45 results on '"Dichgans, Martin"'
Search Results
2. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
- Author
-
Neitzel, Julia, Franzmeier, Nicolai, Rubinski, Anna, Dichgans, Martin, Brendel, Matthias, Malik, Rainer, and Ewers, Michael
- Subjects
Psychology ,Biochemistry and Cell Biology ,Biological Sciences ,Biomedical Imaging ,Dementia ,Neurodegenerative ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Aging ,Neurosciences ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,Alzheimer Disease ,Amyloid beta-Peptides ,Apolipoproteins E ,Brain ,Female ,Gene Expression ,Glucuronidase ,Heterozygote ,Humans ,Klotho Proteins ,Male ,Memory Disorders ,Middle Aged ,Polymorphism ,Single Nucleotide ,Positron-Emission Tomography ,Protein Binding ,tau Proteins ,Alzheimer’s Disease Neuroimaging Initiative - Abstract
Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.
- Published
- 2021
3. Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
- Author
-
Franzmeier, Nicolai, Suárez-Calvet, M, Frontzkowski, Lukas, Moore, Annah, Hohman, Timothy J, Morenas-Rodriguez, Estrella, Nuscher, Brigitte, Shaw, Leslie, Trojanowski, John Q, Dichgans, Martin, Kleinberger, Gernot, Haass, Christian, and Ewers, Michael
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Dementia ,Neurodegenerative ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Aging ,Neurosciences ,Brain Disorders ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Apolipoprotein E4 ,Cognitive Dysfunction ,Female ,Genetic Predisposition to Disease ,Humans ,Male ,Membrane Glycoproteins ,Nerve Degeneration ,Receptors ,Immunologic ,Alzheimer's disease ,ApoE4 ,Microglial activation ,sTREM2 ,Cognitive decline ,Neurodegeneration ,Alzheimer’s Disease Neuroimaging Initiative ,Alzheimer’s disease ,Genetics ,Clinical Sciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
BackgroundThe Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.MethodsWe included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).ResultsAcross the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f2 = 0.137) and memory decline (p = 0.006, Cohen's f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1-42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.ConclusionOur results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
- Published
- 2020
4. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease
- Author
-
Ewers, Michael, Franzmeier, Nicolai, Suárez-Calvet, Marc, Morenas-Rodriguez, Estrella, Caballero, Miguel Angel Araque, Kleinberger, Gernot, Piccio, Laura, Cruchaga, Carlos, Deming, Yuetiva, Dichgans, Martin, Trojanowski, John Q, Shaw, Leslie M, Weiner, Michael W, Haass, Christian, and Initiative, Alzheimer’s Disease Neuroimaging
- Subjects
Medical Biotechnology ,Engineering ,Biomedical and Clinical Sciences ,Biomedical Engineering ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Clinical Research ,Dementia ,Neurodegenerative ,Acquired Cognitive Impairment ,Brain Disorders ,Aging ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Cognition ,Cross-Sectional Studies ,Humans ,Membrane Glycoproteins ,Neuropsychological Tests ,Receptors ,Immunologic ,tau Proteins ,Alzheimer’s Disease Neuroimaging Initiative ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ1-42 (amyloid β-peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ1-42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ1-42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.
- Published
- 2019
5. Vascular dysfunction-The disregarded partner of Alzheimer's disease.
- Author
-
Sweeney, Melanie D, Montagne, Axel, Sagare, Abhay P, Nation, Daniel A, Schneider, Lon S, Chui, Helena C, Harrington, Michael G, Pa, Judy, Law, Meng, Wang, Danny JJ, Jacobs, Russell E, Doubal, Fergus N, Ramirez, Joel, Black, Sandra E, Nedergaard, Maiken, Benveniste, Helene, Dichgans, Martin, Iadecola, Costantino, Love, Seth, Bath, Philip M, Markus, Hugh S, Salman, Rustam A, Allan, Stuart M, Quinn, Terence J, Kalaria, Rajesh N, Werring, David J, Carare, Roxana O, Touyz, Rhian M, Williams, Steve CR, Moskowitz, Michael A, Katusic, Zvonimir S, Lutz, Sarah E, Lazarov, Orly, Minshall, Richard D, Rehman, Jalees, Davis, Thomas P, Wellington, Cheryl L, González, Hector M, Yuan, Chun, Lockhart, Samuel N, Hughes, Timothy M, Chen, Christopher LH, Sachdev, Perminder, O'Brien, John T, Skoog, Ingmar, Pantoni, Leonardo, Gustafson, Deborah R, Biessels, Geert Jan, Wallin, Anders, Smith, Eric E, Mok, Vincent, Wong, Adrian, Passmore, Peter, Barkof, Frederick, Muller, Majon, Breteler, Monique MB, Román, Gustavo C, Hamel, Edith, Seshadri, Sudha, Gottesman, Rebecca F, van Buchem, Mark A, Arvanitakis, Zoe, Schneider, Julie A, Drewes, Lester R, Hachinski, Vladimir, Finch, Caleb E, Toga, Arthur W, Wardlaw, Joanna M, and Zlokovic, Berislav V
- Subjects
Blood-Brain Barrier ,Brain ,Humans ,Alzheimer Disease ,Vascular Diseases ,Cerebrovascular Circulation ,United States ,National Institute on Aging (U.S.) ,Amyloid beta-Peptides ,White Matter ,Biomarkers ,Alzheimer's disease ,Blood-brain barrier ,Cerebral blood flow ,MRI ,Vascular ,National Institute on Aging ,Neurosciences ,Clinical Sciences ,Geriatrics - Abstract
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
- Published
- 2019
6. Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer’s disease
- Author
-
Rubinski, Anna, Franzmeier, Nicolai, Dewenter, Anna, Luan, Ying, Smith, Ruben, Strandberg, Olof, Ossenkoppele, Rik, Dichgans, Martin, Hansson, Oskar, and Ewers, Michael
- Published
- 2022
- Full Text
- View/download PDF
7. Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia
- Author
-
Malo Gaubert, Andrea Dell’Orco, Catharina Lange, Antoine Garnier-Crussard, Isabella Zimmermann, Martin Dyrba, Marco Duering, Gabriel Ziegler, Oliver Peters, Lukas Preis, Josef Priller, Eike Jakob Spruth, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Björn H. Schott, Franziska Maier, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Robert Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Matthias H. Munk, Annika Spottke, Nina Roy, Laura Dobisch, Michael Ewers, Peter Dechent, John Dylan Haynes, Klaus Scheffler, Emrah Düzel, Frank Jessen, Miranka Wirth, for the DELCODE study group, Amthauer Holger, Cetindag Arda Can, Cosma Nicoleta Carmen, Diesing Dominik, Ehrlich Marie, Fenski Frederike, Freiesleben Silka Dawn, Fuentes Manuel, Hauser Dietmar, Hujer Nicole, Incesoy Enise Irem, Kainz Christian, Lange Catharina, Lindner Katja, Megges Herlind, Peters Oliver, Preis Lukas, Altenstein Slawek, Lohse Andrea, Franke Christiana, Priller Josef, Spruth Eike, Villar Munoz Irene, Barkhoff Miriam, Boecker Henning, Brosseron Frederic, Daamen Marcel, Engels Tanja, Faber Jennifer, Fließbach Klaus, Frommann Ingo, Grobe-Einsler Marcus, Hennes Guido, Herrmann Gabi, Jost Lorraine, Kalbhen Pascal, Kimmich Okka, Kobeleva Xenia, Kofler Barbara, McCormick Cornelia, Miebach Lisa, Miklitz Carolin, Müller Anna, Oender Demet, Polcher Alexandra, Purrer Veronika, Röske Sandra, Schneider Christine, Schneider