Authors: Drzezga, Alexander
Article Type: Research Article
Abstract: With longer life expectancy, dementia based on the age-related Alzheimers' disease (AD) has turned into one of the most prevalent disorders of older age, representing a serious medical and socio-economic issue. There has been growing interest in early diagnosis of this disease, particularly regarding the initiation of new treatment strategies ahead of the onset of irreversible neuronal damage. It is accepted that the pathologic changes underlying AD appear in the brain years to decades before the symptomatic stages. Consequently, clinical measures of cognitive impairment, as used for definition of dementia, will not allow early diagnosis of AD-pathology in the mild …or asymptomatic stages. Thus, a need for complementary sensitive biomarkers is apparent. Brain imaging markers are among the most promising candidates for this diagnostic challenge. Particularly, [18F]FDG PET as a marker of regional neuronal function has been demonstrated to represent a most sensitive and specific method for early identification of AD-pathology and thus for prediction of dementia of the Alzheimer type (DAT), even in the mild and asymptomatic stages. Currently, systematic data of comparable quality are hardly available for any other imaging procedure. The purpose of this article is to describe the typical findings of [18F]FDG PET in different stages of AD and to demonstrate its value for early and reliable diagnosis of Alzheimer's disease, particularly ahead of the stage of dementia of the Alzheimer's type. Show more
DOI: 10.3233/BEN-2009-0228
Citation: Behavioural Neurology, vol. 21, no. 1-2, pp. 101-115, 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: Pasquini, Lorenzo | Rahmani, Farzaneh | Maleki-Balajoo, Somayeh | La Joie, Renaud | Zarei, Mojtaba | Sorg, Christian | Drzezga, Alexander | Tahmasian, Masoud
Article Type: Review Article
Abstract: The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer’s disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β …and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events. Show more
Keywords: Alzheimer’s disease, amyloid-β, default mode network, disconnection, hyperexcitability, medial temporal lobe, mild cognitive impairment, posteromedial cortex, tau
DOI: 10.3233/ADR-190121
Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 103-112, 2019
Authors: Sagalajev, Boriss | Lennartz, Lina | Vieth, Lukas | Gunawan, Cecilia Tasya | Neumaier, Bernd | Drzezga, Alexander | Visser-Vandewalle, Veerle | Endepols, Heike | Sesia, Thibaut
Article Type: Research Article
Abstract: Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. Methods: TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent …the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14–16 months old during DMS testing and PET. Results: In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. Conclusions: TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact. Show more
Keywords: Alzheimer’s disease, brain imaging, glucose, microglia, PET, rat model, spatial orientation, working memory
DOI: 10.3233/ADR-230038
Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1085-1094, 2023
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: Richter, Nils | Bischof, Gérard N. | Dronse, Julian | Nellessen, Nils | Neumaier, Bernd | Langen, Karl-Josef | Drzezga, Alexander | Fink, Gereon R. | van Eimeren, Thilo | Kukolja, Juraj | Onur, Oezguer A.
Article Type: Research Article
Abstract: Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer’s disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD. Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild …dementia due to AD. Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18 F]-AV-1451. Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation. Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD. Show more
Keywords: AV-1451, dementia, functional magnetic resonance imaging, mild cognitive impairment, positron emission tomography
DOI: 10.3233/JAD-200835
Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1601-1614, 2020
Authors: Dronse, Julian | Fliessbach, Klaus | Bischof, Gérard N. | von Reutern, Boris | Faber, Jennifer | Hammes, Jochen | Kuhnert, Georg | Neumaier, Bernd | Onur, Oezguer A. | Kukolja, Juraj | van Eimeren, Thilo | Jessen, Frank | Fink, Gereon R. | Klockgether, Thomas | Drzezga, Alexander
Article Type: Short Communication
Abstract: The clinical heterogeneity of Alzheimer’s disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer’s disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer’s disease.
Keywords: Alzheimer’s disease, amyloid, 18F-AV-1451, 18F-FDG, molecular imaging, multimodal imaging, Pittsburghcompound B, positron-emission tomography, T-807, tau protein
DOI: 10.3233/JAD-160316
Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 465-471, 2017
Authors: Brugnolo, Andrea | De Carli, Fabrizio | Pagani, Marco | Morbelli, Slivia | Jonsson, Cathrine | Chincarini, Andrea | Frisoni, Giovanni B. | Galluzzi, Samantha | Perneczky, Robert | Drzezga, Alexander | van Berckel, Bart N.M. | Ossenkoppele, Rik | Didic, Mira | Guedj, Eric | Arnaldi, Dario | Massa, Federico | Grazzini, Matteo | Pardini, Matteo | Mecocci, Patrizia | Dottorini, Massimo E. | Bauckneht, Matteo | Sambuceti, Gianmario | Nobili, Flavio
Article Type: Research Article
Abstract: Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [18 ]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer’s disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer’s Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between [18 ]F-FDG-PET and a …verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [18 ]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods. Show more
Keywords: European Alzheimer Disease Consortium, FDG-PET, head-to-head comparison, prodromal Alzheimer’s disease, statistical parametric mapping, volumetric region of interest
DOI: 10.3233/JAD-181022
Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 383-394, 2019
Authors: Morbelli, Silvia | Brugnolo, Andrea | Bossert, Irene | Buschiazzo, Ambra | Frisoni, Giovanni B. | Galluzzi, Samantha | van Berckel, Bart N.M. | Ossenkoppele, Rik | Perneczky, Robert | Drzezga, Alexander | Didic, Mira | Guedj, Eric | Sambuceti, Gianmario | Bottoni, Gianluca | Arnaldi, Dario | Picco, Agnese | De Carli, Fabrizio | Pagani, Marco | Nobili, Flavio
Article Type: Research Article
Abstract: We aimed to investigate the accuracy of FDG-PET to detect the Alzheimer's disease (AD) brain glucose hypometabolic pattern in 142 patients with amnestic mild cognitive impairment (aMCI) and 109 healthy controls. aMCI patients were followed for at least two years or until conversion to dementia. Images were evaluated by means of visual read by either moderately-skilled or expert readers, and by means of a summary metric of AD-like hypometabolism (PALZ score). Seventy-seven patients converted to AD-dementia after 28.6 ± 19.3 months of follow-up. Expert reading was the most accurate tool to detect these MCI converters from healthy controls (sensitivity 89.6%, …specificity 89.0%, accuracy 89.2%) while two moderately-skilled readers were less (p < 0.05) specific (sensitivity 85.7%, specificity 79.8%, accuracy 82.3%) and PALZ score was less (p < 0.001) sensitive (sensitivity 62.3%, specificity 91.7%, accuracy 79.6%). Among the remaining 67 aMCI patients, 50 were confirmed as aMCI after an average of 42.3 months, 12 developed other dementia, and 3 reverted to normalcy. In 30/50 persistent MCI patients, the expert recognized the AD hypometabolic pattern. In 13/50 aMCI, both the expert and PALZ score were negative while in 7/50, only the PALZ score was positive due to sparse hypometabolic clusters mainly in frontal lobes. Visual FDG-PET reads by an expert is the most accurate method but an automated, validated system may be particularly helpful to moderately-skilled readers because of high specificity, and should be mandatory when even a moderately-skilled reader is unavailable. Show more
Keywords: Alzheimer's disease, amnestic mild cognitive impairment, FDG-PET, PALZ score, visual read
DOI: 10.3233/JAD-142229
Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 815-826, 2015