Juha O Rinne

University of Turku, Turku, Varsinais-Suomi, Finland

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Publications (467)2149.62 Total impact

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    ABSTRACT: The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.
    Journal of Alzheimer's disease: JAD 09/2015; 48(1):123-133. DOI:10.3233/JAD-150190 · 4.15 Impact Factor
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    ABSTRACT: Background: The pathophysiology of the movement disorder progressive ataxia with palatal tremor (PAPT) is unclear. Case report: A 77-year-old male presented with dysarthria, ataxia, and 1-2 Hz palatal tremor. A diagnosis of probable sporadic PAPT was established. Brain magnetic resonance imaging was normal at the presymptomatic phase but later showed olivary hypertrophy. Brain [(18)F]-fludeoxyglucose (FDG) positron emission tomography (PET) showed bilateral hypermetabolism in the olivary nuclei. Discussion: This second reported patient with PAPT and FDG-PET shows that olivary hypertrophy is paralleled with hypermetabolism. The olivary nuclei pathology also appears to be temporally associated with symptom onset.
    09/2015; 5:342. DOI:10.7916/D8PV6JMT
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    ABSTRACT: Objectives We set to investigate the possible role of genes and environment in developing Alzheimer's disease (AD) in monozygotic twin pairs discordant for AD.Methods Three pairs of twins discordant for AD, who were enrolled in the Finnish Twin Cohort, were used in the study and compared with 13 controls. Gray matter changes were assessed with magnetic resonance images using voxel-based morphometry with statistical parametric mapping.ResultsIn the affected twins, the peaks of volume loss were located bilaterally in the temporal (including the hippocampus), the frontal, and the parietal lobes, while in the unaffected siblings, the peaks were located in the frontal gyri and in the parietal lobule. Thus, in the unaffected twins, the pattern of volume loss overlaps with the neocortical but not with the medial temporal areas.DiscussionThese findings suggest that genetic factors more largely control neocortical regions, whereas environmental factors more strongly affect medial temporal regions.
    Acta Neurologica Scandinavica 09/2015; DOI:10.1111/ane.12480 · 2.40 Impact Factor
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    ABSTRACT: Type 2 diabetes is an independent risk factor for cognitive decline. Insulin resistance occurring during midlife may increase the risk of cognitive decline later in life. We hypothesised that insulin resistance is associated with poorer cognitive performance and that sex and APOE*E4 might modulate this association. The association of insulin resistance and APOE*E4 genotype on cognitive function was evaluated in a nationwide Finnish population-based study (n = 5,935, mean age 52.5 years, range 30-97 years). HOMA-IR was used to measure insulin resistance. Cognitive function was tested by word-list learning, word-list delayed-recall, categorical verbal fluency and simple and visual-choice reaction-time tests. Linear regression analysis was used to determine the association between HOMA-IR and the results of the cognitive tests. Higher HOMA-IR was associated with poorer verbal fluency in women (p < 0.0001) but not in men (p = 0.56). Higher HOMA-IR was also associated with poorer verbal fluency in APOE*E4 -negative individuals (p = 0.0003), but not in APOE*E4 carriers (p = 0.28). Furthermore, higher HOMA-IR was associated with a slower simple reaction time in the whole study group (p = 0.02). To our knowledge, this is the first comprehensive, population-based study, including both young and middle-aged adults, to report that female sex impacts the association of HOMA-IR with verbal fluency. Our study was cross-sectional, so causal effects of HOMA-IR on cognition could not be evaluated. However, our results suggest that HOMA-IR could be an early marker for an increased risk of cognitive decline in women.
