Biology subjects

Rinne, J.

Publications and source records attributed to Rinne, J..

16 recordsLinked to original sources

bioRxiv2026

Diurnal and seasonal regulation of brain mu-opioid and dopamine D2 receptor signalling in humans

Purpose: Rhythmic regulation of human neurotransmission systems, particularly the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling, remains poorly understood. Although prior studies indicate possible diurnal fluctuations in D2R signaling, potential existence of diurnal rhythms in MOR signaling has yet to be investigated. Furthermore, whether and how seasonal factors may override or interact with diurnal rhythms in either system remains unexplored. Decoding these temporal dynamics and their possible links to behavioral traits, such as anxiety, may improve mood regulation models and inspire rhythm-tailored interventions. Methods: Based on a historical PET database of healthy humans scanned with [11C]carfentanil (n = 188) and [11C]raclopride (n = 184), we investigated the diurnal patterns of MOR and D2R availability in the brain, using time-of-day (TOD) of scanning as predictor. Furthermore, we examined whether the TOD differences in receptor availability were modulated by seasonal differences in the daylength (D2R and MOR) and trait-anxiety (MOR). Results: The data revealed increased MOR and decreased D2R availability in the afternoon compared to the morning scans. Interaction with the seasonal effect was, however, observed only for MOR availability, spanning brain areas including anterior cingulate, dorsomedial and dorsolateral prefrontal cortex, insula and striatum. Besides, the diurnal variation of MOR availability in these regions was also sensitive to trait-anxiety levels. Conclusions: The current results reveal the diurnal patterns in opioidergic and dopaminergic neurotransmission with an opposing trajectory. Furthermore, the data highlight a unique role of the MOR system, mediating both types of rhythmic regulations, as well as behavioral traits.

neuroscience↗

bioRxiv2025

Striatal dopamine synthesis capacity in Parkinson's disease: Effects of age, sex, and body mass index in a large fluorodopa PET cohort

BACKGROUNDIn Parkinsons disease (PD), the degeneration of nigrostriatal dopaminergic neurons leads to motor symptoms. Positron emission tomography (PET) using radioligand [18F]fluorodopa detects reduced striatal dopamine synthesis capacity in PD patients. Demographic factors such as sex and BMI are also associated with dopamine synthesis capacity. The combined contribution of demographic and clinical effects however remains elusive. It also remains unresolved how the dopamine synthesis capacity is correlated between striatal subregions and how the dopamine synthesis capacity and dopamine receptor function across striatal regions are associated with each other in PD patients and healthy controls. MATERIAL, AIMS, AND METHODSFor this retrospective register-based study, we used baseline [18F]fluorodopa PET data acquired at the Turku PET Centre between the years 1988-2016 with three different scanners (Ecat 931, GE Advance, HRRT). The data included scans of 350 adult human subjects, including 132 healthy controls (65 males and 67 females), and 218 PD patients (134 males and 84 females). The primary aim was to simultaneously investigate the effects of PD, age, sex and BMI on regional dopamine synthesis capacity (influx rate constant Kiref quantified with Patlak) using Bayesian linear regression. Secondary aims were to assess interregional correlations of dopamine synthesis capacity, and the association between regional presynaptic dopamine synthesis and postsynaptic dopamine type 2 receptor (D2R) availability in subjects who also had a proximal [11C]raclopride PET scan. RESULTSWe found modest support for age-dependent decline in dopamine synthesis capacity, increased capacity for higher BMIs, and for higher capacity in females versus males. These effects were smaller than the effect of PD status. Dopamine synthesis capacity across regions was correlated in both patients and controls. Support for positive correlation between the synthesis capacity and the D2R was observed in caudate nucleus. CONCLUSIONSPD and demographic effects are independently associated with the striatal dopamine synthesis capacity. The capacity is reduced by PD, decreased through age (particularly after the age of around 50), higher in females versus males, and weakly increased in higher BMIs. Synthesis capacity is correlated between the striatal and thalamic regions in both PD patients and controls. The dopamine synthesis capacity was positively correlated with the D2R availability in caudate. Scanner affects the estimates of dopamine synthesis capacity measured with [18F]fluorodopa PET, and it is preferrable to adjust for such variation in the data.

neuroscience↗

bioRxiv2025

A multimodal learning approach for automated detection of wildlife trade on social media

