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1.	Skoog, Ingmar, 1954, et al. (author) Association between APOE Genotype and Change in Physical Function in a Population-Based Swedish Cohort of Older Individuals Followed Over Four Years 2016 In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 8 Journal article (peer-reviewed)abstract The association between decline in physical function and age-related conditions, such as reduced cognitive performance and vascular disease, may be explained by genetic influence on shared biological pathways of importance for aging. The apolipoprotein F (APOE) gene is well-known for its association with Alzheimer's disease, but has also been related to other disorders of importance for aging. The aim of this study was to investigate possible associations between APOE allele status and physical function in a population-based longitudinal study of older individuals. In 2005, at the age of 75, 622 individuals underwent neuropsychiatric and physical examinations, including tests of physical function, and APOE-genotyping. Follow-up examinations were performed at age 79. A significantly larger decline in grip strength (p = 0.015) between age 75 and 79 was found when comparing APOE epsilon 4 allele carriers with non carriers [10.3 (+/- 10.8) kg versus 7.8 (+/- 10.1) kg]. No association was seen with decline in gait speed, chair-stand, or balance. The association with grip strength remained after correction for cognitive and educational level, depression, cardiovascular disease, stroke, and BMI.
2.	Dittrich, Anna, 1972, et al. (author) Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg. 2023 In: Neurology. - 1526-632X. ; 101:3 Journal article (peer-reviewed)abstract Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD.Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model.We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aβ 42/40: R = 0.23, p = 0.004 correlated in participants with Aβ42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]).In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.
3.	Dittrich, Anna, 1972, et al. (author) Plasma and CSF NfL are differentially associated with biomarker evidence of neurodegeneration in a community-based sample of 70-year-olds 2022 In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 14:1 Journal article (peer-reviewed)abstract Neurofilament light protein (NfL) in cerebrospinal fluid (CSF) and plasma (P) are suggested to be interchangeable markers of neurodegeneration. However, evidence is scarce from community-based samples. NfL was examined in a small-scale sample of 287 individuals from the Gothenburg H70 Birth cohort 1944 study, using linear models in relation to CSF and magnetic resonance imaging (MRI) biomarker evidence of neurodegeneration. CSF-NfL and P-NfL present distinct associations with biomarker evidence of Alzheimer's disease (AD) pathology and neurodegeneration. P-NfL was associated with several markers that are characteristic of AD, including smaller hippocampal volumes, amyloid beta (A beta)(42), A beta(42/40), and A beta(42)/t-tau (total tau). CSF-NfL demonstrated associations with measures of synaptic and neurodegeneration, including t-tau, phosphorylated tau (p-tau), and neurogranin. Our findings suggest that P-NfL and CSF-NfL may exert different effects on markers of neurodegeneration in a small-scale community-based sample of 70-year-olds.
4.	Dittrich, Anna, 1972, et al. (author) Proportion of Community-Dwelling Individuals Older Than 70 Years Eligible for Lecanemab Initiation: The Gothenburg H70 Birth Cohort Study. 2024 In: Neurology. - 1526-632X. ; 102:9 Journal article (peer-reviewed)abstract To determine the prevalence of individuals with Alzheimer disease (AD) eligible for treatment with the recently FDA-approved lecanemab based on data from a population-based sample of 70-year-olds and extrapolate an estimation of individuals eligible in Europe and the United States.Participants from the Gothenburg H70 Birth Cohort Study with clinical data, CSF-amyloid beta 42, and brain MRI analysis were evaluated for eligibility to receive lecanemab treatment according to FDA-approved recommendations, noting factors requiring special consideration. Results were used to extrapolate the number of eligible individuals in Europe and the United States using public demographic data.Thirty (10.3%) of 290 participants met the indication for treatment of whom 18 (6.2%) were eligible and did not present factors requiring special consideration. Our estimate that 6.2% of all 70-year-olds in the full cohort are eligible for treatment extrapolates to an approximation that around 5.9 million Europeans and 2.2 million US residents could be eligible.Information on proportion of individuals eligible for AD treatment with lecanemab in the general public is limited. We provide information on 70-year-olds in Sweden and extrapolate these data to Europe and the United States. This study opens for larger studies on this proportion and implementation of lecanemab treatment.
5.	Jeppsson, Anna, et al. (author) Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus 2023 In: Fluids and Barriers of the CNS. - 2045-8118. ; 20:1 Journal article (peer-reviewed)abstract Background Neurofilament light chain protein (NFL), a marker of neuronal axonal degeneration, is increased in cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). Assays for analysis of NFL in plasma are now widely available but plasma NFL has not been reported in iNPH patients. Our aim was to examine plasma NFL in iNPH patients and to evaluate the correlation between plasma and CSF levels, and whether NFL levels are associated with clinical symptoms and outcome after shunt surgery. Methods Fifty iNPH patients with median age 73 who had their symptoms assessed with the iNPH scale and plasma and CSF NFL sampled pre- and median 9 months post-operatively. CSF plasma was compared with 50 healthy controls (HC) matched for age and gender. Concentrations of NFL were determined in plasma using an in-house Simoa method and in CSF using a commercially available ELISA method. Results Plasma NFL was elevated in patients with iNPH compared to HC (iNPH: 45 (30-64) pg/mL; HC: 33 (26-50) (median; Q1-Q3), p = 0.029). Plasma and CSF NFL concentrations correlated in iNPH patients both pre- and postoperatively (r = 0.67 and 0.72, p < 0.001). We found only weak correlations between plasma or CSF NFL and clinical symptoms and no associations with outcome. A postoperative NFL increase was seen in CSF but not in plasma. Conclusions Plasma NFL is increased in iNPH patients and concentrations correlate with CSF NFL implying that plasma NFL can be used to assess evidence of axonal degeneration in iNPH. This finding opens a window for plasma samples to be used in future studies of other biomarkers in iNPH. NFL is probably not a very useful marker of symptomatology or for prediction of outcome in iNPH.