Anja, Spottke Annika, Vogt Ina, Wagner Michael, wolfsgruber Steffen, Yilmaz Sagik, Bartels Claudia, Dechent Peter, Hansen Niels, Hassoun Lina, Hirschel Sina, Nuhn Sabine, Pfahlert Ilona, Rausch Lena, Schott Björn, Timäus Charles, Werner Christine, Wiltfang Jens, Zabel Lioba, Zech Heike, Bader Abdelmajid, Baldermann Juan Carlos, Dölle Britta, Drzezga Alexander, Escher Claus, Ghiasi Nasim Roshan, Hardenacke Katja, Jessen Frank, Lützerath Hannah, Maier Franziska, Marquardt Benjamin, Martikke Anja, Meiberth Dix, Petzler Snjezana, Rostamzadeh Ayda, Sannemann Lena, Schild Ann-Katrin, Sorgalla Susanne, Stockter Simone, Thelen Manuela, Tscheuschler Maike, Uhle Franziska, Zeyen Philip, Bittner Daniel, Cardenas-Blanco Arturo, Dobisch Laura, Düzel Emrah, Grieger-Klose Doreen, Hartmann Deike, Metzger Coraline, Nestor Peter, Ruß Christin, Schulze Franziska, Speck Oliver, Yakupov Renat, Ziegler Gabriel, Brauneis Christine, Bürger Katharina, Catak Cihan, Coloma Andrews Lisa, Dichgans Martin, Dörr Angelika, Ertl-Wagner Birgit, Frimmer Daniela, Huber Brigitte, Janowitz Daniel, Kreuzer Max, Markov Eva, Müller Claudia, Rominger Axel, Schmid (ehemals Spreider) Jennifer, Seegerer Anna, Stephan Julia, Zollver Adelgunde, Burow Lena, de Jonge Sylvia, Falkai Peter, Garcia Angarita Natalie, Görlitz Thomas, Gürsel Selim Üstün, Horvath Ildiko, Kurz Carolin, Meisenzahl-Lechner Eva, Perneczky Robert, Utecht Julia, Dyrba Martin, Janecek-Meyer Heike, Kilimann Ingo, Lappe Chris, Lau Esther, Pfaff Henrike, Raum Heike, Sabik Petr, Schmidt Monika, Schulz Heike, Schwarzenboeck Sarah, Teipel Stefan, Weber Marc-Andre, Buchmann Martina, Heger Tanja, Hinderer Petra, Kuder-Buletta Elke, Laske Christoph, Munk Matthias, Mychajliw Christian, Soekadar Surjo, sulzer Patricia, and Trunk Theresia
- Subjects
white matter hyperintensities segmentation ,evaluation ,FLAIR ,deep learning ,aging ,Alzheimer’s disease ,Psychiatry ,RC435-571 - Abstract
BackgroundWhite matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer’s disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.MethodsWe used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).ResultsAcross tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice’s coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.ConclusionTo conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.
- Published
- 2023
- Full Text
- View/download PDF
8. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease
- Author
-
Caballero, Miguel Ángel Araque, Suárez-Calvet, Marc, Duering, Marco, Franzmeier, Nicolai, Benzinger, Tammie, Fagan, Anne M, Bateman, Randall J, Jack, Clifford R, Levin, Johannes, Dichgans, Martin, Jucker, Mathias, Karch, Celeste, Masters, Colin L, Morris, John C, Weiner, Michael, Rossor, Martin, Fox, Nick C, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Yakushev, Igor, Hassenstab, Jason, Schofield, Peter R, Haass, Christian, and Ewers, Michael
- Subjects
Health Services and Systems ,Health Sciences ,Neurosciences ,Dementia ,Biomedical Imaging ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Brain Disorders ,Alzheimer's Disease ,Neurodegenerative ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Alzheimer Disease ,Brain ,Diffusion Tensor Imaging ,Female ,Humans ,Male ,Middle Aged ,White Matter ,Alzheimer's disease ,autosomal dominant ,white matter ,diffusion tensor imaging ,TREM2 ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences ,Psychology - Abstract
White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.
- Published
- 2018
9. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease
- Author
-
Franzmeier, Nicolai, Düzel, Emrah, Jessen, Frank, Buerger, Katharina, Levin, Johannes, Duering, Marco, Dichgans, Martin, Haass, Christian, Suárez-Calvet, Marc, Fagan, Anne M, Paumier, Katrina, Benzinger, Tammie, Masters, Colin L, Morris, John C, Perneczky, Robert, Janowitz, Daniel, Catak, Cihan, Wolfsgruber, Steffen, Wagner, Michael, Teipel, Stefan, Kilimann, Ingo, Ramirez, Alfredo, Rossor, Martin, Jucker, Mathias, Chhatwal, Jasmeer, Spottke, Annika, Boecker, Henning, Brosseron, Frederic, Falkai, Peter, Fliessbach, Klaus, Heneka, Michael T, Laske, Christoph, Nestor, Peter, Peters, Oliver, Fuentes, Manuel, Menne, Felix, Priller, Josef, Spruth, Eike J, Franke, Christiana, Schneider, Anja, Kofler, Barbara, Westerteicher, Christine, Speck, Oliver, Wiltfang, Jens, Bartels, Claudia, Caballero, Miguel Ángel Araque, Metzger, Coraline, Bittner, Daniel, Weiner, Michael, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Schofield, Peter R, Bateman, Randall J, and Ewers, Michael
- Subjects
Clinical Trials and Supportive Activities ,Brain Disorders ,Aging ,Basic Behavioral and Social Science ,Dementia ,Neurosciences ,Behavioral and Social Science ,Acquired Cognitive Impairment ,Clinical Research ,Alzheimer's Disease ,Neurodegenerative ,Biomedical Imaging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Alzheimer Disease ,Amyloid beta-Protein Precursor ,Brain Mapping ,Cognitive Dysfunction ,Female ,Frontal Lobe ,Functional Laterality ,Humans ,Imaging ,Three-Dimensional ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Mutation ,Nerve Net ,Presenilin-1 ,Presenilin-2 ,Alzheimer's disease ,cognitive reserve ,resting state connectivity ,memory ,dementia biomarkers ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
- Published
- 2018
10. Left frontal cortex connectivity underlies cognitive reserve in prodromal Alzheimer disease
- Author
-
Franzmeier, Nicolai, Duering, Marco, Weiner, Michael, Dichgans, Martin, and Ewers, Michael
- Subjects
Prevention ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Brain Disorders ,Aging ,Neurodegenerative ,Clinical Research ,Neurosciences ,Biomedical Imaging ,Acquired Cognitive Impairment ,Alzheimer's Disease ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Alzheimer Disease ,Chi-Square Distribution ,Cognition Disorders ,Cognitive Reserve ,Epilepsy ,Female ,Fluorodeoxyglucose F18 ,Frontal Lobe ,Functional Laterality ,Humans ,Magnetic Resonance Imaging ,Male ,Nerve Net ,Neuropsychological Tests ,Oxygen ,Positron-Emission Tomography ,Prodromal Symptoms ,Alzheimer's Disease Neuroimaging Initiative ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveTo test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory.MethodsForty-four amyloid-PET-positive patients with amnestic mild cognitive impairment (MCI-Aβ+) and 24 amyloid-PET-negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Aβ+, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity × FDG-PET hypometabolism on episodic memory were tested.ResultsFDG-PET metabolism in the precuneus was reduced in MCI-Aβ+ compared to HC (p = 0.028), with stronger reductions observed in MCI-Aβ+ with more years of education (p = 0.006). In MCI-Aβ+, higher gLFC connectivity was associated with more years of education (p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated (p = 0.027).ConclusionsHigher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in early-stage AD.
