| 1. |
- Daniilidou, Makrina, et al.
(författare)
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Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities.
- 2023
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Ingår i: Brain communications. - 2632-1297. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.
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| 2. |
- Mravinacová, Sára, et al.
(författare)
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CSF protein ratios with enhanced potential to reflect Alzheimer’s disease pathology and neurodegeneration
- 2024
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Ingår i: Molecular Neurodegeneration. - : Springer Nature. - 1750-1326. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer’s disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates. Method: We used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from the Swedish GEDOC memory clinic cohort at the Karolinska University Hospital. The cohort comprised 148 amyloid- and tau-negative individuals (A-T-) and 65 amyloid- and tau-positive individuals (A+T+). An independent sample set of 26 A-T- and 26 A+T+ individuals from the Amsterdam Dementia Cohort was used for validation. The measured proteins were clustered based on their correlation to CSF amyloid beta peptides, tau and NfL levels. Further, we used support vector machine modelling to identify protein pairs, matched based on their cluster origin, that reflect AD pathology and cognitive decline with improved performance compared to single proteins. Results: The protein-clustering revealed 11 proteins strongly correlated to t-tau and p-tau (tau-associated group), including mainly synaptic proteins previously found elevated in AD such as NRGN, GAP43 and SNCB. Another 16 proteins showed predominant correlation with Aβ42 (amyloid-associated group), including PTPRN2, NCAN and CHL1. Support vector machine modelling revealed that proteins from the two groups combined in pairs discriminated A-T- from A+T+ individuals with higher accuracy compared to single proteins, as well as compared to protein pairs composed of proteins originating from the same group. Moreover, combining the proteins from different groups in ratios (tau-associated protein/amyloid-associated protein) significantly increased their correlation to cognitive decline measured with cognitive scores. The results were validated in an independent cohort. Conclusions: Combining brain-derived proteins in pairs largely enhanced their capacity to discriminate between AD pathology-affected and unaffected individuals and increased their correlation to cognitive decline, potentially due to adjustment of inter-individual variability. With these results, we highlight the potential of protein pairs to monitor neurodegeneration and thereby possibly the efficacy of AD disease-modifying therapies.
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| 3. |
- Holleman, Jasper, et al.
(författare)
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Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients
- 2024
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 118, s. 499-509
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuroinflammation is a hallmark of the Alzheimer's disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates.METHOD: 134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales.RESULT: Higher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales.CONCLUSION: This study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.
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| 4. |
- Latorre-Leal, María, et al.
(författare)
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CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice
- 2024
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Ingår i: Science advances. - 2375-2548. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.
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| 5. |
- Norgren, Jakob, et al.
(författare)
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APOE-Genotype and Insulin Modulate Estimated Effect of Dietary Macronutrients on Cognitive Performance : Panel Analyses in Nondiabetic Older Adults at Risk of Dementia
- 2023
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Ingår i: Journal of Nutrition. - : Elsevier. - 0022-3166 .- 1541-6100. ; 153:12, s. 3506-3520
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Tidskriftsartikel (refereegranskat)abstract
- Background: The apolipoprotein E gene (APOE e-2/3/4, combined as 6 different genotypes: e-22/23/24/33/34/44) and insulin status modulate dementia risk and play a role in the metabolism of macronutrients.Objectives: We aimed to examine APOE-genotype and fasting insulin as effect modifiers of the slopes between dietary macronutrients and cognitive performance among older adults at risk of dementia. Methods: Panel analyses-with diet and cognition measured at baseline and follow-up at years 1 and 2-were performed in a sub-sample from the FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial (n = 676, 60-77 y, 46% fe -males, all nondiabetics). The associations between macronutrients (3-d food records, z-scores) and global cognition (modified Neuropsy-chological Test Battery, z-score) were analyzed in mixed regression models adjusted for confounders selected a priori. After a gradient was implied by the point estimates in categorical APOE analyses, we investigated a continuous APOE variable [APOE-gradient, coded-1 (for e-23), -0.5 (e-24), 0 (e-33), 1 (e-34), 2 (e-44)] as an effect-modifier.Results: At increasing levels of the APOE-gradient, a relatively more favorable slope between diet and cognition was observed for a lower carbohydrate/fat ratio [p = -0.040, 95% confidence interval (CI): -0.074, -0.006; P = 0.020 for interaction diet x APOE-gradient), and higher protein (p = 0.075, 95% CI: 0.042, 0.109; P = 9.4 x 10-6). Insulin concentration (log-linear) modulated the association between the car-bohydrate/fat ratio and cognition by a quadratic interaction (p = -0.016, P = 0.039). Coherent findings for exploratory predictors (fiber, fat subtypes, composite score, metabolic biomarkers) were compatible with published hypotheses of differential dietary adaptation by APOE, with cognition among e-33 being relatively independent of dietary parameters-implying metabolic flexibility. Antagonistic slopes to cognition for e-23 (positive) compared with e-34 and e-44 (negative) were found for a Higher-carbohydrates-fiber-Lower-fat-protein composite score, even as within-subjects effects. Conclusions: APOE-based precision nutrition appears conceptually promising, but replications in wider samples are warranted, as well as support from trials. Both relative hyper-and hypoinsulinemia might modulate the effect of diet on cognition.
