Authors: Nerius, Michael | Haenisch, Britta | Gomm, Willy | Doblhammer, Gabriele | Schneider, Anja
Article Type: Research Article
Abstract: Background: Recent evidence indicates an important role for neuroinflammation in the pathological cascade of Alzheimer’s disease (AD), and neuroinflammation is increasingly being recognized as a potential therapeutic target. Objective: To assess the impact of glucocorticoids on the risk of developing dementia. Methods: We used health insurance data of the largest German health insurer from 2004–2013 with a baseline sample of 176,485 persons aged 50 years and older to study the association of glucocorticoid treatment and incidence of dementia. Cox proportional-hazard models were calculated adjusting for sex, age, and comorbidities known to be major risk factors for dementia and were given …as hazard ratios (HR) with 95% confidence intervals (CI). We further stratified glucocorticoid treatment by route of application and treatment duration. Results: Of the 176,485 dementia-free persons, 19,938 were diagnosed with dementia by the end of 2013. The risk of suffering from dementia was significantly lower for glucocorticoid users compared to non-users (HR = 0.81, CI = 0.78–0.84). The lowest risk was found among users of inhaled glucocorticoid (HR = 0.65, CI = 0.57–0.75), followed by nasal (HR = 0.76, CI = 0.66–0.87), other (HR = 0.84, CI = 0.80–0.88), and oral users (HR = 0.83, CI = 0.78–0.88). We found no difference in risk reduction between long- and short-term-users. Conclusion: Longitudinal German health insurance data indicate that the use of glucocorticoids is associated with a lower risk of dementia. Prospective clinical trials will be necessary to determine whether glucocorticoids can have a positive impact on neuroinflammation and thus protect persons against dementia. Show more
Keywords: Administrative claims, cohort studies, dementia, epidemiology, glucocorticoids, inflammation
DOI: 10.3233/JAD-190444
Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 175-183, 2020
Authors: Schweda, Mark | Kögel, Anna | Bartels, Claudia | Wiltfang, Jens | Schneider, Anja | Schicktanz, Silke
Article Type: Research Article
Abstract: Background: Biomarker-supported testing for preclinical and prodromal Alzheimer’s disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries. Objectives: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns. Methods: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and percentage distribution. Results: Nearly …half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a ‘right not to know’, 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73–75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested. Conclusions: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed. Show more
Keywords: Alzheimer’s disease, dementia, disclosure, ethics, Germany, questionnaires, surveys
DOI: 10.3233/JAD-170443
Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 145-155, 2018
Authors: Zhang, William I. | Antonios, Gregory | Rabano, Alberto | Bayer, Thomas A. | Schneider, Anja | Rizzoli, Silvio O.
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) is neuropathologically characterized by aggregates of amyloid-β peptides (Aβ) and tau proteins. The consensus in the AD field is that Aβ and tau should serve as diagnostic biomarkers for AD. However, their aggregates have been difficult to investigate by conventional fluorescence microscopy, since their size is below the diffraction limit (∼200 nm). To solve this, we turned to a super-resolution imaging technique, stimulated emission depletion (STED) microscopy, which has a high enough precision to allow the discrimination of low- and high-molecular weight aggregates prepared in vitro . We used STED to analyze the structural organization of Aβ and …tau in cerebrospinal fluid (CSF) from 36 AD patients, 11 patients with mild cognitive impairment (MCI), and 21 controls. We measured the numbers of aggregates in the CSF samples, and the aggregate sizes and intensities. These parameters enabled us to distinguish AD patients from controls with a specificity of ∼87% and a sensitivity of ∼79% . In addition, the aggregate parameters determined with STED microscopy correlated with the severity of cognitive impairment in AD patients. Finally, these parameters may be useful as predictive tools for MCI cases. The STED parameters of two MCI patients who developed AD during the course of the study, as well as of MCI patients whose Aβ ELISA values fall within the accepted range for AD, placed them close to the AD averages. We suggest that super-resolution imaging is a promising tool for AD diagnostics. Show more
