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1.
  • Arvidsson Rådestig, Maya, et al. (författare)
  • Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample
  • 2023
  • Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1
  • Tidskriftsartikel (refereegranskat)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.
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  • Arvidsson Rådestig, Maya, et al. (författare)
  • Cognitive Performance and Cerebrospinal Fluid Markers in Preclinical Alzheimer's Disease: Results from the Gothenburg H70 Birth Cohort Studies.
  • 2021
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 79:1, s. 225-235
  • Tidskriftsartikel (refereegranskat)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.
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  • Bjerke, Maria, 1977, et al. (författare)
  • Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years.
  • 2016
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 49:3, s. 733-741
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio. METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p=0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p=0.019) during follow-up. FABP-3 correlated with CSF T-tau (r=0.88, p< 0.001), P-tau181 (r=0.619, p< 0.001), and CSF:serum albumin ratio (r=0.233, p=0.031), but not with Aβ42 (r=-0.08, p=0.444)Conclusion: CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism.
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  • Kern, Silke, et al. (författare)
  • Does low-dose acetylsalicylic acid prevent cognitive decline in women with high cardiovascular risk? A 5-year follow-up of a non-demented population-based cohort of Swedish elderly women.
  • 2012
  • Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 2:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective The aim of this study was to examine whether low-dose acetylsalicylic acid (ASA) influences the rate of cognitive change in elderly women. Design Prospective, population-based cohort study. Setting The city of Gothenburg, Sweden, including those living in private households as well as in residential care. Participants The sample was derived from the Prospective Population Study of Women and from the H70 Birth Cohort Study in Gothenburg, Sweden. Both samples were obtained from the Swedish Population Register, based on birth date, and included 789 (response rate 71%) women aged 70–92years. After the exclusion of individuals with dementia and users of warfarin, clopidogrel or heparin at baseline, 681 women were examined. Among all participants, 95.4% (N=601) had a high cardiovascular risk (CVD), defined as 10% or higher 10-year risk of any CVD event according to the Framingham heart study and 129 used low-dose ASA (75–160mg daily) at baseline. After 5years a follow-up was completed by 489 women. Primary outcome and secondary outcome measures Cognitive decline and dementia incidence in relation to the use of low-dose ASA and cardiovascular risk factors. Cognition was measured using the Mini Mental State Examination (MMSE), word fluency, naming ability and memory word tests. Dementia was diagnosed according to the DSM-III-R criterion. As secondary outcome incidence of stroke and peptic ulcer in relation to low-dose ASA use was studied. Results Women on regular low-dose ASA declined less on MMSE at follow-up than those not on ASA. This difference was even more pronounced in those who had ASA at both examinations (p=0.004 compared with never users; n=66 vs n=338). All other cognitive tests showed the same trends. There were no differences between the groups regarding short-term risk for dementia (N=41). Conclusion Low-dose ASA treatment may have a neuroprotective effect in elderly women at high cardiovascular risk.
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  • Kern, Silke, et al. (författare)
  • Lower CSF interleukin-6 predicts future depression in a population-based sample of older women followed for 17 years
  • 2013
  • Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591. ; 32, s. 153-158
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6) and related proinflammatory cytokines and current and future depression in a population-based sample of older women who were followed for 17 years. Methods 83 non-demented women aged 70–84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992–3. CSF- IL-6, interleukin-1β (IL-1β), interleukin- 8 (IL-8) and tumor necrosis factor-α (TNF-α) were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. Results At baseline, women with ongoing depression had lower levels of IL-6 (p < 0.04), IL-8 (p < 0.05) and TNF-α (p < 0.05) compared with those without depression. In women without depression at baseline, lower CSF IL-6 levels predicted depression at one or more follow-up examination (p < 0.03). Results from the generalized linear mixed logistic model using all baseline and follow-up data on depression status and Mini Mental State Examination score showed a significant relationship between IL-6 and depression (p = 0.005 OR 0.370 CI [0.184–0.744]). Conclusion Lower levels of CSF IL-6 were associated with current depression and with future depression during a follow-up of almost two decades. Our findings suggest that lower levels of CSF IL-6 may be related to depression vulnerability in later life.
