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1.	Davies, G., et al. (author) Genetic contributions to variation in general cognitive function : a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) 2015 In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 20:2, s. 183-192 Journal article (peer-reviewed)abstract General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
2.	Dohrn, Ing-Mari, et al. (author) Impact of dopamine-related genetic variants on physical activity in old age - a cohort study 2020 In: International Journal of Behavioral Nutrition and Physical Activity. - : Springer Science and Business Media LLC. - 1479-5868. ; 17:1 Journal article (peer-reviewed)abstract Objectives The beneficial effects of a physically active lifestyle in aging are well documented. Understanding the factors of importance for physical activity in older adults are therefore essential. Informed by animal and human data linking the dopamine system to motivation and reward processes, we investigated the associations between variations in dopamine genes and objectively measured physical activity and sedentary behaviour. Further, we aimed to verify whether higher age may exacerbate the impact of dopamine genes on physical activity. Methods We analyzed data from 504 older adults, 66-87 years, from the population-based Swedish National study on Aging and Care in Kungsholmen (SNAC-K). Physical activity was measured with activPAL accelerometers and DNA was extracted from blood samples for genotyping. We assessed the effects of three dopamine relevant genetic variations (DRD1, DRD2, and DRD3) on daily time in sedentary behavior, light-intensity physical activity and moderate-to-vigorous physical activity using analyses of covariance, adjusting for sex, age and physical function. Results Higher dopamine receptor efficacy was related to moderate-to-vigorous physical activity, but not to light-intensity physical activity or sedentary time. DRD1 explained 2.7% of variance in moderate-to-vigorous physical activity, with more pronounced effect in people aged >= 80 years, about 10% of explained variance. Conclusion Stronger genetic effects in older adults are in line with the well-established nonlinear effects of dopamine signaling on performance, expected to be exacerbated with aging. Individuals over 80 years, genetically predisposed to lower dopamine receptor efficacy, engaged on average 100 min/week in moderate-to-high physical activity, below the recommended levels beneficial for healthy aging. Our findings highlight that some individuals might need extra support to maintain a physically active lifestyle.
3.	Gustavsson, Jonatan, et al. (author) Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory 2022 In: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 16 Journal article (peer-reviewed)abstract Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (n = 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.
4.	Gustavsson, Jonatan, et al. (author) The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan 2023 In: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 279 Journal article (peer-reviewed)abstract Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
5.	Johansson, Jarkko, et al. (author) Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan 2023 In: Cell Reports. - 2211-1247. ; 42:9 Journal article (peer-reviewed)abstract Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.
6.	Karalija, Nina, 1984-, et al. (author) A common polymorphism in the dopamine transporter gene predicts working memory performance and in vivo dopamine integrity in aging 2021 In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 245 Journal article (peer-reviewed)abstract Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61–80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64–68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.
7.	Karalija, Nina, 1984-, et al. (author) C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition 2019 In: Journal of cognitive neuroscience. - : MIT Press. - 0898-929X .- 1530-8898. ; 31:2, s. 314-325 Journal article (peer-reviewed)abstract The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-11-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-11-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-11-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-11-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-11-raclopride BP was increased in T-homozygotes. Importantly, C-11-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-11-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-11-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
8.	Karalija, Nina, 1984-, et al. (author) Cardiovascular factors are related to dopamine integrity and cognition in aging 2019 In: Annals of Clinical and Translational Neurology. - : Wiley-Blackwell. - 2328-9503. ; 6:11, s. 2291-2303 Journal article (peer-reviewed)abstract Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.Methods: The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study.Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance.Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.
9.	Karalija, Nina, 1984-, et al. (author) High long-term test-retest reliability for extrastriatal C-11-raclopride binding in healthy older adults 2020 In: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 40:9, s. 1859-1868 Journal article (peer-reviewed)abstract In vivo dopamine D2-receptor availability is frequently assessed with C-11-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-11-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal C-11-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal C-11-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean C-11-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional C-11-raclopride BPND values correlated with previously determined F-18-fallypride BPND values (rho = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: rho = 0.92; p < 0.001; excluding striatum: rho = 0.75; p = 0.067). These observations suggest that extrastriatal C-11-raclopride measurements represent a true D2 signal.
