Browsing by Subject "ALZHEIMERS-DISEASE"

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  • Rovio, Suvi P.; Pahkala, Katja; Nevalainen, Jaakko; Juonala, Markus; Salo, Pia; Kahonen, Mika; Hutri-Kahonen, Nina; Lehtimaki, Terho; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Tossavainen, Paivi; Viikari, Jorma S. A.; Rinne, Juha O.; Raitakari, Olli T. (2017)
    BACKGROUND In adults, high blood pressure (BP), adverse serum lipids, and smoking associate with cognitive deficits. The effects of these risk factors from childhood on midlife cognitive performance are unknown. OBJECTIVES This study sought to investigate the associations between childhood/adolescence cardiovascular risk factors and midlife cognitive performance. METHODS From 1980, a population-based cohort of 3,596 children (baseline age: 3 to 18 years) have been followed for 31 years in 3- to 9-year intervals. BP, serum lipids, body mass index, and smoking were assessed in all follow-ups. Cumulative exposure as the area under the curve for each risk factor was determined in childhood (6 to 12 years), adolescence (12 to 18 years), and young adulthood (18 to 24 years). In 2011, cognitive testing was performed in 2,026 participants aged 34 to 49 years. RESULTS High systolic BP, elevated serum total-cholesterol, and smoking from childhood were independently associated with worse midlife cognitive performance, especially memory and learning. The number of early life risk factors, including high levels (extreme 75th percentile for cumulative risk exposure between ages 6 and 24 years) of systolic BP, total-cholesterol, and smoking associated inversely with midlife visual and episodic memory and visuospatial associative learning (-0.140 standard deviations per risk factor, p <0.0001) and remained significant after adjustment for contemporaneous risk factors. Individuals with all risk factors within recommended levels between ages 6 and 24 years performed 0.29 standard deviations better (p = 0.006) on this cognitive domain than those exceeding all risk factor guidelines at least twice. This difference corresponds to the effect of 6 years aging on this cognitive domain. CONCLUSIONS Cumulative burden of cardiovascular risk factors from childhood/adolescence associate with worse midlife cognitive performance independent of adulthood exposure. (C) 2017 by the American College of Cardiology Foundation.
  • Wang, Liang; Li, Menglu; Bu, Qian; Li, Hongchun; Xu, Wei; Liu, Chunqi; Gu, Hui; Zhang, Jiamei; Wan, Xuemei; Zhao, Yinglan; Cen, Xiaobo (2019)
    Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.
  • van der Lee, Sven J.; Teunissen, Charlotte E.; Pool, Rene; Shipley, Martin J.; Teumer, Alexander; Chouraki, Vincent; van Lent, Debora Melo; Tynkkynen, Juho; Fischer, Krista; Hernesniemi, Jussi; Haller, Toomas; Singh-Manoux, Archana; Verhoeven, Aswin; Willemsen, Gonneke; de Leeuw, Francisca A.; Wagner, Holger; van Dongen, Jenny; Hertel, Johannes; Budde, Kathrin; van Dijk, Ko Willems; Weinhold, Leonie; Ikram, M. Arfan; Pietzner, Maik; Perola, Markus; Wagner, Michael; Friedrich, Nele; Slagboom, P. Eline; Scheltens, Philip; Yang, Qiong; Gertzen, Robert E.; Egert, Sarah; Li, Shuo; Hankemeier, Thomas; van Beijsterveldt, Catharina E. M.; Vasan, Ramachandran S.; Maier, Wolfgang; Peeters, Carel F. W.; Grabe, Hans Joergen; Ramirez, Alfredo; Seshadri, Sudha; Metspalu, Andres; Kivimäki, Mika; Salomaa, Veikko; Demirkan, Ayse; Boomsma, Dorret I.; van der Flier, Wiesje M.; Amin, Najaf; van Duijn, Cornelia M. (2018)
    Introduction: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. Methods: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. Results: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. Discussion: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
  • Rantalainen, Ville; Lahti, Jari; Henriksson, Markus; Kajantie, Eero; Eriksson, Johan G.; Räikkönen, Katri (2018)
    Objective To test if the Finnish Defence Forces Basic Intellectual Ability Test scores at 20.1 years predicted risk of organic dementia or Alzheimer disease (AD). Methods Dementia was defined as inpatient or outpatient diagnosis of organic dementia or AD risk derived from Hospital Discharge or Causes of Death Registers in 2,785 men from the Helsinki Birth Cohort Study, divided based on age at first diagnosis into early onset (= 65 years). The Finnish Defence Forces Basic Intellectual Ability Test comprises verbal, arithmetic, and visuospatial subtests and a total score (scores transformed into a mean of 100 and SD of 15). We used Cox proportional hazard models and adjusted for age at testing, childhood