Authors: Jackisch, Rolf | Förster, Stefan | Kammerer, Miriam | Rothmaier, Anna K. | Ehret, Andreas | Zentner, Josef | Feuerstein, Thomas J.
Article Type: Research Article
Abstract: Fresh specimens of human and rat neocortex were used to determine direct and indirect inhibitory potencies of choline esterase inhibitors (ChEIs) on ChE and the release of acetylcholine (ACh), respectively. Km values of ChE in homogenates of rat and human neocortex did not differ significantly, whereas the specific activity of ChE was > times higher in the rat. Butyryl ChE exhibited a higher Km and a lower specific activity than ACh esterase in human neocortex. Inhibition of ChE in rat and human tissue was similar [IC50 (nM; human): donepezil: 14, physostigmine: 22, tacrine: 95, galanthamine: 575, rivastigmine: 9120]. In neocortex …slices preincubated with [3 H]choline, the electrically evoked release of [3 H]ACh was inhibited up to 60% by ChEIs (IC50 (nM, rat): donepezil: 30, physostigmine: 39, tacrine: 302, galanthamine: 646, rivastigmine: >10000). Similar IC50 -values were also estimated for ACh release in human neocortex, although the maximal inhibitory effects were much smaller (∼20%). We conclude that in comparison to rats: 1) neocortical ChE concentrations are lower and 2) that ChEIs have weaker indirect (muscarine receptor-mediated) presynaptic inhibitory effects in the human brain. We further suggest that a combination of ChEIs with brain-selective muscarine autoreceptor antagonists might help to improve their clinical efficacy. Show more
Keywords: Acetylcholine esterase, acetylcholine release, donepezil, galanthamine, physostigmine, rivastigmine, tacrine
DOI: 10.3233/JAD-2009-1008
Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 635-647, 2009
Authors: Alexopoulos, Panagiotis | Guo, Liang-Hao | Jiang, Meizi | Bujo, Hideaki | Grimmer, Timo | Förster, Stefan | Drzezga, Alexander | Kurz, Alexander | Perneczky, Robert
Article Type: Research Article
Abstract: Background: Biomarker relationships in early stages of Alzheimer’s disease (AD) are elusive. Cerebrospinal fluid (CSF) levels of amyloid-β 1-42 (Aβ42 ) and total tau (tTau) as well as 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) contribute to help unravel AD pathology. Furthermore, peptides related to amyloid-β protein precursor (AβPP) processing [e.g., soluble AβPPα and β (sAβPPα and sAβPPβ, respectively); sortilin-related receptor with A-type repeats (SORL1, also called LR11 or SORLA)] are factors crucially implicated in the formation of pathological hallmarks of AD. Objective: To unveil differences in CSF concentrations of Aβ42 , sAβPPα, sAβPPβ, tTau, and SORL1 between patients with mild …cognitive impairment (MCI) who were categorized according to expert interpretation of FDG scans. Methods: PET results were classified as suggesting high likelihood for AD (MCI-AD high), intermediate likelihood for AD (MCI-AD intermediate), or little likelihood for AD (MCI-AD unlikely). An AD dementia group was also included. Differences between the groups were tested by Kruskal- Wallis test, Mann-Whitney test, or χ2 . Provided statistically significant differences were detected, multiple linear regression models were employed. Results: Aβ42 levels in patients with MCI-AD high (n = 15) were lower compared to MCI-AD intermediate (n = 18) and MCI-AD unlikely patients (n = 25) (p = 0.002), while they did not differ from patients with AD dementia (n = 17). The regression model revealed a significant impact of the metabolic pattern on Aβ42 concentrations. SORL1, tTau, sAβPPα, and sAβPPβ concentrations did not differ between the groups. Conclusion: These findings point to linkages between plaque pathology and glucose cerebral hypometabolism. Show more
Keywords: Amyloid-β, mild cognitive impairment, sAβPPα, sAβPPβ, SORL1, total tau
DOI: 10.3233/JAD-122329
Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 401-408, 2013
Authors: Förster, Stefan | Buschert, Verena C. | Teipel, Stefan J. | Friese, Uwe | Buchholz, Hans-Georg | Drzezga, Alexander | Hampel, Harald | Bartenstein, Peter | Buerger, Katharina
Article Type: Research Article
Abstract: The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18 FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N = 24) or mild AD (N = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches …to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD. Show more
Keywords: FDG PET, cognitive intervention, cognitive training, cognitive stimulation, Alzheimer's disease, mild cognitive impairment
DOI: 10.3233/JAD-2011-0025
Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 337-348, 2011
Authors: Förster, Stefan | Buschert, Verena C. | Buchholz, Hans-Georg | Teipel, Stefan J. | Friese, Uwe | Zach, Christian | la Fougere, Christian | Rominger, Axel | Drzezga, Alexander | Hampel, Harald | Bartenstein, Peter | Buerger, Katharina
Article Type: Research Article
Abstract: The effect of cognitive intervention on brain metabolism in Alzheimer's disease (AD) is largely unexplored. Therefore, we aimed to investigate clinical cognitive parameters and 18 FDG PET to test for effects of a cognitive intervention in patients with amnestic mild cognitive impairment (aMCI) or mild AD. Patients with aMCI (n = 24) or mild AD (n = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET …images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions, and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left superior temporal- and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD. Show more
Keywords: Alzheimer's disease, cognitive intervention, cognitive stimulation, cognitive training, FDG PET, mild cognitive impairment
DOI: 10.3233/JAD-2011-100996
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 695-706, 2011
Authors: Förster, Stefan | Vaitl, Andreas | Teipel, Stefan J. | Yakushev, Igor | Mustafa, Mona | la Fougère, Christian | Rominger, Axel | Cumming, Paul | Bartenstein, Peter | Hampel, Harald | Hummel, Thomas | Buerger, Katharina | Hundt, Walter | Steinbach, Silke
Article Type: Research Article
Abstract: We used [18 F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n = 24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the “Sniffin' Sticks” test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state …FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the “Sniffin' Sticks” test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis. Show more
Keywords: Alzheimer's disease, FDG PET, mild cognitive impairment, olfactory system, smell test
DOI: 10.3233/JAD-2010-091549
Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 581-591, 2010