    Diabetologia 08/2015; DOI:10.1007/s00125-015-3715-4 · 6.67 Impact Factor
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    ABSTRACT: Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 07/2015; 138(Pt 9). DOI:10.1093/brain/awv184 · 9.20 Impact Factor
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    ABSTRACT: Long-term flux measurements of volatile organic compounds (VOC) over boreal forests are rare, although the forests are known to emit considerable amounts of VOCs into the atmosphere. Thus, we measured fluxes of several VOCs and oxygenated VOCs over a Scots pine dominated boreal forest semi-continuously between May 2010 and December 2013. The VOC profiles were obtained with a proton-transfer-reaction mass-spectrometry, and the fluxes were calculated using vertical concentration profiles and the surface layer profile method connected to the Monin-Obukhov similarity theory. In total fluxes that differed significantly from zero on a monthly basis were observed for 14 out 27 measured masses. Monoterpenes had the highest net emission in all seasons and statistically significant positive fluxes were detected from March until November. Other important compounds emitted were methanol, ethanol/formic acid, acetone and isoprene/MBO. Oxygenated VOCs showed also deposition fluxes that were statistically different from zero. Isoprene/methylbutenol and monoterpene fluxes followed well the traditional isoprene algorithm and the hybrid algorithm, respectively. Emission potentials of monoterpenes were largest in late spring and fall which was possibly driven by growth processes and decaying of soil litter, respectively. Conversely, largest emission potentials of isoprene/methylbutenol were found in July. Thus, we concluded that most of the emissions of m/z 69 at the site consisted of isoprene that originated from broadleaved trees. Methanol had deposition fluxes especially before sunrise. This can be connected to water films on surfaces. Based on this assumption, we were able to build an empirical algorithm for bi-directional methanol exchange that described both emission term and deposition term. Methanol emissions were highest in May and June and deposition level increased towards fall, probably as a result of increasing relative humidity levels leading to predominance of deposition.
    Biogeosciences Discussions 06/2015; 12(12):9543-9586. DOI:10.5194/bgd-12-9543-2015
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    ABSTRACT: In this study a long-term volatile organic compounds (VOCs) data set, measured at the SMEAR II (Station for measuring Ecosystem–Atmosphere Relations) boreal forest site at Hyytiälä, Finland during the years 2006–2011, was investigated. VOC mixing ratios were measured using proton transfer reaction mass spectrometry. Four-day backward trajectories and the Unmix 6.0 receptor model were used for source area and source composition analysis. Two major forest fire events, one in Eastern Europe and one in Russia, took place during the measurement period. The effect of these fires was clearly visible in the trajectory analysis, lending confidence to the method employed with this data set. Elevated volume mixing ratios (VMRs) of non-biogenic VOCs, e.g. acetonitrile and aromatic VOCs, related to forest fires were observed. Ten major source areas for long-lived VOCs (methanol, acetonitrile, acetaldehyde, acetone, benzene and toluene) were identified at the SMEAR II site. The main source areas for all the targeted VOCs were Western Russia, Northern Poland, Kaliningrad and Baltic countries. Industrial areas in Northern Continental Europe were also found to be source areas for certain VOCs. Both trajectory and receptor analysis showed that air masses from Northern Fennoscandia were less polluted with both the VOCs studied and with other trace gases (CO, SO2 and NOx) than areas of Eastern and Western Continental Europe, Western Russia and Southern Fennoscandia.
    Atmospheric Chemistry and Physics 05/2015; 15(10):14593-14641. DOI:10.5194/acpd-15-14593-2015 · 4.88 Impact Factor
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    ABSTRACT: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
    JAMA The Journal of the American Medical Association 05/2015; 313(9):1924-1938. DOI:10.1001/jama.2015.4668 · 35.29 Impact Factor
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    ABSTRACT: Importance Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non–AD dementia.Objective To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes.Data Sources The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies.Study Selection Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data.Data Extraction and Synthesis Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non–AD dementia. The reference groups were 1849 healthy control participants (with amyloid PET) and an independent sample of 1369 AD participants (with autopsy data).Main Outcomes and Measures Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method.Results The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non–AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years.Conclusions and Relevance Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.