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  • Kern, Silke, et al. (författare)
  • Prevalence of preclinical Alzheimer disease Comparison of current classification systems
  • 2018
  • Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 90:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden. The sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of beta-amyloid (A beta)(42), A beta(40), total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score > 0 were excluded, leaving 259 cognitively unimpaired individuals. The prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T-/N- was 13.1%, A+/T-/N+ was 7.3%, A+/T+/N+ was 2.3%, A-/T-/N+ was 18.9%, and A-/T+/N+ was 4.6%. When the Dubois criteria were applied, the prevalence of asymptomatic at risk for AD was 36.7% and of preclinical AD was 9.7%. With the NIA-AA criteria, the prevalence of stage 1 was 13.1% and stage 2 was 9.7%. With the IWG-2 criteria, the prevalence of asymptomatic at risk for AD was 9.7%. The APOE epsilon 4 allele was associated with several of the categories. Men more often had total tau pathology, A+/T-/N+, preclinical AD according to Dubois 2016, asymptomatic at risk for AD according to the IWG-2 criteria, and NIA-AA stage 2. The prevalence of pathologic AD markers was very common (46%) in a representative population sample of 70-year-olds. The clinical implications of these findings need to be scrutinized further in longitudinal studies.
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  • Rydberg Sterner, Therese, et al. (författare)
  • The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population.
  • 2019
  • Ingår i: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 34:2, s. 191-209
  • Tidskriftsartikel (refereegranskat)abstract
    • To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014-16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n=1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons.
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  • Ahlner, Felicia, 1987, et al. (författare)
  • Increased Alcohol Consumption Among Swedish 70-Year-Olds 1976 to 2016: Analysis of Data from The Gothenburg H70 Birth Cohort Studies, Sweden
  • 2018
  • Ingår i: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008. ; 42:12, s. 2403-2412
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2018 by the Research Society on Alcoholism Background: The older adult population is increasing worldwide, as is the number of older adults who consume alcohol. Although there is a growing body of research on alcohol consumption among older people, few studies focus on changes in at-risk consumption over time across well-defined birth cohorts of older adults. Methods: This study used a serial cross-sectional design in order to compare alcohol consumption patterns among birth cohorts of Swedish 70-year-olds (total n=2,268) examined in 1976 to 1977 (n=393), 1992 to 1993 (n=248), 2000 to 2002 (n=458), and 2014 to 2016 (n=1,169). Participants took part in a multidisciplinary study on health and aging. Face-to-face interviews were conducted by healthcare professionals. Protocols regarding alcohol consumption were similar for all cohorts. The volume of weekly alcohol consumption was estimated during the past month. At-risk consumption was defined as ≥100g alcohol/wk corresponding roughly to the National Institute on Alcohol Abuse and Alcoholism definition of heavy consumption. Results: The proportion of at-risk consumers among men increased from 16.1% in 1976 to 1977 to 29.9% in 2000 to 2002 (p=0.001) and 45.3% in 2014 to 2016 (p<0.001). In women, proportions were low in 1976 to 1977 (0.5%) and 1992 to 1993 (2.0%; p=0.134), but increased to 9.5% in 2000 to 2002 (p<0.001) and 24.3% in 2014 to 2016 (p<0.001). The male:female ratio regarding consumption of ≥100g/wk decreased from 32.2:1 in 1976 to 1977 to 3.1:1 in 2000 to 2002 to 1.9:1 in 2014 to 2016. Spirit consumption decreased dramatically among men during the study period, while women reported very low spirit consumption at all examinations. Wine consumption increased in both sexes between 2000 to 2002 and 2014 to 2016. Beer consumption increased among men between 2000 to 2002 and 2014 to 2016. Conclusions: Recent cohorts of 70-year-olds in Sweden report significantly higher levels of alcohol consumption than previous cohorts. There was a dramatic increase in at-risk consumption among 70-year-olds from the 1970s to the mid-2010s, and this was particularly pronounced among women.