Keywords: Alzheimer’s disease, amyloid-β, diagnostics, imaging, super-resolution, tau
DOI: 10.3233/JAD-150064
Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1007-1020, 2015
Authors: Bartels, Claudia | Abdel-Hamid, Mona | Wiltfang, Jens | Schneider, Anja | Belz, Michael
Article Type: Research Article
Abstract: Background: The multimodal CORDIAL treatment concept for mild dementia, combining cognitive rehabilitation, cognitive behavioral and humanistic psychology interventions, has proven its feasibility and demonstrated a reduction of depressive symptoms in individual dyadic/triadic settings. Objective: We investigate antidepressant effects of an adapted group-based CORDIAL program in clinical routine care. Methods: During 2013 and 2017, 51 outpatients with mild dementia (45% female, mean age 72.4 years, 67% Alzheimer’s dementia, mean MMST 24.8) periodically received a modified CORDIAL group treatment as part of our regular outpatient care. Treatment comprised 10 bi-weekly sessions, partly involving caregivers. Systematic pre- and post-treatment assessments of clinical routine …data were evaluated retrospectively (median time-interval of 6.6 months). Results: Depressive symptoms as measured by the Geriatric Depression Scale significantly decreased over time (p = 0.007, Cohen’s d = 0.39), and irrespective of gender. Patients with longer disease duration before treatment start showed significantly higher initial levels of depressive symptoms (p = 0.044), followed by a reduction to a level of those with shorter disease duration (ns ). Most secondary outcomes (cognitive symptoms, disease severity, quality of life, caregiver burden) remained unchanged (ns ), while competence in activities of daily living declined from pre- to post-measurement (p = 0.033). Conclusion: A group-based CORDIAL treatment is feasible in a clinical routine setting and demonstrated antidepressant effects comparable to those of the individual treatment design, further suggesting its implementation in regular care. Future trials might also investigate its potentially preventive effects by reducing depressive symptoms in pre-dementia stages, even at a subsyndromal level. Show more
Keywords: Dementia, depression, cognitive rehabilitation, cognitive behavioral therapy, reminiscence, group therapy, activities of daily living, caregiver burden
DOI: 10.3233/JAD-220578
Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1725-1737, 2022
Authors: Bartels, Claudia | Kögel, Anna | Schweda, Mark | Wiltfang, Jens | Pentzek, Michael | Schicktanz, Silke | Schneider, Anja
Article Type: Research Article
Abstract: Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in …Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42 , tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p ≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed. Show more
Keywords: Alzheimer’s disease, biomarker, mild cognitive impairment, prediction, questionnaires, subjective cognitive decline, surveys
DOI: 10.3233/JAD-200794
Citation: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1137-1148, 2020
Authors: Teipel, Stefan J. | Metzger, Coraline D. | Brosseron, Frederic | Buerger, Katharina | Brueggen, Katharina | Catak, Cihan | Diesing, Dominik | Dobisch, Laura | Fliebach, Klaus | Franke, Christiana | Heneka, Michael T. | Kilimann, Ingo | Kofler, Barbara | Menne, Felix | Peters, Oliver | Polcher, Alexandra | Priller, Josef | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Thelen, Manuela | Thyrian, René J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group
Article Type: Research Article
Abstract: Background: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer’s disease (AD). Objective: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. Methods: We determined rs-fMRI functional connectivity based on Pearson’s correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination …accuracy based on penalized logistic regression to account for multicollinearity of predictors. Results: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. Conclusion: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD. Show more