Social media data and machine learning methods for automated content analysis are increasingly being used in ecology and conservation science. A current limitation is the lack of methods for automated multimodal analysis of textual and visual content among other data modalities. In this study, we introduce a multimodal content analysis method applied to the investigation of wildlife trade on YouTube. Our approach consists of analyzing text through transformer based neural networks and video keyframes using convolutional neural networks as part of multimodal filtering followed by classification where a decision fusion module identifies instances of wildlife trade. The decision fusion module achieved an F-score of 0.72 among textual classifiers for trade detection and of 0.77 among visual classifiers for species identification. This multimodal classification helped detect wildlife trade in 3,715 out of 86,321 filtered YouTube posts, featuring 226 species for sale, including 51 Critically Endangered, 62 Endangered, 60 Vulnerable, 25 Near Threatened, and 28 Least Concern species. The proposed multimodal learning methods can be used more broadly for other ecological and biodiversity conservation applications. The bigger pictureThe unsustainable trade in wildlife is a major driver of biodiversity loss, threatening thousands of species across the Tree of Life. While online platforms have become popular spaces for advertising wildlife and exotic pets for sale, monitoring these platforms remains extremely challenging. Traditional surveillance methods are not scalable, and automated tools have typically focused on either text or image analysis in isolation, limiting their effectiveness in identifying nuanced instances of wildlife trade. Our study introduces a multimodal machine learning framework that integrates textual and visual data to detect potential wildlife trade on YouTube. By combining natural language processing with deep learning for image analysis, and filtering millions of posts down to those most relevant, our method significantly improves detection accuracy. This dual-layered approach uncovered thousands of posts featuring hundreds of species, many of which are threatened. This work demonstrates how advances in machine learning can support ecological monitoring and conservation by providing timely, data-driven, insights into online trade networks. In the pursuit of reducing biodiversity loss, this study offers an approach for bridging the gap between online behavior and real-world ecological outcomes. HighlightsO_LIIntroduces a multimodal content analysis approach for detecting wildlife trade on YouTube by integrating textual and visual data. C_LIO_LIA multimodal filtering technique reduces irrelevant text and video content, enhancing analytical efficiency. C_LIO_LIA decision fusion module then combines results from text and video filtering improving wildlife trade detection accuracy. C_LIO_LIThe proposed methods are applicable across multiple online platforms and suitable for diverse tasks in ecology and biodiversity conservation. C_LI

ecology↗

bioRxiv2024

Protective variant in PLCgamma2 mitigates Alzheimer's disease associated pathology via enhancing beneficial microglia functions

BackgroundPLC{gamma}2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimers disease. Recently, it was shown to decrease {beta}-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLC{gamma}2-P522R variant in a less aggressive mouse model of AD as well as to assess the underlying mechanisms at the molecular and cellular level using mouse and human microglia models. MethodsThe effects of the protective PLC{gamma}2-P522R variant on microglia activation, AD-related {beta}-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLC{gamma}2-P522R knock-in mice crossbred with APP/PS1 AD model mice. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLC{gamma}2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLC{gamma}2-P522R variant carriers were employed to translate the key findings to human cells. ResultsOur results demonstrate that the PLC{gamma}2-P522R variant reduced brain {beta}-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLC{gamma}2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around {beta}-amyloid plaques, leading to reduced {beta}-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLC{gamma}2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLC{gamma}2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLC{gamma}2-P522R increased mitochondrial respiration in iPSC-derived microglial cells. ConclusionsTogether, these findings suggest that PLC{gamma}2-P522R variant exerts protection against AD-associated {beta}-amyloid and neuronal pathologies via enhancing microglial barrier formation around {beta}-amyloid plaques and suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLC{gamma}2-P522R variant are mediated through an anti-ageing mechanism.

