findings indicate that clinical and biochemical markers may differentiate phenotypically homogeneous etiological subtypes and predict long-term mortality. Further studies with larger patient numbers are needed to investigate possible causative mechanisms.

Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease.

BACKGROUND: There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD). METHODS: CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels. RESULTS: Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts. CONCLUSIONS: Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.

Complement system changes in blood in Parkinson's disease and progressive Supranuclear Palsy/Corticobasal Syndrome.

Parkinson's Disease (PD) is diagnosed clinically, and early PD is often challenging to differentiate from atypical parkinsonian disorders such as the Four-repeat (4R-) Tauopathies Progressive Supranuclear Palsy and Corticobasal Syndrome. Diagnostic biomarkers are needed, and proteomic studies have suggested that the plasma complement system is altered in PD, but validation studies are lacking. In this study, plasma from 148 individuals (PD, 4R-Tauopathies, and healthy controls (HC)) were used to quantify 12 complement proteins with immunoassays, and CH50 classical pathway complement activity was quantified in sera from further 78 individuals (PD and HC). Complement factors C1q and C3 in plasma were lower in individuals with 4R-Tauopathies (ANOVA, p = 0.0041, p = 0.0057 respectively) compared to both PD and HC. None of the complement proteins were altered between PD and HC, however a few proteins correlated with clinical parameters within the PD group. Notably, levels of C3 correlated with non-motor symptoms in female patients. Classical pathway complement activity was not altered in PD serum, but did correlate with mental fatigue. In conclusion, individuals with 4R-Tauopathies showed lower plasma C1q and C3 compared PD and HC. Neither complement levels nor CH50 activity were significantly altered in PD versus HC but may associate with PD symptom severity.

Reading Alterations in Parkinson's Disease Indicate Worse Cognitive Status.

Background: Reading difficulties are commonly reported in Parkinson's disease (PD). So far, only a few studies have assessed reading in PD, most of them confirming a different pattern in patients compared with healthy populations. Impaired oculomotor control is an early feature of PD. Cognitive deficits, on the other hand, may appear early, but they are most prominent at later stages. Although these two factors are thought to be responsible for the alterations in reading performance, it is unclear how each factor contributes to them. Objectives: To evaluate eye movements during reading in PD and healthy controls (HCs). Methods: Data from 42 HCs (36% men) and 48 patients with PD (67% men) at Hoehn and Yahr stages ≤3 were analyzed. PD participants were further divided into 2 groups based on their Montreal Cognitive Assessment (MoCA) score using a cutoff of ≥26. Eye movements were recorded with Tobii Pro Spectrum, a screen-based eye tracker with a sampling rate of 1200 Hz. Results: PD participants performed fewer fixations per second (P = 0.033), with a longer mean (P = 0.037) and standard deviation fixation duration (P = 0.033) than HC, and further analysis showed that only patients with a lower MoCA score performed worse than HCs. Reading parameters were weakly associated with MoCA scores, irrespective of age and education. Conclusion: Changes in the reading pattern of PD patients are probably attributed to cognitive rather than pure oculomotor alterations.

Pupil light reflex dynamics in Parkinson's disease.

Introduction: Visual disturbance is common symptom in Parkinson's disease (PD), and defective pupil light reflex (PLR) is an anticipated contributing factor that may be associated to the presence of autonomic dysfunction, which is a common non-motor feature of PD. Studies investigating the intercorrelation between PLR and dysautonomia in PD are limited. Methods: The aim of this study was to investigate differences of PLR parameters, measured by eye-tracker, between patients with PD, with and without signs of dysautonomia, and healthy controls (HC). In total, 43 HC and 50 patients with PD were recruited and PLR parameters were measured with Tobii Pro Spectrum, during a long (1,000 ms) and a short (100 ms) light stimulus. Presence of orthostatic hypotension (OH) was used as proxy marker of dysautonomia. Linear mixed-effects model and non-parametric comparative statistics were applied to investigate differences among groups. Results: Peak constriction velocity was slower in PD compared with HC, after adjustment for age and sex in the mixed model, and the difference was greater in the subgroup of PD with OH (unadjusted). Dilation amplitude and velocity were also gradually slower in HC vs. PD without OH vs. PD with OH (unadjusted for confounders). In the mixed model, age was significant predictor of dilation response. Discussion: Our results support previous observations on defective PLR in PD, evaluated with eye-tracker, and show a possible association with autonomic dysfunction. Further studies with more patients and rigorous evaluation of autonomic dysfunction are needed to validate these findings.

Neurocognitive profile of adults with the Norrbottnian type of Gaucher disease.

INTRODUCTION: Gaucher disease (GD) is a monogenic, lysosomal storage disorder, classified according to the presence of acute (type 2), chronic (type 3), or no (type 1) neurological manifestations. The Norrbottnian subtype of neuronopathic GD type 3 (GD3) is relatively frequent in the northern part of Sweden. It exhibits a wide range of neurological symptoms but is characterized by extended life expectancy compared to GD3 in other countries. The aim of our study was to describe the cognitive profile of adult patients with Norrbottnian GD3. MATERIALS AND METHODS: Ten patients with GD3 (five males and five females) underwent neurocognitive testing with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). RBANS consists of different short tests that assess Immediate Memory, Visuospatial and Constructional function, Language, Attention, and Delayed Memory. General neurological symptoms of the patients were assessed with the modified severity scoring tool. RESULTS: Patients (median age 41.5 range 24-57) performed lower than average in all cognitive domains. The overall index score was low (median 58.5, Interquartile range [IQR] 25.5), with the most profound deficit in attention (median 57, IQR 32.5) and immediate memory (median 76.5, IQR 13). Higher scores were found in language (median 83, IQR 21.5), delayed memory (median 81, IQR 41), and visuospatial/constructional function (median 86, IQR 32.35). CONCLUSION: Norrbottnian GD3 patients showed a unique neurocognitive profile with low overall performance, mostly derived from low scores in attention and memory domains whereas language and visuospatial/constructional ability were relatively spared.