Keywords: diagnostic accuracy, functional MRI, multicenter, subjective cognitive decline, contstartabstract
DOI: 10.3233/JAD-180106
Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 801-813, 2018
Authors: Teipel, Stefan J. | Kuper-Smith, Jan O. | Bartels, Claudia | Brosseron, Frederic | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Janowitz, Daniel | Dechent, Peter | Dobisch, Laura | Ertl-Wagner, Birgit | Fließbach, Klaus | Haynes, John-Dylan | Heneka, Michael T. | Kilimann, Ingo | Laske, Christoph | Li, Siyao | Menne, Felix | Metzger, Coraline D. | Priller, Josef | Pross, Verena | Ramirez, Alfredo | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group
Article Type: Research Article
Abstract: Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer’s disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis …(p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases. Show more
Keywords: amyloid, anisotropy, cerebral white matter, cognition, diagnosis, diffusion tensor imaging, mild cognitive impairment, subjective cognitive decline
DOI: 10.3233/JAD-190446
Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 455-465, 2019
Authors: Wolfsgruber, Steffen | Kleineidam, Luca | Weyrauch, Anne-Sophie | Barkhoff, Miriam | Röske, Sandra | Peters, Oliver | Preis, Lukas | Gref, Daria | Spruth, Eike Jakob | Altenstein, Slawek | Priller, Josef | Fließbach, Klaus | Schneider, Anja | Wiltfang, Jens | Bartels, Claudia | Jessen, Frank | Maier, Franziska | Düzel, Emrah | Metzger, Coraline | Glanz, Wenzel | Buerger, Katharina | Janowitz, Daniel | Perneczky, Robert | Rauchmann, Boris-Stephan | Kilimann, Ingo | Teipel, Stefan | Laske, Christoph | Munk, Matthias H. | Roy, Nina | Spottke, Annika | Ramirez, Alfredo | Heneka, Michael T. | Brosseron, Frederic | Wagner, Michael | on behalf of the DELCODE study group
Article Type: Research Article
Abstract: Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n = 236 healthy controls without FHAD from the DELCODE study. We …measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression. Show more
Keywords: Alzheimer’s disease, cerebrospinal fluid, family history, subjective cognitive decline
DOI: 10.3233/JAD-215416
Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 545-555, 2022
Authors: Teipel, Stefan J. | Dyrba, Martin | Ballarini, Tommaso | Brosseron, Frederic | Bruno, Davide | Buerger, Katharina | Cosma, Nicoleta-Carmen | Dechent, Peter | Dobisch, Laura | Düzel, Emrah | Ewers, Michael | Fliessbach, Klaus | Haynes, John D. | Janowitz, Daniel | Kilimann, Ingo | Laske, Christoph | Maier, Franziska | Metzger, Coraline D. | Munk, Matthias H. | Peters, Oliver | Pomara, Nunzio | Preis, Lukas | Priller, Josef | Ramírez, Alfredo | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Schott, Björn H. | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Jessen, Frank | Heneka, Michael T.
Article Type: Research Article
Abstract: Background: Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume …and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42 /ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples. Show more
Keywords: Alzheimer’s disease, cerebrospinal fluid, cholinergic system, neuroinflammation, MRI, plasma, sTREM2
DOI: 10.3233/JAD-215196
Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1267-1282, 2022
Authors: Daamen, Marcel | Scheef, Lukas | Li, Shumei | Grothe, Michel J. | Gaertner, Florian C. | Buchert, Ralph | Buerger, Katharina | Dobisch, Laura | Drzezga, Alexander | Essler, Markus | Ewers, Michael | Fliessbach, Klaus | Herrera Melendez, Ana Lucia | Hetzer, Stefan | Janowitz, Daniel | Kilimann, Ingo | Krause, Bernd Joachim | Lange, Catharina | Laske, Christoph | Munk, Matthias H. | Peters, Oliver | Priller, Josef | Ramirez, Alfredo | Reimold, Matthias | Rominger, Axel | Rostamzadeh, Ayda | Roeske, Sandra | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Boecker, Henning
Article Type: Research Article
Abstract: Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer’s disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with …cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at “grey zone” levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings. Show more
Keywords: Acetylcholine, Alzheimer’s disease, amyloid, atrophy, basal forebrain, cognitive decline
DOI: 10.3233/JAD-230141
Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1013-1028, 2023