6.	Marseglia, Anna, et al. (author) Metabolic Syndrome Is Associated With Poor Cognition : A Population-Based Study of 70-Year-Old Adults Without Dementia 2021 In: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 76:12, s. 2275-2283 Journal article (peer-reviewed)abstract Background: Individual conditions of metabolic syndrome (MetS) have been related to dementia; however, their combined impact on the preclinical stage is unknown. We investigated the associations between MetS and domain-specific cognitive function as well as the role of sociodemographic, cardiovascular, and genetic factors.Methods: Within the Gothenburg H70 Birth Cohort Study-Birth cohort 1944, 1131 dementia-free participants (aged 70 years) were examined during 2014-2016. MetS (central obesity plus at least 2 factors [reduced HD11.-cholesterol, elevated triglycerides, blood pressure, or blood glucose]) was identified according to the International Diabetes Federation criteria. Five cognitive domains (memory, attention/perceptual speed, executive function, verbal fluency, visuospatial abilities) were generated after z-standardizing raw scores from 10 neuropsychological tests. Education, heart disease, claudication (indicating peripheral atherosclerosis), and apolipoprotein genotype were ascertained by trained staff. Data were analyzed with linear regression models.Results: Overall, 618 participants (55%) had MetS. In multiadjusted linear regressions, MetS was related to poorer performance in attention/ perceptual speed (beta -0.14 [95% CI -0.25, -0.02]), executive function (beta -0.12 [95% CI -0.23, -0.01]), and verbal fluency (beta -0.19 [95% CI -0.30, -0.08]). These associations were present only among individuals who did not carry any APOE-epsilon 4 allele or were highly educated. However, among those with MetS, high education was related to better cognitive performance. MetS together with comorbid heart disease or claudication was associated with even worse cognitive performance than each alone.Conclusions: MetS is associated with poor attention/perceptual speed, executive function, and verbal fluency performance. Education, apolipoprotein E-epsilon 4 allele, and comorbid cardiovascular disease influenced the observed associations.
7.	Novak, Masuma, 1969, et al. (author) Cardiovascular and all-cause mortality attributable to loneliness in older Swedish men and women. 2020 In: BMC geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 20:1 Journal article (peer-reviewed)abstract This study examined whether loneliness predicts cardiovascular- and all-cause mortality in older men and women.Baseline data from the Gothenburg H70 Birth Cohort Studies, collected during 2000 on 70-year-olds born 1930 and living in Gothenburg were used for analysis (n=524). Mortality data were analyzed until 2012 through Swedish national registers.Perceived loneliness was reported by 17.1% of the men and 30.9% of the women in a face-to-face interview with mental health professional. A total of 142 participants died during the 12-year follow-up period, with 5334 person-years at risk, corresponding to 26.6 deaths/1000 person-years. Cardiovascular disease accounted for 59.2% of all deaths. The cumulative rates/1000 person-years for cardiovascular mortality were 20.8 (men) and 11.5 (women), and for all-cause mortality 33.8 (men) and 20.5 (women), respectively. In Cox regression models, no significant increased risk of mortality was seen for men with loneliness compared to men without loneliness (cardiovascular mortality HR 1.52, 95% CI 0.78-2.96; all-cause HR 1.32, 95% CI 0.77-2.28). Increased risk of cardiovascular mortality was observed in women with loneliness compared to those without (HR 2.25 95% CI 1.14-4.45), and the risk remained significant in a multivariable-adjusted model (HR 2.42 95% CI 1.04-5.65).Loneliness was shown to be an independent predictor of cardiovascular mortality in women. We found no evidence to indicate that loneliness was associated with an increased risk of either cardiovascular- or all-cause mortality in men.
8.	Novak, Masuma, 1969, et al. (author) Six-year mortality associated with living alone and loneliness in Swedish men and women born in 1930 2023 In: BMC Geriatrics. - 1471-2318. ; 23:1 Journal article (peer-reviewed)abstract Background: This study examined how living alone and loneliness associate with all-cause mortality in older men and women. Methods: Baseline data from the Gothenburg H70 Birth Cohort Studies, including 70-year-olds interviewed in 2000 and 75-year-olds (new recruits) interviewed in 2005were used for analyses (N = 778, 353 men, 425 women). Six-year mortality was based on national register data. Results: At baseline, 36.6% lived alone and 31.9% reported feelings of loneliness. A total of 72 (9.3%) participants died during the 6-year follow-up period. Cumulative mortality rates per 1000 person-years were 23.9 for men and 9.6 for women. Mortality was increased more than twofold among men who lived alone compared to men living with someone (HR 2.40, 95% CI 1.34–4.30). Elevated risk remained after multivariable adjustment including loneliness and depression (HR 2.56, 95% CI 1.27–5.16). Stratification revealed that mortality risk in the group of men who lived alone and felt lonely was twice that of their peers who lived with someone and did not experience loneliness (HR 2.52, 95% CI 1.26–5.05). In women, a more than fourfold increased risk of mortality was observed in those who experienced loneliness despite living with others (HR 4.52, 95% CI 1.43–14.23). Conclusions: Living alone was an independent risk factor for death in men but not in women. Mortality was doubled in men who lived alone and felt lonely. In contrast, mortality was particularly elevated in women who felt lonely despite living with others. In the multivariable adjusted models these associations were attenuated and were no longer significant after adjusting for mainly depression in men and physical inactivity in women. Gender needs to be taken into account when considering the health consequences of living situation and loneliness.
9.	Remnestål, Julia, et al. (author) Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds. 2021 In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1 Journal article (peer-reviewed)abstract Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer's disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains.In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology.The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins' role in AD pathophysiology.
10.	Rydberg Sterner, Therese, et al. (author) Depression and neuroticism decrease among women but not among men between 1976-2016 in Swedish septuagenarians 2019 In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 139:4, s. 381-394 Journal article (peer-reviewed)abstract Objectives: We evaluated birth cohort differences in depressive symptom burden, prevalence of depression diagnoses, and neuroticism, among Swedish 70-year-olds examined between 1976 and 2016. Methods: We used a repeated cross-sectional design examining four representative population samples of Swedish 70-year-olds (total n=2279) with identical methods in 1976-77 (n=392), 1992-93 (n=226), 2000-02 (n=487), and 2014-16 (n=1166). Depressive symptom burden was rated with the Montgomery Åsberg Depression Rating Scale. Major depression was diagnosed according to DSM-5, and minor depression according to DSM-IV-TR research criteria. Neuroticism was rated with the Eysenck Personality Inventory. Results: For women in 2014-16, MADRS score (4.4 vs. 6.1 vs. 5.8; p<0.05) and neuroticism (6.6 vs. 7.7 vs. 9.2; p<0.05) were lower compared to 1992-93 and 1976-77, and the prevalence of any depression was lower compared to 2000-02 and 1992-93 (10.9% vs. 16.9% vs. 18.1%; p<0.05). For men, we observed no birth cohort differences in depression, while neuroticism was found to be lower in 2014-16 compared to 1976-77 among men without depression (5.1 vs. 5.9; p<0.01). The sex difference for MADRS and neuroticism declined between 1976-77 and 2014-16 (cohort*sex p<0.05). Conclusions: Depressive burden and neuroticism decreased in 70-year-old women between 1976 and 2016.