- Published
- 2017
11. Mapping 3-year changes in gray matter and metabolism in Aβ-positive nondemented subjects
- Author
-
Caballero, Miguel Ángel Araque, Brendel, Matthias, Delker, Andreas, Ren, Jinyi, Rominger, Axel, Bartenstein, Peter, Dichgans, Martin, Weiner, Michael W, Ewers, Michael, and Initative, Alzheimer's Disease Neuroimaging
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Alzheimer's Disease ,Brain Disorders ,Biomedical Imaging ,Dementia ,Clinical Research ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Neurodegenerative ,Neurosciences ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Neurological ,Aged ,Aged ,80 and over ,Amyloid beta-Peptides ,Atrophy ,Cognitive Dysfunction ,Female ,Glucose ,Gray Matter ,Humans ,Magnetic Resonance Imaging ,Male ,Positron-Emission Tomography ,Time Factors ,Longitudinal ,Neurodegeneration ,Alzheimer's ,Neuroimaging ,Multivariate ,Multimodal ,Alzheimer's Disease Neuroimaging Initative ,Neurology & Neurosurgery ,Biological psychology - Abstract
Gray matter (GM) atrophy and brain glucose hypometabolism are already detected in the predementia stages of Alzheimer's disease (AD), but the regional and longitudinal associations between the two are not well understood. Here, we analyzed the patterns of longitudinal atrophy (magnetic resonance imaging [MRI]) and (18)F-Fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) metabolism decline in 40 cognitively healthy control (HC) and 52 mildly impaired (mild cognitive impairment [MCI]) subjects during 3 years. Based on cerebrospinal fluid and brain amyloid-PET, the subjects were divided into amyloid-beta (Aβ)- and Aβ+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Aβ-subgroups, within each diagnostic group. In joint-independent component analyses, we assessed the patterns of covariation between longitudinal change in GM volume and glucose metabolism. MCI-Aβ+ showed faster atrophy than MCI-Aβ- within the temporal, medial temporal, and medial parietal lobes. HC-Aβ+ showed faster atrophy within the precuneus than HC-Aβ-. For FDG-PET metabolism, MCI-Aβ+ exhibited faster decline than MCI-Aβ- in temporoparietal regions, whereas no differences between HC subgroups were observed. Joint-independent component analysis showed that accelerated atrophy and metabolism decline correlated across distant brain regions for MCI-Aβ+. In conclusion, abnormally increased levels of Aβ in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns.
- Published
- 2015
12. Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- Author
-
de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Mónica, Lage, Carmen, García-González, Pablo, Valero, Sergi, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Mecocci, Patrizia, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Smith, A. David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G., Janowitz, Daniel, Craig, David, Mann, David M., Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M., Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R. L. C., Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M., Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J., Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C., Salvadori, Nicola, Hooper, Nigel M., Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M., Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rosende-Roca, M., Ruiz, A., Sáez, M.E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Alonso, M.D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., Garcia Madrona, S., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M.A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W., Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo, García-Alberca, Jose María, Bullido, María J., Álvarez, Victoria, Lleó, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustín, Smith, A David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G, Janowitz, Daniel, Craig, David, Mann, David M, Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M, Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R L C, Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M, Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J, Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C, Salvadori, Nicola, Hooper, Nigel M, Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M, Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón-Anchuelo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M. T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J. A., Preckler, S., Quintela, I., Real, L. M., Rosende-Roca, M., Ruiz, A., Sáez, M. E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A. D., Alarcón-Martín, E., Alonso, M. D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M. J., Burguera, J. A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M. J., Clarimón, J., Cruz-Gamero, J. M., de Pancorbo, M. M., Del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., García-Alberca, J. M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M. A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J. L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J. L., Sanchez Del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M. P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W, Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Rongve, Arvid, Brussels Heritage Lab, Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
- Subjects
polygenic risk scores ,Multidisciplinary ,Common variants ,Neuroscience(all) ,neurology ,Medizin ,General Physics and Astronomy ,ddc:500 ,General Chemistry ,Alzheimer's disease ,General Biochemistry, Genetics and Molecular Biology ,RISK STRATIFICATION - Abstract
The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern
- Published
- 2023
13. Functional network segregation is associated with attenuated tau spreading in Alzheimer's disease
- Author
-
Steward, Anna, Biel, Davina, Initiative, Alzheimer's Disease Neuroimaging, Brendel, Matthias, Dewenter, Anna, Roemer, Sebastian, Rubinski, Anna, Luan, Ying, Dichgans, Martin, Ewers, Michael, and Franzmeier, Nicolai
- Subjects
tau positron emission tomography ,tau spreading ,ddc:610 ,Alzheimer's disease ,functional magnetic resonance imaging ,network segregation - Abstract
Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity-mediated tau spreading.We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomography (PET) in 42 betamyloid-negative controls and 81 amyloid beta positive individuals across the AD spectrum. Network segregation was determined using resting-state fMRI-assessed connectivity among 400 cortical regions belonging to seven networks.AD subjects with higher network segregation exhibited slower brain-wide tau accumulation relative to their baseline entorhinal tau PET burden (typical onset site of tau pathology). Second, by identifying patient-specific tau epicenters with highest baseline tau PET we found that stronger epicenter segregation was associated with a slower rate of tau accumulation in the rest of the brain in relation to baseline epicenter tau burden.Our results indicate that tau spreading is facilitated by a more diffusely organized connectome, suggesting that brain network topology modulates tau spreading in AD.Higher brain network segregation is associated with attenuated tau pathology accumulation in Alzheimer's disease (AD). A patient-tailored approach allows for the more precise localization of tau epicenters. The functional segregation of subject-specific tau epicenters predicts the rate of future tau accumulation.