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  • Arnoldussen, Ilse A. C., et al. (författare)
  • A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older
  • 2018
  • Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 63:4, s. 1325-1335
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Adiposity measured in mid-or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures.Objective: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence.Methods: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used.Results: Within 5 years of baseline, low BMI (<20 kg/m(2)) was associated with higher odds of dementia compared to those in the healthy BMI category (>= 20-24.9 kg/m(2)). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05).Conclusion: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age >= 70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.
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  • Arnoldussen, I. A. C., et al. (författare)
  • A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older
  • 2018
  • Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 63:4, s. 1325-1335
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Adiposity measured in mid-or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures. Objective: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence. Methods: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used. Results: Within 5 years of baseline, low BMI (<20 kg/m(2)) was associated with higher odds of dementia compared to those in the healthy BMI category (>= 20-24.9 kg/m(2)). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05). Conclusion: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age >= 70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.
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  • Arvidsson Rådestig, Maya, et al. (författare)
  • Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study
  • 2023
  • Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 91:1, s. 291-303
  • Tidskriftsartikel (refereegranskat)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.
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  • Badji, A., et al. (författare)
  • Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults
  • 2022
  • Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
  • Tidskriftsartikel (refereegranskat)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.
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  • Bethlehem, RAI, et al. (författare)
  • Brain charts for the human lifespan
  • 2022
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 604:79057906, s. 525-
  • Tidskriftsartikel (refereegranskat)abstract
    • Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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  • Borda, Miguel German, et al. (författare)
  • Nutrient Intake and Its Association with Appendicular Total Lean Mass and Muscle Function and Strength in Older Adults: A Population-Based Study
  • 2024
  • Ingår i: NUTRIENTS. - : MDPI. - 2072-6643. ; 16:4
  • Tidskriftsartikel (refereegranskat)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.
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  • Borda, Miguel German, et al. (författare)
  • Temporal Muscle Thickness: A Practical Approximation for Assessing Muscle Mass in Older Adults
  • 2024
  • Ingår i: JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION. - 1525-8610 .- 1538-9375. ; 25:4
  • Tidskriftsartikel (refereegranskat)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.
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  • Borda, Miguel German, et al. (författare)
  • Using magnetic resonance imaging to measure head muscles: An innovative method to opportunistically determine muscle mass and detect sarcopenia
  • 2024
  • Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - 2190-5991 .- 2190-6009. ; 15:1, s. 189-197
  • Tidskriftsartikel (refereegranskat)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.
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23.
  • Cedres, Nira, et al. (författare)
  • Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
  • 2022
  • Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 99:15, s. e1619-e1629
  • Tidskriftsartikel (refereegranskat)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 Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 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 ε4 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 Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 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 (T201 = −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.
  •  
24.
  • Cedres, N., et al. (författare)
  • Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
  • 2022
  • Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:15
  • Tidskriftsartikel (refereegranskat)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.
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25.
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26.
  • Chatterjee, Ruchira, et al. (författare)
  • XANES and EXAFS of dilute solutions of transition metals at XFELs
  • 2019
  • Ingår i: Journal of Synchrotron Radiation. - : INT UNION CRYSTALLOGRAPHY. - 0909-0495 .- 1600-5775. ; 26, s. 1716-1724
  • Tidskriftsartikel (refereegranskat)abstract
    • This work has demonstrated that X-ray absorption spectroscopy (XAS), both Mn XANES and EXAFS, of solutions with millimolar concentrations of metal is possible using the femtosecond X-ray pulses from XFELs. Mn XAS data were collected using two different sample delivery methods, a Rayleigh jet and a drop-on-demand setup, with varying concentrations of Mn. Here, a new method for normalization of XAS spectra based on solvent scattering that is compatible with data collection from a highly variable pulsed source is described. The measured XANES and EXAFS spectra of such dilute solution samples are in good agreement with data collected at synchrotron sources using traditional scanning protocols. The procedures described here will enable XFEL-based XAS on dilute biological samples, especially metalloproteins, with low sample consumption. Details of the experimental setup and data analysis methods used in this XANES and EXAFS study are presented. This method will also benefit XAS performed at high-repetition-rate XFELs such as the European XFEL, LCLS-II and LCLS-II-HE.