socioeconomic status, mother's age at delivery, parity, participant's birthweight, education, and stroke or coronary heart disease diagnosis. Results Lower cognitive ability total and verbal ability (hazard ratio [HR] per 1 SD disadvantage > 1.69, 95% confidence interval [CI] 1.01-2.63) scores predicted higher early-onset any dementia risk across the statistical models; arithmetic and visuospatial ability scores were similarly associated with early-onset any dementia risk, but these associations weakened after covariate adjustments (HR per 1 SD disadvantage > 1.57, 95% CI 0.96-2.57). All associations were rendered non-significant when we adjusted for participant's education. Cognitive ability did not predict late-onset dementia risk. Conclusion These findings reinforce previous suggestions that lower cognitive ability in early life is a risk factor for early-onset dementia.
  • Alenius, Minna; Koskinen, Sanna; Hallikainen, Ilona; Ngandu, Tiia; Lipsanen, Jari; Sainio, Päivi; Tuulio-Henriksson, Annamari; Hänninen, Tuomo (2019)
    Background/Aims: To detect cognitive decline in older adults, measures of verbal fluency and verbal memory are widely used. Less is known about performance in these measures in younger persons or according to education level and gender. We investigated cognitive performance according to age, education and gender among cognitively healthy adults aged 30-100 years. Methods: The study population comprised 4,174 cognitively healthy persons participating in the nationally representative Finnish Health 2011 survey. Cognitive assessment included verbal fluency, word list memory, word list recall and word list savings from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Results: Total variance in the cognitive test performance explained by age, education and gender varied from 12.3 to 31.2%. A decreasing trend in cognitive performance existed in all subtests by advancing age, with differences appearing between 50 and 55 years. Persons with the highest-education level performed best for all measures. For the participants <55 years, education explained part of the variance, while age and gender did not. Conclusions: When assessing cognition, age and education should be accounted for in more detail in research and clinical practice. Additionally, the cohort effect and its potential impact on the renewal cycle of future normative values for cognitive tests should be considered. (C) 2019 The Author(s) Published by S. Karger AG, Basel
  • Kivimäki, Mika; Walker, Keenan A.; Pentti, Jaana; Nyberg, Solja; Mars, Nina; Vahtera, Jussi; Suominen, Sakari B.; Lallukka, Tea; Rahkonen, Ossi; Pietiläinen, Olli; Koskinen, Aki; Vaananen, Ari; Kalsi, Jatinderpal K.; Goldberg, Marcel; Zins, Marie; Alfredsson, Lars; Westerholm, Peter J. M.; Knutsson, Anders; Theorell, Tores; Ervasti, Jenni; Oksanen, Tuula; Sipilä, Pyry N.; Tabak, Adam G.; Ferrie, Jane E.; Williams, Stephen A.; Livingston, Gill; Gottesman, Rebecca F.; Singh-Manoux, Archana; Zetterberg, Henrik; Lindbohm, Joni (2021)
    OBJECTIVES To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN Multicohort study with three sets of analyses. SETTING United Kingdom, Europe, and the United States. PARTICIPANTS Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted r3 -0.34, P(0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted r3 -0.33, P(0.001), and peptidyl-glycine alpha-amidating monooxygenase (AMD, fully adjusted r3 -0.32, P(0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that
  • Sarkamo, Teppo (2018)
    Music has the capacity to engage auditory, cognitive, motor, and emotional functions across cortical and subcortical brain regions and is relatively preserved in aging and dementia. Thus, music is a promising tool in the rehabilitation of aging-related neurological illnesses, such as stroke and Alzheimer disease. As the population ages and the incidence and prevalence of these illnesses rapidly increases, music-based interventions that are enjoyable and effective in the everyday care of the patients are needed. In addition to formal music therapy, musical leisure activities, such as music listening and singing, which patients can do on their own or with a caregiver, are a promising way to support psychological well-being during aging and in neurological rehabilitation. This review article provides an overview of current evidence on the cognitive, emotional, and neural effects of musical leisure activities both during normal aging and in the rehabilitation and care of stroke patients and people with dementia. (C) 2017 Elsevier Masson SAS. All rights reserved.