- Published
- 2022
14. Functional network segregation is associated with attenuated tau spreading in Alzheimer's disease.
- Author
-
Steward, Anna, Biel, Davina, Brendel, Matthias, Dewenter, Anna, Roemer, Sebastian, Rubinski, Anna, Luan, Ying, Dichgans, Martin, Ewers, Michael, and Franzmeier, Nicolai
- Abstract
Introduction: Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity‐mediated tau spreading. Methods: We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomography (PET) in 42 betamyloid‐negative controls and 81 amyloid beta positive individuals across the AD spectrum. Network segregation was determined using resting‐state fMRI–assessed connectivity among 400 cortical regions belonging to seven networks. Results: AD subjects with higher network segregation exhibited slower brain‐wide tau accumulation relative to their baseline entorhinal tau PET burden (typical onset site of tau pathology). Second, by identifying patient‐specific tau epicenters with highest baseline tau PET we found that stronger epicenter segregation was associated with a slower rate of tau accumulation in the rest of the brain in relation to baseline epicenter tau burden. Discussion: Our results indicate that tau spreading is facilitated by a more diffusely organized connectome, suggesting that brain network topology modulates tau spreading in AD. Highlights: Higher brain network segregation is associated with attenuated tau pathology accumulation in Alzheimer's disease (AD).A patient‐tailored approach allows for the more precise localization of tau epicenters.The functional segregation of subject‐specific tau epicenters predicts the rate of future tau accumulation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
15. Disentangling the effects of Alzheimer's and small vessel disease on white matter fibre tracts
- Author
-
Dewenter, Anna, Jacob, Mina A, Dichgans, Martin, Franzmeier, Nicolai, Duering, Marco, Consortium, SVDs@target, Initiative, Alzheimer’s Disease Neuroimaging, Cai, Mengfei, Gesierich, Benno, Hager, Paul, Kopczak, Anna, Biel, Davina, Ewers, Michael, Tuladhar, Anil M, and de Leeuw, Frank Erik
- Subjects
cerebral small vessel disease ,Amyloidogenic Proteins ,CADASIL ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,diagnostic imaging [White Matter] ,pathology [Alzheimer Disease] ,Cross-Sectional Studies ,All institutes and research themes of the Radboud University Medical Center ,pathology [Brain] ,pathology [White Matter] ,methods [Diffusion Magnetic Resonance Imaging] ,Humans ,pathology [Cerebral Small Vessel Diseases] ,Neurology (clinical) ,ddc:610 ,Vascular Diseases ,diagnostic imaging [Cerebral Small Vessel Diseases] ,diagnostic imaging [Alzheimer Disease] ,diagnostic imaging [Brain] ,Alzheimer’s disease ,fixel-based analysis ,diffusion magnetic resonance imaging - Abstract
Alzheimer’s disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer’s and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer’s disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer’s disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer’s disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine.
- Published
- 2022
16. Polygenic Effect on Tau Pathology Progression in Alzheimer's Disease.
- Author
-
Rubinski, Anna, Frerich, Simon, Malik, Rainer, Franzmeier, Nicolai, Ramirez, Alfredo, Dichgans, Martin, and Ewers, Michael
- Subjects
ALZHEIMER'S disease ,DISEASE risk factors ,TAU proteins ,PATHOLOGY ,GENOME-wide association studies - Abstract
Objective: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar‐tau accumulation as a key driver of dementia symptoms is unclear. Methods: We combined the to‐date largest number of genetic risk variants of AD (n = 85 lead single‐nucleotide polymorphisms [SNPs]) from recent genome‐wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau‐positron emission tomography (PET), amyloid‐PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid‐PET, we predicted the rate of tau‐PET increases in Braak‐stage regions‐of‐interest and cognitive decline. We also assessed PGS‐risk enrichment effects on the required sample size in clinical trials targeting tau pathology. Results: We found that a higher PGS was associated with higher rates of tau‐PET accumulation, in particular at elevated amyloid‐PET levels. The tau‐PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Interpretation: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819–829 [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
17. Subjective cognitive decline and stage 2 of Alzheimer disease in patients from memory centers.
- Author
-
Jessen, Frank, Wolfsgruber, Steffen, Kleineindam, Luca, Spottke, Annika, Altenstein, Slawek, Bartels, Claudia, Berger, Moritz, Brosseron, Frederic, Daamen, Marcel, Dichgans, Martin, Dobisch, Laura, Ewers, Michael, Fenski, Friederike, Fliessbach, Klaus, Freiesleben, Silka D., Glanz, Wenzel, Görß, Doreen, Gürsel, Selim, Janowitz, Daniel, and Kilimann, Ingo
- Abstract
Introduction: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. Methods: Cross‐sectional and longitudinal data from the multicenter, memory clinic–based DELCODE study. Results: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD–A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO–A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. Discussion: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD‐A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Disentangling the effects of Alzheimer's and small vessel disease on white matter fibre tracts.
- Author
-
Dewenter, Anna, Jacob, Mina A, Cai, Mengfei, Gesierich, Benno, Hager, Paul, Kopczak, Anna, Biel, Davina, Ewers, Michael, Tuladhar, Anil M, Leeuw, Frank-Erik de, Dichgans, Martin, Franzmeier, Nicolai, Duering, Marco, and (ADNI), for the SVDs@target Consortium and Alzheimer's Disease Neuroimaging Initiative
- Subjects
CEREBRAL amyloid angiopathy ,ALZHEIMER'S disease ,CEREBRAL small vessel diseases ,LEUKOENCEPHALOPATHIES ,DIFFUSION magnetic resonance imaging ,WHITE matter (Nerve tissue) - Abstract
Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
19. Brain endothelium: a nexus for cerebral small vessel disease.
- Author
-
Dichgans, Martin, Faraci, Frank M, and Network, BRENDA
- Subjects
CEREBRAL small vessel diseases ,ENDOTHELIUM ,ALZHEIMER'S disease ,LACUNAR stroke ,ENDOTHELIUM diseases - Abstract
Brain endothelial cells (BECs) have unique roles in controlling cerebral blood flow (CBF) and as a cornerstone of the blood-brain barrier (BBB). Graph: Figure 1 The BRENDA network will define mechanisms linking risk genes for cerebral small vessel disease and stroke to brain endothelial cell dysfunction and brain injury, applying cutting edge technology to novel disease models, including human inducible pluripotent stem cell-based models of the blood-brain barrier and neurovascular unit (Aim 1); test whether genetic predisposition synergizes with hypertension to augment brain endothelial cell dysfunction and brain injury (Aim 2, "two-hit" model); and determine whether brain endothelial cell heterogeneity underlies differences in brain injury across regions (Aim 3). Genome-wide association studies[8] implicate BEC dysfunction in disease initiation and propagation.[5] For instance, common variants of I FOXF2 i are associated with small vessel stroke and white matter lesions (WMLs). [Extracted from the article]
- Published
- 2023
- Full Text
- View/download PDF
20. Earlier Alzheimer's disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading.
- Author
-
Frontzkowski, Lukas, Ewers, Michael, Brendel, Matthias, Biel, Davina, Ossenkoppele, Rik, Hager, Paul, Steward, Anna, Dewenter, Anna, Römer, Sebastian, Rubinski, Anna, Buerger, Katharina, Janowitz, Daniel, Binette, Alexa Pichet, Smith, Ruben, Strandberg, Olof, Carlgren, Niklas Mattsson, Dichgans, Martin, Hansson, Oskar, and Franzmeier, Nicolai
- Subjects
ALZHEIMER'S disease ,BRAIN diseases ,TAU proteins ,DISEASE progression - Abstract
In Alzheimer's disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline. Individuals with young onset sporadic Alzheimer's disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer's disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
21. Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates.
- Author
-
Zellner, Andreas, Müller, Stephan A., Lindner, Barbara, Beaufort, Nathalie, Rozemuller, Annemieke J. M., Arzberger, Thomas, Gassen, Nils C., Lichtenthaler, Stefan F., Kuster, Bernhard, Haffner, Christof, and Dichgans, Martin
- Subjects
CEREBRAL amyloid angiopathy ,AMYLOID beta-protein ,CEREBRAL small vessel diseases ,LIQUID chromatography-mass spectrometry ,PROTEOMICS ,ALZHEIMER'S disease - Abstract
Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC–MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ
1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
22. The BIN1 rs744373 Alzheimer’s disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline.
- Author
-
Franzmeier, Nicolai, Ossenkoppele, Rik, Brendel, Matthias, Rubinski, Anna, Smith, Ruben, Kumar, Atul, Mattsson-Carlgren, Niklas, Strandberg, Olof, Duering, Marco, Buerger, Katharina, Dichgans, Martin, Hansson, Oskar, and Ewers, Michael
- Abstract
Introduction: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer’s disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation. Methods: We included two samples (Alzheimer’s Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal 18F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline. Results: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P < .001/P < .001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = –0.35/0.15, P = .021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P = .005). Discussion: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
23. Prediction of dementia using diffusion tensor MRI measures: the OPTIMAL collaboration.
- Author
-
Egle, Marco, Hilal, Saima, Tuladhar, A. M., Pirpamer, Lukas, Hofer, Edith, Duering, Marco, Wason, James, Morris, Robin G., Dichgans, Martin, Schmidt, Reinhold, Tozer, Daniel, Chen, Christopher, de Leeuw, Frank-Erik, and Markus, Hugh S.
