| 1. |
- Almkvist, Ove, et al.
(författare)
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Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes
- 2019
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Ingår i: Neurobiology of Aging. - : ELSEVIER SCIENCE INC. - 0197-4580 .- 1558-1497. ; 82, s. 40-47
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Tidskriftsartikel (refereegranskat)abstract
- The purpose was to compare longitudinal cognitive changes in APP and PSEN1 gene mutation carriers and noncarriers from four autosomal-dominant Alzheimer's disease (ADAD) families across preclinical and early clinical stages of disease. Carriers (n = 34) with four different mutations (PSEN1(M146V), PSEN1(H163Y), APP(SWE), and APP(ARC)) and noncarriers (n = 41) were followed up longitudinally with repeated cognitive assessments starting many years before the expected clinical onset. The relationship between cognition and years to expected clinical onset, education, age, and type of mutation was analyzed using mixed-effects models. Results showed an education-dependent and time-related cognitive decline with linear and quadratic predictors in mutation carriers. Cognitive decline began close to the expected clinical onset and was relatively rapid afterward in PSEN1 mutation carriers, whereas decline was slower and started earlier than 10 years before expected clinical onset in APP mutation carriers. In noncarriers, the decline was minimal across time in accordance with normal aging. These results suggest that phenotypes for onset and rate of cognitive decline vary with PSEN1 and APP genes, suggesting a behavioral heterogeneity in ADAD. (C) 2019 Elsevier Inc. All rights reserved.
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| 2. |
- Andersson, Christin, et al.
(författare)
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Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
- 2008
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:10, s. 1466-1473
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression. OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline. METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up. CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.
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| 3. |
- 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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| 4. |
- Darreh-Shori, Taher, et al.
(författare)
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Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
- 2013
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:11, s. 2465-2481
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Tidskriftsartikel (refereegranskat)abstract
- Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.
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| 5. |
- Forsberg, Anton, et al.
(författare)
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PET imaging of amyloid deposition in patients with mild cognitive impairment
- 2008
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:10, s. 1456-1465
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Tidskriftsartikel (refereegranskat)abstract
- It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with 11C-PIB, and 18F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps < 0.01). The PIB retention in MCI converters was comparable to AD patients (p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ1-42, total Tau and episodic memory, respectively.
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| 6. |
- Kadir, Ahmadul, et al.
(författare)
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Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 33:1, s. 198.e1-198.e14
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Tidskriftsartikel (refereegranskat)abstract
- In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer’s disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [11C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole (11C-PIB) and 18F-fluorodeoxyglucose (18F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.
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| 7. |
- Kadir, Ahmadul, et al.
(författare)
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PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD
- 2008
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:8, s. 1204-1217
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Tidskriftsartikel (refereegranskat)abstract
- The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients’ cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16–24 mg/day) and 6 patients the placebo, and this was followed by 9 months’ galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity (11C-PMP) and 11C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30–40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical 11C-nicotine binding was observed during the study. 11C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and 11C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and 11C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.
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| 8. |
- Schöll, Michael, et al.
(författare)
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Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 32:8, s. 1388-1399
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Tidskriftsartikel (refereegranskat)abstract
- Six young related pre-symptomatic carriers of a His 163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucos metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.
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