neuroscience↗

bioRxiv2023

Seasonal variation in D2/3 dopamine receptor availability in the human brain

Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic in vivo dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. Here, based on historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. We found that daylength at the time of scanning was negatively correlated with availability of this type of receptors in the striatum. Likely, seasonally varying D2/3 receptor signaling also underlies the seasonality of mood, feeding, and motivational processes. Significance of the studyBrain in vivo neurotransmitter signaling demonstrates seasonal patterns. The dopamine D2/3 receptor, with both pre- and postsynaptic expressions, has been targeted by major antipsychotic and antiparkinsonian pharmaceuticals. The current study, based on a large dataset of healthy brain PET images quantifying these receptors, shows that dark seasons are associated with increased receptor availability in the striatum. Considering the previous findings of increased dopamine synthesis and lowered number of transporters, findings may suggest elevated presynaptic control of dopamine release and increased dopamine receptor sensitivity during dark seasons. The rhythmic D2/3 receptor availability may be a mechanism underlying seasonality in mood, feeding, and motivational processes.

neuroscience↗

bioRxiv2023

UPP affects chloroplast development by interfering with chloroplast proteostasis

Arabidopsis uracil phosphoribosyltransferase (UPP) is an essential enzyme which appears to have a previously unknown, moonlighting activity. Our analysis of UPP amiRNA mutants has confirmed that this vital function is crucial for chloroplast development and growth. Interestingly, this function appears to be unrelated to nucleotide homeostasis since nucleotide levels were not altered in the studied mutants. Transcriptomics and proteomic analysis suggest that UPP plays a role in chloroplast proteostasis, especially under high light (HL). Immunoblots of mature plants and a de-etiolation experiment with young seedlings revealed PetC, the iron-sulfur protein of the cytochrome b6f complex, as a putative UPP target. In addition, UPP and PetC were identified in a high molecular weight complex. Consistently, we show that PetC is massively reduced in UPP knock-down plants. The block observed in photosynthetic electron transport, as evidenced by reduced high light-induced non-photochemical quenching (NPQ) but increased unregulated energy dissipation (NO), might be therefore a consequence of reduced PetC. After HL treatment, UPP amiRNA mutants showed impaired photosynthesis and reduced carbohydrate contents, resulting in an inability to induce flavonoid biosynthesis. In addition, the levels of the osmoprotectants raffinose, proline and fumarate were found to be reduced. Proteases, including thylakoid filamentation temperature-sensitive 1, 5 (FtsH), caseinolytic protease proteolytic subunit 1 (ClpP1), and processing peptidases, as well as components of the chloroplast protein import machinery, were up-regulated. In sum, our work suggests that UPP assists in stabilizing and protection of PetC during the assembly of the Fe-S cluster and targeting to the thylakoid.

molecular biology↗

bioRxiv2023

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort

Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability using Bayesian mixed effects modeling. Subjects with PD showed clearest decline in D2R availability. Healthy controls and patients with PD showed high interregional correlation of D2R availability, while this pattern was weaker in schizophrenia, severe violent behavior, and depression. Subjects with pathological gambling or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also the connectivity between the regions. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region connectivity might be disrupted in affective symptoms. HighlightsWe compared human striatal and thalamic type 2 dopamine receptor (D2R) availability between healthy controls, and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We present the mean brain maps of group specific D2R availabilities in NeuroVault (https://neurovault.org; https://identifiers.org/neurovault.collection:12799). Dopamine type 2 receptor availability is lowered in PD in caudate nucleus, nucleus accumbens and thalamus. Antipsychotic-naive schizophrenia, severe violent behavior, and depression were associated with decreased connectivity between the striatal and thalamic D2R availability. Altered regional D2R availability in the striatum and thalamus is linked with motor disorders, while lowered regional connectivity in D2R might relate to affective disturbance.

neuroscience↗

bioRxiv2022

APOE ε4 gene dose effect on imaging and blood biomarkers of glial reactivity and β-amyloid pathology

Increased reactivity of microglia and astrocytes is known to be present at various stages of the Alzheimers continuum but their relationship with core Alzheimers disease pathology in the preclinical stages is less clear. We investigated glial reactivity and {beta}-amyloid pathology in cognitively unimpaired APOE {varepsilon}4 homozygotes, heterozygotes and non-carriers using 11C-PK11195 PET (targeting 18-kDa translocator protein), 11C-PiB PET (targeting {beta}-amyloid), brain MRI, and a preclinical cognitive composite (APCC). Plasma glial fibrillary acidic protein (GFAP) by and plasma A{beta}1-42/1-40 were measured using single molecule array and immunoprecipitation combined with mass spectrometry, respectively. We observed that (i) 11C-PiB-binding was significantly higher in APOE {varepsilon}4 homozygotes compared with non-carriers in all evaluated regions, (ii) regional 11C-PK11195-binding did not differ between the APOE {varepsilon}4 gene doses or between A{beta}-positive and -negative individuals, and (iii) higher 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, and elevated 11C-PiB-binding and plasma GFAP concentration with lower APCC scores. Increased glial reactivity might emerge in later stages of preclinical Alzheimers disease in parallel with early neurodegenerative changes.

