| 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. |
- Almkvist, Ove, et al.
(författare)
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Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease
- 2017
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Ingår i: Journal of the International Neuropsychological Society. - : CAMBRIDGE UNIV PRESS. - 1355-6177 .- 1469-7661. ; 23:3, s. 195-203
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. Methods: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. Results: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. Conclusions: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers.
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| 3. |
- Li, Xiaozhen, et al.
(författare)
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The Effects of Gene Mutations onDefaultMode Network inFamilialAlzheimer's Disease.
- 2017
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 56:1, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- Familial Alzheimer's disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel's time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.
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| 4. |
- Li, Xiaozhen, et al.
(författare)
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The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer’s Disease
- 2017
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 56:1, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.
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| 5. |
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| 6. |
- Rodriguez-Vieitez, Elena, et al.
(författare)
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Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease
- 2016
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 139:3, s. 922-936
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Tidskriftsartikel (refereegranskat)abstract
- The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.See Schott and Fox (doi: 10.1093/brain/awv405) for a scientific commentary on this article. The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-beta, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer C-11-deuterium-L-deprenyl), fibrillar amyloid-beta plaque deposition (C-11-Pittsburgh compound B), and glucose metabolism (F-18-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 +/- 10.3 years old) and non-carriers (n = 16; 51.1 +/- 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 +/- 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 +/- 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into C-11-Pittsburgh compound B-positive (n = 13; 62.0 +/- 6.4; seven male) and C-11-Pittsburgh compound B-negative (n = 4; 61.8 +/- 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 +/- 0.6 years. By using linear mixed-effects models, fibrillar amyloid-beta plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-beta plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-beta plaque deposition. Patients with sporadic mild cognitive impairment who were C-11-Pittsburgh compound B-positive at baseline showed increasing amyloid-beta plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-beta plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.
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| 7. |
- Scholl, Michael, et al.
(författare)
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Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers
- 2012
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 79:3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD). Methods: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with C-11-labeled Pittsburgh compound B (PiB) and F-18-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs). Results: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of A beta(1-42), total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs. Conclusions: The lack of fibrillar beta-amyloid (A beta) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of A beta(1-42) in CSF, that other forms of A beta such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease. Neurology(R) 2012;79:229-236
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| 8. |
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| 9. |
- Thordardottir, Steinunn
(författare)
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Biomarkers in preclinical familial Alzheimer disease
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Alzheimer disease (AD) is a neurodegenerative disorder, characterized by the accumulation of b-amyloid (Ab) plaques and tangles consisting of hyperphosphorylated tauprotein in the brain. It accounts for 60-70% of dementia cases, making it the most common cause of dementia. In rare cases the disease is inherited in autosomal dominant early onset form caused by mutations in APP, PSEN1 or PSEN2. These familial forms of AD (FAD) allow for studies of the long preclinical stage of the disease and may thereby address unanswered questions about the natural history of AD which can be used to develop optimal tools for early diagnosis and for monitoring treatment response, as well as finding new possible treatment targets. To this end we conducted a prospective study, involving repeated clinical evaluations and collection of biomarkers from asymptomatic carriers of mutations leading to FAD with non-carriers (NC) from the same families as controls. The asymptomatic mutation carriers (MC) are good representatives of the preclinical stage of AD as they will develop symptoms of the disease in the future at an age which can be estimated based on the age at