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- Biechele, Gloria, et al.
(author)
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Associations between sex, body mass index and the individual microglial response in Alzheimer's disease
- 2024
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In: JOURNAL OF NEUROINFLAMMATION. - 1742-2094. ; 21:1
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Journal article (peer-reviewed)abstract
- Background and objectives18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between beta-amyloid-accumulation and microglial activation in AD.Methods49 patients with AD (29 females, all A beta-positive) and 15 A beta-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and beta-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional A beta-PET on TSPO-PET was used to determine the A beta-plaque-dependent microglial response (slope) and the A beta-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI).ResultsIn AD, females showed higher mean cortical TSPO-PET z-scores (0.91 +/- 0.49; males 0.30 +/- 0.75; p = 0.002), while A beta-PET z-scores were similar. The A beta-plaque-independent microglial response was stronger in females with AD (+ 0.37 +/- 0.38; males with AD - 0.33 +/- 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the A beta-plaque-dependent microglial response was not different between sexes. The A beta-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the A beta-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005).ConclusionWhile microglia response to fibrillar A beta is similar between sexes, women with AD show a stronger A beta-plaque-independent microglia response. This sex difference in A beta-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the A beta-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.
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| 3. |
- Finze, Anika, et al.
(author)
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Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies
- 2023
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In: MOLECULAR PSYCHIATRY. - 1359-4184 .- 1476-5578. ; 28:10, s. 4438-4450
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Journal article (peer-reviewed)abstract
- & beta;-amyloid (A & beta;) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, A & beta;-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of A & beta; (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional A & beta; (AD: & beta;(T) = 0.412 & PLUSMN; 0.196 vs. & beta;(A) = 0.142 & PLUSMN; 0.123, p < 0.001; AD-CBS: & beta;(T) = 0.385 & PLUSMN; 0.176 vs. & beta;(A) = 0.131 & PLUSMN; 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (& beta;(T) = 0.418 & PLUSMN; 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and A & beta; related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.
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| 4. |
- Huber, Maria, et al.
(author)
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Metabolic correlates of dopaminergic loss in dementia with lewy bodies
- 2020
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In: Movement Disorders. - : WILEY. - 0885-3185 .- 1531-8257. ; 35, s. 595-605
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Journal article (peer-reviewed)abstract
- Background Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by I-123-Ioflupane brain single-photon emission computed tomography of dopamine transporter and F-18-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood. Objective We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. Methods We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls. Results There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. Conclusions Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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| 5. |
- Rominger, Axel, et al.
(author)
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Validation of the Octamouse for Simultaneous 18F-Fallypride Small-Animal PET Recordings from 8 Mice
- 2010
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:10, s. 1576-1583
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Journal article (peer-reviewed)abstract
- Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D-2/3 ligand F-18-fallypride serving as a test substance for brain receptor imaging. Methods: The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the F-18-fallypride binding potential (BPND) in the striatum were tested in groups of mice receiving F-18-fallypride at 2 different specific activities (140 and 50 GBq/mu mol), with and without scatter correction. Finally, the relationship between BPND and injected dose of F-18-fallypride (3.5-17 MBq/mouse) was tested. Results: Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of F-18-fallypride BPND in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BPND by a mean of 6%; covariances of the inter-and intraoperator variability of BPND were 10%. There was a positive correlation between radiochemical dose and BPND with (R-2 = 0.53) and without (R-2 = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum. Conclusion: The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of F-18-fallypride BPND was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BPND on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify F-18-fallypride BPND in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of diverse radioligands.
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| 6. |
- Stockbauer, Anna, et al.
(author)
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Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission
- 2024
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 51:4, s. 1023-1034
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Journal article (peer-reviewed)abstract
- Purpose Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA).Methods FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level.Results Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912).Conclusion Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.
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