11.	Rydberg Sterner, Therese, et al. (author) Depression in relation to sex and gender expression among Swedish septuagenarians-Results from the H70 study 2020 In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 15:9 Journal article (peer-reviewed)abstract Objective Little is known about the role of gender expression (femininity, masculinity, or androgyny) in relation to sex differences in depression. This study tested if gender expression was associated with depression and burden of depressive symptoms in a 70-year-old population. Methods A cross-sectional population-based sample of 70-year-olds from The Gothenburg H70 Birth Cohort Study (n = 1203) was examined in 2014-16. Data were collected using psychiatric examinations and structured questionnaires, including the Positive-Negative Sex-Role Inventory to assess gender expression. Depression was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders criteria, and symptom burden was assessed with Montgomery angstrom sberg Depression Rating Scale (MADRS). Results Gender expression was related to MADRS score and depression diagnosis. In fully adjusted models, feminine traits with low social desirability (FEM-) were associated with a higher MADRS score (R(2)0.16; B 0.16; CI 0.1-0.2), while androgyny (t ratio) (R(2)0.12; B 0.42; CI 0.1-0.7) and masculine traits with high social desirability (MAS+) (R(2)0.13; B -0.06; CI -0.1--0.01) were associated with a lower MADRS score. Also, feminine traits with low social desirability (FEM-) were positively associated with depression (OR 1.04; CI 1.01-1.1). No associations between depression and masculinity or androgyny were observed in adjusted models. There were no interactions between sex and gender expression in relation to depression or MADRS score, indicating that the effects of gender expression were similar in men and women. Conclusions We found that gender expression was associated to both depression and burden of depressive symptoms. More specifically, we found that femininity was associated to higher levels of depression, irrespective of biological sex. In addition, masculinity and androgyny were associated with lower levels of depression. These results highlight the importance of taking gender expression into consideration when studying sex differences in depression among older populations in future studies.
12.	Rydén, Lina, 1982, et al. (author) Attrition in the Gothenburg H70 birth cohort studies, an 18-year follow-up of the 1930 cohort 2023 In: Frontiers in Epidemiology. - 2674-1199. ; 3 Journal article (peer-reviewed)
13.	Samuelsson, Jessica, et al. (author) Associations between dietary patterns and dementia-related neuroimaging markers 2023 In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:10, s. 4629-4640 Journal article (peer-reviewed)abstract BACKGROUNDThe exploration of associations between dietary patterns and dementia-related neuroimaging markers can provide insights on food combinations that may impact brain integrity. METHODSData were derived from the Swedish Gothenburg H70 Birth Cohort Study (n = 610). Three dietary patterns were obtained using principal component analysis. Magnetic resonance imaging markers included cortical thickness, an Alzheimer's disease (AD) signature score, small vessel disease, and white matter microstructural integrity. Adjusted linear/ordinal regression analyses were performed. RESULTSA high-protein and alcohol dietary pattern was negatively associated with cortical thickness in the whole brain (Beta: -0.011; 95% confidence interval [CI]: -0.018 to -0.003), and with an Alzheimer's disease cortical thickness signature score (Beta: -0.013; 95% CI: -0.024 to -0.001). A positive association was found between a Mediterranean-like dietary pattern and white matter microstructural integrity (Beta: 0.078; 95% CI: 0.002-0.154). No associations were found with a Western-like dietary pattern. DISCUSSIONDietary patterns may impact brain integrity through neurodegenerative and vascular pathways. HighlightsCertain dietary patterns were associated with dementia-related neuroimaging markers.A Mediterranean dietary pattern was positively associated with white matter microstructure.A high-protein and alcohol pattern was negatively associated with cortical thickness.
14.	Westerlund, Marie, et al. (author) Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. 2011 In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 25:4, s. 1345-52 Journal article (peer-reviewed)abstract The serine-protease OMI/HTRA2, required for several cellular processes, including mitochondrial function, autophagy, chaperone activity, and apoptosis, has been implicated in the pathogenesis of both Alzheimer's disease (AD) and Parkinson's disease (PD). Western blot quantification of OMI/HTRA2 in frontal cortex of patients with AD (n=10) and control subjects (n=10) in two separate materials indicated reduced processed (active, 35 kDa) OMI/HTRA2 levels, whereas unprocessed (50 kDa) enzyme levels were not significantly different between the groups. Interestingly, the specific protease activity of OMI/HTRA2 was found to be significantly increased in patients with AD (n=10) compared to matched control subjects (n=10) in frontal cortex in two separate materials. Comparison of OMI/HTRA2 mRNA levels in frontal cortex and hippocampus, two brain areas particularly affected by AD, indicated similar levels in patients with AD (n=10) and matched control subjects (n=10). In addition, we analyzed the occurrence of the OMI/HTRA2 variants A141S and G399S in Swedish case-control materials for AD and PD and found a weak association of A141S with AD, but not with PD. In conclusion, our genetic, histological, and biochemical findings give further support to an involvement of OMI/HTRA2 in the pathology of AD; however, further studies are needed to clarify the role of this gene in neurodegeneration.
15.	Wetterberg, Hanna, et al. (author) Representativeness in population-based studies of older adults: five waves of cross-sectional examinations in the Gothenburg H70 Birth Cohort Study 2022 In: Bmj Open. - : BMJ. - 2044-6055. ; 12:12 Journal article (peer-reviewed)abstract ObjectivesTo describe representativeness in the Gothenburg H70 1930 Birth Cohort Study.DesignRepeated cross-sectional examinations of a population-based study.SettingGothenburg, Sweden.ParticipantsAll residents of Gothenburg, Sweden, born on specific birth dates in 1930 were invited to a comprehensive health examination at ages 70, 75, 79, 85 and 88. The number of participants at each examination was 524 at age 70, 767 at age 75, 580 at age 79, 416 at age 85, and 258 at age 88.Primary outcome measuresWe compared register data on sociodemographic characteristics and hospital discharge diagnoses between participants and (1) refusals, (2) all same-aged individuals in Gothenburg and (3) all same-aged individuals in Sweden. We also compared mortality rates between participants and refusals.ResultsRefusal rate increased with age. At two or more examination waves, participants compared with refusals had higher educational level, more often had osteoarthritis, had lower mortality rates, had lower prevalence of neuropsychiatric, alcohol-related and cardiovascular disorders, and were more often married. At two examination waves, participants compared with same-aged individuals in Gothenburg had higher education and were more often born in Sweden. At two examination waves or more, participants compared with same-aged individuals in Sweden had higher education, had higher average income, less often had ischaemic heart disease, were less often born in Sweden and were more often divorced.ConclusionsParticipants were more similar to the target population in Gothenburg than to refusals and same-aged individuals in Sweden. Our study shows the importance of having different comparison groups when assessing representativeness of population studies, which is important in evaluating generalisability of results. The study also contributes unique and up-to-date knowledge about participation bias in these high age groups.
16.	Zettergren, Anna, 1978, et al. (author) Proteomic analyses of limbic regions in neonatal male, female and androgen receptor knockout mice 2017 In: Bmc Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 18 Journal article (peer-reviewed)abstract Background: It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (AR(NesDel)) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics. Results: Our proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between AR(NesDel) and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes < 1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes. Conclusions: Overall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.
