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Authors: Kawasaki, Aki | Ouanes, Sami | Crippa, Sylvain V. | Popp, Julius

Article Type: Research Article

Abstract: Background: Pathologic changes in cerebral and retinal structures governing the pupillary light reflex occur in Alzheimer’s disease (AD). Analysis of pupillary responses originating from different retinal cells may allow for non-invasive detection of cerebral AD pathology. Objective: This study aimed to quantify the pupil light reflex using a portable chromatic pupillometer in patients with early stage AD and compare their responses to those of a healthy control group. Methods: Participants in this case-control pilot study were recruited from a well-characterized cohort of elderly people participating in a larger prospective study on early AD. Cognitive testing, volumetric brain imaging, and lumbar …puncture were performed in all participants to define two groups: early AD, i.e., cognitively impaired subjects with biomarker-confirmed AD pathology, and control group of subjects with normal cognition and normal CSF biomarker profile. Pupil responses to red and blue light stimuli intended to activate cone photoreceptors and melanopsin ganglion cells were recorded under photopic conditions. Results: Sixteen patients with AD (mean age 77 years) and sixteen controls (mean age 71 years) were tested. Baseline pupil size was significantly smaller in AD patients. Pupillary contraction amplitude to all red and blue lights was also smaller in AD patients but did not reach statistical significance. The post-illumination pupillary response was the same between the two groups. Conclusion: Compared to healthy controls, we found only a smaller resting size of the pupil in patients with early AD. The pupillary dynamics to light stimulation remained relatively preserved. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, dementia, melanopsin ganglion cell, pupil, pupil light reflex

DOI: 10.3233/JAD-200120

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1273-1282, 2020

Authors: Oikonomidi, Aikaterini | Tautvydaitė, Domilė | Gholamrezaee, Mehdi M. | Henry, Hugues | Bacher, Michael | Popp, Julius

Article Type: Research Article

Abstract: Background: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer’s disease (AD) pathology. Objective: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. Methods: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1–42 , tau, and …ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. Results: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1–42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1–42 and tau levels. Conclusion: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, cognitive decline, macrophage migration inhibitory factor, neuroinflammation

DOI: 10.3233/JAD-170335

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 273-281, 2017

Authors: Popp, Julius | Lewczuk, Piotr | Frommann, Ingo | Kölsch, Heike | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1–42 (Aβ1–42 ) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1–42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1–42 and pTau181 concentrations in 280 adults with normal cognition …across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1–42 and pTau181, and of the APOEε4 genotype on the Aβ1–42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1–42 concentrations in middle-aged and older participants. In the group of participants with AD, the Aβ1–42 levels were significantly lower in the APOEε4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF Aβ1–42 and pTau181 across lifespan. They also suggest that the decrease of Aβ1–42 , but not the increase of pTau181 CSF levels is accelerated by the APOEε4 genotype in middle-aged and older adults with normal cognition. Show more

Keywords: Alzheimer's disease, amyloid-β, APOEε4, cerebrospinal fluid, hyperphosphorylated tau, normal aging

DOI: 10.3233/JAD-2010-100561

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 459-468, 2010

Authors: Lewczuk, Piotr | Popp, Julius | Lelental, Natalia | Kölsch, Heike | Maier, Wolfgang | Kornhuber, Johannes | Jessen, Frank

Article Type: Research Article

Abstract: In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical …dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biomarkers, cerebrospinal fluid

DOI: 10.3233/JAD-2011-110857

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 119-125, 2012

Authors: Arlt, Sönke | Schwedhelm, Edzard | Kölsch, Heike | Jahn, Holger | Linnebank, Michael | Smulders, Yvo | Jessen, Frank | Böger, Rainer H. | Popp, Julius

Article Type: Research Article

Abstract: Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42 ), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as …CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis. Show more

Keywords: Alzheimer's disease, asymmetric dimethylarginine, cerebrospinal fluid, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine

DOI: 10.3233/JAD-2012-112138

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 751-758, 2012

Authors: Popp, Julius | Lewczuk, Piotr | Linnebank, Michael | Cvetanovska, Gabriela | Smulders, Yvo | Kölsch, Heike | Frommann, Ingo | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Aβ1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β = 0.490; p < 0.001), 5-MTHF (β …= -0.273; p = 0.010) levels, and SAM/SAH ratio (β = -0.319; p = 0.013) in controls, and with SAH (β = 0.529; p = 0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, homocysteine, phosphorylated tau