10.	Karalija, Nina, 1984-, et al. (author) Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging 2022 In: Neurology. - 1526-632X .- 0028-3878. ; 99 Journal article (peer-reviewed)abstract BACKGROUND AND OBJECTIVES: Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates. METHODS: We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity. RESULTS: Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion. DISCUSSION: These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
11.	Karalija, Nina, 1984-, et al. (author) Longitudinal support for the correlative triad among aging, dopamine D2-like receptor loss, and memory decline 2024 In: NEUROBIOLOGY OF AGING. - 0197-4580 .- 1558-1497. ; 136, s. 125-132 Journal article (peer-reviewed)abstract Dopamine decline is suggested to underlie aging -related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5 -year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5 -year follow-up: n = 129) who underwent positron emission tomography with 11C- raclopride to assess dopamine D2 -like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A datadriven approach (k -means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age -sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide -ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5 -year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.
12.	Karalija, Nina, 1984-, et al. (author) Sex differences in dopamine integrity and brain structure among healthy older adults : Relationships to episodic memory 2021 In: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 105, s. 272-279 Journal article (peer-reviewed)abstract Normal brain aging is a multidimensional process that includes deterioration in various brain structures and functions, with large heterogeneity in patterns and rates of decline. Sex differences have been reported for various cognitive and brain parameters, but little is known in relation to neuromodulatory aspects of brain aging. We examined sex differences in dopamine D2-receptor (D2DR) availability in relation to episodic memory, but also, grey-matter volumes, white-matter lesions, and cerebral perfusion in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging study. Women had higher D2DR availability in midbrain and left caudate and putamen, as well as superior episodic memory performance. Controlling for left caudate D2DR availability attenuated sex differences in memory performance. In men, lower left caudate D2DR levels were associated with lower cortical perfusion and higher burden of white-matter lesions, as well as with episodic memory performance. However, sex was not a significant moderator of the reported links to D2DR levels. Our findings suggest that sex differences in multiple associations among DA receptor availability, vascular factors, and structural connectivity contribute to sex differences in episodic memory. Future longitudinal studies need to corroborate these patterns by lead-lag associations. This manuscript is part of the Special Issue entitled 'Cognitive Neuroscience of Healthy and Pathological Aging' edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza.
13.	Korkki, Saana M., et al. (author) Fronto-striatal dopamine D2 receptor availability is associated with cognitive variability in older individuals with low dopamine integrity 2021 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1 Journal article (peer-reviewed)abstract Within-person, moment-to-moment, variability in behavior increases with advancing adult age, potentially reflecting the influence of reduced structural and neurochemical brain integrity, especially that of the dopaminergic system. We examined the role of dopamine D2 receptor (D2DR) availability, grey-, and white-matter integrity, for between-person differences in cognitive variability in a large sample of healthy older adults (n = 181; 64–68years) from the Cognition, Brain, and Aging (COBRA) study. Intra-individual variability (IIV) in cognition was measured as across-trial variability in participants’ response times for tasks assessing perceptual speed and working memory, as well as for a control task of motor speed. Across the whole sample, no associations of D2DR availability, or grey- and white-matter integrity, to IIV were observed. However, within-person variability in cognition was increased in two subgroups of individuals displaying low mean-levelcognitive performance, one of which was characterized by low subcortical and cortical D2DR availability. In this latter group, fronto-striatal D2DR availability correlated negatively with within-person variability in cognition. This finding suggests that the influence of D2DR availability on cognitive variability may be more easily disclosed among individuals with low dopamine-system integrity, highlighting the benefits of large-scale studies for delineating heterogeneity in brain-behavior associations in older age.
