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  • Ni, Ruiqing; Gillberg, Per-Goran; Bogdanovic, Nenad; Viitanen, Matti; Myllykangas, Liisa; Nennesmo, Inger; Langstrom, Bengt; Nordberg, Agneta (2017)
    Introduction: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-beta aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 E Delta 9 mutations, 13 sporadic AD, and 14 control cases. Results: H-3-PIB, H-3-florbetaben, H-3-AZD2184, and BTA-1 shared a high-and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The H-3-AZD2184 and H-3-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on H-3-AZD84 binding followed by H-3-florbetaben and minimal on H-3-PIB. Discussion: This study implies amyloid tracers of different structures detect different sites on amyloid-beta fibrils or conformations. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
  • Moisala, Mona; Salmela, Viljami; Salo, Emma; Carlson, Synnove; Vuontela, Virve; Salonen, Oili; Alho, Kimmo (2015)
  • Tikka, Saara; Baumann, Marc; Siitonen, Maija; Pasanen, Petra; Poyhonen, Minna; Myllykangas, Liisa; Viitanen, Matti; Fukutake, Toshio; Cognat, Emmanuel; Joutel, Anne; Kalimo, Hannu (2014)
  • Peltola, Elina; Hannula, Paivi; Huhtala, Heini; Metso, Saara; Kiviniemi, Ulla; Vornanen, Martine; Sand, Juhani; Laukkarinen, Johanna; Tiikkainen, Mirja; Schalin-Jantti, Camilla; Arola, Johanna; Siren, Jukka; Piiroinen, Antti; Soinio, Minna; Nuutila, Pirjo; Soderstrom, Mirva; Hamalainen, Hanna; Moilanen, Leena; Laaksonen, David; Pirinen, Elina; Sundelin, Fia; Ebeling, Tapani; Salmela, Pasi; Makinen, Markus J.; Jaatinen, Pia (2018)
    Objective. Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods. Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. Results. Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0 002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p <0 001). Seventy- one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions. The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.
  • Alitalo, Okko; Rantamäki, Tomi; Huhtala, Tuulia (2020)
    Autoradiography (ARG) is a high-resolution imaging method for localization of radiolabeled biomarkers in ex vivo specimen. ARG using 2-deoxy-D-glucose (2-DG) method is used in to study drug actions on brain functional activity, as it provides results comparable to clinically used functional positron-emission tomography (PET). The requirement of slow analog detection methods and emerging advances in small animal PET imaging have, however, reduced the interest in ARG. In contrast to ARG, experimental animals need to be restrained or sedated/anesthetized for PET imaging, which strongly influence functional activity and thus complicate the interpretation of the results. Digital direct particle-counting ARG systems have gained attraction during the last decade to overcome the caveats of conventional ARG methods. Here we demonstrate that the well-established 2-DG imaging method can be adapted into use with contemporary digital detectors. This method readily and rapidly captures the characteristic effects of phencyclidine (5 mg/kg, i.p.), a dissociative agent targeting the NMDAR (N-methyl-D-aspartate receptor), on regional glucose utilization in the adult mouse brain. Pretreatment with antipsychotic drug clozapine (6 mg/kg, i.p.) essentially abolishes these effects of phencyclidine on brain functional activity. Digital ARG produces viable data for the regional analysis of functional activity in a fraction of time required for film development. These results support the use of digital ARG in preclinical drug research, where high throughput and response linearity are preferred and use of sedation/anesthesia has to be avoided.
  • Martikainen, Ilkka K.; Hagelberg, Nora; Jääskelainen, Satu K.; Hietala, Jarmo; Pertovaara, Antti (2018)
    Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D-2/D-3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D-2/D-3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D-2/D-3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D-2/D-3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D-2/D-3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D-2/D-3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D-2/D-3 receptors. These findings suggest that dopamine acting on striatal dopamine D-2/D-3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.
  • Eskian, Mahsa; Alavi, Abass; Khorasanizadeh, MirHojjat; Viglianti, Benjamin L.; Jacobsson, Hans; Barwick, Tara D.; Meysamie, Alipasha; Yi, Sun K.; Iwano, Shingo; Bybel, Bohdan; Caobelli, Federico; Lococo, Filippo; Gea, Joaquim; Sancho-Munoz, Antonio; Schildt, Jukka; Tatci, Ebru; Lapa, Constantin; Keramida, Georgia; Peters, Michael; Boktor, Raef R.; John, Joemon; Pitman, Alexander G.; Mazurek, Tomasz; Rezaei, Nima (2019)
    Objectives To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in F-18-FDG-PET scan. Methods A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, F-18-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (200 mg/dl). Results Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p <0.001, p <0.001,) and muscle (p <0.001, p <0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p=0.008, p200 mg/dl had significantly lower SUVmax. Conclusion If BGL is lower than 200mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.