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27.
  • Chibnik, L. B., et al. (författare)
  • Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium
  • 2017
  • Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 32:10, s. 931-938
  • Tidskriftsartikel (refereegranskat)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.
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28.
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29.
  • de Rojas, I., et al. (författare)
  • Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)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).
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30.
  • De, S., et al. (författare)
  • Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression
  • 2019
  • Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Soluble aggregates of amyloid-beta (A beta) have been associated with neuronal and synaptic loss in Alzheimer's disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we characterised soluble aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls using a range of sensitive biophysical methods. We used super-resolution imaging and atomic force microscopy to characterise the size and structure of the aggregates present in CSF and correlate this with their ability to permeabilise lipid membranes and induce an inflammatory response. We found that these aggregates are extremely heterogeneous and exist in a range of sizes, varying both structurally and in their mechanisms of toxicity during the disease progression. A higher proportion of small aggregates of A beta that can cause membrane permeabilization are found in MCI CSF; in established AD, a higher proportion of the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells, while there was no detectable change in aggregate concentration. These results show that large aggregates, some longer than 100nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.
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31.
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32.
  • Dittrich, Anna, 1972, et al. (författare)
  • Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg.
  • 2023
  • Ingår i: Neurology. - 1526-632X. ; 101:3
  • Tidskriftsartikel (refereegranskat)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.
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33.
  • Dittrich, Anna, 1972, et al. (författare)
  • Plasma and CSF NfL are differentially associated with biomarker evidence of neurodegeneration in a community-based sample of 70-year-olds
  • 2022
  • Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 14:1
  • Tidskriftsartikel (refereegranskat)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.
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34.
  • Dittrich, Anna, 1972, et al. (författare)
  • Proportion of Community-Dwelling Individuals Older Than 70 Years Eligible for Lecanemab Initiation: The Gothenburg H70 Birth Cohort Study.
  • 2024
  • Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 102:9
  • Tidskriftsartikel (refereegranskat)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.
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35.
  • Dorr, Felix, et al. (författare)
  • Dissociating memory and executive function impairment through temporal features in a word list verbal learning task
  • 2023
  • Ingår i: NEUROPSYCHOLOGIA. - 0028-3932 .- 1873-3514. ; 189
  • Tidskriftsartikel (refereegranskat)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.
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36.
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37.
  • Fatima, Tahzeeb, et al. (författare)
  • Association between serum urate and CSF markers of Alzheimer's disease pathology in a population-based sample of 70-year-olds
  • 2021
  • Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
  • Tidskriftsartikel (refereegranskat)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.
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38.
  • Fuller, Franklin D, et al. (författare)
  • Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers
  • 2017
  • Ingår i: Nature Methods. - : Macmillan Publishers Ltd.. - 1548-7091 .- 1548-7105. ; 14, s. 443-449
  • Tidskriftsartikel (refereegranskat)abstract
    • X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly affects the data quality. We present here a robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.
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39.
  • Gudmundsson, Pia, 1978, et al. (författare)
  • White Matter Lesions and Temporal Lobe Atrophy Related to incidence of both Dementia and Major Depression in 70-year-olds followed over 10 years
  • 2015
  • Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 22:5, s. 781-788
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Background: A number of studies have suggested associations between dementia and depression in older adults. One reason could be that these disorders share structural correlates, such as white matter lesions (WMLs) and cortical atrophy. No study has examined whether these lesions precede both dementia and depression independently of each other in the general population. Methods: We investigated whether WMLs and cortical atrophy on computed tomography (CT) predict dementia and depression in a population-based sample of 70-year-olds (n=380) followed over 10 years. Exclusion criteria were dementia, major depression, history of stroke and a Mini-Mental State Examination score below 26 at baseline in 2000-01. Dementia was diagnosed according to DSM-III-R and depression according to DSM-5. Primary outcomes included dementia and major depression at 10-year follow-up. Results: Adjusted logistic regression models, including both WMLs and temporal lobe atrophy, showed that moderate-to-severe WMLs (OR 3.96, 95% CI 1.23-12.76) and temporal lobe atrophy (OR 2.93, 95% CI 1.13-7.60) predicted dementia during 10-year follow-up independently of major depression. Similarly, both moderate-to-severe WMLs (OR 3.84, 95% CI 1.25-11.76) and temporal lobe atrophy (OR 2.52, 95% CI 1.06-5.96) predicted depression even after controlling for incident dementia. Conclusion: WMLs and temporal lobe atrophy preceded 10-year incidence of both dementia and depression in 70-year-olds. Shared structural correlates could explain the reported associations between dementia and depression. These brain changes may represent independent and complementary pathways to dementia and depression. Strategies to slow progression of vascular pathology and neurodegeneration could indirectly prevent both dementia and depression in older adults.
