Cerebral glucose metabolism,cerebrospinal fluid-beta-amyloid1-42 (CSF-Abeta42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients

We evaluated cerebral glucose metabolism (CMRglc) and cerebrospinal fluid (CSF) levels of tau and beta-amyloid(1-42) (Abeta42), in relation to apolipoprotein E (ApoE) genotype, in patients with mild Alzheimer disease (AD) treated with rivastigmine (n=11) and tacrine (n=16) for 1 year; and two untreated AD groups. The rivastigmine-treated AD patients showed a significant increase in CMRglc as compared to both tacrine-treated and untreated AD subjects. The rivastigmine-treated AD group showed no change in CSF-tau levels after 1 year, while in contrast a significant increase as seen in tacrine-treated and untreated AD patients. The CSF-tau changes were mainly seen in ApoE epsilon4 carriers. There was no significant change in Abeta42 after 1-year treatment with either rivastigmine or tacrine. This study shows that the two long-term cholinesterase inhibitor treatments exert different effects on biological markers for AD.     

CSF beta-amyloid 1-42 and tau in Tunisian patients with Alzheimer's disease: the effect of APOE epsilon4 allele

Alzheimer's disease (AD) is the leading cause of dementia. Currently, no definitive diagnostic test for AD exists. An accurate, convenient and objective test to detect AD is urgently needed for efficient drug development and effective clinical use of emerging therapies. The aim of the present work is to investigate the usefulness of cerebrospinal fluid (CSF) beta-amyloid protein (Abeta1-42) and total tau protein (t-tau) analyses in the diagnosis of AD and whether apolipoprotein E (ApoE) epsilon4 allele is a factor for AD affecting Tunisian people. Abeta1-42 and t-tau levels were measured in CSF from AD patients (n=73), non-Alzheimer dementia (nAD, n=35) and healthy controls (HC, n=38) by sandwich enzyme-linked immunosorbent assay. Abeta1-42 levels were decreased and t-tau increased in AD patients. The combination of Abeta1-42 and t-tau at baseline yielded a sensitivity of 87.4% for detection of AD. The specificities were 97.3% for controls and 82.7% for other dementia. The ApoE epsilon4 allele frequency (29.5%) was significantly higher in the AD patients than in the nAD patients (17.1%) or in the control groups (9.5%). AD patients carrying ApoE epsilon4 allele had lower Abeta1-42 (p<0.001) levels than those without a epsilon4 allele. The combination of t-tau and Abeta1-42 is a robust and reliable assay that may be useful in discriminating cases at risk for AD such as ApoE epsilon4 allele carriers from nAD patients or from age-matched control subjects.     

Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease

Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.     

Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat

Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.     

Alzheimer's disease as brain amyloidosis: diagnosis using cerebrospinal fluid abeta and tau

Recent progress in the treatment for Alzheimer's disease (AD) emphasizes the need for early diagnosis of AD. It is also becoming a noteworthy issue to determine if a patient with mild cognitive impairment (MCI) has incipient AD. Three cerebrospinal fluid (CSF) biomarkers: beta-amyloid42 (Abeta42), total tau (t-tau) and phosphorylated tau (p-tau) have been evaluated in numerous scientific papers. Summary of these large-scale studies suggested that measurements of Abeta40/42 and t-tau in CSF are clinically useful for the diagnosis of AD, especially when they are combined. Studies showed that measurement of p-tau improves the early and differential diagnosis of AD. They are also useful markers to identify incipient AD in MCI cases. Early diagnosis of AD using these assays is an evidence-based biomarker that can be the basis for treatment with drugs aimed at targeting the degenerating processes of AD.     

Relationship between apoE genotype and CSF beta-amyloid (1-42) and tau in patients with probable and definite Alzheimer's disease

We investigated the usefulness of cerebrospinal fluid (CSF) beta-amyloid42 (Abeta42), beta-amyloid40 (Abeta40) and tau analyses in the diagnosis of Alzheimer's disease (AD). The study included 41 definite AD cases, 80 patients with probable AD. 27 with other dementias and 39 neurological controls. Abeta42, Abeta340 and tau protein concentrations in CSF were measured of using ELISA assays. Abeta42 levels were decreased and tau increased in AD. Combination of Abeta42 and tau resulted a sensitivity of 50.4% for AD and specificities of 94.8% for controls and 85.2% for other dementias. Ninety-one percent of the patients with Abeta42 below the cutoff value (340 pg/ml) and tau above the cutoff value (380 pg/ml) had AD. AD patients carrying apoE epsilon4 allele had lower Abeta42 (P < 0.005) and higher tau (P < 0.05) levels than those without an E4 allele, and 18 (81.8%) of the 22 AD patients who had normal Abeta42 and tau levels were apoE e4 allele non-carriers. Low Abeta42 and high tau concentration in CSF strongly support the diagnosis of AD. Measurement of Abeta42 may help the early diagnosis of cases at risk for AD such as apoE E4 allele carriers.     

Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease

This study aimed to identify preclinical Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) using measurements of both regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) biomarkers. Baseline rCBF assessments ((133)Xe method) were performed in 70 patients with MCI who were cognitively stable for 4-6 years, 69 patients with MCI who subsequently developed AD, and 33 healthy individuals. CSF was collected at baseline and analyzed for beta-amyloid(1-42), total tau and phophorylated tau. In contrast to patients with stable MCI, those who subsequently developed AD had decreased rCBF in the temporo-parietal cortex already at baseline. The relative risk of future progression to AD was particularly increased in MCI patients with decreased rCBF in parietal cortex (hazard ratio 3.1, P<0.0001). Subjects with pathological levels of both CSF tau and beta-amyloid(1-42) were also at high risk of developing AD (hazard ratio 13.4, P<0.0001). The MCI patients with a combination of decreased parietal rCBF and pathological CSF biomarkers at baseline had a substantially increased risk of future development of AD, with a hazard ratio of 24.3 (P<0.0001), when compared to those with normal CSF biomarkers. Moreover, decreased parietal rCBF (but not CSF biomarkers) was associated with a more rapid progression to AD. In conclusion, the combination of rCBF and CSF biomarkers improves the risk assessment of progression to AD in patients with MCI.     

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease

While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer's disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by epsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in epsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study.     

CSF tau markers are correlated with hippocampal volume in Alzheimer's disease

Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimer's disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.     

The apolipoprotein E ε4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase

The apolipoprotein E (ApoE) ε4 allele has consistently been established as an Alzheimer's disease (AD) risk factor, but its pathological contribution to AD is obscure. Certain butyrylcholinesterase (BuChE) polymorphisms together with the ApoE ε4 allele synergistically increase the risk of AD. In addition, AD risk factors, i.e. advanced age, female gender and ApoE ε4 are associated with different levels of CSF BuChE in AD patients, and BuChE protein attenuates Aβ fibrillization in vitro. Here we investigated the roles of ApoE and BuChE gene products as modulators of pathological features of AD in vivo. We found that AD risk factors were associated with different levels of ApoE protein in the CSF of AD patients (n = 115). Women and ApoE ε4 carriers had the highest levels of ApoE protein (up by 50-120%, p < 0.01-0.0001), which were increased with age (r = 0.30, p < 0.0006). The CSF surrogate markers of pathological features of AD, i.e. high tau and P-tau, low Aβ₄₂ and high tau/Aβ₄₂ ratio, were associated with high levels of ApoE protein. Intriguingly, high ApoE protein levels were not only associated with low amounts of BuChE, but they also altered the aging and activity of this enzyme in concentration- and isoform-dependent manners, particularly in the presence of Aβ peptides. Both ApoE and BuChE levels were also differentially related to levels of the proinflammatory cytokine IL-1β. In conclusion, ApoE ε4 might impart its pathological role through high protein expression and interaction with BuChE, which in turn might modulate central cholinergic activity and Aβ load in the brain.     

Influence of delayed CSF storage on concentrations of phospho-tau protein (181), total tau protein and beta-amyloid (1-42)

It is generally accepted that cerebrospinal fluid (CSF) biomarkers such as tau protein, phosphorylated tau protein (threonine 181) and beta-amyloid (1-42) can facilitate early and differential diagnosis of Alzheimer's disease (AD). Since the respective concentrations can only be measured in a number of specialized centers, time to CSF specimen work-up has been considered as crucial for the stability of the respective biomarkers. When shipping of CSF samples is needed for biomarker measurement and immediate freezing of samples is not available, an overnight delay of up to 24h frequently occurs. Therefore, we investigated the potential impact of a 24h delayed freezing on CSF biomarker concentrations and compared it to 2h storage (room temperature, 20 degrees C) and an immediate freezing. First, storage at room temperature for 2h had only marginal, non-significant effects on the concentrations of CSF total tau protein and phospho-tau protein (181) compared to immediate freezing. Second, storage at room temperature for 24h did not significantly affect total tau protein or phospho-tau protein but beta-amyloid (1-42) concentrations which increased significantly compared to the samples frozen immediately. These results indicate that CSF samples for the evaluation of total tau and phospho-tau protein may be kept at room temperature for up to 24h whereas CSF samples for beta-amyloid (1-42) need to be frozen immediately.     

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI

Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.     

Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo

Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ₄₂ peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was “turned on” by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.     

The use of proteomics in biomarker discovery in neurodegenerative diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.     

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1–42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1–42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.     