  • Näsi, Tiina; Mäki, Hanna; Kotilahti, Kalle; Nissila, Ilkka; Haapalahti, Petri; Ilmoniemi, Risto J. (2011)
  • Tian, Li; Hui, Chin Wai; Bisht, Kanchan; Tan, Yunlong; Sharma, Kaushik; Chen, Song; Zhang, Xiangyang; Tremblay, Marie-Eve (2017)
    Mounting evidence indicates the importance of microglia for proper brain development and function, as well as in complex stress-related neuropsychiatric disorders and cognitive decline along the aging trajectory. Considering that microglia are resident immune cells of the brain, a homeostatic maintenance of their effector functions that impact neuronal circuitry, such as phagocytosis and secretion of inflammatory factors, is critical to prevent the onset and progression of these pathological conditions. However, the molecular mechanisms by which microglial functions can be properly regulated under healthy and pathological conditions are still largely unknown. We aim to summarize recent progress regarding the effects of psychosocial stress and oxidative stress on microglial phenotypes, leading to neuroinflammation and impaired microglia-synapse interactions, notably through our own studies of inbred mouse strains, and most importantly, to discuss about promising therapeutic strategies that take advantage of microglial functions to tackle such brain disorders in the context of adult psychosocial stress or aging-induced oxidative stress. (c) 2017 Elsevier Inc. All rights reserved.
  • Vidakovic, Maja Rogic; Jerkovic, Ana; Juric, Tomislav; Vujovic, Igor; Soda, Josko; Erceg, Nikola; Bubic, Andreja; Schonwald, Marina Zmajevic; Lioumis, Pantelis; Gabelica, Dragan; Dogas, Zoran (2016)
    Transcranial magnetic stimulation studies have so far reported the results of mapping the primary motor cortex (M1) for hand and tongue muscles in stuttering disorder. This study was designed to evaluate the feasibility of repetitive navigated transcranial magnetic stimulation (rTMS) for locating the M1 for laryngeal muscle and premotor cortical area in the caudal opercular part of inferior frontal gyrus, corresponding to Broca's area in stuttering subjects by applying new methodology for mapping these motor speech areas. Sixteen stuttering and eleven control subjects underwent rTMS motor speech mapping using modified patterned rTMS. The subjects performed visual object naming task during rTMS applied to the (a) left M1 for laryngeal muscles for recording corticobulbar motor-evoked potentials (CoMEP) from cricothyroid muscle and (b) left premotor cortical area in the caudal opercular part of inferior frontal gyrus while recording long latency responses (LLR) from cricothyroid muscle. The latency of CoMEP in control subjects was 11.75 +/- A 2.07 ms and CoMEP amplitude was 294.47 +/- A 208.87 A mu V, and in stuttering subjects CoMEP latency was 12.13 +/- A 0.75 ms and 504.64 +/- A 487.93 A mu V CoMEP amplitude. The latency of LLR in control subjects was 52.8 +/- A 8.6 ms and 54.95 +/- A 4.86 in stuttering subjects. No significant differences were found in CoMEP latency, CoMEP amplitude, and LLR latency between stuttering and control-fluent speakers. These results indicate there are probably no differences in stuttering compared to controls in functional anatomy of the pathway used for transmission of information from premotor cortex to the M1 cortices for laryngeal muscle representation and from there via corticobulbar tract to laryngeal muscles.
  • Tuominen, Lauri; Miettunen, Jouko; Cannon, Dara M.; Drevets, Wayne C.; Frokjaer, Vibe G.; Hirvonen, Jussi; Ichise, Masanori; Jensen, Peter S.; Keltikangas-Järvinen, Liisa; Klaver, Jacqueline M.; Knudsen, Gitte M.; Takano, Akihiro; Suhara, Tetsuya; Hietala, Jarmo (2017)
    Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P = .008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P = .014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.