17.	Zettergren, Anna, 1978, et al. (author) The ACE Gene Is Associated with Late-Life Major Depression and Age at Dementia Onset in a Population-Based Cohort. 2017 In: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. - : Elsevier BV. - 1064-7481 .- 1545-7214. ; 25:2, s. 170-177 Journal article (peer-reviewed)abstract Depression and dementia in the elderly have been suggested to share similar risk factors and pathogenetic background, and recently the authors reported that the APOEɛ4 allele is a risk factor for both disorders in the general population. The aim of the present study was to examine the influence of the well-known polymorphisms rs1799752 in the angiotensin-converting enzyme (ACE) and rs5186 in the angiotensin receptor II type 1 (AGTR1) on late-life depression and dementia in a population-based Swedish cohort of older individuals followed over 12 years.In 2000-2001, 900 individuals underwent neuropsychiatric and neuropsychological examinations. Follow-up evaluations were performed in 2005-2006 and 2009-2010, and register data on dementia to 2012 were included. Cross-sectional associations between genotypes/alleles and depression and dementia at baseline and between genotypes/alleles and depression on at least one occasion during the study period and dementia onset to 2012 were investigated.As previously found for rs1799752 in ACE, rs5186 in AGTR1 was associated with dementia at baseline (OR: 3.25 [CI: 1.42-7.06], z=2.90, p=0.004). These associations became substantially weaker, or disappeared, when dementia onset to 2012 was included. For rs1799752 this could be explained by a significant association with age at onset (mean: 79.5 [SD: 6.45] years for risk-genotype carriers and 81.7 [SD: 7.12] years for carriers of other genotypes, b=-2.43, t=-2.38, df=192, p=0.02). When individuals with major depression on at least one occasion were analyzed, a significant association (OR: 2.14 [95% CI: 1.13-4.20], z=2.28, p=0.02), remaining after exclusion of dementia, with rs1799752 in ACE was found.In this population-based sample of older individuals, genetic variations in ACE seem to be important both for late-life major depression and dementia.
18.	Ahlner, Felicia, 1987, et al. (author) Patterns of Alcohol Consumption and Associated Factors in a Population-Based Sample of 70-Year-Olds: Data from the Gothenburg H70 Birth Cohort Study 2014-16 2022 In: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1660-4601 .- 1661-7827. ; 19:14 Journal article (peer-reviewed)abstract Older adults of today consume more alcohol, yet knowledge about the factors associated with different consumption levels is limited in this age group. Based on the data from a population-based sample (n = 1156, 539 men and 617 women) in The Gothenburg H70 Birth Cohort Study 2014-16, we examined sociodemographic, social, and health-related factors associated with alcohol consumption levels in 70-year-olds, using logistic regression. Total weekly alcohol intake was calculated based on the self-reported amount of alcohol consumed. Alcohol consumption was categorized as lifetime abstention, former drinking, moderate consumption (<= 98 g/week), and at-risk consumption (>98 g/week). At-risk consumption was further categorized into lower at-risk (98-196 g/week), medium at-risk (196-350 g/week), and higher at-risk (>= 350 g/week). We found that among the 1156 participants, 3% were lifetime abstainers, 3% were former drinkers, 64% were moderate drinkers, and 30% were at-risk drinkers (20% lower, 8% medium, 2% higher). Among several factors, former drinking was associated with worse general self-rated health (OR 1.65, 95% CI 1.08-2.51) and lower health-related quality of life (measured by physical component score) (OR 0.94, 95% CI 0.91-0.97), higher illness burden (OR 1.16, 95% CI 1.07-1.27), and weaker grip strength (OR 0.96, 95% CI 0.94-0.98). Higher at-risk drinkers more often had liver disease (OR 11.41, 95% CI 3.48-37.37) and minor depression (OR 4.57, 95% CI 1.40-14.95), but less contacts with health care (OR 0.32, 95% CI 0.11-0.92). Our findings demonstrate the importance of classifications beyond abstinence and at-risk consumption, with implications for both the prevention and clinical management of unhealthy consumption patterns in older adults.
19.	Arvidsson Rådestig, Maya, et al. (author) Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample 2023 In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1 Journal article (peer-reviewed)abstract BackgroundNeurofilament light (NfL) and neurogranin (Ng) are promising candidate AD biomarkers, reflecting axonal and synaptic damage, respectively. Since there is a need to understand the synaptic and axonal damage in preclinical Alzheimer's disease (AD), we aimed to determine the cerebrospinal fluid (CSF) levels of NfL and Ng in cognitively unimpaired elderly from the Gothenburg H70 Birth Cohort Studies classified according to the amyloid/tau/neurodegeneration (A/T/N) system.MethodsThe sample consisted of 258 cognitively unimpaired older adults (age 70, 129 women and 129 men) from the Gothenburg Birth Cohort Studies. We compared CSF NfL and Ng concentrations in A/T/N groups using Student's T-test and ANCOVA.ResultsCSF NfL concentration was higher in the A-T-N+ group (p=0.001) and the A-T+N+ group (p=0.006) compared with A-T-N-. CSF Ng concentration was higher in the A-T-N+, A-T+N+, A+T-N+, and A+T+N+ groups (p<0.0001) compared with A-T-N-. We found no difference in NfL or Ng concentration in A+ compared with A- (disregarding T- and N- status), whereas those with N+ had higher concentrations of NfL and Ng compared with N- (p<0.0001) (disregarding A- and T- status).ConclusionsCSF NfL and Ng concentrations are increased in cognitively normal older adults with biomarker evidence of tau pathology and neurodegeneration.
20.	Arvidsson Rådestig, Maya, et al. (author) Cognitive Performance and Cerebrospinal Fluid Markers in Preclinical Alzheimer's Disease: Results from the Gothenburg H70 Birth Cohort Studies. 2021 In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 79:1, s. 225-235 Journal article (peer-reviewed)abstract We have previously shown that older adults with preclinical Alzheimer's disease (AD) pathology in cerebrospinal fluid (CSF) had slightly worse performance in Mini-Mental State Examination (MMSE) than participants without preclinical AD pathology.We therefore aimed to compare performance on neurocognitive tests in a population-based sample of 70-year-olds with and without CSF AD pathology.The sample was derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (n=316, 70 years old) underwent comprehensive cognitive examinations, and CSF Aβ-42, Aβ-40, T-tau, and P-tau concentrations were measured. Participants were classified according to the ATN system, and according to their Clinical Dementia Rating (CDR) score. Cognitive performance was examined in the CSF amyloid, tau, and neurodegeneration (ATN) categories.Among participants with CDR 0 (n=259), those with amyloid (A+) and/or tau pathology (T+, N+) showed similar performance on most cognitive tests compared to participants with A-T-N-. Participants with A-T-N+ performed worse in memory (Supra span (p=0.003), object Delayed (p=0.042) and Immediate recall (p=0.033)). Among participants with CDR 0.5 (n=57), those with amyloid pathology (A+) scored worse in category fluency (p=0.003).Cognitively normal participants with amyloid and/or tau pathology performed similarly to those without any biomarker evidence of preclinical AD in most cognitive domains, with the exception of slightly poorer memory performance in A-T-N+. Our study suggests that preclinical AD biomarkers are altered before cognitive decline.
