| 1. |
- Andersson, Annika, et al.
(författare)
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Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease
- 2019
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Ingår i: Clinica Chimica Acta. - : Elsevier B.V.. - 0009-8981 .- 1873-3492. ; 494, s. 79-93
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Tidskriftsartikel (refereegranskat)abstract
- Detailed knowledge of protein changes in cerebrospinal fluid (CSF) across healthy and diseased individuals would provide a better understanding of the onset and progression of neurodegenerative disorders. In this study, we selected 20 brain-enriched proteins previously identified in CSF by antibody suspension bead arrays (SBA) to be potentially biomarkers for Alzheimer's disease (AD) and verified these using an orthogonal approach. We examined the same set of 94 CSF samples from patients affected by AD (including preclinical and prodromal), mild cognitive impairment (MCI), non-AD dementia and healthy individuals, which had previously been analyzed by SBA. Twenty-eight parallel reaction monitoring (PRM) assays were developed and 13 of them could be validated for protein quantification. Antibody profiles were verified by PRM. For seven proteins, the antibody profiles were highly correlated with the PRM results (r > 0.7) and GAP43, VCAM1 and PSAP were identified as potential markers of preclinical AD. In conclusion, we demonstrate the usefulness of targeted mass spectrometry as a tool for the orthogonal verification of antibody profiling data, suggesting that these complementary methods can be successfully applied for comprehensive exploration of CSF protein levels in neurodegenerative disorders.
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| 2. |
- Andersson, Christin, et al.
(författare)
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Differential CSF biomarker levels in APOE-epsilon4-positive and -negative patients with memory impairment.
- 2007
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Ingår i: Dementia and geriatric cognitive disorders. - Basel : S. Karger AG. - 1420-8008 .- 1421-9824. ; 23:2, s. 87-95
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the relationships between episodic memory, APOE genotype, CSF markers (total tau, T-tau; phospho-tau, P-tau; beta-amyloid, Abeta42) and longitudinal cognitive decline. METHODS: 124 memory clinic patients were retrospectively divided into 6 groups based on (i) episodic memory function (Rey Auditory Verbal Learning Test, RAVLT): severe, moderate or no impairment (SIM, MIM or NIM), and (ii) APOE genotype (epsilon4+ or epsilon4-). CSF marker levels and cognitive decline were compared across groups. RESULTS: Episodic memory function, according to RAVLT scores, was significantly correlated with CSF marker levels only among epsilon4+ subjects and not among epsilon4- subjects. When comparing the 6 subgroups, SIM epsilon4+ and MIM epsilon4+ groups showed significantly lower Abeta42 levels than the other groups. T-tau and P-tau levels were significantly increased in SIM epsilon4+ when compared to all the other groups, including the SIM epsilon4- group. However, both SIM epsilon4+ and SIM epsilon4- declined cognitively during the follow-up. CONCLUSION: It remains to be determined whether APOE genotype affects the expression of biomarkers in CSF, or whether the different biomarker patterns reflect different types of disease processes in patients with progressive cognitive dysfunction.
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| 3. |
- Cedres, Nira, et al.
(författare)
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Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
- 2022
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 99:15, s. e1619-e1629
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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.
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| 4. |
- Darreh-Shori, Taher, et al.
(författare)
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Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 32:12, s. 2320.e15-2320.e32
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ42peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was “turned on” by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.
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| 5. |
- 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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| 6. |
- Degerman Gunnarsson, Malin, et al.
(författare)
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Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study.
- 2010
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Ingår i: Dementia and geriatric cognitive disorders. - Basel : S. Karger AG. - 1421-9824 .- 1420-8008. ; 29:3, s. 204-12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring beta-amyloid (Abeta) load. Associations between PET PIB and cerebrospinal fluid (CSF) Abeta1-42 and apolipoprotein E epsilon4 (APOE epsilon4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer's disease (AD) are less investigated. METHOD: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD. RESULTS: PIB retention was constant over 1 year, inversely related to low CSF Abeta1-42 (p = 0.01) and correlated positively to the numbers of the APOE epsilon4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = -0.59, p = 0.07), and plasma cystatin C (r = -0.56, p = 0.09). CONCLUSION: PIB retention is strongly related to CSF Abeta1-42, and to the numbers of the APOE epsilon4 allele.
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| 7. |
- Dong, Yi, et al.
(författare)
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Plasma Amyloid-β, Total Tau, and Neurofilament Light Chain Across the Alzheimer's Disease Clinical Spectrum: A Population-Based Study
- 2023
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Ingår i: JOURNAL OF ALZHEIMERS DISEASE. - 1387-2877 .- 1875-8908. ; 96:2, s. 845-858
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Tidskriftsartikel (refereegranskat)abstract
- Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age >= 60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-beta (A beta), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma A beta(40) and NfL increased, whereas A beta(42)/A beta(40) ratio decreased. Plasma t-tau was higher in people withADdementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma A beta, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma A beta and t-tau for defining the clinical spectrum.
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| 8. |
- Eriksdotter-Jönhagen, Maria, et al.
(författare)
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Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease.
- 2012
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 33:1, s. 18-28
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Tidskriftsartikel (refereegranskat)abstract
- Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer's disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability.
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| 9. |
- Kadir, Ahmadul, et al.
(författare)
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Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease.
- 2008
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 63:5, s. 621-31
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function. METHODS: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMRglc (8F-FDG) and amyloid load (11C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging. RESULTS: Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (Abeta40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Abeta40 levels and the ratio Abeta/beta-secretase-cleaved amyloid precursor protein. In CSF, Abeta40 correlated positively with the attention domain of cognition. INTERPRETATION: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.
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| 10. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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