A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.

OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study. METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts. RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD. CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease.

It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Decreased cerebrospinal fluid amyloid beta (1-40) levels in frontotemporal lobar degeneration.

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.

Cerebral beta-amyloid angiopathy in aged squirrel monkeys.

Cerebral beta-amyloid angiopathy (CAA) is an age-related disorder of the brain vasculature that is involved in up to 20% of non-traumatic cerebral hemorrhage in humans. CAA is a risk factor for cognitive decline, and may exacerbate the dementia of Alzheimer's disease. Progress in discovering the cause and potential therapies for this disorder has been hindered by the paucity of animal models, particularly models of idiopathic CAA. The squirrel monkey (Saimiri spp) develops significant CAA in the natural course of aging. To evaluate the suitability of Saimiri as a model of human CAA, we studied the distribution and composition of Abeta subtypes in CAA and parenchymal (senile plaque) deposits in the brains of aged squirrel monkeys, as well as the relationship between vascular beta-amyloid deposition and comorbid vasculopathies that occur in aged humans. Our findings show that: 1) CAA consists ultrastructurally of classical amyloid fibrils and is the principal type of cerebral beta-amyloidosis in squirrel monkeys; 2) The two primary isoforms of Abeta (Abeta40 and Abeta42) coexist in most microvascular and parenchymal lesions of Saimiri, although Abeta40 tends to predominate in larger arterioles; 3) CAA and parenchymal plaques overlap to a considerable degree in most affected brain areas, and are distributed symmetrically in the two hemispheres; 4) Both CAA and plaques are particularly abundant in rostral regions and comparatively sparse in the occipital lobe; 5) Capillaries are especially vulnerable to CAA in squirrel monkeys; and 6) When CAA is severe, it is associated with a small, but significant, increase in other vasculopathies, including microhemorrhage, fibrinoid extravasation and focal gliosis. These findings, in the context of genetic, vascular and immunologic similarities between squirrel monkeys and humans, support the squirrel monkey as a biologically advantageous model for studying the basic biology of idiopathic, age-related CAA, and for testing emerging therapies for human beta-amyloidoses such as Alzheimer's disease.

Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease.

BACKGROUND: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid beta-peptide (Abeta) in vitro in neuronal cultures and in vivo in the CSF of normal older adults. OBJECTIVE: To determine whether insulin affected plasma Abeta levels and whether such effects differed for patients with AD compared with normal older adults. METHODS: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU.kg(-1).min(-1)) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU.kg(-1).min(-1)) and higher (1.67 mU.kg(-1).min(-1)) rate. Plasma insulin and Abeta were measured after 120 minutes of infusion. RESULTS: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Abeta levels at the middle (1.0 mU.kg(-1).min(-1)) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Abeta levels at the two higher doses (1.0 and 1.67 mU.kg(-1).min(-1)). CONCLUSIONS: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid beta-peptide (Abeta) elevation. Abnormal regulation of peripheral Abeta by insulin may contribute to AD risk.

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment.

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.

Protein markers for Alzheimer disease in the frontal cortex and cerebellum.

OBJECTIVE: To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD (LOAD) and nondemented control subjects. METHODS: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain. RESULTS: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta40 and Abeta42 (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged. CONCLUSIONS: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

MRI and CSF studies in the early diagnosis of Alzheimer's disease.

The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.

Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: relation to age, mortality, and risk.

BACKGROUND: Plasma amyloid [beta]-peptide (A[beta]) 40 and A[beta]42 levels are increased in persons with mutations causing early-onset familial Alzheimer's disease (AD). Plasma A[beta]42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. METHODS: The authors measured plasma A[beta]40 and A[beta]42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma A[beta]40 and A[beta]42 levels were repeated in 307 subjects 3 years after baseline. RESULTS: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A[beta]42, but not A[beta]40, plasma levels. The risk of AD in the highest quartile of plasma A[beta]42 was increased by more than twofold over that in the lowest quartile. The highest plasma A[beta]42 levels were observed in patients with AD who died during the follow-up. Plasma A[beta]42, but not A[beta]40, levels decreased over time in patients with newly acquired AD. CONCLUSIONS: Plasma A[beta]40 and A[beta]42 increase with age and are strongly correlated with each other. Plasma A[beta]40 and A[beta]42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A[beta]42 levels may also be associated with mortality in patients with AD.

Detection of apolipoprotein E phenotype in unconcentrated cerebrospinal fluid.

We developed a simple method to detect apolipoprotein E (Apo E) polymorphism distribution in approximately 20 microL of unconcentrated cerebrospinal fluid (CSF). A combination of isoelectric focusing in 3 M urea gel and immunoblotting was employed. Apo E phenotypes were identified in CSF samples from 45 patients with probable Alzheimer disease (AD), 15 with multiple sclerosis (MS), and 25 with other neurological diseases (OND). When the data were compared with a set of matched plasma samples, the results were identical. The method is useful for Apo E phenotyping from fresh or frozen unconcentrated CSF, when blood or plasma is not available.

Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment.

Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta (beta) are of diagnostic importance for Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most longitudinal studies of tau fail to demonstrate progression. Because predominantly brain-derived proteins such as tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for the ventricular enlargement of AD would correct for the dilution of tau, and improve detection of longitudinal change. Abeta which is not exclusively brain derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1 year longitudinal study of eight MCI and ten controls, we examined CSF levels of hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular volumes. Longitudinally, only after adjusting for the ventricular volume and only for Ptau231, were increases seen in MCI. Further studies are warranted on mechanisms of tau clearance and on using imaging to interpret CSF studies.