- Subjects
BRAIN ,CEREBRAL small vessel diseases ,RESEARCH ,RESEARCH methodology ,MAGNETIC resonance imaging ,COGNITION ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,DEMENTIA ,LONGITUDINAL method - Abstract
Objectives: It has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.Methods: Among the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.Results: The DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.Conclusions: Our results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
24. Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals.
- Author
-
Biel, Davina, Brendel, Matthias, Rubinski, Anna, Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, and Franzmeier, Nicolai
- Subjects
PROGNOSIS ,OLDER people ,COGNITION disorders ,MILD cognitive impairment ,DEMENTIA ,EPISODIC memory ,COGNITION - Abstract
Background: To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods: In this longitudinal study, we included 396 cognitively normal to dementia subjects with
18 F-Florbetapir/18 F-Florbetaben-amyloid-PET,18 F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+ )/negative(− ) at pre-established cut-offs, classifying subjects as Braak0 /BraakI+ /BraakI–IV+ /BraakI–VI+ /Braakatypical+ . In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results: Baseline global tau-PET SUVRs explained more variance (partial R2 ) in future cognitive decline than Centiloid across all cognitive tests (Cohen's d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion: Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
25. Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.
- Author
-
Ewers, Michael, Luan, Ying, Frontzkowski, Lukas, Neitzel, Julia, Rubinski, Anna, Dichgans, Martin, Hassenstab, Jason, Gordon, Brian A, Chhatwal, Jasmeer P, Levin, Johannes, Schofield, Peter, Benzinger, Tammie L S, Morris, John C, Goate, Alison, Karch, Celeste M, Fagan, Anne M, McDade, Eric, Allegri, Ricardo, Berman, Sarah, and Chui, Helena
- Subjects
ALZHEIMER'S disease ,EPISODIC memory ,CEREBRAL amyloid angiopathy ,ALZHEIMER'S patients ,FUNCTIONAL magnetic resonance imaging ,TEMPORAL lobe ,BRAIN ,RESEARCH ,NERVOUS system ,RESEARCH methodology ,COGNITION ,MAGNETIC resonance imaging ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,DISEASE complications - Abstract
Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
26. Common polygenic variation enhances risk prediction for Alzheimer's disease
- Author
-
Escott-Price, Valentina, Sims, Rebecca, Passmore, Peter, ODonovan, Michael, Owen, Michael J, Holmes, Clive, Powell, John, Brayne, Carol, Gill, Michael, Mead, Simon, Goate, Alison, Cruchaga, Carlos, Lambert, Jean-Charles, van Duijn, Cornelia, Bannister, Christian, Maier, Wolfgang, Ramirez, Alfredo, Holmans, Peter, Jones, Lesley, Hardy, John, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Abraham, Richard, Harold, Denise, Hollingworth, Paul, Gerrish, Amy, Chapman, Jade, Russo, Giancarlo, Hamshere, Marian, Pahwa, Jaspreet Singh, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Vronskaya, Maria, Stretton, Alexandra, Morgan, Angharad, Taylor, Sarah, Lovestone, Simon, Proitsi, Petroula, Lupton, Michelle K, Rubinsztein, David C, Lawlor, Brian, Lynch, Aoibhinn, Brown, Kristelle, Majounie, Elisa, Craig, David, McGuinness, Bernadette, Todd, Stephen, Johnston, Janet, Mann, David, Smith, A David, Love, Seth, Kehoe, Patrick G, Fox, Nick, Rossor, Martin, Badarinarayan, Nandini, Collinge, John, Jessen, Frank, Heun, Reiner, Schürmann, Britta, Becker, Tim, Herold, Christine, Lacour, Andre, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, GERAD/PERADES, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Kauwe, John S K, Nowotny, Petra, Morris, John C, consortia, IGAP, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Al-Chalabi, Ammar, Shaw, Christopher E, Singleton, Andrew B, Morgan, Kevin, Guerreiro, Rita, Mühleisen, Thomas W, Nöthen, Markus M., Moebus, Susanne, Jöckel, Karl-Heinz, Klopp, Norman, Wichmann, H-Erich, Carrasquillo, Minerva M, Pankratz, V Shane, Younkin, Steven G, and Epidemiology
- Subjects
Apolipoprotein E ,Oncology ,Risk ,Multifactorial Inheritance ,medicine.medical_specialty ,Genotype ,genetics [Alzheimer Disease] ,Bioinformatics ,Logistic regression ,Apolipoproteins E ,Alzheimer Disease ,Positive predicative value ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Genetic Testing ,genetics [Genetic Predisposition to Disease] ,genetics [Multifactorial Inheritance] ,Alleles ,Receiver operating characteristic ,Case-control study ,Genetic Variation ,Original Articles ,medicine.disease ,Confidence interval ,genetics [Genetic Variation] ,Logistic Models ,ROC Curve ,Case-Control Studies ,genetics [Apolipoproteins E] ,Neurology (clinical) ,Alzheimer's disease ,Psychology ,Genome-Wide Association Study - Abstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.
- Published
- 2015
27. Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID‐19 pandemic, now and in the future.
- Author
-
Mok, Vincent C.T., Pendlebury, Sarah, Wong, Adrian, Alladi, Suvarna, Au, Lisa, Bath, Philip M, Biessels, Geert Jan, Chen, Christopher, Cordonnier, Charlotte, Dichgans, Martin, Dominguez, Jacqueline, Gorelick, Philip B., Kim, SangYun, Kwok, Timothy, Greenberg, Steven M., Jia, Jianping, Kalaria, Rajesh, Kivipelto, Miia, Naegandran, Kandiah, and Lam, Linda C.W.
- Abstract
We have provided an overview on the profound impact of COVID‐19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health‐care settings, including hospital, out‐patient, care homes, and the community during the COVID‐19 pandemic. We have also proposed a conceptual framework and practical suggestions for health‐care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health‐care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD‐19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
28. Modifiable pathways in Alzheimer's disease : Mendelian randomisation analysis
- Author
-
Larsson, Susanna C, Traylor, Matthew, Malik, Rainer, Dichgans, Martin, Burgess, Stephen, Markus, Hugh S, CoSTREAM Consortium, On Behalf Of The International Genomics Of Alzheimer’s Project, Traylor, Matthew [0000-0001-6624-8621], Burgess, Stephen [0000-0001-5365-8760], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,medicine.medical_specialty ,etiology [Alzheimer Disease] ,genetics [Alzheimer Disease] ,Disease ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Alzheimer Disease ,Risk Factors ,Internal medicine ,Odds Ratio ,Humans ,Medicine ,Genetic Predisposition to Disease ,ddc:610 ,Risk factor ,Life Style ,Socioeconomic status ,business.industry ,Mendelian Randomization Analysis ,Public Health, Global Health, Social Medicine and Epidemiology ,General Medicine ,Odds ratio ,medicine.disease ,Diet ,3. Good health ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,030104 developmental biology ,Bonferroni correction ,symbols ,Mendelian inheritance ,Educational Status ,Alzheimer's disease ,business ,030217 neurology & neurosurgery - Abstract
OBJECTIVE: To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease. DESIGN: Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. SETTING: International Genomics of Alzheimer's Project. PARTICIPANTS: 17 008 cases of Alzheimer's disease and 37 154 controls. MAIN OUTCOME MEASURES: Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. RESULTS: This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P
- Published
- 2017
29. Age‐dependent amyloid deposition is associated with white matter alterations in cognitively normal adults during the adult life span.