DOI: 10.3233/JAD-2009-1187

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 819-828, 2009

Authors: Dayon, Loïc | Wojcik, Jérôme | Núñez Galindo, Antonio | Corthésy, John | Cominetti, Ornella | Oikonomidi, Aikaterini | Henry, Hugues | Migliavacca, Eugenia | Bowman, Gene L. | Popp, Julius

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimer’s disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia. Objective: Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis. Methods: We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n  = 72) or without (n  = 48) cognitive impairment. CSF Aβ1-42 , tau, and …phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42  > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42  < 724 pg/mL. Results: Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%. Conclusion: Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloidosis, biomarker, dementia, protein, tau

DOI: 10.3233/JAD-170426

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1641-1652, 2017

Authors: Jessen, Frank | Lewczuk, Piotr | Gür, Okan | Block, Wolfgang | Ende, Gabriele | Frölich, Lutz | Hammen, Thilo | Arlt, Sönke | Kornhuber, Johannes | Kucinski, Thomas | Popp, Julius | Peters, Oliver | Maier, Wolfgang | Träber, Frank | Wiltfang, Jens

Article Type: Research Article

Abstract: The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β42 (Aβ42 ), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial function, the …correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production. Show more

Keywords: Alzheimer's disease, amyloid-β42, N-acetylaspartate, medial temporal lobe, mitochondria, proton MR spectrocopy

DOI: 10.3233/JAD-2011-110398

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 393-399, 2011

Authors: Lewczuk, Piotr | Lelental, Natalia | Lachmann, Ingolf | Holzer, Max | Flach, Katharina | Brandner, Sebastian | Engelborghs, Sebastiaan | Teunissen, Charlotte E. | Zetterberg, Henrik | Molinuevo, José Luis | Mroczko, Barbara | Blennow, Kaj | Popp, Julius | Parnetti, Lucilla | Chiasserini, Davide | Perret-Liaudet, Armand | Spitzer, Philipp | Maler, Juan Manuel | Kornhuber, Johannes

Article Type: Research Article

Abstract: Background: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF). Objective: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF. Methods: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method. Results: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. …Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6–15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% – 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer’s disease in stage of mild cognitive impairment or dementia (AD/MCI, n  = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n  = 42, 62.1±9.3 pg/mL, p  < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. Conclusion: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF. Show more

Keywords: Biomarkers, cerebrospinal fluid, phosphorylation, tau

DOI: 10.3233/JAD-160448

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 159-170, 2017

Authors: Klafki, Hans-Wolfgang | Lewczuk, Piotr | Kamrowski-Kruck, Heike | Maler, Juan Manuel | Müller, Katharina | Peters, Oliver | Heuser, Isabella | Jessen, Frank | Popp, Julius | Frölich, Lutz | Wolf, Stefanie | Prinz, Berit | Luckhaus, Christian | Schröder, Johannes | Pantel, Johannes | Gertz, Hermann-Josef | Kölsch, Heike | Müller, Bernhard W. | Esselmann, Hermann | Bibl, Mirko | Kornhuber, Johannes | Wiltfang, Jens

Article Type: Research Article

Abstract: The clinical diagnosis of neurodegenerative disorders can be supported by soluble biomarkers in cerebrospinal fluid (CSF), such as tau protein, phospho-tau, and amyloid-β peptides. In particular, increased CSF levels of phospho-tau in Alzheimer's disease appear to reflect disease specific pathological processes. We report here evidence for the presence of soluble MAP-kinase ERK1/2 in a small set of human CSF samples from patients with Alzheimer's disease, frontotemporal degeneration, and mild cognitive impairment. The level of total ERK1/2 in CSF as measured by electrochemiluminescent assay was correlated with that of total tau and phospho-tau. A small fraction of ERK1/2 in a pooled …CSF sample was found to be in the doubly phosphorylated (activated) state. Our findings suggest that i) MAP kinase ERK1/2 is apparently released under neurodegenerative conditions in parallel with tau and phospho-tau and ii) in the future, it might be possible to find in CSF samples evidence for disease related alterations in brain kinase signaling pathways by use of highly sensitive and activation-state specific anti-kinase antibodies. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, ERK1/2, frontotemporal degeneration, MAP kinase, mild cognitive impairment, tau

DOI: 10.3233/JAD-2009-1167

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 613-622, 2009