neuroscience↗

bioRxiv2022

An inosine triphosphate pyrophosphatase safeguards nucleic acids from aberrant purine nucleotides and prevents a constitutive salicylic acid response

- In plants, inosine is enzymatically introduced in some tRNAs but not in other RNAs or DNA. Nonetheless, our data show that RNA and DNA from Arabidopsis thaliana contain (deoxy)inosine, probably derived from non-enzymatic adenosine deamination in nucleic acids and usage of (deoxy)inosine triphosphate (dITP and ITP) during nucleic acid synthesis. - We combined biochemical approaches, sample preparation and LC-MS, as well as RNA-Seq to characterize a plant INOSINE TRIPHOSPHATE PYROPHOSPHATASE (ITPA) from Arabidopsis thaliana, which is conserved in many organisms, and investigated the sources of deaminated purine nucleotides in plants. - ITPA dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates. ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated (deoxy)inosine content in DNA and RNA, as well as salicylic acid (SA) accumulation, early senescence and upregulation of transcripts associated with immunity and senescence. Cadmium-induced oxidative stress leads to more ITP in the wildtype, and this effect is enhanced in itpa mutants, suggesting that ITP originates from ATP deamination. - ITPA is part of a molecular protection system, preventing accumulation of (d)ITP, its usage for nucleic acid synthesis, and probably nucleic acid stress leading to SA accumulation, stress gene induction and early senescence.

plant biology↗

bioRxiv2021

Age and sex dependent variability of type 2 dopamine receptors in the human brain: A large-scale PET cohort

BACKGROUNDThe dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. METHODSIn this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. RESULTSStriatal D2R availability decreased through age for both sexes and was higher in females versus males throughout age. BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). CONCLUSIONSD2R density is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.

neuroscience↗

bioRxiv2020

Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study

Positron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. {micro}-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.

neuroscience↗

bioRxiv2019

Interindividual variability and lateralization of μ-opioid receptors in the human brain

The brains {micro}-opioid receptors (MORs) are involved in analgesia, reward and mood regulation. Several neuropsychiatric diseases have been associated with dysfunctional MOR system, and there is also considerable variation in receptor density among healthy individuals. Sex, age, body mass and smoking have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. Here we quantified in vivo MOR availability in the brains of 204 individuals with no neurologic or psychiatric disorders using positron emission tomography (PET) with tracer [11C]carfentanil. We then used Bayesian hierarchical modeling to estimate the effects of sex, age, body mass index (BMI) and smoking on [11C]carfentanil binding potential. We also examined hemispheric lateralization of MOR availability. Age had regionally specific effects on MOR availability, with age-dependent increase in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders.

neuroscience↗

bioRxiv2019

Magia: Robust automated modeling and image processing toolbox for PET neuroinformatics

IntroductionModelling of the radioactivity images produced by PET scanners into biologically meaningful quantities, such as binding potential, is a complex multi-stage process involving data retrieval, preprocessing, drawing reference regions, kinetic modelling, and post-processing of parametric images. The process is challenging to automatize mainly because of manual work related to input generation, thus prohibiting large-scale standardized analysis of brain PET data. To resolve this problem, we introduce the Magia pipeline that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia in the automatic brain-PET data processing with four tracers binding to different binding sites: [11C]raclopride, [11C]carfentanil, [11C]MADAM, and [11C]PiB.\n\nMaterials and methodsFor each tracer, we processed 30 historical control subjects data with manual and automated methods. Five persons manually delineated the reference regions (cerebellar or occipital cortex depending on tracer) for each subject according to written and visual instructions. The automatic reference-region extraction was based on FreeSurfer parcellations. We first assessed inter-operator variance resulting from manual delineation of reference regions. Then we compared the differences between the manually and automatically produced reference regions and the subsequently obtained metrics.\n\nResultsThe manually delineated reference regions were remarkably different from each other. The differences translated into differences in outcome measures (binding potential or SUV-ratio), and the intra-class correlation coefficients were between 47 % and 96 % for the tracers. While the Magia-derived reference regions were topographically very different from the manually defined reference regions, Magia produced outcome measures highly consistent with average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3-5 % higher binding potentials as a result of slightly lower time-integrals of reference region time-activity curves.\n\nConclusionEven if Magia produces reference regions that are anatomically different from manually drawn reference regions, the resulting outcome measures are highly similar. Based on these results and considering the high inter-operator variance of the manual method, the high level of standardization and strong scalability of Magia, we conclude that Magia can be reliably used to process brain PET data.