    JAMA The Journal of the American Medical Association 05/2015; 313(19). DOI:10.1001/jama.2015.4669 · 35.29 Impact Factor
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    ABSTRACT: Atrophy of the medial temporal lobe (MTL) is the main structural magnetic resonance imaging (MRI) finding in the brain of patients with Alzheimer's disease (AD). However, evaluating the degree of atrophy is still demanding. The visual rating method (VRM) was compared with multi-template tensor-based morphometry (TBM), in terms of its efficacy in diagnosing of mild cognitive impairment (MCI) and AD. Forty-seven patients with MCI, 80 patients with AD and 84 controls were studied. TBM seems to be more sensitive than VRM at the early stage of dementia in the areas of MTL and ventricles. The methods were equally good in distinguishing controls and the MCI group from the AD group. At the frontal areas TBM was better than VRM in all comparisons. A user-friendly VRM is still useful for the clinical evaluation of MCI patients, but multi-template TBM is more sensitive for diagnosing the early stages of dementia. However, TBM is currently too demanding to use for daily clinical work. © The Foundation Acta Radiologica 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    Acta Radiologica 05/2015; DOI:10.1177/0284185115584656 · 1.60 Impact Factor
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    ABSTRACT: Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.
    Journal of Neuroinflammation 04/2015; 12(1):81. DOI:10.1186/s12974-015-0305-9 · 5.41 Impact Factor
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    ABSTRACT: Proton transfer reaction mass spectrometry (PTR-MS) and gas chromatography mass spectrometry GC-MS) allow real-time measurements of various atmospheric volatile organic compounds (VOC). By taking parallel measurements in ambient conditions, two PTR-MSs and two GC-MSs were studied for their ability to measure methanol, acetaldehyde, acetone, benzene and toluene. The measurements were conducted at a rural boreal forest site in southern Finland between 13 April and 14 May 2012. This paper presents correlations and possible biases between the concentrations measured using the four instruments. This paper presents correlations and possible biases between the concentrations measured using the four instruments. A very good correlation was found for benzene and acetone measurements between all instruments (the mean R value was 0.88 for both compounds), while for acetaldehyde and toluene the correlation was weaker (with a mean R value of 0.50 and 0.62, respectively). For some compounds, notably for methane, there were considerable systematic differences in the mixing ratios measured by the different instruments, despite the very good correlation between the instruments (mean R = 0.90). The systematic difference arises as a difference in the linear regression slope between measurements conducted between instruments, rather than as an offset. This mismatch indicates that the systematic uncertainty in the sensitivity of a given instrument can lead to an uncertainty of 50–100% in the methanol emissions measured by commonly used methods.
    04/2015; 8(4):3753-3802. DOI:10.5194/amtd-8-3753-2015
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    ABSTRACT: We measured the long-term test-retest reliability of [(11)C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [(11)C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [(11)C]raclopride binding in the striatum. A novel finding is the relatively low variability of [(11)C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [(11)C]raclopride PET to be verified in future studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 April 2015; doi:10.1038/jcbfm.2015.53.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2015; 35(7). DOI:10.1038/jcbfm.2015.53 · 5.41 Impact Factor
  • Juha O. Rinne · Mira Karrasch
    Muistisairaudet [Dementias], Edited by Timo Erkinjuntti, Anne Remes, Juha O. Rinne, Hilkka Soininen, 03/2015; Kustannus Oy Duodecim.
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    ABSTRACT: Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250±10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.Journal of Cerebral Blood Flow & Metabolism advance online publication, 4 February 2015; doi:10.1038/jcbfm.2014.261.
    Journal of Cerebral Blood Flow & Metabolism 02/2015; 35(5). DOI:10.1038/jcbfm.2014.261 · 5.41 Impact Factor
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    ABSTRACT: There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions as this is thought to be driving the widespread neuronal damage. Recently, 'second generation' positron emission tomography (PET) radioligands have been developed which can reveal the extent of microglial activation by quantifying the increased expression of the 18 kDa translocator (TSPO) protein. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion following treatment with fingolimod, an established MS therapy. Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotaxic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund's adjuvant. This results in a delayed type hypersensitivity (DTH)-like EAE-lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/day po, 28 days) or vehicle as a control. In addition to this, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results. The chronic DTH-EAE lesion led to increased ligand binding in the ipsilateral compared to contralateral hemisphere when PET imaging was performed with the TSPO-binding radioligand (18)F-GE180. Treatment with fingolimod led to highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, p<0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry. PET-imaging, unlike magnetic resonance imaging (MRI), can be used to visualise the microglial activation surrounding a chronic DTH-EAE lesion. Importantly, treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH-EAE lesion. This work gives promise for introduction of new outcome measures applicable in treatment studies of progressive MS. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 01/2015; 56(2). DOI:10.2967/jnumed.114.149955 · 6.16 Impact Factor
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    ABSTRACT: Background: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer's disease (AD). Objective: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. Methods: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints. Results: 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9-16% in active, 3.5% placebo) were the most frequent adverse events. Conclusions: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients.