21.	Arvidsson Rådestig, Maya, et al. (author) Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study 2023 In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 91:1, s. 291-303 Journal article (peer-reviewed)abstract Background: Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. Objective: We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. Methods: The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid beta(1-42), total tau, and phosphorylated tau, were measured. Results: Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, p = 0.013) and a language test (FAS, p = 0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (p = 0.035). When stratified according to CSF tau and A beta(42) concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, p = 0.003). In participants with high NfL, those with pathologic A beta(42) concentrations performed worse on the Delayed recall memory (p = 0.044). In the high Ng group, participants with pathological A beta(42) concentrations had lower MMSE scores (p = 0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. Conclusion: Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds.
22.	Ayala, Marcelo, 1965, et al. (author) Association of Single Nucleotide Polymorphisms Located in LOXL1 with Exfoliation Glaucoma in Southwestern Sweden 2021 In: Genes. - : MDPI AG. - 2073-4425. ; 12:9 Journal article (peer-reviewed)abstract Introduction: Glaucoma is an optic neuropathy that leads to visual field defects. Genetic mechanisms seem to be involved in glaucoma development. Lysyl Oxidase Like 1 (LOXL1) has been described in previous studies as a predictor factor for exfoliation glaucoma. The present article studied the association between three single nucleotide polymorphisms (SNPs) in the LOXL1 gene and the presence of exfoliation glaucoma in Southwestern Sweden. Methods: Case-control study for genetic association. In total, 136 patients and 1011 controls were included in the study. Patients with exfoliation glaucoma were recruited at the Eye Department of Sahlgrenska University Hospital and Skaraborgs Hospital, Sweden. Controls were recruited from the Gothenburg H70 Birth Cohort Study. Three different SNPs were genotyped: LOXL1_rs3825942, LOXL1_rs2165241 and LOXL1_rs1048661. Results: The distribution of allele frequencies was significantly different between controls and glaucoma patients; for rs3825942 (p = 2 x 10(-12)), for rs2165241 (p = 3 x 10(-16)) and for rs1048661 (p = 2 x 10(-6)). Logistic regression analyses using an additive genetic model, adjusted for sex and age, also showed associations between the studied SNPs and glaucoma (p = 9 x 10(-6); p = 2 x 10(-14); p = 1 x 10(-4)). Conclusion: A strong association was found between allele frequencies of three different SNPs (LOXL1_rs3825942, LOXL1_rs2165241, and LOXL1_rs1048661) and the presence of exfoliation glaucoma in a Southwestern Swedish population.
23.	Ayala, Marcelo, 1965, et al. (author) Single nucleotide polymorphisms in LOXL1 as biomarkers for progression of exfoliation glaucoma in Sweden 2023 In: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 101:5, s. 521-529 Journal article (peer-reviewed)abstract Purpose: Exfoliation glaucoma is a common and aggressive type of glaucoma with high prevalence in Scandinavia. The aim of this study was to elucidate whether the allele frequencies of two single nucleotide polymorphisms (SNPs) located in LOXL1 were associated with the progression of exfoliation glaucoma in Swedish patients. Methods: In this non-randomised cohort study, we enrolled patients with exfoliation glaucoma, and they performed at least five reliable visual field tests. Blood samples were collected, and genotyping was performed using competitive allele-specific PCR genotyping. Glaucoma progression was evaluated using the guided glaucoma progression analysis (GPA), mean deviation (MD) difference and rate of progression (ROP). In addition, associations between allele frequencies and glaucoma progression were tested using logistic regression for GPA and linear regression for MD and ROP. Results: We enrolled a total of 130 patients in the study. The general genetic model showed statistical significance for LOXL1_rs2165241 (p=8 × 10−7, Fisher's exact test) and LOXL1_rs1048661 (p=2 × 10−6, Fisher's exact test). Regression analyses using an additive genetic model showed significant values for LOXL1_rs2165241SNP in relation to GPA, MD and ROP as outcomes (p=1.8 × 10−4, 4 × 10−2, 6 × 10−4) and for LOXL1_rs1048661 SNP in relation to GPA, MD and ROP (p=7 × 10−5, 8 × 10−3, 2 × 10−4). Conclusions: This was the first study to show an association of the SNPs LOXL1_rs2165241 and LOXL1_rs1048661 with the progression of exfoliation glaucoma. Further large-scale studies are required to verify these findings.
24.	Badji, A., et al. (author) Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults 2022 In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13 Journal article (peer-reviewed)abstract Background: Hypertension is an important risk factor for Alzheimer's disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances.Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies.Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-beta(42), phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities.Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups.Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.
25.	Borda, Miguel German, et al. (author) Nutrient Intake and Its Association with Appendicular Total Lean Mass and Muscle Function and Strength in Older Adults: A Population-Based Study 2024 In: NUTRIENTS. - : MDPI. - 2072-6643. ; 16:4 Journal article (peer-reviewed)abstract Treatment options for sarcopenia are currently limited, and primarily rely on two main therapeutic approaches: resistance-based physical activity and dietary interventions. However, details about specific nutrients in the diet or supplementation are unclear. We aim to investigate the relationship between nutrient intake and lean mass, function, and strength. Data were derived from the Gothenburg H70 birth cohort study in Sweden, including 719,70-year-olds born in 1944 (54.1% females). For independent variables, the diet history method (face-to-face interviews) was used to estimate habitual food intake during the preceding three months. Dependent variables were gait speed (muscle performance), hand grip strength (muscle strength), and the appendicular lean soft tissue index (ALSTI). Linear regression analyses were performed to analyze the relationship between the dependent variables and each of the covariates. Several nutrients were positively associated with ALSTI, such as polyunsaturated fatty acids (DHA, EPA), selenium, zinc, riboflavin, niacin equivalent, vitamin B12, vitamin D, iron, and protein. After correction for multiple comparisons, there were no remaining correlations with handgrip and gait speed. Findings of positive correlations for some nutrients with lean mass suggest a role for these nutrients in maintaining muscle volume. These results can be used to inform clinical trials to expand the preventive strategies and treatment options for individuals at risk of muscle loss and sarcopenia.