- Author
-
Caballero, Miguel Á. Araque, Song, Zhuang, Rubinski, Anna, Duering, Marco, Dichgans, Martin, Park, Denise C., and Ewers, Michael
- Abstract
Introduction: Both beta‐amyloid (Ab) deposition and decline in white matter integrity, are brain alterations observed in Alzheimer's disease (AD) and start to occur by the fourth and fifth decades. However, the association between both brain alterations in asymptomatic subjects is unclear. Methods: Amyloid positron emission tomography (PET) and diffusion tensor imaging (DTI) were obtained in 282 cognitively normal subjects (age 30‐89 years). We assessed the interaction of age by abnormal amyloid PET status (Florbetapir F‐18 PET >1.2 standard uptake value ratio [SUVR]) on regional mean diffusivity (MD) and global white matter hyperintensity (WMH) volume, controlled for sex, education, and hypertension. Results: Subjects with abnormal amyloid PET (n = 87) showed stronger age‐related increase in global WMH and regional MD, particularly within the posterior parietal regions of the white matter. Discussion: Sporadic Aβ deposition is associated with white matter alterations in AD predilection areas in an age‐dependent manner in cognitively normal individuals. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
30. Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease‐informed machine‐learning.
- Author
-
Franzmeier, Nicolai, Koutsouleris, Nikolaos, Benzinger, Tammie, Goate, Alison, Karch, Celeste M., Fagan, Anne M., McDade, Eric, Duering, Marco, Dichgans, Martin, Levin, Johannes, Gordon, Brian A., Lim, Yen Ying, Masters, Colin L., Rossor, Martin, Fox, Nick C., O'Connor, Antoinette, Chhatwal, Jasmeer, Salloway, Stephen, Danek, Adrian, and Hassenstab, Jason
- Abstract
Introduction: Developing cross‐validated multi‐biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. Methods: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid‐PET and fluorodeoxyglucose positron‐emission tomography (FDG‐PET) to predict rates of cognitive decline. Prediction models were trained in autosomal‐dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross‐validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model‐based risk enrichment was estimated. Results: A model combining all biomarker modalities and established in ADAD predicted the 4‐year rate of decline in global cognition (R2 = 24%) and memory (R2 = 25%) in sporadic AD. Model‐based risk‐enrichment reduced the sample size required for detecting simulated intervention effects by 50%–75%. Discussion: Our independently validated machine‐learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
31. Mapping 3-year changes in gray matter and metabolism in Aβ-positive nondemented subjects
- Author
-
Araque Caballero, Miguel Ángel, Brendel, Matthias, Delker, Andreas, Ren, Jinyi, Rominger, Axel, Bartenstein, Peter, Dichgans, Martin, Weiner, Michael W, Ewers, Michael, and Alzheimer's Disease Neuroimaging Initative (ADNI)
- Subjects
Male ,Aging ,Time Factors ,Clinical Sciences ,Neuroimaging ,Neurodegenerative ,Alzheimer's Disease ,Clinical Research ,80 and over ,Acquired Cognitive Impairment ,Alzheimer's Disease Neuroimaging Initative ,Humans ,Cognitive Dysfunction ,Gray Matter ,Neurodegeneration ,Aged ,screening and diagnosis ,Amyloid beta-Peptides ,Neurology & Neurosurgery ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's ,Magnetic Resonance Imaging ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,Glucose ,Positron-Emission Tomography ,Multimodal ,Neurological ,Longitudinal ,Biomedical Imaging ,Female ,Dementia ,Atrophy ,Multivariate - Abstract
Gray matter (GM) atrophy and brain glucose hypometabolism are already detected in the predementia stages of Alzheimer's disease (AD), but the regional and longitudinal associations between the two are not well understood. Here, we analyzed the patterns of longitudinal atrophy (magnetic resonance imaging [MRI]) and (18)F-Fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) metabolism decline in 40 cognitively healthy control (HC) and 52 mildly impaired (mild cognitive impairment [MCI]) subjects during 3years. Based on cerebrospinal fluid and brain amyloid-PET, the subjects were divided into amyloid-beta (Aβ)- and Aβ+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Aβ-subgroups, within each diagnostic group. In joint-independent component analyses, we assessed the patterns of covariation between longitudinal change in GM volume and glucose metabolism. MCI-Aβ+ showed faster atrophy than MCI-Aβ- within the temporal, medial temporal, and medial parietal lobes. HC-Aβ+ showed faster atrophy within the precuneus than HC-Aβ-. For FDG-PET metabolism, MCI-Aβ+ exhibited faster decline than MCI-Aβ- in temporoparietal regions, whereas no differences between HC subgroups were observed. Joint-independent component analysis showed that accelerated atrophy and metabolism decline correlated across distant brain regions for MCI-Aβ+. In conclusion, abnormally increased levels of Aβ in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns.
- Published
- 2015
32. Vascular dysfunction—The disregarded partner of Alzheimer's disease.
- Author
-
Sweeney, Melanie D., Montagne, Axel, Sagare, Abhay P., Nation, Daniel A., Schneider, Lon S., Chui, Helena C., Harrington, Michael G., Pa, Judy, Law, Meng, Wang, Danny J. J., Jacobs, Russell E., Doubal, Fergus N., Ramirez, Joel, Black, Sandra E., Nedergaard, Maiken, Benveniste, Helene, Dichgans, Martin, Iadecola, Costantino, Love, Seth, and Bath, Philip M.