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40.
  • Guo, Xinxin, 1972, et al. (författare)
  • Increased risk for dementia both before and after stroke: A population-based study in women followed over 44 years
  • 2018
  • Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:10, s. 1253-1260
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Longitudinal studies are needed to understand the long-term associations between stroke and dementia. Methods: A population sample of 1460 women without stroke or dementia at baseline was followed over 44 years, from 1968 to 2012. Information on stroke and dementia was obtained from neuropsychiatric examinations, key-informant interviews, hospital registry, and medical records. Results: During 44 years follow-up, 362 women developed stroke and 325, dementia. The age-specific incidence of the two disorders was similar. The incidence of dementia was higher in those with stroke than among those without (33.7% vs. 18.5%; age-adjusted hazard ratio 1.44, 95% confidence interval 1.15-1.81). The increased risk of dementia started already 5 years before stroke, was highest 1 year after stroke, and continued more than 11 years after stroke. Discussion: There is an increased risk for dementia both before and after stroke. This has implications for understanding the relation between the two disorders and for prevention of dementia and stroke. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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41.
  • Guo, Xinxin, 1972, et al. (författare)
  • Midlife stress-related exhaustion and dementia incidence: a longitudinal study over 50 years in women
  • 2024
  • Ingår i: BMC PSYCHIATRY. - 1471-244X. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundsCognitive problems are common symptoms among individuals with stress-related exhaustion. It is still unknown whether these individuals are at a higher risk of developing dementia later. This study aims to examine the relationship between midlife stress-related exhaustion and dementia incidence.MethodsA population sample of 777 women (aged 38, 46, 50 and 54 years) without dementia at baseline was followed over 50 years, from 1968 to 2019. Stress-related exhaustion was based on information from the psychiatric examination in 1968/69. Information on dementia incidence between 1968 and 2019 was obtained from neuropsychiatric examinations, key-informant interviews, and hospital registry. Dementia was diagnosed according to the DSM-III-R criteria. A subgroup of non-demented women (n = 284) was examined for cognitive functions by the Gottfries-Br & aring;ne-Steen scale 24 years after baseline.ResultsStress-related exhaustion in midlife was associated with higher risk for development of dementia before age 75 (Hazard ratio and 95% confidence interval: 2.95 and 1.35-6.44). The association remained after adjustment for age, major depression, and anxiety disorder. Mean age of dementia onset was younger for women with stress-related exhaustion than women without stress (mean +/- SD, 76 +/- 9 vs. 82 +/- 8 . p = 0.009). Women with stress-related exhaustion in midlife still showed more cognitive impairments 24 years later compared with women without stress (Odds ratio and 95% confidence interval: 2.64 and 1.15-6.06).ConclusionsWe found that women with stress-related exhaustion in midlife were at a higher risk to develop dementia at relatively younger age. These women showed persistently lower cognitive functions over years even without dementia. Present study results need to be interpreted with caution due to small sample size and should be confirmed in future studies with larger sample size. Our study findings may imply the importance of long-term follow-up regarding cognitive function among individuals with stress-related exhaustion.
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42.
