| 1. |
- Chiotis, Konstantinos, et al.
(författare)
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Dual tracer tau PET imaging reveals different molecular targets for C-11-THK5351 and C-11-PBB3 in the Alzheimer brain
- 2018
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 45:9, s. 1605-1617
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Tidskriftsartikel (refereegranskat)abstract
- Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (C-11-THK5351 and C-11-PBB3) in a head-to-head, in vivo, multimodal design. Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers C-11-THK5351 and C-11-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer C-11-AZD2184, a T1-MRI sequence, and neuropsychological assessment. The load and regional distribution of binding differed between C-11-THK5351 and C-11-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of C-11-PBB3, but not that of C-11-THK5351, in the temporal lobe resembled that of C-11-AZD2184, with strong correlations detected between C-11-PBB3 and C-11-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with C-11-THK5351 than with C-11-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with C-11-THK5351 than with C-11-PBB3 binding. This research suggests different molecular targets for these tracers; while C-11-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of C-11-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- Thordardottir, Steinunn, et al.
(författare)
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Reduced penetrance of the PSEN1 H163Y autosomal dominant Alzheimer mutation : A 22-year follow-up study
- 2018
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years. Methods: Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [F-18] fluorodeoxyglucose positron emission tomography, and [C-11] Pittsburgh compound B positron emission tomography. Results: Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer's disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer's disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer's disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer's disease pathology was detected, either on imaging examinations or in cerebrospinal fluid. Conclusions: The average (SD) age of symptom onset for PSEN1 H163Y is 51 +/- 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.
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| 6. |
- Vilaplana, Eduard, et al.
(författare)
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Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease
- 2020
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Ingår i: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 94:19, s. e2026-E2036
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with C-11-deuterium-L-deprenyl (C-11-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD).Methods: The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 10.6 years old; n = 3 symptomatic, 55.5 2.0 years old) and noncarriers (n = 18, 44.0 +/- 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent C-11-DED-PET.Results: Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between C-11-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher C-11-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, C-11-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.Conclusions: Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
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