    Journal of Alzheimer's disease: JAD 12/2014; 45(1). DOI:10.3233/JAD-141959 · 4.15 Impact Factor
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    ABSTRACT: Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [(11)C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [(11)C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40-50 minutes) and intervention (60-85 minutes) revealed an average 12.6% decrease in [(11)C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=-0.87, P=0.003) and putamen (r=-0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.209.
    Journal of Cerebral Blood Flow & Metabolism 12/2014; 35(3). DOI:10.1038/jcbfm.2014.209 · 5.41 Impact Factor
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    ABSTRACT: This study explored the use of the α2C-adrenoceptor PET tracer [11C]ORM-13070 to monitor α2C-AR occupancy in the human brain. The subtype-nonselective α2-AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions.We assessed occupancy from the bound-to-free ratio measured during 5-30 minutes post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [11C]ORM-13070 uptake (Emax) achievable by atipamezole was 78 % (95 % CI 69-87 %) in the caudate nucleus and 65 % (53-77 %) in the putamen. The EC50 estimates of atipamezole (1.6 ng/ml and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C-ARs. These findings represent clear support for the use of [11C]ORM-13070 for monitoring drug occupancy of α2C-ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16 % average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine and the cold pressor test; p < 0.05 for all), but insulin-induced hypoglycaemia did not affect tracer uptake. The tracer is suitable for studying CNS receptor occupancy by α2C-AR ligands in human subjects. [11C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies. This article is protected by copyright. All rights reserved.
    Synapse 12/2014; 69(3). DOI:10.1002/syn.21798 · 2.13 Impact Factor

Publication Stats

15k Citations
2,149.62 Total Impact Points


  • 1985–2015
    • University of Turku
      • • Turku PET Centre
      • • Department of Neurology
      • • Division of Psychology
      Turku, Varsinais-Suomi, Finland
  • 2004–2014
    • University of Helsinki
      • • Department of Physics
      • • Department of Physical Sciences
      Helsinki, Uusimaa, Finland
  • 1999–2014
    • Turku PET Centre
      Turku, Varsinais-Suomi, Finland
    • Finnish Meteorological Institute
      • Air Quality Research
      Helsinki, Southern Finland Province, Finland
  • 1996–2014
    • Turku University Hospital
      • Turku PET Centre
      Turku, Varsinais-Suomi, Finland
  • 2013
    • University of Eastern Finland
      • Institute of Clinical Medicine
      Kuopio, Northern Savo, Finland
  • 2006–2012
    • Åbo Akademi University
      Turku, Province of Western Finland, Finland
  • 2011
    • Imperial College London
      Londinium, England, United Kingdom
    • Karolinska Institutet
      • Aging Research Center - ARC
      Solna, Stockholm, Sweden
  • 2008
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Oulu
      Uleoborg, Oulu, Finland
    • Kuopio University Hospital
      • Department of Neurosurgery
      Kuopio, Province of Eastern Finland, Finland
  • 2000–2002
    • National Center for Atmospheric Research
      • Division of Atmospheric Chemistry
      Boulder, Colorado, United States
  • 1999–2001
    • Research Institute of the Finnish Economy, Finland, Helsinki
      Helsinki, Uusimaa, Finland
  • 1994
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
  • 1992
    • University Center Rochester
      • Department of Neurology
      Рочестер, Minnesota, United States
  • 1991
    • Turku centre for biotechnology, finland
      Turku, Province of Western Finland, Finland