  • Hansson, Karl, 1985, et al. (författare)
  • Expanding the cerebrospinal fluid endopeptidome
  • 2017
  • Ingår i: Proteomics. - : Wiley. - 1615-9853. ; 17:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Biomarkers of neurodegenerative disorders are needed to assist in diagnosis, to monitor disease progression and therapeutic interventions, and to provide insight into disease mechanisms. One route to identify such biomarkers is by proteomic and peptidomic analysis of cerebrospinal fluid (CSF). In the current study, we performed an in-depth analysis of the human CSF endopeptidome to establish an inventory thatmay serve as a basis for future targeted biomarker studies. High-pH RP HPLC was employed for off-line sample prefractionation followed by low-pH nano-LC-MS analysis. Different software programs and scoring algorithms for peptide identification were employed and compared. A total of 18 031 endogenous peptides were identified at a FDR of 1%, increasing the number of known endogenous CSF peptides 10fold compared to previous studies. The peptides were derived from 2 053 proteins of which more than 60 have been linked to neurodegeneration. Notably, among the findings were six peptides derived from microtubule-associated protein tau, three of which span the diagnostically interesting threonine-181 (Tau-F isoform). Also, 213 peptides from amyloid precursor protein were identified, 58 of which were partially or completely within the sequence of amyloid beta 1-40/42, as well as 109 peptides from apolipoprotein E, spanning sequences that discriminate between the E2/E3/E4 isoforms of the protein.
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43.
  • Höglund, Kina, 1976, et al. (författare)
  • Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration
  • 2017
  • Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
  • Tidskriftsartikel (refereegranskat)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.
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44.
  • Hörder, Helena M, et al. (författare)
  • Midlife cardiovascular fitness and dementia A 44-year longitudinal population study in women
  • 2018
  • Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 90:15
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To investigate whether greater cardiovascular fitness in midlife is associated with decreased dementia risk in women followed up for 44 years. A population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of these, a systematic subsample comprising 191 women completed a stepwise-increased maximal ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009. Dementia was diagnosed according to DSM-III-R criteria on the basis of information from neuropsychiatric examinations, informant interviews, hospital records, and registry data up to 2012. Cox regressions were performed with adjustment for socioeconomic, lifestyle, and medical confounders. Compared with medium fitness, the adjusted hazard ratio for all-cause dementia during the 44-year follow-up was 0.12 (95% confidence interval [CI] 0.03-0.54) among those with high fitness and 1.41 (95% CI 0.72-2.79) among those with low fitness. High fitness delayed age at dementia onset by 9.5 years and time to dementia onset by 5 years compared to medium fitness. Among Swedish women, a high cardiovascular fitness in midlife was associated with a decreased risk of subsequent dementia. Promotion of a high cardiovascular fitness may be included in strategies to mitigate or prevent dementia. Findings are not causal, and future research needs to focus on whether improved fitness could have positive effects on dementia risk and when during the life course a high cardiovascular fitness is most important.
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45.
  • Jansen, Iris E, et al. (författare)
  • Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
  • 2022
  • Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
  • Tidskriftsartikel (refereegranskat)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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46.
  • Jansen, Willemijn J, et al. (författare)
  • Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
  • 2022
  • Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
  • Tidskriftsartikel (refereegranskat)abstract
    • One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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47.
  • Jaraj, Daniel, et al. (författare)
  • Vascular factors in suspected normal pressure hydrocephalus. A population-based study
  • 2016
  • Ingår i: Neurology. - 0028-3878. ; 86:7, s. 592-599
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: We examined clinical and imaging findings of suspected idiopathic normal pressure hydrocephalus (iNPH) in relation to vascular risk factors and white matter lesions (WMLs), using a nested case-control design in a representative, population-based sample. Methods: From a population-based sample, 1,235 persons aged 70 years or older were examined with CT of the brain between 1986 and 2000. We identified 55 persons with hydrocephalic ventricular enlargement, i.e., radiologic findings consistent with iNPH. Among these, 26 had clinical signs that fulfilled international guideline criteria for probable iNPH. These cases were labeled suspected iNPH. Each case was matched to 5 controls from the same sample, based on age, sex, and study cohort. Data on risk factors were obtained from clinical examinations and the Swedish Hospital Discharge Register. History of hypertension, diabetes mellitus (DM), smoking, overweight, history of coronary artery disease, stroke/TIA, and WMLs on CT were examined. Risk factors associated with iNPH with a p value <0.1 in χ2 tests were included in conditional logistic regression models. Results: In the regression analyses, suspected iNPH was related to moderate to severe WMLs (odds ratio [OR] 5.2; 95% confidence interval [CI]: 1.5–17.6), while hydrocephalic ventricular enlargement was related to hypertension (OR 2.7; 95% CI: 1.1–6.8), moderate to severe WMLs (OR 6.5; 95% CI: 2.1–20.3), and DM (OR 4.3; 95% CI: 1.1–16.3). Conclusions: Hypertension, WMLs, and DM were related to clinical and imaging features of iNPH, suggesting that vascular mechanisms are involved in the pathophysiology. These findings might have implications for understanding disease mechanisms in iNPH and possibly prevention.