  • Turunen, Merita; Hokkanen, Laura; Bäckman, Lars; Stigsdotter-Neely, Anna; Hänninen, Tuomo; Paajanen, Teemu; Soininen, Hilkka; Kivipelto, Miia; Ngandu, Tiia (2019)
    The possibilities of computer-based cognitive training (CCT) in postponing the onset of dementia are currently unclear, but promising. Our aim is to investigate older adults ' adherence to a long-term CCT program, and which participant characteristics are associated with adherence to the CCT. This study was part of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were 60-77-year-old individuals with increased dementia risk, recruited from previous population-based studies. The participants included in this study (n = 631) had been randomized to receive a multi-domain lifestyle intervention, including CCT. The measure of adherence was the number of completed CCT sessions (max = 144) as continuous measure. Due to a substantial proportion of participants with 0 sessions, the zero inflated negative binomial regression analyses were used to enable assessment of both predictors of starting the training and predictors of completing a higher number of training sessions. Several cognitive, demographic, lifestyle, and health-related variables were examined as potential predictors of adherence to CCT. Altogether, 63% of the participants participated in the CCT at least once, 20% completed at least half of the training, and 12% completed all sessions. Previous experience with computers, being married or cohabiting, better memory performance, and positive expectations toward the study predicted greater odds for starting CCT. Previous computer use was the only factor associated with a greater number of training sessions completed. Our study shows that there is a large variation in adherence to a long-lasting CCT among older adults with an increased risk of dementia. The results indicate that encouraging computer use, and taking into account the level of cognitive functioning, may help boost adherence to CCT.
  • Choo, Xin Yi; Liddell, Jeffrey R.; Huuskonen, Mikko T.; Grubman, Alexandra; Moujalled, Diane; Roberts, Jessica; Kysenius, Kai; Patten, Lauren; Quek, Hazel; Oikari, Lotta E.; Duncan, Clare; James, Simon A.; McInnes, Lachlan E.; Hayne, David J.; Donnelly, Paul S.; Pollari, Eveliina; Vähätalo, Suvi; Lejavova, Katarina; Kettunen, Mikko; Malm, Tarja; Koistinaho, Jari; White, Anthony R.; Kanninen, Katja M. (2018)
    Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex Cu-II(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of Cu-II(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). Cu-II(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of Cu-II(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.