26.	Borda, Miguel German, et al. (author) Temporal Muscle Thickness: A Practical Approximation for Assessing Muscle Mass in Older Adults 2024 In: JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION. - 1525-8610 .- 1538-9375. ; 25:4 Journal article (peer-reviewed)abstract Objective: Ongoing research has evidenced the importance of muscle measurement in predicting adverse outcomes. Measurement of other muscles is promising in current research. This study aimed to determine the correlation between temporal muscle thickness (TMT) and appendicular lean soft tissue (ALSTI) in older adults. Design: Cross-sectional study. Settings and Participants: Single cohort gathered in Gothenburg, Sweden, consisting of individuals born in 1944 (n = 1203). Methods: We studied 657 magnetic resonance images to measure TMT. Comparisons of TMT with dual -energy X-ray absorptiometry ALSTI (kg/m 2 ) as a reference standard were performed. Finally, TMT associations with cognition evaluated using the Mini -Mental State Examination (MMSE), gait speed, and handgrip strength were explored with linear regressions. Results: The correlation between TMT and ALSTI was weak yet signi ficant (r = 0.277, P < .001). TMT exhibited signi ficant associations with MMSE (estimate = 0.168, P = .002), gait speed (estimate =1.795, P < .001), and ALSTI (estimate = 0.508, P < .001). These associations varied when analyzed by sex. In women, TMT was signi ficantly associated with gait speed (estimate = 1.857, P = .005) and MMSE (estimate = 0.223, P = .003). In men, TMT scores were signi ficantly correlated with ALSTI scores (estimate = 0.571, P < .001). Conclusion and Implications: Repurposing head images can be an accessible alternative to detect muscle mass and ultimately detect sarcopenia. These studies have the potential to trigger interventions or further evaluation to improve the muscle and overall health of individuals. However, additional research is warranted before translating these findings into clinical practice. (c) 2024 AMDA - The Society for Post -Acute and Long -Term Care Medicine.
27.	Borda, Miguel German, et al. (author) Using magnetic resonance imaging to measure head muscles: An innovative method to opportunistically determine muscle mass and detect sarcopenia 2024 In: Journal of Cachexia, Sarcopenia and Muscle. - 2190-5991 .- 2190-6009. ; 15:1, s. 189-197 Journal article (peer-reviewed)abstract Background: Sarcopenia is associated with multiple adverse outcomes. Traditional methods to determine low muscle mass for the diagnosis of sarcopenia are mainly based on dual-energy X-ray absorptiometry (DXA), whole-body magnetic resonance imaging (MRI) and bioelectrical impedance analysis. These tests are not always available and are rather time consuming and expensive. However, many brain and head diseases require a head MRI. In this study, we aim to provide a more accessible way to detect sarcopenia by comparing the traditional method of DXA lean mass estimation versus the tongue and masseter muscle mass assessed in a standard brain MRI. Methods: The H70 study is a longitudinal study of older people living in Gothenburg, Sweden. In this cross-sectional analysis, from 1203 participants aged 70years at baseline, we included 495 with clinical data and MRI images available. We used the appendicular lean soft tissue index (ALSTI) in DXA images as our reference measure of lean mass. Images from the masseter and tongue were analysed and segmented using 3D Slicer. For the statistical analysis, the Spearman correlation coefficient was used, and concordance was estimated with the Kappa coefficient. Results: The final sample consisted of 495 participants, of which 52.3% were females. We found a significant correlation coefficient between both tongue (0.26) and masseter (0.33) with ALSTI (P<0.001). The sarcopenia prevalence confirmed using the alternative muscle measure in MRI was calculated using the ALSTI (tongue=2.0%, masseter=2.2%, ALSTI=2.4%). Concordance between sarcopenia with masseter and tongue versus sarcopenia with ALSTI as reference has a Kappa of 0.989 (P<0.001) for masseter and a Kappa of 1 for the tongue muscle (P<0.001). Comorbidities evaluated with the Cumulative Illness Rating Scale were significantly associated with all the muscle measurements: ALSTI (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.07–1.26, P<0.001), masseter (OR 1.16, 95% CI 1.07–1.26, P<0.001) and tongue (OR 1.13, 95% CI 1.04–1.22, P=0.002); the higher the comorbidities, the higher the probability of having abnormal muscle mass. Conclusions: ALSTI was significantly correlated with tongue and masseter muscle mass. When performing the sarcopenia diagnostic algorithm, the prevalence of sarcopenia calculated with head muscles did not differ from sarcopenia calculated using DXA, and almost all participants were correctly classified using both methods.
28.	Cedres, N., et al. (author) Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals 2022 In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:15 Journal article (peer-reviewed)abstract Background and Objectives Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. Methods The contribution of amyloid and tau pathology was assessed through CSF levels of the A beta(42/40) ratio and phosphorylated tau (p-tau). CSF A beta(38) levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE epsilon 4 carriership were also included in the analysis as variables of interest. Results We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of A beta(38) and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The A beta(42/40) ratio did not contribute notably to the models (IncMSE<3.0%). APOE epsilon 4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T-201 = -1.55; p = 0.123). Discussion In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
29.	Cedres, N., et al. (author) Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities 2020 In: Aging-Us. - : Impact Journals, LLC. - 1945-4589. ; 12:1, s. 894-901 Journal article (peer-reviewed)abstract Different measurements of white matter signal abnormalities (WMSA) are often used across studies
30.	Chibnik, L. B., et al. (author) Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium 2017 In: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 32:10, s. 931-938 Journal article (peer-reviewed)abstract Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
31.	de Rojas, I, et al. (author) Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores 2023 In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1, s. 716- Journal article (other academic/artistic)
32.	de Rojas, I., et al. (author) Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores 2021 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1 Journal article (peer-reviewed)abstract Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
33.	Dehlin, Mats, 1968, et al. (author) Reply to "Pathway for ascertaining the role of uric acid in neurodegenerative diseases," Roman Youssef. 2022 In: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 14:1 Journal article (peer-reviewed)
34.	Dorr, Felix, et al. (author) Dissociating memory and executive function impairment through temporal features in a word list verbal learning task 2023 In: NEUROPSYCHOLOGIA. - 0028-3932 .- 1873-3514. ; 189 Journal article (peer-reviewed)abstract The Rey Auditory Verbal Learning Test (RAVLT) is an established verbal learning test commonly used to quantify memory impairments due to Alzheimer's Disease (AD) both at a clinical dementia stage or prodromal stage of mild cognitive impairment (MCI). Focal memory impairment-as quantified e.g. by the RAVLT-at an MCI stage is referred to as amnestic MCI (aMCI) and is often regarded as the cognitive phenotype of prodromal AD. However, recent findings suggest that not only learning and memory but also other cognitive domains, especially executive functions (EF) and processing speed (PS), influence verbal learning performance. This research investigates whether additional temporal features extracted from audio recordings from a participant's RAVLT response can better dissociate memory and EF in such tasks and eventually help to better describe MCI subtypes. 675 age-matched participants from the H70 Swedish birth cohort were included in this analysis; 68 participants were classified as MCI (33 aMCI and 35 due to executive impairment). RAVLT performances were recorded and temporal features extracted. Novel temporal features were correlated with established neuropsychological tests measuring EF and PS. Lastly, the downstream diagnostic potential of temporal features was estimated using group differences and a machine learning (ML) classification scenario. Temporal features correlated moderately with measures of EF and PS. Performance of an ML classifier could be improved by adding temporal features to traditional counts. We conclude that RAVLT temporal features are in general related to EF and that they might be capable of dissociating memory and EF in a word list learning task.