- Abstract
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
33. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (vol 41, pg 1088, 2009)
- Author
-
Harold, Denise, Abraham, Richard, Hollingworth, Paul, Sims, Rebecca, Gerrish, Amy, Hamshere, Marian L., Pahwa, Jaspreet Singh, Moskvina, Valentina, Dowzell, Kimberley, Williams, A., Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad R., Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K., Brayne, Carol, Rubinsztein, David C., Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Morgan, Kevin, Brown, Kristelle S., Passmore, Peter A., Craig, David, McGuinness, Bernadette, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A. David, Love, Seth, Kehoe, Patrick G., Hardy, John, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Schürmann, Britta, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison M., Kauwe, John S. K., Cruchaga, Carlos, Nowotny, Petra, Morris, John C., Mayo, Kevin, Sleegers, Kristel, Bettens, Karolien, Engelborghs, Sebastiaan, De Deyn, Peter P., Van Broeckhoven, Christine, Livingston, Gill, Bass, Nicholas J., Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Al-Chalabi, Ammar, Shaw, Christopher E., Tsolaki, Magda, Singleton, Andrew B., Guerreiro, Rita, Muehleisen, Thomas W., Noethen, Markus M., Moebus, Susanne, Jöckel, Karl-Heinz, Klopp, Norman, Wichmann, H-Erich, Carrasquillo, Minerva M., Pankratz, V. Shane, Younkin, Steven G., Holmans, Peter A., O'Donovan, Michael, Owen, Michael J., Williams, Julie, Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
- Subjects
Medicine(all) ,Alzheimer's disease - Published
- 2013
34. Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology
- Author
-
Zou, Fanggeng, Belbin, Olivia, Petersen, Ronald C, disease, Genetic and Environmental Risk for Alzheimer’s, Morgan, Kevin, Younkin, Steven G, Harold, Denise, Sims, Rebecca, Gerrish, Amy, Chapman, Jade, Moskvina, Valentina, Abraham, Richard, Carrasquillo, Minerva M, Hollingworth, Paul, Hamshere, Marian, Pahwa, Jaspreet Singh, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad, Williams, Kate, Culley, Oliver J, Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K, Brayne, Carol, Rubinsztein, David C, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Hunter, Talisha A, Brown, Kristelle, Passmore, Peter, Craig, David, McGuinness, Bernadette, Johnston, Janet A, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A David, Love, Seth, Ma, Li, Kehoe, Patrick G, Hardy, John, Guerreiro, Rita, Singleton, Andrew, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Bisceglio, Gina D, Heun, Reiner, Schürmann, Britta, Ramirez, Alfredo, Herold, Christine, Lacour, André, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Allen, Mariet, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison, Kauwe, John S K, Cruchaga, Carlos, Nowotny, Petra, Morris, John C, Dickson, Dennis W, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Nöthen, Markus M, Holmans, Peter, O'Donovan, Michael, Graff-Radford, Neill R, Owen, Michael J, Williams, Julie, and Wiltfang, Jens (Beitragende*r)
- Subjects
Male ,Pathology ,Heredity ,Medizin ,lcsh:Medicine ,Gene Expression ,genetics [Alzheimer Disease] ,pathology [Alzheimer Disease] ,0302 clinical medicine ,Polymorphism (computer science) ,Risk Factors ,genetics [Adaptor Proteins, Signal Transducing] ,Senile plaques ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Temporal Lobe ,Neurology ,genetics [Polymorphism, Single Nucleotide] ,Medicine ,Female ,Alzheimer's disease ,Research Article ,medicine.medical_specialty ,Genotypes ,genetics [Genetic Loci] ,Biology ,metabolism [RNA, Messenger] ,Polymorphism, Single Nucleotide ,metabolism [Temporal Lobe] ,Cell Line ,Molecular Genetics ,03 medical and health sciences ,metabolism [Adaptor Proteins, Signal Transducing] ,genetics [RNA, Messenger] ,Genetic Heterogeneity ,Apolipoproteins E ,Meta-Analysis as Topic ,Alzheimer Disease ,genetics [Haplotypes] ,medicine ,GAB2 protein, human ,Genetics ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,RNA, Messenger ,Allele ,Genetic Association Studies ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Aged ,Evolutionary Biology ,Population Biology ,Genetic heterogeneity ,lcsh:R ,Case-control study ,Computational Biology ,Neurofibrillary tangle ,pathology [Temporal Lobe] ,Human Genetics ,Epistasis, Genetic ,Odds ratio ,medicine.disease ,R1 ,Haplotypes ,Genetic Loci ,Case-Control Studies ,Postmortem Changes ,Genetics of Disease ,North America ,Genetic Polymorphism ,Epistasis ,genetics [Apolipoproteins E] ,lcsh:Q ,Dementia ,030217 neurology & neurosurgery ,Population Genetics - Abstract
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p
- Published
- 2013
35. Tract-specific white matter hyperintensities disrupt neural network function in Alzheimer's disease.
- Author
-
Taylor, Alexander N.W., Kambeitz-Ilankovic, Lana, Gesierich, Benno, Simon-Vermot, Lee, Franzmeier, Nicolai, Araque Caballero, Miguel Á., Müller, Sophia, Hesheng, Liu, Ertl-Wagner, Birgit, Bürger, Katharina, Weiner, Michael W., Dichgans, Martin, Duering, Marco, and Ewers, Michael
- Abstract
Introduction White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated. Method Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of interest (ROIs) and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN). Results WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas. Conclusions High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
36. Spatial Patterns of Longitudinal Gray Matter Change as Predictors of Concurrent Cognitive Decline in Amyloid Positive Healthy Subjects.
- Author
-
Caballero, Miguel Angel Araque, Kloppel, Stefan, Dichgans, Martin, and Ewers, Michael
- Subjects
GRAY matter (Nerve tissue) ,AMYLOID ,ALZHEIMER'S disease risk factors ,DEMENTIA ,COGNITIVE psychology - Abstract
A substantial proportion of cognitively healthy elders (HC) show abnormally high amyloid-β (Aβ) deposition, a major pathology of Alzheimer's disease (AD). These subjects are at increased risk of Alzheimer's disease (AD) dementia, and biomarkers are needed to predict their cognitive deterioration. Here we used relevance vector regression (RVR), a pattern-recognition method, to predict concurrent cognitive decline on the basis of longitudinal gray matter (GM) changes, within two a priori, meta-analytically defined functional networks subserving episodic memory and executive function. Ninety-six HC subjects were assessed annually for three years with structural MRI and cognitive tests within the Alzheimer's Disease Neuroimaging Initiative. Presence of abnormal biomarker values of Aβ (Aβ+) were determined with cerebrospinal fluid and amyloid-PET (HC-Aβ+, n = 30; with n = 66 for normal HC-Aβ-). Using leave-one-out cross-validation, we found that in HC-Aβ+patterns of GM changes within both networks predicted decline in episodic memory (r = 0.61, p < 0.001; r = 0.40, p = 0.03), but not executive function. In HC-Aβ-, GM changes within the executive function network predicted decline in executive function (r = 0.44,p < 0.001). Previously established region-of-interest (ROI)-based predictors such as changes in hippocampal volume, within an AD-signature multi-ROI, or total GM volume were not predictive of cognitive decline in any group or cognitive domain. RVR analyses unrestricted to the a priori networks yielded compatible results with the restricted case. In conclusion, RVR-derived patterns of subtle cortical GM changes are biomarker candidates of concurrent cognitive decline in aging and subjects at risk for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
37. A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms.
- Author
-
Baykara, Ebru, Gesierich, Benno, Adam, Ruth, Tuladhar, Anil Man, Biesbroek, J. Matthijs, Koek, Huiberdina L., Ropele, Stefan, Jouvent, Eric, Chabriat, Hugues, Ertl‐Wagner, Birgit, Ewers, Michael, Schmidt, Reinhold, de Leeuw, Frank‐Erik, Biessels, Geert Jan, Dichgans, Martin, and Duering, Marco
- Subjects
ALZHEIMER'S disease ,BRAIN ,COMPARATIVE studies ,MAGNETIC resonance imaging ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH evaluation ,EVALUATION research ,CEREBRAL small vessel diseases ,DISEASE complications - Abstract
Objective: To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.Methods: We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.Results: PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.Interpretation: PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