  • Vus, Kateryna; Girych, Mykhailo; Trusova, Valeriya; Gorbenko, Galyna; Kurutos, Atanas; Vasilev, Aleksey; Gadjev, Nikolai; Deligeorgiev, Todor (2019)
    The potential of novel cyanine dyes to inhibit the insulin amyloid formation was evaluated using thioflavin T fluorescence assay, quantum-chemical calculations, molecular docking and molecular dynamics simulations. According to the ability to suppress the insulin fibrillization under physiological conditions the examined compounds were found to follow the order: trimethines > pentamethines > monomethines > heptamethines. Of these, the trimethines 3-3 and 3-5, and pentamethines 5-3 and 5-9 almost completely prevented the protein aggregation by retarding both nucleation (except 3-3) and elongation processes. The quantum-chemical calculations revealed a complex relationship between the dye structure and its inhibitory effects. The molecular docking studies showed that most cyanines bind specifically to the L17 ladder of the B chain, located at the dry steric zipper of the insulin fibril protofilament, and form the stable complexes with the helices of the insulin monomer. The molecular dynamics simulations provided evidence for the increase of insulin helicity in the presence of cyanines. Collectively, the presented findings highlight two possible mechanisms by which cyanines can inhibit the insulin fibrillization: i) stabilization of the native protein structure followed by the retardation of the protein nucleation (all dyes); and ii) blocking the lateral extension of beta-sheets via the dye-protein stacking interactions (3-3, 3-5, 5-3, 5-9). Overall, the obtained results may prove of importance for the design of small molecules capable of preventing amyloid fibril formation by insulin and other proteins. (C) 2018 Elsevier B.V. All rights reserved.
  • Lehtisalo, Jenni; Lindstrom, Jaana; Ngandu, Tiia; Kivipelto, Miia; Ahtiluoto, Satu; Ilanne-Parikka, Pirjo; Keinanen-Kiukaanniemi, Sirkka; Eriksson, Johan G.; Uusitupa, Matti; Tuomilehto, Jaakko; Luchsinger, Jose A.; Finnish Diabet Prevention Study DP (2016)
    BackgroundType 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented. MethodsThe Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n=522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4years) and follow-up (additional 9years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes. ResultsCognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA(1C) during the intervention period predicted better performance in the TMT (p=0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p=0.001) whereas those with long duration of diabetes did not (p=0.844). ConclusionsBetter glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration. Copyright (c) 2015 John Wiley & Sons, Ltd.
  • Lehtisalo, Jenni; Levälahti, Esko; Lindström, Jaana; Hänninen, Tuomo; Paajanen, Teemu; Peltonen, Markku; Antikainen, Riitta; Laatikainen, Tiina; Strandberg, Timo; Soininen, Hilkka; Tuomilehto, Jaakko; Kivipelto, Miia; Ngandu, Tiia (2019)
    Introduction: Association between healthy diet and better cognition is well established, but evidence is limited to evaluate the effect of dietary changes adopted in older age. Methods: We investigated the role of dietary changes in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) with 1260 at-risk participants (60-77 years) who were randomized to intensive multidomain intervention (including dietary counseling) or regular health advice for 2 years. Parallel process latent growth curves of adherence to dietary recommendations and cognitive performance were analyzed. Results: Adherence to healthy diet at baseline predicted improvement in global cognition, regardless of intervention allocation (P = .003). Dietary improvement was associated with beneficial changes in executive function, especially in the intervention group (P = .008; P = .051 for groups combined). Discussion: Dietary changes initiated during the intervention were related to changes in executive function in 2 years. Long-term diet appeared more influential for global cognition. (C) 2018 The Authors. Published by Elsevier Inc.
  • Solomon, Alina; Handels, Ron; Wimo, Anders; Antikainen, Riitta; Laatikainen, Tiina; Levälahti, Esko; Peltonen, Markku; Soininen, Hilkka; Strandberg, Timo; Tuomilehto, Jaakko; Kivipelto, Miia; Ngandu, Tiia (2021)
    We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60-77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was -0.16 (95 % CI -0.31 to 0.00) (p = 0.013), corresponding to a relative dementia risk reduction between 6.04-6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.
  • Lindgren, Noora; Kaprio, Jaakko; Karjalainen, Tomi; Ekblad, Laura; Helin, Semi; Karrasch, Mira; Teuho, Jarmo; Rinne, Juha O.; Vuoksimaa, Eero (2021)
    We studied the association between episodic memory and cortical fibrillar β-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([11C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [11C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions.
