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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.

Background Cerebral small vessel disease (SVD), often manifesting as white matter lesions (WMLs), and Parkinson's disease (PD) are common disorders whose prevalence increases with age. Vascular risk factors contribute to SVD, but their role in PD is less clear. Objectives The study objective was to investigate the frequency and grade of WMLs in PD, and their association with clinical and biochemical parameters. Methods In total, 100 consecutive patients with available magnetic resonance imaging were included. Vascular risk factors including smoking, hypertension, diabetes type 2, atrial fibrillation, heart insufficiency and hypercholesterolemia were assessed. In 50 patients that had underwent lumbar puncture, cerebrospinal fluid (csf) levels of beta-amyloid1-42, tau and phospho-tau were measured. Results WMLs were present in 86 of 100 patients. Increasing WML severity was independently associated with increased age and lower csf beta-amyloid1-42. Conclusions In our study, WMLs were very common in patients with PD, and were associated with low levels of csf beta-amyloid1-42. Longitudinal studies would increase understanding of the interplay between WMLs and amyloid pathology in PD.

Cognitive impairment is highly prevalent in patients with Parkinson’s disease (PD) and causes adverse health outcomes. Novel procognitive therapies are needed to address this unmet need. It is now established that there is an increased risk of dementia in patients with type 2 diabetes mellitus (T2DM) and, moreover, T2DM and PD may have common underlying biological mechanisms. As such, T2DM medications are emerging as potential therapies in the context of PD dementia (PDD). In this review, we provide an update on pathophysiological mechanisms underlying cognitive impairments and PDD, focusing on diabetes-related pathways. Finally, we have conducted a review of ongoing clinical trials in PD patients with dementia, highlighting the multiple pharmacological mechanisms that are targeted to achieve cognitive enhancement.

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.

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.

International audience; Objective: Decreased amyloid beta (Aβ) 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 Aβ42 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.

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.

International audience; 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 (

International audience; INTRODUCTION:Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY.METHODS:A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.RESULTS:Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors.DISCUSSION:Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

Aims To qualitatively evaluate the optimal intervention (food-voucher approach vs. free daily meal distribution), aimed at reducing food insecurity and promoting healthy eating among students attending public schools in socioeconomically disadvantaged areas. Methods We randomly assigned 34 schools to one of the two interventions: students in 17 schools received a daily lunch-box and parents in the other 17 schools received a food voucher of equal value once a month. All students were offered the opportunity to participate. We conducted 30 focus groups in all participating schools (17 in the meal distribution and 13 in the food voucher schools). Eligible participants included parents (n = 106), educators (n = 66) and school principals (n = 34). We qualitatively evaluated their perceptions and attitudes towards the program. Results Important differences were observed between the two approaches, with more favourable perceptions being reported for the meal distribution approach. More specifically, social stigmatization was minimized in the meal distribution approach, through the participation of all students, compared with the food-voucher participants who reported feelings of embarrassment and fear of stigmatization. Secondly, the meal distribution approach alleviated child food insecurity through the provision of the daily meal, while the food-voucher intervention helped manage household food insecurity, as vouchers were mainly used for purchasing food for family meals. Furthermore, the educational and experiential nature of the meal distribution approach intensified healthy eating promotion, while the food-voucher intervention was efficient mainly for conscious parents regarding healthy eating. Conclusions The meal distribution intervention was considered more effective than the food-voucher one. Hence, for interventions aiming at tackling food insecurity of children and adolescents, public health focus could be oriented towards school-based in kind food assistance.

BackgroundAlthough advances in the understanding of neurodegenerative diseases (NDDs) have led to improvements in classification and diagnosis and most importantly to new therapies, the unmet medical needs remain significant due to high treatment failure rates. The AETIONOMY project funded by the Innovative Medicine Initiative (IMI) aims at using multi-OMICs and bioinformatics to identify new classifications for NDDs based on common molecular pathophysiological mechanisms in view of improving the availability of personalised treatments.ObjectivesThe purpose of the AETIONOMY cross-sectional study is to validate novel patient classification criteria provided by these tools.MethodsThis was a European multi centre, cross-sectional, clinical study conducted at 6 sites in 3 countries. Standardised clinical data, biosamples from peripheral blood, cerebrospinal fluid, skin biopsies, and data from a multi-OMICs approach were collected in patients suffering from Alzheimer’s and Parkinson’s disease, as well as healthy controls.ResultsFrom September 2015 to December 2017 a total of 421 participants were recruited including 95 Healthy Controls. Nearly 1,500 biological samples were collected. The study achieved its objective with respect to Parkinson’s disease (PD) recruitment, however it was unable to recruit many new Alzheimer Disease (AD) patients. Overall, data from 413 evaluable subjects (405 PD and 8 AD) are available for analysis. PD patients and controls were well matched with respect to age (mean 63.4 years), however, close gender matching was not achieved. Approximately half of all PD patients and one At-Risk subject were taking dopamine agonists; rates of Levodopa usage were slightly higher (∼60%). Median MDS-UPDRS Part III Scores (OFF state) ranged from 45 (SD 18) in those with Genetic PD to 2 (SD 3) in Healthy Controls. The standardised methodologies applied resulted in a high-quality database with very few missing data.ConclusionThis is one of the collaborative multi-OMICs studies in individuals suffering from PD and AD involving a control group. It is expected that the integration of data will provide new biomarker-led descriptions of clusters of patient subgroups.