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| 6. |
- Norgren, Jakob, et al.
(författare)
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Capillary blood tests may overestimate ketosis : triangulation between three different measures of beta-hydroxybutyrate
- 2020
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:2, s. e184-E188
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Tidskriftsartikel (refereegranskat)abstract
- The ketone body beta-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.
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| 7. |
- Norgren, Jakob, et al.
(författare)
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Ketosis After Intake of Coconut Oil and Caprylic Acid-With and Without Glucose : A Cross-Over Study in Healthy Older Adults
- 2020
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Ingår i: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Medium-chain-triglycerides (MCT), formed by fatty acids with a length of 6-12 carbon atoms (C6-C12), constitute about two thirds of coconut oil (Coc). MCT have specific metabolic properties which has led them to be described as ketogenic even in the absence of carbohydrate restriction. This effect has mainly been demonstrated for caprylic acid (C8), which constitutes about 6-8% of coconut oil. Our aim was to quantify ketosis and blood glucose after intake of Coc and C8, with and without glucose intake. Sunflower oil (Suf) was used as control, expected to not break fasting ketosis, nor induce supply-driven ketosis. Method: In a 6-arm cross-over design, 15 healthy volunteers-age 65-73, 53% women-were tested once a week. After a 12-h fast, ketones were measured during 4 h after intake of coffee with cream, in combination with each of the intervention arms in a randomized order: 1. Suf (30 g); 2. C8 (20 g) + Suf (10 g); 3. C8 (20 g) + Suf (10 g) + Glucose (50 g); 4. Coc (30 g); 5. Coc (30 g) + Glucose (50 g); 6. C8 (20 g) + Coc (30 g). The primary outcome was absolute blood levels of the ketone beta-hydroxybutyrate, area under the curve (AUC). ANOVA for repeated measures was performed to compare arms. Results: beta-hydroxybutyrate, AUC/time (mean +/- SD), for arms were 1: 0.18 +/- 0.11; 2: 0.45 +/- 0.19; 3: 0.28 +/- 0.12; 4: 0.22 +/- 0.12; 5: 0.08 +/- 0.04; 6: 0.45 +/- 0.20 (mmol/L). Differences were significant (all p <= 0.02), except for arm 2 vs. 6, and 4 vs. 1 & 3. Blood glucose was stable in arm 1, 2, 4, & 6, at levels slightly below baseline (p <= 0.05) at all timepoints hours 1-4 after intake. Conclusions: C8 had a higher ketogenic effect than the other components. Coc was not significantly different from Suf, or C8 with glucose. In addition, we report that a 16-h non-carbohydrate window contributed to a mild ketosis, while blood glucose remained stable. Our results suggest that time-restricted feeding regarding carbohydrates may optimize ketosis from intake of MCT.
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| 8. |
- Norgren, Jakob, et al.
(författare)
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Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF : Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC).Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65–75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0–2 h to changes in BDNF at 0–4 h). ICC estimates were calculated from baseline levels from the three study days.Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07–0.44; p = 0.007). Individual change in BHB 0–2 h, predicted change in proBDNF 0–4 h, (β = 0.40, CI 0.12–0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0–2 h (β = −0.88, CI −1.37 to −0.40; p < 0.001) and cumulatively 0–4 h (β = −1.01, CI −1.75 to −0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92–0.99) for proBDNF, and 0.72 (CI 0.47–0.89) for mBDNF.Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health.Clinical Trial Registration: ClinicalTrials.gov, NCT03904433.
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| 9. |
- Parrado-Fernández, Cristina, et al.
(författare)
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Reduction of PINK1 or DJ-1 impair mitochondrial motility in neurites and alter ER-mitochondria contacts
- 2018
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : Wiley. - 1582-1838 .- 1582-4934. ; 22:11, s. 5439-5449
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Tidskriftsartikel (refereegranskat)abstract
- Subcellular distribution of mitochondria in neurons is crucial for meeting the energetic demands, as well as the necessity to buffer Ca2+ within the axon, dendrites and synapses. Mitochondrial impairment is an important feature of Parkinson disease (PD), in which both familial parkinsonism genes DJ-1 and PINK1 have a great impact on mitochondrial function. We used differentiated human dopaminergic neuroblastoma cell lines with stable PINK1 or DJ-1 knockdown to study live motility of mitochondria in neurites. The frequency of anterograde and retrograde mitochondrial motility was decreased in PINK1 knockdown cells and the frequency of total mitochondrial motility events was reduced in both cell lines. However, neither the distribution nor the size of mitochondria in the neurites differed from the control cells even after downregulation of the mitochondrial fission protein, Drp1. Furthermore, mitochondria from PINK1 knockdown cells, in which motility was most impaired, had increased levels of GSK3 beta Ser9 and higher release of mitochondrial Ca2+ when exposed to CCCP-induced mitochondrial uncoupling. Further analysis of the ER-mitochondria contacts involved in Ca2+ shuttling showed that PINK1 knockdown cells had reduced contacts between the two organelles. Our results give new insight on how PINK1 and DJ-1 influence mitochondria, thus providing clues to novel PD therapies.
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