Authors: Schwerthöffer, Dirk | Haselwarter, Tim | Grimmer, Timo
Article Type: Research Article
Abstract: Background: Obstructive sleep apnea (OSA) is associated with cognitive disorders, but little is known about prevalence of co-occurring OSA and mild cognitive impairment (MCI) as well as about co-occurring OSA and Alzheimer’s disease (AD). Pathophysiological models integrating OSA, cognitive deficits and neurodegeneration remain speculative. Findings in this area could contribute to the knowledge about pathophysiological processes in cognitive disorders and neurodegenerative processes, be helpful for the diagnosis of cognitive disorders and provide approaches for the treatment of cognitive disorders. Objective: Examining the prevalence of OSA and patterns of cognitive deficits as well as AD biomarker profiles associated with OSA in …a cohort of 104 MCI patients. Methods: Assessments used include: respiratory polygraphy, The Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD NB), Tau, phosphoTau181, amyloid-β-1–42/1–40, 18F-fluorodeoxyglucose positron emission tomography (F18-FDG-PET). Results: Prevalence of OSA of any severity: 58,7% (Apnea Hypopnea Index (AHI)≥5/h), OSA in a moderate-to-severe extent (AHI≥15/h): 25%. Only 13.1% of MCI patients with OSA reported daytime sleepiness. MCI-OSA patients showed no specific neuropsychological pattern. Presence of OSA was not associated with specific AD biomarker profiles in the whole study group besides a positive association between AD positivity in an AD biomarker sub cohort. Conclusions: OSA is highly prevalent in patients with MCI. It might often remain undiagnosed as only a small number of MCI-OSA patients report daytime sleepiness. OSA could contribute to MCI symptoms and even to AD pathology. Further research is needed to validate these findings and to investigate possible pathophysiological relationships between OSA and MCI as well as between OSA and AD. Show more
Keywords: Alzheimer’s disease, daytime sleepiness, mild cognitive impairment, obstructive sleep apnea
DOI: 10.3233/JAD-240251
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Zebhauser, Paul Theo | Berthele, Achim | Franz, Marie-Sophie | Goldhardt, Oliver | Diehl-Schmid, Janine | Priller, Josef | Ortner, Marion | Grimmer, Timo
Article Type: Research Article
Abstract: Background: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient’s age. Objective: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. Methods: We analyzed cerebrospinal fluid …samples of 76 carefully selected cognitively healthy adults and included amyloid-β 1–40 as a potential marker of drainage from the brain’s interstitial system. Results: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-β 1–40 concentrations. These findings were replicated under varied inclusion criteria. Conclusion: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-β 1–40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, amyloid-beta 1–40, tau proteins, total-Tau
DOI: 10.3233/JAD-210286
Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 155-162, 2021
Authors: Hedderich, Dennis M. | Spiro, Judith E. | Goldhardt, Oliver | Kaesmacher, Johannes | Wiestler, Benedikt | Yakushev, Igor | Zimmer, Claus | Boeckh-Behrens, Tobias | Grimmer, Timo
Article Type: Research Article
Abstract: Background: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming. Objective: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer’s disease (AD) compared to visual reading. Methods: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists …and 1 clinical dementia expert, assessed the patients’ MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested. Results: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers. Conclusion: Volumetric information from volBrain increases the radiologist’s diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD. Show more
Keywords: Alzheimer’s disease, magnetic resonance imaging, mild cognitive impairment, neurodegenerative disease
DOI: 10.3233/JAD-180532
Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1459-1467, 2018
Authors: Pasquini, Lorenzo | Benson, Gloria | Grothe, Michel J. | Utz, Lukas | Myers, Nicholas E. | Yakushev, Igor | Grimmer, Timo | Scherr, Martin | Sorg, Christian | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: In Alzheimer’s disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in …areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments. Show more
Keywords: Alzheimer’s disease, amyloid-β, intrinsic functional connectivity, mild cognitive impairment, multimodal imaging
DOI: 10.3233/JAD-170096
Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 763-773, 2017
Authors: Oeckl, Patrick | Halbgebauer, Steffen | Anderl-Straub, Sarah | Steinacker, Petra | Huss, André M. | Neugebauer, Hermann | von Arnim, Christine A.F. | Diehl-Schmid, Janine | Grimmer, Timo | Kornhuber, Johannes | Lewczuk, Piotr | Danek, Adrian | Consortium for Frontotemporal Lobar Degeneration German | Ludolph, Albert C. | Otto, Markus
Article Type: Short Communication
Abstract: Reliable blood biomarkers for Alzheimer’s disease (AD) are missing. We measured astroglial GFAP in patients with AD (n = 28), frontotemporal dementia (bvFTD, n = 35), Parkinson’s disease (n = 11), Lewy body dementias (n = 19), and controls (n = 34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r = –0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be …the first blood biomarker in the differential diagnosis of AD and bvFTD. Show more
Keywords: Alzheimer’s disease, astrocyte, biomarker, cerebrospinal fluid, differential diagnosis, frontotemporal dementia, GFAP, Lewy body dementia, Parkinson’s disease, serum
DOI: 10.3233/JAD-180325
Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 481-488, 2019
Authors: Alexopoulos, Panagiotis | Thierjung, Nathalie | Economou, Polychronis | Werle, Lukas | Buhl, Felix | Kagerbauer, Simone | Papanastasiou, Anastasios D. | Grimmer, Timo | Gourzis, Philippos | Berthele, Achim | Hemmer, Bernhard | Kübler, Hubert | Martin, Jan | Politis, Antonios | Perneczky, Robert
Article Type: Short Communication
Abstract: Cost- and time-effective markers of Alzheimer’s disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAβPPβ levels did not differ between the studied groups. This provides further evidence for the potential of sAβPPβ in plasma as an AD biomarker candidate.