symptom onset in their family members who have already become symptomatic. Aims: To map biomarker changes in preclinical AD, as well as their temporal trajectories and sequence, through repeated collection and analysis of biomarkers in asymptomatic FAD MC and NC. Results: There were significant differences in the levels of the cerebrospinal fluid (CSF) biomarkers Ab42, total-tau protein (t-tau) and phosphorylated tau-protein (p-tau), as well as in the Ab42/p-tau ratio when comparing MC to NC, more than 7 years before the expected onset of symptoms in the MC. Ab42 and the Ab42/p-tau ratio were lower in MC than NC, while ttau and p-tau were higher in MC than NC. There was a trend of Ab42 and the Ab42/p-tau ratio decreasing as the onset of symptoms approached in MC, while t-tau and p-tau showed a trend of increasing with approaching symptom onset. On structural magnetic resonance imaging (MRI) of the brain, the MC had reduced volume of the left precuneus, left superior temporal gyrus and left fusiform gyrus, 9 years before the expected symptom onset. However, there was no observable decline in grey matter thickness or volume as the onset of symptoms approached, making the temporality of these changes difficult to assess. In the same group of subjects there was no significant difference on neuropsychological assessments between MC and NC, but a trend of poorer results was observed in the MC regarding immediate memory, episodic memory and attention/executive function. The CSF biomarkers YKL-40, reflecting glial activation, and neurogranin, a synaptic marker, were compared between asymptomatic MC and NC and found not to differ between the groups. A longitudinal study of changes in YKL-40 and neurogranin with approaching symptom onset was also conducted, revealing an increase in YKL-40 in both MC and NC as the age of symptom onset drew nearer, with a steeper increase in MC than NC. No such correlation to years to symptom onset was found for neurogranin. The APP processing products sAPPa, sAPPb, Ab42, Ab40 and Ab38 were compared both between the MC group as a whole and the NC and between subgroups of MC carrying specific mutations and the NC. The whole MC group had lower levels of Ab42, Ab40 and Ab38, as well as a lower Ab42/Ab40 ratio than NC. No significant correlation was observed between any of the aforementioned APP processing products and years to symptom onset in MC. When comparing different MC subgroups to each other, the whole MC group and the NC group, some mutation specific differences in the levels of the APP processing products and their temporality emerged. During the biomarker studies presented above the presence of a statistical outlier came to our attention, an MC carrying the PSEN1 H163Y mutation who had passed the age at symptom onset in his family but displayed no cognitive decline and no abnormalities in CSF biomarkers. This individual had been followed-up within the FAD study for 22 years and had opted for a presymptomatic genetic test, making his mutation status known to him and to the researchers involved in the study. His clinical case was characterized in paper III, with his brother serving as a control. The brother was only one year older than the outlier but had already passed away from AD at the end of the follow-up time, having displayed typical signs and symptoms of the disease in the preceding years. Conclusions: The study revealed early preclinical changes in CSF biomarkers, reflecting Ab aggregation, glial activation, tau phosphorylation and neurodegeneration, as well as loss of volume in specific areas in the left hemisphere of the brain on structural MRI in asymptomatic carriers of FAD mutations. When assessing the temporality of specific biomarkers in the CSF, Ab42 and the Ab42/p-tau ratio seemed to decrease with approaching symptom onset, while ttau and p-tau increased as symptom onset drew nearer. These results are based on crosssectional data, but only longitudinal studies can properly assess temporal changes, as we did for CSF neurogranin and YKL-40 (with YKL-40 increasing at a faster rate in MC than in NC). However, the overall results give an important indication of the true nature of these preclinical temporal changes. We also observed mutation specific differences in APP processing products in the CSF and characterized a case of reduced penetrance of the PSEN1 H163Y mutation. In conclusion, the study sheds light on preclinical biomarker changes in FAD and the possible sequence of these changes. It also emphasizes the differences in phenotype between specific FAD mutations and the presence of reduced penetrance which affects the estimation of symptom onset in these families and has an impact on genetic counseling and possibly on the design of clinical trials in this population.
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| 10. |
- Thordardottir, Steinunn, et al.
(författare)
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Preclinical Cerebrospinal Fluid and Volumetric Magnetic Resonance Imaging Biomarkers in Swedish Familial Alzheimer's Disease.
- 2015
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 43:4, s. 1393-1402
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. Objective: To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers (NC) and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for Aβ42, total tau (T-tau) and phospho-tau (P-tau). Results: The MC had significantly lower levels of CSF Aβ42 and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in Aβ42 15-20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms.
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