  • Rasila, Tiina; Lehtonen, Alexandra; Kanerva, Kristiina; Mäkitie, Laura T.; Haglund, Caj; Andersson, Leif C. (2016)
    Ornithine decarboxylase (ODC) antizyme inhibitor 2 (AZIN2), originally called ODCp, is a regulator of polyamine synthesis that we originally identified and cloned. High expression of ODCp mRNA was found in brain and testis. We reported that AZIN2 is involved in regulation of cellular vesicle transport and/or secretion, but the ultimate physiological role(s) of AZIN2 is still poorly understood. In this study we used a peptide antibody (K3) to human AZIN2 and by immunohistochemistry mapped its expression in various normal tissues. We found high expression in the nervous system, in type 2 pneumocytes in the lung, in megakaryocytes, in gastric parietal cells co-localized with H, K-ATPase beta subunit, in selected enteroendocrine cells, in acinar cells of sweat glands, in podocytes, in macula densa cells and epithelium of collecting ducts in the kidney. The high expression of AZIN2 in various cells with secretory or vesicle transport activity indicates that the polyamine metabolism regulated by AZIN2 is more significantly involved in these events than previously appreciated.
  • El-Khoury, Riyad; Kaulio, Eveliina; Lassila, Katariina A.; Crowther, Damian C.; Jacobs, Howard T.; Rustin, Pierre (2016)
    Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease. (C) 2016 The Authors. Published by Elsevier Inc.
  • Huovinen, Joel; Kastinen, Sami; Komulainen, Simo; Oinas, Minna; Avellan, Cecilia; Frantzen, Janek; Rinne, Jaakko; Ronkainen, Antti; Kauppinen, Mikko; Lonnrot, Kimmo; Perola, Markus; Pyykko, Okka T.; Koivisto, Anne M.; Remes, Anne M.; Soininen, Hilkka; Hiltunen, Mikko; Helisalmi, Seppo; Kurki, Mitja; Jaaskelainen, Juha E.; Leinonen, Ville (2016)
    Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE epsilon 4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH. (C) 2016 Elsevier B.V. All rights reserved.
  • Kallio, Eeva-Liisa; Ohman, H.; Carlson, S.; Kautiainen, H.; Hietanen, M.; Pitkala, K. H. (2017)
    Introduction: Evidence is unclear whether cognitive training (CT) has efficacy in patients with dementia. We present the recruitment and baseline findings of a carefully designed Finnish cognitive training (FINCOG) trial exploring the effectiveness of CT among community-dwelling older persons with mild-to-moderate dementia. Methods: Participants were recruited from adult day care centres in Helsinki, Finland, and randomised into two groups: (1) day care with systematic CT twice a week for 12 weeks (n = 76) and (2) day care as usual (n = 71). Demographics, diagnoses and drug use were retrieved from medical records, and baseline cognition, functioning, health-related quality of life (HRQoL) and psychological well-being were assessed. A subgroup of participants was planned to undergo functional magnetic resonance imaging (fMRI) to measure changes in brain activity. Feedback from those attending CT was collected. Primary trial outcomes will be participants' cognition and HRQoL. Results: The mean (SD) age of the randomised participants was 83.1 (5.4) years, 72% were female and 37% at a moderate stage of dementia. The intervention and control groups were comparable at baseline. Compliance with CT was good, with a mean attendance of 22/24 sessions. General subjective gain was achieved by three-fourths of the feedback respondents. However, the fMRI was not feasible in this patient group. Conclusions: We successfully randomised 147 persons with mild-to-moderate dementia in the FINCOG trial. The feedback from participants in cognitive intervention was favourable. The trial will provide important information on the effects of CT in patients with dementia. (C) 2017 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
  • Korpi, Esa R.; Lindholm, Dan; Panula, Pertti; Tienari, Pentti J.; Haltia, Matti (2020)
  • Cattaneo, Annamaria; Cattane, Nadia; Malpighi, Chiara; Czamara, Darina; Suarez, Anna; Mariani, Nicole; Kajantie, Eero; Luoni, Alessia; Eriksson, Johan G.; Lahti, Jari; Mondelli, Valeria; Dazzan, Paola; Räikkönen, Katri; Binder, Elisabeth B.; Riva, Marco A.; Pariante, Carmine M. (2018)
    To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.