35.	Fan, XR, et al. (author) A longitudinal resource for population neuroscience of school-age children and adolescents in China 2023 In: Scientific data. - 2052-4463. ; 10:1, s. 545- Journal article (peer-reviewed)
36.	Fardell, Camilla, et al. (author) S100B polymorphisms are associated with age of onset of Parkinson's disease 2018 In: Bmc Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 19:42 Journal article (peer-reviewed)abstract Background: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.
37.	Fatima, Tahzeeb, et al. (author) Association between serum urate and CSF markers of Alzheimer's disease pathology in a population-based sample of 70-year-olds 2021 In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1 Journal article (peer-reviewed)abstract Introduction: The relationship between urate and biomarkers for Alzheimer's disease (AD) pathophysiology has not been investigated. Methods: We examined whether serum concentration of urate was associated with cerebrospinal fluid biomarkers, amyloid beta (A beta)(42), A beta(40), phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), and A beta(42)/A beta(40) ratio, in cognitively unimpaired 70-year-old individuals from Gothenburg, Sweden. We also evaluated whether possible associations were modulated by the apolipoprotein E (APOE) epsilon 4 allele. Results: Serum urate was positively associated with A beta(42) in males (beta = 0.55 pg/mL, P = .04). There was a positive urate-APOE epsilon 4 interaction (1.24 pg/mL, P-interaction = .02) in relation to A beta(42) association. The positive urate and A beta(42) association strengthened in male APOE epsilon 4 carriers (beta = 1.28 pg/mL, P = .01). Discussion: The positive association between urate and A beta(42) in cognitively healthy men may suggest a protective effect of urate against deposition of amyloid protein in the brain parenchyma, and in the longer term, maybe against AD dementia.
38.	Göthberg, Hanna, 1973, et al. (author) Cross-sectional assessment of hearing acuity of an unscreened 85-year-old cohort - Including a 10-year longitudinal study of a sub-sample. 2019 In: Hearing research. - : Elsevier BV. - 1878-5891 .- 0378-5955. ; 382 Journal article (peer-reviewed)abstract As the proportion of older people increases, it is important to investigate hearing acuity in older individuals and to calculate hearing decline for older ages, using standardised test protocols. The main aim of this study was to determine pure-tone hearing thresholds in an unscreened birth cohort of 85-year-olds born in 1930, living in an industrial Swedish city. A further aim was to describe hearing decline in men and women from 75 to 85 years of age with the aid of longitudinal data. The study was part of the Gothenburg H70 Birth Cohort Studies in Sweden. Hearing thresholds (0.25-8kHz) were measured using automated pure-tone audiometry for 286 85-year-old participants. A subsample (n=182) was hearing examined at 75 years of age and studied longitudinally from 75 to 85 years. At age 85 years, men had better hearing at low frequencies but poorer hearing at high frequencies than women. The longitudinal study showed a considerable decline between 75 and 85yearsat mid-high frequencies (>1kHz) and the amount of decline was similar between sexes. The results contribute to the estimation of the future need for hearing health services.
39.	Hasselgren, Caroline, 1987, et al. (author) APOE ε4 and the long arm of social inequity: estimated effects of socio-economic status and sex on the timing of dementia onset 2019 In: Ageing & Society. - 0144-686X .- 1469-1779. ; 39:9, s. 1951-1975 Journal article (peer-reviewed)abstract It is well established that carriers of the apolipoprotein E (APOE) ε4 allele run a greater risk of developing Alzheimer's disease, the most common form of dementia and a strongly age-related condition known to disproportionally affect women. Low educational attainment also stands out as a prominent risk factor, and it has been suggested that occupational class plays a similar role in disease susceptibility. Not yet fully explored, however, is the question of whether socio-economic status (SES) could moderate the effect of APOE ε4. In the present paper, we address this issue. As substantial inequities in workforce participation and educational opportunities have existed between men and women in previous generations, we further examine whether SES-related moderations of the relationship between dementia and APOE ε4 are sex-specific. Our analyses are based on a sample of 580 individuals from the H70 Birth Cohort Study and the Prospective Population Study on Women in Gothenburg, Sweden. Data were analysed using Cox proportional hazards regression, and the results suggest that while high SES postpones dementia onset among male APOE ε4 carriers, this is not the case for women. These findings underscore the long-term impact of social inequity on health as well as the importance of considering potential interactions between social and genetic risk factors if we are to understand better the complex aetiology of dementia.
40.	Hasselgren, Caroline, 1987, et al. (author) Genes and the long arm of social inequality: Effects of socioeconomic status and sex on the timing of dementia onset 2016 In: 18TH EPA SECTION MEETING IN EPIDEMIOLOGY & SOCIAL PSYCHIATRY: Social Psychiatry and Epidemiology in a changing world. Conference paper (other academic/artistic)
41.	Hasselgren, Caroline, 1987, et al. (author) Job environment exposures and dementia risk in late life – do they moderate the effect of APOE e4? 2018 In: 24th Nordic Congress of Gerontology. Oslo, Norway: 2-4 May 2018. Conference paper (other academic/artistic)
42.	Hasselgren, Caroline, 1987, et al. (author) Sex differences in dementia: on the potentially mediating effects of educational attainment and experiences of psychological distress 2020 In: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 20:1 Journal article (peer-reviewed)abstract Background: Old-age dementias are known to disproportionally affect women as well as individuals with low educational attainment. The higher lifetime risk of dementia among women is usually attributed to their longer life expectancy. However, the impact of sex, and subsequent gender inequity, is likely to be more multifaceted than this explanation implies. Not least because of historical inequities in access to education between the sexes and the gender and socio-economic gradients in risk factors such as stress, depression and social isolation. Consequently, the present study sought to test whether differences in educational attainment and experiences of general psychological distress mediate the association between female sex and dementia. Methods: The study utilizes data obtained through the Gothenburg H70 Birth Cohort Study and the Prospective Populations Study on Women (n = 892). Data were analysed using Confirmatory Factor Analysis (CFA) and Structural Equation Modelling (SEM) with Weighted Least Squares Means and Variance adjusted (WLSMV) estimation. General psychological distress was indicated by a latent variable and constructed from five manifest items (previous depression, stress, self-esteem, chronic loneliness and satisfaction with social situation) that were all measured at baseline. Results: While the results could not corroborate that education directly mediates the effect of sex on dementia, level of distress was predicted by both female sex (0.607, p < .001) and education (- 0.166, p < .01) and, in turn, shown to be significantly associated with dementia (0.167, p < .05), also after controlling for confounders. When time from baseline to diagnosis was increased through sequential exclusion of dementia cases, the effect of distress on dementia was no longer significant. Conclusion: The overall findings suggest that social (dis) advantage predicts general psychological distress, which thereby constitutes a potential, and rarely acknowledged, pathway between female sex, education, and dementia. They further underline the importance of attending to both education and distress as 'gendered' phenomena when considering the nature of their associations with dementia. However, the possibility of reverse causality bias must be acknowledged and the need for longitudinal studies with longer follow-up stressed.
