| 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. |
- Benedict, Christian, et al.
(författare)
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Association between physical activity and brain health in older adults
- 2013
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:1, s. 83-90
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Tidskriftsartikel (refereegranskat)abstract
- In the present cross-sectional study, we examined physical activity (PA) and its possible association with cognitive skills and brain structure in 331 cognitively healthy elderly. Based on the number of self-reported light and hard activities for at least 30 minutes per week, participants were assigned to 4 groups representing different levels of PA. The cognitive skills were assessed by the Mini Mental State Examination score, a verbal fluency task, and the Trail-making test as a measure of visuospatial orientation ability. Participants also underwent a magnetic resonance imaging of the brain. Multiple regression analysis revealed that greater PA was associated with a shorter time to complete the Trail-making test, and higher levels of verbal fluency. Further, the level of self-reported PA was positively correlated with brain volume, white matter, as well as a parietal lobe gray matter volume, situated bilaterally at the precuneus. These present cross-sectional results indicate that PA is a lifestyle factor that is linked to brain structure and function in late life.
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| 4. |
- Benedict, Christian, et al.
(författare)
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The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 32:6, s. 1159.e1-1159.e5
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Tidskriftsartikel (refereegranskat)abstract
- Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.
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| 5. |
- Beyer, Anja-Silke, et al.
(författare)
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Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-beta precursor protein
- 2010
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 33:4, s. 732-743
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies identified engulfment adapter phosphotyrosine binding (PTB) domain containing 1 (GULP1) as an NPXY-motif interactor of low-density lipoprotein receptor-related protein 1 (LRP1) and suggested a potential relevance in Alzheimer's disease (AD). Since AD associated proteins amyloid-beta A4 precursor protein (APP) and LRP1 were shown to interact with the PTB domain of Fe65 and several other adapters via their intracellular NPXY-motifs, we examined a possible interaction of GULP1 PTB domain with the YENPTY-motif of APP. Here we demonstrate that GULP1 is present in human hippocampal and neocortical neurons. Confocal live cell imaging revealed that coexpressed and endogenous GULP1 colocalizes with APP in the Golgi and endoplasmic reticulum. Analysis of the interacting domains by co-immunoprecipitation of point and deletion mutants revealed that the interaction depends on the PTB domain of GULP1 and the YENPTY-motif of APP. Coexpression of GULP1 affected APP cell surface localization and suppressed generation of Abeta40/42 and sAPPalpha. Taken together, these data identify GULP1 as a novel neuronal APP interacting protein that alters trafficking and processing of APP.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Darreh-Shori, T., et al.
(författare)
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Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine
- 2008
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 29:2, s. 168-184
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months Galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by C-11-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.
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| 9. |
- 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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| 10. |
- Giannakopoulos, Panteleimon, et al.
(författare)
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Less agreeable, better preserved? : A PET amyloid and MRI study in a community-based cohort
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 89, s. 24-31
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between personality profiles and brain integrity in old age is still a matter of debate. We examined the association between Big Five factor and facet scores and MRI brain volume changes on a 54-month follow-up in 65 elderly controls with 3 neurocognitive assessments (baseline, 18 months, and 54 months), structural brain MRI (baseline and 54 months), brain amyloid PET during follow-up, and APOE genotyping. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of volume loss including time, age, sex, personality, amyloid load, presence of APOE epsilon 4 allele, and cognitive evolution. Lower agreeableness factor scores (and 4 of its facets) were associated with lower volume loss in the hippocampus, entorhinal cortex, amygdala, mesial temporal lobe, and precuneus bilaterally. Higher openness factor scores (and 2 of its facets) were also associated with lower volume loss in the left hippocampus. Our findings persisted when adjusting for confounders in multivariable models. These data suggest that the combination of low agreeableness and high openness is an independent predictor of better preservation of brain volume in areas vulnerable to neurodegeneration. (C) 2020 Elsevier Inc. All rights reserved.
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