Keywords: Biomarker candidate, NIA-AA research framework diagnostic criteria, soluble amyloid-β protein precursor β
DOI: 10.3233/JAD-181088
Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 83-90, 2019
Authors: Ortner, Marion | Lanz, Korbinian | Goldhardt, Oliver | Müller-Sarnowski, Felix | Diehl-Schmid, Janine | Förstl, Hans | Hedderich, Dennis M. | Yakushev, Igor | Logan, Chad A. | Weinberger, Jan-Philipp | Simon, Maryline | Grimmer, Timo
Article Type: Research Article
Abstract: Background: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer’s disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. Objective: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. Methods: Frozen CSF samples (n = 84) were measured using Elecsys β-Amyloid(1–42) (Aβ42 ), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International …Ltd), and a robust prototype β-Amyloid(1–40) (Aβ40 ) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman’s correlation, sensitivity/specificity, and logistic/linear regression analyses. Results: The extent of WMH showed significant correlation with Aβ42 /Aβ40 ratio (Rho=-0.250; p = 0.040), tTau (Rho = 0.292; p = 0.016), tTau/Aβ42 ratio (Rho = 0.247; p = 0.042), age (Rho = 0.373; p = 0.002), and MMSE (Rho=-0.410; p = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. Conclusion: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebral small vessel diseases, cerebrospinal fluid, diagnosis, differential
DOI: 10.3233/JAD-221187
Citation: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1537-1549, 2023
Authors: Angermann, Susanne | Schier, Johannes | Baumann, Marcus | Steubl, Dominik | Hauser, Christine | Lorenz, Georg | Günthner, Roman | Braunisch, Matthias C. | Kemmner, Stephan | Satanovskij, Robin | Haller, Bernhard | Heemann, Uwe | Lehnert, Thomas | Bieber, Richard | Pachmann, Martin | Braun, Jürgen | Scherf, Julia | Schätzle, Gabriele | Fischereder, Michael | Grimmer, Timo | Schmaderer, Christoph
Article Type: Research Article
Abstract: Background: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality. Objective: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients. Methods: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA). Cognitive impairment was defined as a MoCA test score ≤24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model …adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality. Results: A MoCA test score ≤24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683–4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007–3.038; p = 0.047). Conclusion: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population. Show more
Keywords: Cognitive dysfunction, hemodialysis, Montreal Cognitive Assessment, mortality
DOI: 10.3233/JAD-180767
Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1529-1537, 2018
Authors: Nave, Stephane | Doody, Rachelle S. | Boada, Mercè | Grimmer, Timo | Savola, Juha-Matti | Delmar, Paul | Pauly-Evers, Meike | Nikolcheva, Tania | Czech, Christian | Borroni, Edilio | Ricci, Benedicte | Dukart, Juergen | Mannino, Marie | Carey, Tracie | Moran, Emma | Gilaberte, Inma | Muelhardt, Nicoletta Milani | Gerlach, Irene | Santarelli, Luca | Ostrowitzki, Susanne | Fontoura, Paulo
Article Type: Research Article
Abstract: Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the …difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p = 0.014; 1 mg) and – 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline. Show more
Keywords: Alzheimer’s disease, dementia, monoamine oxidase B, Phase II clinical trial
DOI: 10.3233/JAD-161309
Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1217-1228, 2017