43.	Hasselgren, Caroline, 1987, et al. (author) Sex differences in dementia: On the potentially mediating effects of educational attainment and experiences of psychological distress 2021 In: Scientific program, NKG 25 Nordic Gerontology Congress. Conference paper (other academic/artistic)
44.	Hasselgren, Caroline, 1987, et al. (author) Socioeconomic status, gender and dementia: The influence of work environment exposures and their interactions with APOE ɛ4. 2018 In: SSM - population health. - : Elsevier BV. - 2352-8273. ; 5, s. 171-179 Journal article (peer-reviewed)abstract It is a well-established fact that unfavourable social and economic conditions have a negative impact on health and longevity. Recent findings suggest that this is also true of age-related dementias. Yet most common indicators of socioeconomic status (SES) say very little about the actual mechanisms at play in disease development. The present paper explores five work exposure characteristics, all of which have a clear social gradient, that could potentially shed further light on the relationship between SES and dementia. Specifically, it investigates whether these exposures could moderate the impact of a well-known genetic risk factor: the APOE ɛ4 allele. The empirical analyses are based on data from a Swedish population study (n = 1019). Main occupation was linked to The Job Exposure Matrix to estimate the individuals' exposure to the following work environment factors: work control, support, psychological demands, physical demands and job hazards. All analyses were conducted using binary logistic regression and focused specifically on gene-work exposure interactions. A significant main effect of work control on dementia risk was detected for males (OR = 0.68; p< 0.05), but not for females. However, control was found to significantly moderate the effect of APOE ɛ4 in both genders, albeit in different ways. These findings do not only underscore the importance of considering interactions between social and genetic risk factors to better understanding multifactorial diseases such as dementia. They also propose that gender- and class-based inequities interact, and hence must be considered simultaneously, also in relation to this particular disease.
45.	Hasselgren, Caroline, 1987, et al. (author) Socioeconomic status, gender and dementia: The influence of work environment exposures and their interactions with genetic risk factor APOE e4 2018 In: BSA 50th Anniversary Medical Sociology Annual Conference. Glasgow Caledonian University, 12-14 September 2018.. Conference paper (other academic/artistic)
46.	Henningsson, Susanne, 1977, et al. (author) Association between polymorphisms in NOS3 and KCNH2 and social memory 2015 In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 9 Journal article (peer-reviewed)abstract Social memory, including the ability to recognize faces and voices, is essential for social relationships. It has a large heritable component, but the knowledge about the contributing genes is sparse. The genetic variation underlying inter-individual differences in social memory was investigated in an exploratory sample (n = 55), genotyped with a chip comprising approximately 200,000 single nucleotide polymorphisms (SNPs), and in a validation sample (n = 582), where 30 SNPs were targeted. In the exploratory study face identity recognition was measured. The validation study also measured vocal sound recognition, as well as recognition of faces and vocal sounds combined (multimodal condition). In the exploratory study, the 30 SNPs that were associated with face recognition at puncorrected < 0.001 and located in genes, were chosen for further study. In the validation study two of these SNPs showed significant associations with recognition of faces, vocal sounds, and multimodal stimuli: rs1800779 in the gene encoding nitric oxide synthase 3 (NOS3) and rs3807370 in the gene encoding the voltage-gated channel, subfamily H, member 2 (KCNH2), in strong linkage disequilibrium with each other. The uncommon alleles were associated with superior performance, and the effects were present for men only (p < 0.0002). The exploratory study also showed a weaker but significant association with (non-emotional) word recognition, an effect that was independent of the effect on face recognition. This study demonstrates evidence for an association between NOS3 and KCNH2SNPs and social memory.
47.	Hovey, Daniel, et al. (author) Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples. 2016 In: Molecular psychiatry. - Stockholm : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 16, s. 983-988 Journal article (peer-reviewed)abstract The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires-Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)-designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 × 10(-7) in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 × 10(-5). Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one potential target in the treatment of aggressive antisocial behavior.Molecular Psychiatry advance online publication, 22 September 2015; doi:10.1038/mp.2015.144.
48.	Hovey, Daniel, et al. (author) Emotion recognition associated with polymorphism in oxytocinergic pathway gene ARNT2 2018 In: Social Cognitive & Affective Neuroscience. - : Oxford University Press (OUP). - 1749-5024 .- 1749-5016. ; 13:2, s. 173-181 Journal article (peer-reviewed)abstract The ability to correctly understand the emotional expression of another person is essential for social relationships and appears to be a partly inherited trait. The neuropeptides oxytocin and vasopressin have been shown to influence this ability as well as face processing in humans. Here, recognition of the emotional content of faces and voices, separately and combined, was investigated in 492 subjects, genotyped for 25 single nucleotide polymorphisms (SNPs) in eight genes encoding proteins important for oxytocin and vasopressin neurotransmission. The SNP rs4778599 in the gene encoding aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a transcription factor that participates in the development of hypothalamic oxytocin and vasopressin neurons, showed an association that survived correction for multiple testing with emotion recognition of audio-visual stimuli in women (). This study demonstrates evidence for an association that further expands previous findings of oxytocin and vasopressin involvement in emotion recognition.
49.	Höglund, Kina, 1976, et al. (author) Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration 2017 In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7 Journal article (peer-reviewed)abstract Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n = 1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of beta-amyloid (A beta 42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of A beta 42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, A beta 40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF A beta 42 levels below 530 pg ml(-1). These individuals displayed significantly higher CSF concentrations of t-tau (P < 0.001), p-tau (181) (P < 0.001), neurogranin (P = 0.009) and FABP3 (P = 0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of A beta. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE epsilon 4 and amyloid pathology in healthy older individuals.
50.	Jansen, Iris E, et al. (author) Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers. 2022 In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842 Journal article (peer-reviewed)abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

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