38. Tipping points in neurodegeneration.
- Author
-
Simons, Mikael, Levin, Johannes, and Dichgans, Martin
- Subjects
- *
ALZHEIMER'S disease , *NEURODEGENERATION , *CARDIOVASCULAR system , *DRUG target - Abstract
In Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial proportion of affected individuals remains non-demented despite AD pathology, raising questions about the underlying factors that determine the transition to clinical disease. Here, we emphasize the critical function of resilience and resistance factors, which we extend beyond the concept of cognitive reserve to include the glial, immune, and vascular system. We review the evidence and use the metaphor of "tipping points" to illustrate how gradually forming AD neuropathology in the preclinical stage can transition to dementia once adaptive functions of the glial, immune, and vascular system are lost and self-reinforcing pathological cascades are unleashed. Thus, we propose an expanded framework for pathomechanistic research that focuses on tipping points and non-neuronal resilience mechanisms, which may represent previously untapped therapeutic targets in preclinical AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
39. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL
- Author
-
Dichgans, Martin, Markus, Hugh S, Salloway, Stephen, Verkkoniemi, Auli, Moline, Margaret, Wang, Qin, Posner, Holly, and Chabriat, Hugues S
- Subjects
- *
PARASYMPATHOMIMETIC agents , *CHOLINESTERASE inhibitors , *DEMENTIA , *ALZHEIMER'S disease , *MEDICAL sciences - Abstract
Summary: Background: Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer''s disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL''s early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. Methods: 168 patients with CADASIL (mean age 54·8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10–27 or a trail making test (TMT) B time score at least 1·5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. Findings: 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was −0·81 (SE 0·59) in the placebo group and −0·85 (SE 0·57) in the donepezil group (p=0·956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0·023), TMT A time (p=0·015), and EXIT25 (p=0·022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. Interpretation: Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment. Funding: Eisai Medical Research (Ridgefield Park, NJ, USA). [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
40. Microbiota-derived short chain fatty acids modulate microglia and promote Ab plaque deposition.
- Author
-
Colombo, Alessio Vittorio, Sadler, Rebecca Katie, Llovera, Gemma, Singh, Vikramjeet, Roth, Stefan, Heindl, Steffanie, Monasor, Laura Sebastian, Verhoeven, Aswin, Peters, Finn, Parhizkar, Samira, Kamp, Frits, Gomez de Aguero, Mercedes, MacPherson, Andrew J., Winkler, Edith, Herms, Jochen, Benakis, Corinne, Dichgans, Martin, Steiner, Harald, Giera, Martin, and Haass, Christian
- Subjects
- *
FATTY acids , *MICROBIAL metabolites , *MICROGLIA , *PHENOTYPIC plasticity , *GUT microbiome , *ALZHEIMER'S disease - Abstract
Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Ab deposition. Germ-free (GF) AD mice exhibit a substantially reduced Ab plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Ab plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Ab plaques upon SCFA supplementation, microglia contained less intracellular Ab. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Ab deposition likely via modulation of the microglial phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
41. Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease.
- Author
-
Franzmeier, Nicolai, Dewenter, Anna, Frontzkowski, Lukas, Dichgans, Martin, Rubinski, Anna, Neitzel, Julia, Smith, Ruben, Strandberg, Olof, Ossenkoppele, Rik, Buerger, Katharina, Duering, Marco, Hansson, Oskar, and Ewers, Michael
- Subjects
- *
ALZHEIMER'S disease , *ENTORHINAL cortex , *NEUROFIBRILLARY tangles , *FORECASTING , *GAUSSIAN mixture models , *PATHOLOGY , *GENERAL Data Protection Regulation, 2016 - Abstract
The article discusses in Alzheimer's disease the Braak staging scheme suggests a stereotypical tau spreading pattern that has not capture interindividual variability in tau deposition. Topics include a connectivity-based, patient-centered tau spreading model improved the assessment of tau accumulation rates compared to Braak stage–specific readouts and reduced sample sizes by 40%; and tau pathology have hallmark pathologies of Alzheimer's disease.
- Published
- 2020
- Full Text
- View/download PDF
42. Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel.
- Author
-
Iadecola, Costantino, Duering, Marco, Hachinski, Vladimir, Joutel, Anne, Pendlebury, Sarah T., Schneider, Julie A., and Dichgans, Martin
- Subjects
- *
UNILATERAL neglect , *ALZHEIMER'S disease , *DEMENTIA , *DISABILITIES , *ETIOLOGY of diseases ,WESTERN countries - Abstract
Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer's disease is the leading cause of clinically diagnosed dementia in Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer's disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
43. Enhanced resting-state functional connectivity between core memory-task activation peaks is associated with memory impairment in MCI.
- Author
-
Zhang, Yifei, Simon-Vermot, Lee, Araque Caballero, Miguel Á., Gesierich, Benno, Taylor, Alexander N.W., Duering, Marco, Dichgans, Martin, and Ewers, Michael
- Subjects
- *
MILD cognitive impairment , *ALZHEIMER'S disease , *MEMORY disorders , *FUNCTIONAL magnetic resonance imaging , *DEMENTIA patients , *EPISODIC memory - Abstract
Resting-state functional connectivity (FC) is altered in Alzheimer's disease (AD) but its predictive value for episodic memory impairment is debated. Here, we aimed to assess whether resting-state FC in core brain regions activated during memory-task functional magnetic resonance imaging is altered and predictive of memory performance in AD and amnestic mild cognitive impairment (aMCI). Twenty-three elderly cognitively healthy controls (HC), 76 aMCI subjects, and 19 AD dementia patients were included. We computed resting-state FC between 18 meta-analytically determined peak coordinates of brain activation during successful memory retrieval. Higher FC between the parahippocampus, parietal cortex, and the middle frontal gyrus was observed in both AD and mild cognitive impairment compared to HC (false-discovery rate—corrected p < 0.05). The increase in FC between the parahippocampus and middle frontal gyrus was associated with reduced episodic memory in aMCI, independent of amyloid-beta positron emission tomography binding and apolipoprotein E ε4-carrier status. In conclusion, increased parahippocampal-prefrontal FC is predictive of impaired episodic memory in aMCI and may reflect a dysfunctional change within the episodic memory–related neural network. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
44. Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
- Author
-
Zieren, Nikola, Duering, Marco, Peters, Nils, Reyes, Sonia, Jouvent, Eric, Hervé, Dominique, Gschwendtner, Andreas, Mewald, Yvonne, Opherk, Christian, Chabriat, Hugues, and Dichgans, Martin
- Subjects
- *
CEREBROVASCULAR disease , *EDUCATIONAL attainment , *COGNITIVE ability , *VASCULAR diseases , *CADASIL syndrome , *ALZHEIMER'S disease , *COGNITION disorders , *NEUROPSYCHOLOGY - Abstract
Abstract: A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer''s disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
45. Influence of SORL1 gene variants: Association with CSF amyloid-β products in probable Alzheimer's disease
- Author
-
Kölsch, Heike, Jessen, Frank, Wiltfang, Jens, Lewczuk, Piotr, Dichgans, Martin, Kornhuber, Johannes, Frölich, Lutz, Heuser, Isabella, Peters, Oliver, Schulz, Jörg B., Schwab, Sibylle G., and Maier, Wolfgang
- Subjects
- *
ALZHEIMER'S disease , *DEMENTIA , *PATHOLOGY , *DISEASES in older people - Abstract
Abstract: SORL1 gene variants were described as risk factors of Alzheimer''s disease (AD). We investigated the association of four SORL1 variants with CSF levels of Aβ42 and Aβ40 in 153 AD patients recruited from a multicenter study of the German Competence Net Dementias. Only one SORL1 SNP was associated with altered Aβ42 levels in the single marker analysis (SNP21: p =0.011), the other SNPs did not show an association with Aβ42 or Aβ40 CSF levels. Haplotype analysis identified a three marker SORL1 haplotype consisting of SNP19 T-allele, SNP21 G-allele and SNP23 A-allele (T/G/A) which was associated with reduced Aβ42 CSF levels in AD patients (p =0.003). Aβ40 levels were also lower in carriers of this haplotype; however, this did not reach statistical significance (p =0.15). We found a SORL1 haplotype which was associated with CSF levels of amyloid-β cleavage products, measured as altered levels of Aβ42. Thus our data suggest that SORL1 gene variants might influence AD pathology. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.