The cathepsin D rs17571 polymorphism: effects on CSF tau concentrations in Alzheimer disease

The lysosomal protease cathepsin D (CtsD, EC 3.4.23.5; gene, CTSD) has been associated with Alzheimer disease (AD) due to its cerebral expression being increased early in the course of AD; additionally, a CTSD exon 2 polymorphism (rs17571; NT_009237.17:g.569834T>C) may confer risk to AD. Functionally, it may be implicated in amyloid precursor protein (APP) processing and tau protein degradation. The objective of this study was to determine whether the CTSD exon 2 polymorphism affects cerebrospinal fluid (CSF), concentrations of beta-amyloid (Abeta42) and tau in two independent samples from Germany (n=73) and Sweden (n=66). Patients carrying the CTSD rs17571-T allele had significantly decreased CSF levels of tau (Munich, p=0.003; Swedish, p=0.029; combined sample, p<0.001), whereas no significant effect was observed on Abeta42 concentrations. Likewise, no significant impact was observed on Mini Mental State Examination (MMSE) scores. The data of both independent samples suggest that the CTSD rs17571 polymorphism does not affect APP processing but shows significant effects on tau processing. The result may corroborate the implication of the lysosomal system in the pathogenesis of AD and is of particular importance if CSF tau is used as a diagnostic biomarker.     

Serial CSF sampling in Alzheimer's disease: specific versus non-specific markers

In this longitudinal study we investigated change over time in cerebrospinal fluid (CSF) levels of amyloid-beta 40 and 42 (Aβ40 and Aβ42), total tau (tau), tau phosphorylated at threonine 181 (ptau-181), isoprostane, neurofilaments heavy (NfH) and light (NfL). Twenty-four nondemented subjects, 62 mild cognitive impairment (MCI) and 68 Alzheimer's disease (AD) patients underwent 2 lumbar punctures, with minimum interval of 6, and a mean ± SD of 24 ± 13 months. Linear mixed models were used to assess change over time. Amyloid-beta 42, tau, and tau phosphorylated at threonine 181, differentiated between diagnosis groups (p < 0.05), whereas isoprostane, neurofilaments heavy, and NfL did not. In contrast, effects of follow-up time were only found for nonspecific CSF biomarkers: levels of NfL decreased, and levels of isoprostane, amyloid-beta 40, and tau increased over time (p < 0.05). Isoprostane showed the largest increase. In addition, increase in isoprostane was associated with progression of mild cognitive impairment to AD, and with cognitive decline as reflected by change in Mini Mental State Examination (MMSE). Contrary to AD-specific markers, nonspecific CSF biomarkers, most notably isoprostane, showed change over time. These markers could potentially be used to monitor disease progression in AD.     

Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer's disease

Earlier studies have shown elevated levels of tau protein and decreased levels of amyloid beta42 in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD). We investigated the concentrations of Abeta42, Abeta40 and tau in CSF from AD patients on the baseline and after follow-up period of 3 years using ELISA assays. There was a significant decrease of Abeta42 (P<0.05) and Abeta40 (P<0.05) levels with time. AD patients with the duration of the disease 2 years or less at baseline had more pronounced decrease of Abeta42 concentrations compared to those with the duration of the disease more than 2 years at baseline (P<0.05). CSF tau protein concentrations increased in 9/17 but decreased in 8/17 patients. These results suggest that Abeta42 and Abeta40 may be useful in monitoring the long-term progression of AD particularly in the early stages of the disease.     

CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases

The therapeutic imperative for Alzheimer disease (AD) and Parkinson disease (PD) calls for discovery and validation of biomarkers. Increased cerebrospinal fluid (CSF) tau and decreased amyloid (A) beta42 have been validated as biomarkers of AD. In contrast, there is no validated CSF biomarker for PD. We validated our proteomics-discovered multianalyte profile (MAP) in CSF from 95 control subjects, 48 patients with probable AD, and 40 patients with probable PD. An optimal 8-member MAP agreed with expert diagnosis for 90 control subjects (95%), 36 patients with probable AD (75%), and 38 patients with probable PD (95%). This MAP consisted of the following (in decreasing order of contribution): tau, brain-derived neurotrophic factor, interleukin 8, Abeta42, beta2-microglobulin, vitamin D binding protein, apolipoprotein (apo) AII, and apoE. This first large-scale validation of a proteomic-discovered MAP suggests a panel of 8 CSF proteins that are highly effective at identifying PD and moderately effective at identifying AD.     

Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid

The diagnosis of Alzheimer's disease (AD) is currently based on clinical and neuropsychological examination. To date there is no blood test available that can discriminate dementia patients from healthy individuals. In the present paper, an overview of the current state of knowledge on biologic markers in serum (plasma) and CSF is presented. The combination of characteristic plaque markers tau and amyloid bèta may constitute a specific and sensitive CSF marker for AD. Glial fibrillary acidic protein and antibodies in CSF may be a marker for severe neurodegeneration. CSF concentrations of the oxidative stress markers 3-nitrotyrosine, 8-hydroxy-2'-deoxyguanosine and isoprostanes are increased in AD patients. Serum 24S-OH-cholesterol may be an early whereas glial fibrillary acidic protein autoantibody level may be a late marker for neurodegeneration. To date, serum alpha(1)-Antichymotripsin concentration is the most convincing marker for CNS inflammation. Increased serum homocysteine concentrations have also been consistently reported in AD. In summary, a large overlap in mean concentrations has been observed in studies comparing AD patients with healthy controls for single markers. These studies together support the theory of testing several serum markers in combination for the diagnosis of AD.