Mechanical thrombectomy in stroke patients of working age: Real-world outcomes in Sweden.

Introduction: Outcomes after mechanical thrombectomy (MT) in young stroke patients remain elusive due to small patient cohorts. We sought to determine outcomes after MT in stroke patients between ages 18 and 64 years and compare with outcomes in older patients in a large national stroke cohort. Patients and methods: We used the Swedish National Stroke Registry and the Swedish National Endovascular Thrombectomy Registry to identify all patients treated with MT for anterior circulation occlusions. We examined outcome measures in terms of functional independence at 90 days (modified Rankin Scale score of 0-2), symptomatic intracerebral hemorrhage (sICH), and mortality at 90 days with multivariable logistic regression analysis. Results: Of 2143 patients, 565 were between 18 and 64 years (26.4%) and 1179 (55.0%) were males. Analysis showed that patient aged 18-64 achieved higher rate of functional independence at 90 days (46.2% vs 28.4%, p < .001), had less often sICH (5.5% vs 6.8%, p = .008), and lower 90-day mortality rate (6.9% vs 17.7%, p < .001). Increasing age was associated with a lesser probability of functional independence at 90 days (adjusted odds ratio (aOR), 0.94; [95% confidence intervals (CIs) 0.93-0.95]), higher odds of mortality at 90 days (aOR, 1.05; [95% CIs 1.03-1.06]), and of sICH (aOR 1.03; [95% CIs 1.01-1.05]). Conclusion: Patients aged 18-64 years demonstrated better outcome after thrombectomy regarding functional independence, sICH, and mortality at 90 days when compared to older ages.

A replication study, systematic review and meta-analysis of automated image-based diagnosis in parkinsonism.

Differential diagnosis of parkinsonism early upon symptom onset is often challenging for clinicians and stressful for patients. Several neuroimaging methods have been previously evaluated; however specific routines remain to be established. The aim of this study was to systematically assess the diagnostic accuracy of a previously developed 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) based automated algorithm in the diagnosis of parkinsonian syndromes, including unpublished data from a prospective cohort. A series of 35 patients prospectively recruited in a movement disorder clinic in Stockholm were assessed, followed by systematic literature review and meta-analysis. In our cohort, automated image-based classification method showed excellent sensitivity and specificity for Parkinson Disease (PD) vs. atypical parkinsonian syndromes (APS), in line with the results of the meta-analysis (pooled sensitivity and specificity 0.84; 95% CI 0.79-0.88 and 0.96; 95% CI 0.91 -0.98, respectively). In conclusion, FDG-PET automated analysis has an excellent potential to distinguish between PD and APS early in the disease course and may be a valuable tool in clinical routine as well as in research applications.

Glucocerebrosidase variant T369M is not a risk factor for Parkinson's disease in Sweden.

INTRODUCTION: Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden. METHOD: In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease. RESULTS: The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82-1.83. CONCLUSION: Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population.

Fixation Duration and Pupil Size as Diagnostic Tools in Parkinson's Disease.

BACKGROUND: Visual and oculomotor problems are very common in Parkinson's disease (PD) and by using eye-tracking such problems could be characterized in more detail. However, eye-tracking is not part of the routine clinical investigation of parkinsonism. OBJECTIVE: To evaluate gaze stability and pupil size in stable light conditions, as well as eye movements during sustained fixation in a population of PD patients and healthy controls (HC). METHODS: In total, 50 PD patients (66% males) with unilateral to mild-to-moderate disease (Hoehn & Yahr 1-3, Schwab and England 70-90%) and 43 HC (37% males) were included in the study. Eye movements were recorded with Tobii Pro Spectrum, a screen-based eye tracker with a sampling rate of 1200 Hz. Logistic regression analysis was applied to investigate the strength of association of eye-movement measures with diagnosis. RESULTS: Median pupil size (OR 0.811; 95% CI 0.666-0.987; p = 0.037) and longest fixation period (OR 0.798; 95% CI 0.691-0.921; p = 0.002), were the eye-movement parameters that were independently associated with diagnosis, after adjustment for sex (OR 4.35; 95% CI 1.516-12.483; p = 0.006) and visuospatial/executive score in Montreal Cognitive Assessment (OR 0.422; 95% CI 0.233-0.764; p = 0.004). The area under the ROC curve was determined to 0.817; 95% (CI) 0.732-0.901. CONCLUSION: Eye-tracking based measurements of gaze fixation and pupil reaction may be useful biomarkers of PD diagnosis. However, larger studies of eye-tracking parameters integrated into the screening of patients with suspected PD are necessary, to further investigate and confirm their diagnostic value.

Multi-cohort profiling reveals elevated CSF levels of brain-enriched proteins in Alzheimer's disease.

OBJECTIVE: Decreased amyloid beta (Aß) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. METHODS: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification. RESULTS: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aß42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. INTERPRETATION: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.