Alzheimer Disease: Mulder C

Mulder C, Scheltens P, Visser JJ, van Kamp GJ, Schutgens RB. · Department of Clinical Chemistry, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. · Ann Clin Biochem. · Pubmed #11026514 No free full text.

This publication has no abstract.

Verwey NA, Schuitemaker A, van der Flier WM, Mulder SD, Mulder C, Hack CE, Scheltens P, Blankenstein MA, Veerhuis R. · Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #19052452 No free full text.

Abstract: BACKGROUND: Serum amyloid P component (SAP), present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD), may protect Abeta deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. METHODS: SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 +/- 1.0 and 2.1 +/- 0.8 years). RESULTS: Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 mg/l, range 3.3-199.3 mg/l) than MCI nonprogressors (20.2 mg/l, range 7.0-127.7 mg/l; p < 0.05). A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9-5.4). CONCLUSION: Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.

Pijnenburg YA, Schoonenboom SN, Mehta PD, Mehta SP, Mulder C, Veerhuis R, Blankenstein MA, Scheltens P. · Alzheimer Centre and Department of Neurology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #17371907 No free full text.

Abstract: The role of amyloid metabolism in the pathophysiology of frontotemporal lobar degeneration (FTLD) has yet to be elucidated. We compared CSF levels of amyloid beta 1-40 (Abeta40) and amyloid beta 1-42 (Abeta42) in patients with FTLD (n = 21) versus patients with Alzheimer's disease (AD, n = 39) and in control subjects (n = 30). While in AD cases Abeta42 levels were lower and CSF Abeta40 levels equal to those in controls, a significant decrease in Abeta40 and increase in the CSF Abeta42/Abeta40 ratio was observed in FTLD compared with AD and control subjects. These findings favour a differential involvement of amyloid beta peptides in FTLD compared with AD.

Pijnenburg YA, Janssen JC, Schoonenboom NS, Petzold A, Mulder C, Stigbrand T, Norgren N, Heijst H, Hack CE, Scheltens P, Teunissen CE. · Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands, and Chelsea and Westminster, Brompton and Charing Cross Hospitals, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #17290105 No free full text.

Abstract: BACKGROUND: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer's disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-beta(1-42), tau and tau phosphorylated at threonine-181. METHODS: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. RESULTS: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. CONCLUSION: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.

Pijnenburg YA, Schoonenboom SN, Barkhof F, Knol DL, Mulder C, Van Kamp GJ, Van Swieten JC, Scheltens P. · Alzheimer Center, Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16421130 links to  free full text

Abstract: In order to better understand the large variation in cerebrospinal fluid (CSF) tau and amyloid-beta(1-42) (Abeta42) in frontotemporal lobar degeneration (FTLD), relations between these biomarkers and clinical parameters, neuroimaging characteristics, and apolipoprotein E (ApoE) genotype were studied in 31 patients with FTLD, including 16 patients with the frontal variant and 15 with the temporal variant. CSF tau was highest in FTLD with predominant temporal involvement. In the frontal subgroup, CSF tau level was influenced by the number of ApoE epsilon3 alleles. In the temporal subgroup, CSF tau level was dependent on a combination of CSF Abeta42, age, disease duration, and disease severity. No relation with degree of atrophy or asymmetry on neuroimaging could be established. CSF Abeta42 variability remained unexplained. Future research could study the role of ApoE genotype and Abeta42 in FTLD, as well as establish measures for disease intensity.

Mulder C, Schoonenboom NS, Jansen EE, Verhoeven NM, van Kamp GJ, Jakobs C, Scheltens P. · Department of Clinical Chemistry, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. · Neurosci Lett. · Pubmed #16040194 No free full text.

Abstract: Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.

Schoonenboom NS, Mulder C, Van Kamp GJ, Mehta SP, Scheltens P, Blankenstein MA, Mehta PD. · Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands. · Ann Neurol. · Pubmed #15984010 No free full text.

Abstract: Various C-terminally truncated amyloid beta peptides (Abeta) are linked to Alzheimer's disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Abeta38, Abeta40, and Abeta42 were measured by enzyme-linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Abeta42 levels was decreased in patients with AD, whereas CSF Abeta38 and Abeta40 levels were similar in patients with AD and control subjects. All three Abeta peptides were interrelated, particularly CSF Abeta38 and Abeta40. Diagnostic accuracy of CSF Abeta42 concentrations was not improved by applying the ratios of CSF Abeta42 to Abeta38 or Abeta40.

Schoonenboom NS, Mulder C, Vanderstichele H, Pijnenburg YA, Van Kamp GJ, Scheltens P, Mehta PD, Blankenstein MA. · Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Clin Chem. · Pubmed #15845801 links to  free full text

This publication has no abstract.

Schoonenboom SN, Visser PJ, Mulder C, Lindeboom J, Van Elk EJ, Van Kamp GJ, Scheltens PH. · Department of Neurology Alzheimer Centre, VU University Medical Centre, Amsterdam, the Netherlands. · Neurocase. · Pubmed #15804919 No free full text.

Abstract: The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer's disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Abeta42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Abeta32 or high CSF tau (intermediate-risk) and 20% a normal CSF Abeta42 and tau (low-risk). Both high-and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS),which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Abeta42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.