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48.
  • Jeppsson, Anna, et al. (författare)
  • Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus
  • 2023
  • Ingår i: Fluids and Barriers of the CNS. - 2045-8118. ; 20:1
  • Tidskriftsartikel (refereegranskat)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.
  •  
49.
  • Joas, Erik, 1983, et al. (författare)
  • Sex differences in time trends of blood pressure among Swedish septuagenarians examined three decades apart: a longitudinal population study
  • 2017
  • Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 35:7, s. 1424-1431
  • Tidskriftsartikel (refereegranskat)abstract
    • Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.OBJECTIVE:: The aim of this study was to analyze the influence of birth cohort, sex and age on the trajectories of SBP and DBP in two birth cohorts of 70-year-olds, examined 3 decades apart and followed up at ages 75 and 79–80 years. METHODS:: Two population samples of 70-year-olds from Gothenburg, Sweden, were examined. The first, born in 1901–1902, was examined in 1971–1972 (n?=?973). The second, born in 1930, was examined in 2000 (n?=?509). Both samples were re-examined at ages 75 and 79–80 years. RESULTS:: We found that SBP and DBP were considerably lower in septuagenarian men and women born 1930 compared with those born 1901–1902, also when adjusting for antihypertensive treatment in different ways. The decline was especially pronounced in women. Blood pressure was higher in women than in men in the 1970s, whereas there were no sex differences in the 2000s. The age-related decline in SBP started earlier and was more accentuated in those born in 1930 than in those born in 1901–1902. CONCLUSION:: Blood pressure decreased, and the age-related decline in SBP started earlier in septuagenarians examined in the 2000s compared with those examined in the 1970s. The decrease was especially pronounced in women and diminished the sex differences. Antihypertensive treatment only partly explained our findings, suggesting that other mostly unknown factors played an important role.
  •  
50.
  • Johansson, Lena, 1972, et al. (författare)
  • Longstanding psychological stress in relation to biomarkers of neuronal dysfunction in cerebrospinal fluid: a 25-year follow-up study in women
  • 2019
  • Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 80, s. 111-115
  • Tidskriftsartikel (refereegranskat)abstract
    • Longstanding psychological stress has been associated with increased risk of neurodegenerative disorders, such as dementia and Alzheimer's disease. In a prospective population study of women (n = 81), we tested if midlife stress (mean age 49 years) was associated with late-life biomarkers of neuro-degeneration in cerebrospinal fluid (CSF) (mean age 74 years) in linear regression models. It was found that women who report of stress at baseline (n = 20) had higher levels of CSF visinin-like protein-1 (VILIP-1) (age adjusted beta = 0.113, p = 0.017) and CSF myelin basic protein (beta = 0.060, p = 0.030) compared with women without midlife stress (n = 61). There was also a trend observed for higher CSF neurofilament light (beta = 0.133, p = 0.056). In addition, longer periods of stress (i.e., stress at 2-3 midlife examinations) were associated with higher levels of CSF VILIP-1. The results suggest that longstanding stress might be associated with neurodegenerative processes in the brain, as CSF VILIP-1 is an unspecific marker for neuronal injury and CSF myelin basic protein reflects neuroaxonal demyelination. (C) 2019 Elsevier Inc. All rights reserved.
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