  • Päivärinta, Johanna; Oikonen, Vesa; Räisänen-Sokolowski, Anne; Tolvanen, Tuula; Löyttyniemi, Eliisa; Hidehiro, Iida; Nuutila, Pirjo; Metsärinne, Kaj; Koivuviita, Niina (2019)
    Background Despite improvement in short-term outcome of kidney transplants, the long-term survival of kidney transplants has not changed over past decades. Kidney biopsy is the gold standard of transplant pathology but it's invasive. Quantification of transplant blood flow could provide a novel non-invasive method to evaluate transplant pathology. The aim of this retrospective cross-sectional pilot study was to evaluate positron emission tomography (PET) as a method to measure kidney transplant perfusion and find out if there is correlation between transplant perfusion and histopathology. Methods Renal cortical perfusion of 19 kidney transplantation patients [average time from transplantation 33 (17-54) months; eGFR 55 (47-69) ml/min] and 10 healthy controls were studied by [(15) O]H2O PET. Perfusion and Doppler resistance index (RI) of transplants were compared with histology of one-year protocol transplant biopsy. Results Renal cortical perfusion of healthy control subjects and transplant patients were 2.7 (2.4-4.0) ml min(- 1) g(- 1) and 2.2 (2.0-3.0) ml min(- 1) g(- 1), respectively (p = 0.1). Renal vascular resistance (RVR) of the patients was 47.0 (36.7-51.4) mmHg mL(- 1)min(- 1)g(- 1) and that of the healthy 32.4 (24.6-39.6) mmHg mL(- 1)min(-1)g(-1) (p = 0.01). There was a statistically significant correlation between Doppler RI and perfusion of transplants (r = - 0.51, p = 0.026). Transplant Doppler RI of the group of mild fibrotic changes [0.73 (0.70-0.76)] and the group of no fibrotic changes [0.66 (0.61-0.72)] differed statistically significantly (p = 0.03). No statistically significant correlation was found between cortical perfusion and fibrosis of transplants (p = 0.56). Conclusions [(15) O]H2O PET showed its capability as a method in measuring perfusion of kidney transplants. RVR of transplant patients with stage 2-3 chronic kidney disease was higher than that of the healthy, although kidney perfusion values didn't differ between the groups. Doppler based RI correlated with perfusion and fibrosis of transplants.
  • Le Joncour, Vadim; Laakkonen, Pirjo (2018)
    Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures - sometimes in a patient specific manner -that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/ or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor's location. Peptide vaccines are outside of the scope of this review. (C) 2017 The Authors. Published by Elsevier Ltd.
  • Kandolin, Riina M.; Wiefels, Christiane C.; Mesquita, Claudio Tinoco; Chong, Aun-Yeong; Boland, Paul; Glineur, David; Sun, Louise; Beanlands, Rob S.; Mielniczuk, Lisa M. (2019)
    This review describes the current evidence and controversies for viability imaging to direct revascularization decisions and the impact on patient outcomes. Balancing procedural risks and possible benefit from revascularization is a key question in patients with heart failure of ischemic origin (IHF). Different stages of ischemia induce adaptive changes in myocardial metabolism and function. Viable but dysfunctional myocardium has the potential to recover after restoring blood flow. Modern imaging techniques demonstrate different aspects of viable myocardium; perfusion (single-photon emission computed tomography [SPECT], positron emission tomography [PET], cardiovascular magnetic resonance [CMR]), cell metabolism (PET), cell membrane integrity and mitochondrial function (201Tl and 99mTc-based SPECT), contractile reserve (stress echocardiography, CMR) and scar (CMR). Observational studies suggest that patients with IHF and significant viable myocardium may benefit from revascularization compared with medical treatment alone but that in patients without significant viability, revascularization appears to offer no survival benefit or could even worsen the outcome. This was not supported by 2 randomized trials (Surgical Treatment for Ischemic Heart Failure [STICH] and PET and Recovery Following Revascularization [PARR] -2) although post-hoc analyses suggest that benefit can be achieved if decisions had been strictly based on viability imaging recommendations. Based on current evidence, viability testing should not be the routine for all patients with IHF considered for revascularization but rather integrated with clinical data to guide decisions on revascularization of high-risk patients with comorbidities.
  • Dahoun, Tarik; Pardinas, Antonio F.; Veronese, Mattia; Bloomfield, Michael A. P.; Jauhar, Sameer; Bonoldi, Ilaria; Froudist-Walsh, Sean; Nosarti, Chiara; Korth, Carsten; Hennah, William; Walters, James; Prata, Diana; Howes, Oliver D. (2018)
    Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISCI single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [F-18]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant K-i(cer) in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1. rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal K-i(cer) compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial eta(2) = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1. is of functional interest in the aetiology of major mental illness.
  • Heymans, Stephane; Eriksson, Urs; Lehtonen, Jukka; Cooper, Leslie T. (2016)
    Myocarditis is a diverse group of heart-specific immune processes classified by clinical and histopathological manifestations. Up to 40% of dilated cardiomyopathy is associated with inflammation or viral infection. Recent experimental studies revealed complex regulatory roles for several microribonucleic acids and T-cell and macrophage subtypes. Although the prevalence of myocarditis remained stable between 1990 and 2013 at about 22 per 100,000 people, overall mortality from cardiomyopathy and myocarditis has decreased since 2005. The diagnostic and prognostic value of cardiac magnetic resonance has increased with new, higher-sensitivity sequences. Positron emission tomography has emerged as a useful tool for diagnosis of cardiac sarcoidosis. The sensitivity of endomyocardial biopsy may be increased, especially in suspected sarcoidosis, by the use of electrogram guidance to target regions of abnormal signal. Investigational treatments on the basis of mechanistic advances are entering clinical trials. Revised management recommendations regarding athletic participation after acute myocarditis have heightened the importance of early diagnosis. (C) 2016 by the American College of Cardiology Foundation.