| 1. |
- Wightman, D. P., et al.
(författare)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Tidskriftsartikel (refereegranskat)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 2. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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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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| 3. |
- Vergallo, A., et al.
(författare)
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Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 96, s. 22-32
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis. © 2020 Elsevier Inc.
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| 4. |
- Chatterjee, P., et al.
(författare)
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Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-beta Load
- 2020
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 76:1, s. 291-301
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Tidskriftsartikel (refereegranskat)abstract
- Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-beta load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n = 65) and >= 1.35 (n = 35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE epsilon 4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma A beta(42/40) ratio (AUC = 0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.
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| 5. |
- Brockmann, K., et al.
(författare)
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Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies
- 2021
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (alpha-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded alpha-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to alpha-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC alpha-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive alpha-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive alpha-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between alpha-Syn seeding activity and reduced CSF levels of proteins linked to alpha-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of alpha-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting alpha-Syn.
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| 6. |
- Hossain, I., et al.
(författare)
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Admission Levels of Total Tau and β-Amyloid Isoforms 1–40 and 1–42 in Predicting the Outcome of Mild Traumatic Brain Injury
- 2020
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of this study was to investigate if admission levels of total tau (T-tau) and β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42) could predict clinical outcome in patients with mild traumatic brain injury (mTBI). Methods: A total of 105 patients with mTBI [Glasgow Coma Scale (GCS) ≥ 13] recruited in Turku University Hospital, Turku, Finland were included in this study. Blood samples were drawn within 24 h of admission for analysis of plasma T-tau, Aβ40, and Aβ42. Patients were divided into computed tomography (CT)-positive and CT-negative groups. The outcome was assessed 6–12 months after the injury using the Extended Glasgow Outcome Scale (GOSE). Outcomes were defined as complete (GOSE 8) or incomplete (GOSE < 8) recovery. The Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) was also used to assess mTBI-related symptoms. Predictive values of the biomarkers were analyzed independently, in panels and together with clinical parameters. Results: The admission levels of plasma T-tau, Aβ40, and Aβ42 were not significantly different between patients with complete and incomplete recovery. The levels of T-tau, Aβ40, and Aβ42 could poorly predict complete recovery, with areas under the receiver operating characteristic curve 0.56, 0.52, and 0.54, respectively. For the whole cohort, there was a significant negative correlation between the levels of T-tau and ordinal GOSE score (Spearman ρ = −0.231, p = 0.018). In a multivariate logistic regression model including age, GCS, duration of posttraumatic amnesia, Injury Severity Score (ISS), time from injury to sampling, and CT findings, none of the biomarkers could predict complete recovery independently or together with the other two biomarkers. Plasma levels of T-tau, Aβ40, and Aβ42 did not significantly differ between the outcome groups either within the CT-positive or CT-negative subgroups. Levels of Aβ40 and Aβ42 did not significantly correlate with outcome, but in the CT-positive subgroup, the levels of T-tau significantly correlated with ordinal GOSE score (Spearman ρ = −0.288, p = 0.035). The levels of T-tau, Aβ40, and Aβ42 were not correlated with the RPCSQ scores. Conclusions: The early levels of T-tau are correlated with the outcome in patients with mTBI, but none of the biomarkers either alone or in any combinations could predict complete recovery in patients with mTBI. © Copyright © 2020 Hossain, Mohammadian, Takala, Tenovuo, Azurmendi Gil, Frantzén, van Gils, Hutchinson, Katila, Maanpää, Menon, Newcombe, Tallus, Hrusovsky, Wilson, Gill, Blennow, Sanchez, Zetterberg and Posti.
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| 7. |
- Lerche, S., et al.
(författare)
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CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB
- 2021
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:11, s. 2595-2604
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Tidskriftsartikel (refereegranskat)abstract
- Background Molecular pathways associated with alpha-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. Objective The objective of this study was to evaluate CSF protein profiles of pathways related to alpha-synuclein proteostasis. Methods We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with alpha-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated alpha-synuclein pathology with pronounced clinical trajectories. Results (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total alpha-synuclein, with lower levels of proteostasis proteins related to lower levels of total alpha-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of alpha-synuclein longitudinally compared with PD patients with a normal proteostasis profile. Conclusion CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to alpha-synuclein proteostasis in PD and DLB. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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| 8. |
- Michno, Wojciech, 1992, et al.
(författare)
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Following spatial Aβ aggregation dynamics in evolving Alzheimer's disease pathology by imaging stable isotope labeling kinetics
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:25
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Tidskriftsartikel (refereegranskat)abstract
- β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer's disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible. Copyright © 2021 The Authors, some rights reserved.
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| 9. |
- Onatsu, J., et al.
(författare)
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Tau, S100B and NSE as Blood Biomarkers in Acute Cerebrovascular Events
- 2020
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Ingår i: In Vivo. - : Anticancer Research USA Inc.. - 0258-851X .- 1791-7549. ; 34:5, s. 2577-2586
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: We aimed to analyze the diagnostic value of total tau (T- tau), S-100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) as blood-based biomarkers in acute ischemic stroke (AIS) or transient ischemic attack (TIA), and their correlation with symptom severity, infarct size, etiology and outcome. Patients and Methods: A total of 102 patients with stroke and 35 with TIA were analyzed. Subacute (63.8 +/- 50.1 h) plasma T-tau was measured with the single-molecule array (Simoa) method and NSE and S100B were evaluated for comparison. We evaluated biomarkers associations with: (i) diagnosis of AIS or TIA, (ii) cerebral infarction volume in the brain computed tomography, (iii) stroke etiology, (iv) clinical stroke severity and (iv) functional outcome after three months. Results: T-tau was higher in patients with stroke (1.0 pg/ml (IQR=0.3-2 2)] than with TIA (05 pg/ml (IQR=0.2- 1 .0), p=0.02] . The levels of S100B were also increased in stroke [0.082 mu g/l (IQR=0.049-0.157)] patients compared to TIA patients (0.045 mu g/l (IQR=0.03 -0.073 ), p<0.001]. However, when the results were adjusted for confounders, significance was lost. Serum levels of NSE among patients with AIS [11.85 mu g/l (IQR=9.30-16.14)] compared to those with TIA (10.96 mu g/l (IQR=7 .98-15.33), p=0.301 were equal. T-tau and S100B concentrations significantly correlated with cerebral infarction volume (r=0.412, p<0.001) and (r=0.597, p<0.001), also after corrections (p<0.001). mRS scores at three-month follow-up correlated with T-tau (r=0.248, p=0.016) and S100B concentrations (r=0.205, p=0.045). Conclusion: For the diagnosis of TIA vs. AIS, blood T-tau and S100B concentrations discriminated only modestly. Additionally, groups were not separable after measuring of T-tau and S100B levels in the blood. T-tau and S100B concentrations correlated with the infarct size, but were not alone predictive for functional outcome at 3 months.
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| 10. |
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