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 cholesterolwas associated with older age,lower blood pressure (BP),presenceof 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 5.0001 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

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.

Background Ischemic stroke is a leading cause of death worldwide, despite preventive and therapeutic advances during the last twenty years. Blood-borne biomarkers have been studied in association to short- and long-term outcome, in order to investigate possible modifiable predictors of disability and death. Increased homocysteine has been associated with increased vascular risk and unfavorable outcome, but homocysteine lowering treatment has not consistently been successful in risk reduction. The aim of this study was to investigate homocysteine levels upon acute ischemic stroke in association to long-term mortality. Methods Of 622 patients included in our hospital-based registry, 331 survived the first month after admission, and had a diagnosis of ischemic stroke and available homocysteine values. All-cause and vascular mortality were investigated based on the national patient- and cause of death-registries. Survival analysis and Cox proportional hazard models were used to investigate time to death and predictors of outcome. Results Of 331 patients, 148 (45%) had low homocysteine ( = 13 micromol/L). During 10 years of follow-up (median 5.5 years), 47 patients (32%) with low homocysteine and 94 (51%) with high homocysteine died (p = 13 micromol/L) upon acute ischemic stroke was not independently associated with mortality in our study. In the subgroup of women, high homocysteine was associated with increased five-year risk of death. Our study’s retrospective design and the exploratory nature of subgroup analysis, prevent robust conclusions based on that observation. Future studies on homocysteine levels before as well as upon stroke will shed further light on a possible causal association.

PURPOSE: To evaluate and quantify the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor–binding protein 3 (IGFBP-3). SUBJECTS AND METHODS: Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of total energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression. RESULTS: We observed that serum levels of IGF-1 are positively associated with consumption of redmeats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. Finally, serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat. CONCLUSION: Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms.

Background: admission hyperglycaemia (HG) is associated with worse prognosis and higher mortality within 3 months after stroke. Reports on long-term mortality are inconsistent. Objective: to evaluate the influence of admission HG [blood glucose (BG) levels >8 mmol/L] on long-term mortality after ischaemic stroke (IS) and transient ischaemic attack (TIA). Methods: consecutive patients with IS or TIA, admitted from January 1997 until December 2002, were retrospectively screened. BG was measured within 3 days from onset of symptoms. Information on the date of death was obtained within 10 years after onset. Results: a total of 509 patients (78% IS; 22% TIA) were included. Admission HG was present in 28% and 18% of the IS and TIA patients, respectively (P = 0.05). Mean admission BG was 7.6 ± 3.2 mmol/L in the IS and 6.7 ± 2.3 mmol/L in TIA (P = 0.002). During a mean observation of 66 ± 35 months, the overall 1- and 10-year mortality rate was 12% and 51% in IS compared to 4% and 38% in TIA patients (P = 0.004). Normoglycaemic IS patients had a longer median survival than those with HG (113 vs 84 months, P = 0.04). Admission HG did not affect the mortality rates in TIA patients. Conclusion: admission HG is associated with greater mortality rates up to 5 years after stroke but does not influence the survival of TIA patients.

PURPOSE: Insulin-like growth factor (IGF-1) and its major binding protein (IGF-BP3) have recently been implicated in the pathogenesis of several malignancies. However, anthropometric and lifestyle predictors of these hormones have not been elucidated. Here we report the results of a cross-sectional study. SUBJECTS AND METHODS: This cross-sectional study examines the relationship of a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) with IGF-1 and IGF-BP3 in a sample of 130 healthy adults. RESULTS: We observed that serum levels of IGF-1 are higher, whereas levels of IGF-BP3 are lower, in men than in women. In addition, serum levels of IGF-1 are independently and negatively associated with age and positively associated with pack-year history of smoking. Finally, serum levels of IGF-BP3 are independently and negatively associated with the number of cigarettes smoked per day or pack-year history of smoking. CONCLUSION: Age, sex, and smoking are independent predictors of IGF-1 and/or IGF-BP3. The influence of these epidemiologic variables on the pathogenesis of disease states associated with IGF-1 and IGF-BP3 warrants further exploration.