Publications by authors named "Ioanna Markaki"

14 Publications

  • Page 1 of 1

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

Ann Clin Transl Neurol 2021 Jul 15;8(7):1456-1470. Epub 2021 Jun 15.

Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1002/acn3.51402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283172PMC
July 2021

Euglycemia Indicates Favorable Motor Outcome in Parkinson's Disease.

Mov Disord 2021 06 26;36(6):1430-1434. Epub 2021 Feb 26.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1002/mds.28545DOI Listing
June 2021

Novel targeted therapies for Parkinson's disease.

Mol Med 2021 02 25;27(1):17. Epub 2021 Feb 25.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1186/s10020-021-00279-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905684PMC
February 2021

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

J Parkinsons Dis 2021 ;11(2):865-875

Department of Clinical Neuroscience, Neuro, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.3233/JPD-202427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150520PMC
January 2021

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

Eur J Public Health 2021 02;31(1):143-150

Institute of Preventive Medicine, Environmental and Occupational Health, Prolepsis, Athens, Greece.

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.
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http://dx.doi.org/10.1093/eurpub/ckaa178DOI Listing
February 2021

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

Mov Disord 2020 11 15;35(11):2101-2106. Epub 2020 Aug 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1002/mds.28192DOI Listing
November 2020

Repurposing GLP1 agonists for neurodegenerative diseases.

Int Rev Neurobiol 2020 11;155:91-112. Epub 2020 Aug 11.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center of Neurology, Academic Specialist Center, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

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.
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http://dx.doi.org/10.1016/bs.irn.2020.02.007DOI Listing
August 2020

Decreased Cerebrospinal Fluid Aβ42 in Patients with Idiopathic Parkinson's Disease and White Matter Lesions.

J Parkinsons Dis 2019 ;9(2):361-367

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.3233/JPD-181486DOI Listing
April 2020

Novel Treatment Opportunities Against Cognitive Impairment in Parkinson's Disease with an Emphasis on Diabetes-Related Pathways.

CNS Drugs 2019 02;33(2):143-160

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King´s College London, London, UK.

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.
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http://dx.doi.org/10.1007/s40263-018-0601-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373401PMC
February 2019

Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women.

PLoS One 2017 28;12(8):e0183571. Epub 2017 Aug 28.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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) and 183 (55%) had high 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<0.0001). Estimated median survival was not reached for the low homocysteine group, and was 80 months in the high homocysteine group (p with log-rank test 0.002). High homocysteine was not independently associated with increased risk for death after adjustment for age, sex, comorbidities, and eGFR (HR 1.29, 95% CI 0.86-1.93; p = 0.2). Subgroup analysis by sex showed that high homocysteine was an independent predictor of mortality in women after adjustment for age and vascular comorbidities (HR 1.85; 95% CI 1.03-3.31; p = 0.04), but not in men (HR 0.87; 95% CI 0.52-1.43; p = 0.6).

Conclusion: Increased plasma homocysteine (> = 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183571PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573214PMC
October 2017

Reduced incidence of Parkinson's disease after dipeptidyl peptidase-4 inhibitors-A nationwide case-control study.

Mov Disord 2016 09 19;31(9):1422-3. Epub 2016 Jul 19.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1002/mds.26734DOI Listing
September 2016

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

J Stroke Cerebrovasc Dis 2014 Jan 6;23(1):e47-53. Epub 2013 Oct 6.

Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.08.009DOI Listing
January 2014

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

Cerebrovasc Dis 2013 5;35(3):213-9. Epub 2013 Mar 5.

Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1159/000346094DOI Listing
December 2013

Hyperglycaemia in acute ischaemic stroke is associated with an increased 5-year mortality.

Age Ageing 2009 Sep 14;38(5):590-4. Epub 2009 Jul 14.

Department of Neurology, Neuro-Angiological Research Center, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.

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.
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http://dx.doi.org/10.1093/ageing/afp120DOI Listing
September 2009