Schoonenboom NS, Mulder C, Vanderstichele H, Van Elk EJ, Kok A, Van Kamp GJ, Scheltens P, Blankenstein MA. · Alzheimer Center and Department of Neurology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. · Clin Chem. · Pubmed #15539465 links to  free full text

Abstract: BACKGROUND: Reported concentrations of amyloid beta (1-42) (A beta 42) and tau in cerebrospinal fluid (CSF) differ among reports. We investigated the effects of storage temperature, repeated freeze/thaw cycles, and centrifugation on the concentrations of A beta 42 and tau in CSF. METHODS: Stability of samples stored at -80 degrees C was determined by use of an accelerated stability testing protocol according to the Arrhenius equation. A beta 42 and tau concentrations were measured in CSF samples stored at 4, 18, 37, and -80 degrees C. Relative CSF concentrations (%) of the biomarkers after one freeze/thaw cycle were compared with those after two, three, four, five, and six freeze/thaw cycles. In addition, relative A beta 42 and tau concentrations in samples not centrifuged were compared with samples centrifuged after 1, 4, 48, and 72 h. RESULTS: A beta 42 and tau concentrations were stable in CSF when stored for a long period at -80 degrees C. CSF A beta 42 decreased by 20% during the first 2 days at 4, 18, and 37 degrees C compared with -80 degrees C. CSF tau decreased after storage for 12 days at 37 degrees C. After three freeze/thaw cycles, CSF A beta 42 decreased 20%. CSF tau was stable during six freeze/thaw cycles. Centrifugation did not influence the biomarker concentrations. CONCLUSIONS: Repeated freeze/thaw cycles and storage at 4, 18, and 37 degrees C influence the quantitative result of the A beta 42 test. Preferably, samples should be stored at -80 degrees C immediately after collection.

Schoonenboom NS, Pijnenburg YA, Mulder C, Rosso SM, Van Elk EJ, Van Kamp GJ, Van Swieten JC, Scheltens P. · Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Neurology. · Pubmed #15136685 No free full text.

Abstract: OBJECTIVE: To determine the diagnostic value of CSF amyloid beta(1-42) (Abeta42), CSF total tau, and CSF tau phosphorylated at threonine-181 (Ptau-181) in early-onset Alzheimer disease (EAD) vs frontotemporal lobar degeneration (FTLD). METHODS: Levels of Abeta42, total tau, and Ptau-181 in CSF were measured using commercially available ELISA in 47 EAD patients, 28 FTLD patients, and 21 nondemented control subjects. RESULTS: CSF Abeta42 was significantly lower and CSF total tau and CSF Ptau-181 significantly higher in EAD patients than FTLD patients and control subjects. There was an increase in diagnostic accuracy for CSF Ptau-181 vs CSF total tau (p = 0.067). Combining low CSF Abeta42 and high CSF Ptau-181 allowed EAD patients to be distinguished from FTLD patients with a sensitivity of 72% and a specificity of 93%. Logistic regression analysis with CSF Abeta42 and CSF Ptau-181 as independent continuous variables resulted in correct classification of 46 of 47 (98%) EAD patients and 23 of 28 (82%) FTLD patients. The diagnostic accuracy for EAD was independent of gender, disease duration, and disease severity. CONCLUSION: The combination of CSF Abeta42 and CSF Ptau-181 may help in differentiating EAD from FTLD.

Mulder C, Wahlund LO, Teerlink T, Blomberg M, Veerhuis R, van Kamp GJ, Scheltens P, Scheffer PG. · Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands. · J Neural Transm. · Pubmed #12898349 No free full text.

Abstract: Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

Mulder C, Schoonenboom SN, Wahlund LO, Scheltens P, van Kamp GJ, Veerhuis R, Hack CE, Blomberg M, Schutgens RB, Eikelenboom P. · Department of Clinical Chemistry, Research Institute Neurosciences, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. · J Neural Transm. · Pubmed #12486489 No free full text.

Abstract: Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity.Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Mulder C, Wahlund LO, Blomberg M, de Jong S, van Kamp GJ, Scheltens P, Teerlink T. · Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Sweden. · J Neural Transm. · Pubmed #12203047 No free full text.

Abstract: Nitric oxide (NO) may play a role in the pathophysiology of Alzheimer's disease (AD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is involved in regulation of NO production. Recently it has been reported that dimethylarginine dimethylaminohydrolase, an enzyme that hydrolyses ADMA into citrulline and dimethylamine, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in AD. We hypothesized that this could lead to altered CSF concentrations of ADMA in AD. Measurement of ADMA and dimethylamine in CSF revealed no significant differences between AD patients (n = 20) and age-matched control subjects (n = 20). Our results suggest that in early stages of AD overall regulation of NO production by ADMA is not aberrant.

Konings CH, Kuiper MA, Teerlink T, Mulder C, Scheltens P, Wolters EC. · Department of Clinical Chemistry, Academisch Ziekenhuis Vrije Universiteit, P.O. Box 7057, 1007 MG, Amsterdam, The Netherlands. · J Neurol Sci. · Pubmed #10526192 No free full text.

Abstract: We measured total glutathione concentrations in the cerebrospinal fluid (CSF) of non-demented Parkinson's disease patients (PD; n=71), demented PD patients (PDD; n=13), multiple system atrophy patients (MSA; n=10), Alzheimer's disease patients (AD; n=17) and age-matched controls (n=21). No statistically significant differences in the mean total CSF glutathione concentrations were found between groups and dopaminomimetic treatment was not found to have any effect on total CSF glutathione levels. Our main conclusion is that total glutathione is not useful as a CSF marker for assumed oxidative stress in patients with PD, MSA or AD.

Mulder C, van der Flier WM, Veerhuis R, Bouwman F, Jakobs C, Verhoeven NM, Barkhof F, Scheltens P, Blankenstein MA. · No affiliation provided · J Am Geriatr Soc. · Pubmed #17537101 No free full text.

This publication has no abstract.

Mulder C, Scheltens P, Barkhof F, Gundy C, Verstraeten RA, de Leeuw FE. · No affiliation provided · J Am Geriatr Soc. · Pubmed #15935040 No free full text.

This publication has no abstract.