14.	Köhncke, Ylva, et al. (author) Self-rated intensity of habitual physical activities is positively associated with dopamine D-2/3 receptor availability and cognition 2018 In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 181, s. 605-616 Journal article (peer-reviewed)abstract Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D(2/3)DA receptor (D2/3DR) availability, and cognitive performance. D2/3DR availability was measured with [C-11]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and D2/3DR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with D2/3DR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to D2/3DR availability. Physical activity intensity was positively related to episodic memory and working memory. D2/3DR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity.
15.	Larsson, Maria, et al. (author) Olfactory memory in the old and very old : relations to episodic and semantic memory and APOE genotype 2016 In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 38, s. 118-126 Journal article (peer-reviewed)abstract The neuroanatomical organization that underlies olfactory memory is different from that of other memory types. The present work examines olfactory memory in an elderly population-based sample (Swedish National Study on Aging and Care in Kungsholmen) aged 60-100 years (n = 2280). We used structural equation modeling to investigate whether olfactory memory in old age is best conceptualized as a distinct category, differentiated from episodic and semantic memory. Further, potential olfactory dedifferentiation and genetic associations (APOE) to olfactory function in late senescence were investigated. Results are in support of a 3-factor solution where olfactory memory, as indexed by episodic odor recognition and odor identification, is modeled separately from episodic and semantic memory for visual and verbal information. Increasing age was associated with poorer olfactory memory performance, and observed age-related deficits were further exacerbated for carriers of the APOE epsilon 4 allele; these effects tended to be larger for olfactory memory compared to episodic and semantic memory pertaining to other sensory systems (vision, auditory). Finally, stronger correlations between olfactory and episodic memory, indicating dedifferentiation, were observed in the older age groups.
16.	Laukka, Erika J., et al. (author) Microstructural White Matter Properties Mediate the Association between APOE and Perceptual Speed in Very Old Persons without Dementia 2015 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8 Journal article (peer-reviewed)abstract Background Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the epsilon 4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS. Objective To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia. Method Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78-90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS. Results APOE was associated with white matter microstructure in 2 out of 14 tracts; e4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004). Conclusion Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia.
17.	Le Guen, Yann, et al. (author) Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB104 subtypes. 2023 In:* Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36 Journal article (peer-reviewed)abstract Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB104 subtypes best accounted for the association, strongest with HLA-DRB104:04 and HLA-DRB104:07, and intermediary with HLA-DRB104:01 and HLA-DRB104:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB104 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
18.	Li, Shu-Chen, et al. (author) Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory 2013 In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:1, s. 358.e1-358.e10 Journal article (peer-reviewed)abstract Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory).
19.	Li, Shu-Chen, et al. (author) Ebbinghaus Revisited : Influences of the BDNF Val66Met Polymorphism on Backward Serial Recall Are Modulated by Human Aging. 2010 In: Journal of cognitive neuroscience. - Cambridge, Mass. : MIT Press - Journals. - 0898-929X .- 1530-8898. ; 22:10, s. 2164-2173 Journal article (peer-reviewed)abstract Abstract The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve-a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age.