neuroscience↗

bioRxiv2019

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre PBR28 HRRT PET study

PurposeTo investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; n=78 with HAB and n=62 MAB genotype; age range 19-80 years; BMI range 17.6 - 36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (n=53), Turku PET centre (n=62) and Yale University PET Center (n=25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. ConclusionThese findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

immunology↗

bioRxiv2018

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

Alzheimers disease (AD) results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. As life style factors largely modulate the disease risk, we hypothesised that the disease associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Reduced Representation Bisulfite Sequencing, single cell RNA-sequencing and gene array data were utilised to examine DNA methylation signatures and associated gene expression changes in blood and hippocampus, and targeted bisulfite sequencing in cross cohort validation. Our results reveal that discordant twin pairs have disease associated differences in their peripheral blood epigenomes. A subset of affected genes, e.g. ADARB2 contain differentially methylated sites also in anterior hippocampus. The DNA methylation differences seem to influence gene expression in brain rather than in blood cells. The affected genes are associated with neuronal functions and pathologies. These DNA methylation signatures are valuable disease marker candidates and may provide insights into the molecular mechanisms of pathogenesis.

genomics↗

bioRxiv2017

Long-Term Leisure-Time Physical Activity and Other Health Habits as Predictors of Objectively Monitored Late-Life Physical Activity: A 40-Year Twin Study

IMPORTANCEModerate-to-vigorous physical activity (MVPA) in old age is an important indicator of good health and functional capacity enabling independent living.\n\nOBJECTIVETo investigate whether physical activity and other health habits at ages 31-48 years predict objectively measured MVPA decades later.\n\nDESIGN, SETTING, AND PARTICIPANTSThis prospective twin cohort study in Finland comprised 616 individuals (197 complete twin pairs, including 91 monozygotic pairs, born 1940-1944), who responded to baseline questionnaires in 1975, 1981, and 1990, and participated in accelerometer monitoring at follow-up (mean age, 73 years).\n\nEXPOSURESPrimary exposure was long-term leisure-time physical activity, 1975-1990 (LT-mMET index). Covariates were body mass index (BMI), work-related physical activity, smoking, heavy alcohol use and health status in 1990, and socioeconomic status.\n\nMAIN OUTCOMES AND MEASURESPhysical activity was measured with a waist-worn triaxial accelerometer (at least 10 hours per day for at least 4 days) to obtain daily mean MVPA values.\n\nRESULTSHigh baseline LT-mMET index predicted higher amounts of MVPA (increase in R2 of 6.9% after age and sex adjustment, P<.001) at follow-up. After addition of BMI to the regression model, the R2 value of the whole multivariate model was 17.2%, and with further addition of baseline smoking, socioeconomic status, and health status, the R2 increased to 20.3%. In pairwise analyses, differences in MVPA amount were seen only among twin pairs who were discordant at baseline for smoking (n=40 pairs, median follow-up MVPA 25 vs. 35 min, P=.037) or for health status (n=69 pairs, 30 vs. 44 min, P=.014). For smoking, the difference in MVPA also was seen for monozygotic pairs, but for health status, it was seen only for dizygotic pairs. Mediation analysis showed that shared genetic factors explained 82% of the correlation between LT-mMET and MVPA.\n\nCONCLUSIONS AND RELEVANCELow leisure-time physical activity at younger age, overweight, smoking, low socioeconomic status, and health problems predicted low MVPA in old age in individual-based analyses. However, based on the pairwise analyses and quantitative trait modeling, genetic factors and smoking seem to be important determinants of later-life MVPA.

epidemiology↗