20.	Li, Yuanjing, et al. (author) Association Between Behavioral, Biological, and Genetic Markers of Cardiovascular Health and MRI Markers of Brain Aging : A Cohort Study 2023 In: Neurology. - 0028-3878 .- 1526-632X. ; 100:1, s. e38-e48 Journal article (peer-reviewed)abstract Background and Objective The life’s simple 7 approach was proposed to define cardiovascular health (CVH) metrics. We sought to investigate the associations between behavioral, biological, and genetic markers for CVH and vascular brain aging in older adults.Methods This population-based cohort study included participants who had repeated brain MRI measures from 2001 to 2003 to 2007–2010 (i.e., count of perivascular spaces, volumes of white matter hyperintensity [WMH] and gray matter, and lacunes). At baseline, global, behavioral, and biological CVH metrics were defined and scored following the life’s simple 7 approach and categorized into unfavorable, intermediate, and favorable profiles according to tertiles. The metabolic genetic risk score was calculated by counting 15 risk alleles associated with hypertension, diabetes, or dyslipidemia. Data were analyzed using linear mixed-effects and Cox proportional hazards models, adjusting for age, sex, and education.Results The study sample consisted of 317 participants (age 60 years or older; 61.8% women). Favorable and intermediate (vs unfavorable) global CVH profiles were related to slower WMH progression, with β-coefficients (95% CI) being −0.019(-0.035–0.002) and −0.018(-0.034–0.001), respectively. Favorable and intermediate (vs unfavorable) biological CVH profiles were significantly related to slower WMH increase only in people aged 60–72 years. CVH profiles were not related to progression of other brain measures. Furthermore, a higher metabolic genetic risk score (range: 6–21) was associated with faster WMH increase (β-coefficient = 0.005; 95% CI: 0.003–0.008). There were statistical interactions of metabolic genetic risk score with global and behavioral CVH profiles on WMH accumulation. A higher metabolic genetic risk score was related to faster WMH accumulation, with β-coefficients being 0.015(0.007–0.023), 0.005(0.001–0.009), and 0.003(-0.001 to 0.006) among people with unfavorable, intermediate, and favorable global CVH profiles, respectively; the corresponding β-coefficients were 0.013(0.006–0.020), 0.006(0.003–0.009), and 0.002(-0.002 to 0.006) among people with unfavorable, intermediate, and favorable behavioral CVH profiles.Discussion Intermediate to favorable global CVH profiles in older adults are associated with slower vascular brain aging. The association of metabolic genetic risk load with accelerated vascular brain aging was evident among people with unfavorable to intermediate, but not favorable, CVH profiles. These findings highlight the importance of adhering to favorable CVH profiles, especially healthy behaviors, in vascular brain health.
21.	Liu, T., et al. (author) No association between CTNNBL1 and episodic memory performance 2014 In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 4 Journal article (peer-reviewed)abstract Polymorphisms in the gene encoding catenin-β-like 1 (CTNNBL1) were recently reported to be associated with verbal episodic memory performance--in particular, delayed verbal free recall assessed between 5 and 30 min after encoding--in a genome-wide association study on healthy young adults. To further examine the genetic effects of CTNNBL1, we tested for association between 455 single-nucleotide polymorphisms (SNPs) in or near CTNNBL1 and 14 measures of episodic memory performance from three different tasks in 1743 individuals. Probands were part of a population-based study of mentally healthy adult men and women, who were between 20 and 70 years old and were recruited as participants for the Berlin Aging Study II. Associations were assessed using linear regression analysis. Despite having sufficient power to detect the previously reported effect sizes, we found no evidence for statistically significant associations between the tested CTNNBL1 SNPs and any of the 14 measures of episodic memory. The previously reported effects of genetic polymorphisms in CTNNBL1 on episodic memory performance do not generalize to the broad range of tasks assessed in our cohort. If not altogether spurious, the effects may be limited to a very narrow phenotypic domain (that is, verbal delayed free recall between 5 and 30 min). More studies are needed to further clarify the role of CTNNBL1 in human memory.
22.	Luo, Jiao, et al. (author) Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease 2023 In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5 Journal article (peer-reviewed)abstract IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
23.	Lövdén, Martin, et al. (author) Latent-Profile Analysis Reveals Behavioral and Brain Correlates of Dopamine-Cognition Associations 2018 In: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 28:11, s. 3894-3907 Journal article (peer-reviewed)abstract Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with C-11-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.
24.	Nordin, Kristin, et al. (author) DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes : A new window into cognitive aging 2022 In: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 100:6, s. 1296-1320 Journal article (peer-reviewed)abstract Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain’s structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20–80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.
25.	Nyberg, Lars, et al. (author) Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory 2016 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:28, s. 7918-7923 Journal article (peer-reviewed)abstract D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [C-11]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.

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