Effect of cladribine treatment on beta-2 microglobulin and soluble intercellular adhesion molecule 1 (ICAM-1) in patients with multiple sclerosis.

beta-2 Microglobulin (beta 2M) is a low molecular weight protein located extracellularly and associated with class 1 antigens of the major histocompatibility complex and is considered a marker for disease activity in immune disorders. Cladribine (2-chloro-2-deoxyadenosine, 2-CDA) is a potent lymphocytotoxic agent under investigation in the treatment in MS patients. As beta 2M levels may indicate inflammatory events in CNS we determined CSF-beta 2M and serum beta 2M levels in patients with relapsing-remitting MS before and after cladribine treatment as well as in a control group. There was a significant beta 2M decrease in sera but not in CSF in MS patients after the cladribine treatment, associated with a slight but significant clinical improvement measured by Kurtzke's Expanded Disability Status Scale. We also found a significant decrease in sICAM-1 level in CSF but not in sera in MS patients. The data support a role of cladribine in MS therapy and deliver new information on cladribine immunological effects in MS patients.

Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice.

Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils.

Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease.

We quantitated amyloid beta proteins 1-40 (Abeta40) and 1-42 (Abeta42), and alpha1- antichymotrypsin (ACT) in matched cerebrospinal fluid (CSF) and plasma of 50 patients with probable Alzheimer disease, and analyzed the relationships with age, sex, Mini-Mental State Examination (MMSE), and apolipoprotein E phenotype. There was no relation between CSF Abeta40 and Abeta42 levels with those of plasma. CSF and plasma Abeta40 and Abeta42 levels showed no association with age, sex, and MMSE score. There was a significant correlation between CSF ACT and plasma ACT levels. The data suggest that plasma ACT crosses the blood-brain barrier. However, a lack of correlation between CSF Abeta40 and Abeta42 levels with those of plasma suggests that Abeta in CSF and plasma originates from different sources.

Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in adults with Down syndrome.

We compared levels of plasma amyloid beta-peptides Abeta1-42 and Abeta1-40 in 108 demented and nondemented adults with Down syndrome (DS) and 64 adults from the general population. Abeta1-42 and Abeta1-40 levels were significantly higher in adults with DS than in controls (P=0.0001). Compared to nondemented adults with DS, Abeta1-42 levels in demented adults with DS were selectively increased by 26% (28.2 pg/ml vs. 22.4 pg/ml, P=0.004). In addition, mean plasma levels of Abeta1-42 were 22% higher in DS cases with the apolipoprotein varepsilon4 allele than in DS subjects without an varepsilon4 allele (25.9 pg/ml vs. 21.2 pg/ml, P=0.01), while mean plasma levels of Abeta1-40 did not vary by APOE genotype. These results support the hypothesis that Abeta1-42 plays an important role in the pathogenesis of dementia associated with DS, as it does in Alzheimer's disease, and that variations in plasma levels may be related to disease progression.

Alpha2 macroglobulin elevation without an acute phase response in depressed adults with Down's syndrome: implications.

Studies of immune function during depression in persons without intellectual disability (ID) have revealed elevated levels of alpha2 macroglobulin (alpha2M) and an acute phase protein (APP) response. Clinical observation suggests that people with Down's syndrome (DS) may have associated genetic abnormalities in their immune systems. The APP response and alpha2M changes in depressed versus non-depressed adults with DS was the subject of the present study. The serum pan-proteinase inhibitor alpha2M, and the AP proteins c-reactive protein (CRP), alpha1 antitrypsin (alpha1AT), ceruloplasmin (Cp), beta2 Macroglobulin (beta2M), transthyretin (Trans), serum amyloid protein (SAP), and albumin (Alb) were measured in 38 adults with DS, 19 of whom were diagnosed with and 19 without depression using a sandwich enzyme-linked immunosorbent assay (ELISA). The DSM-IV criteria were used for diagnoses. Medical and neurological examinations excluded medical disorders associated with APP response. Only alpha2M and CRP were significantly different in the depressed versus non-depressed groups. The alpha2M was higher, a response similar to one observed in depressed people without ID, but the CRP was lower in the depressed group, especially in those subjects not on psychotropic medications, contrary to the expected APP response to depression. The results suggest that alpha2M elevation in depressed adults with DS is independent of the APP response. An alternative explanation for its elevation is proposed linking the core symptom of depression with the mammalian dormancy/hibernation process. Further studies are needed to confirm that alpha2M elevation is specific to depression and that it might provide a helpful marker for the diagnosis of depression in people with ID.

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.

Apolipoprotein E (APOE) phenotype and APOE concentrations in multiple sclerosis and acute herpes zoster.

OBJECTIVES: There are three major isoforms of apolipoprotein E (apoE), namely apoE2, apoE3, and apoE4, that are products of three alleles (epsilon2,epsilon3,epsilon4) at a single gene locus on chromosome 19. It is well known that the presence of apoE4 increases the risk for the development of Alzheimer's disease and atherosclerosis. The aim of the study was to examine if apoE polymorphism or apoE levels contribute to the severity of the disease in patients with multiple sclerosis or the outcome of nerve damage in patients with herpes zoster infection. MATERIAL AND METHODS: We examined apoE phenotype of 105 MS patients and 41 patients with herpes zoster. We also measured serum and cerebrospinal fluid (CSF) levels of apoE from 93 patients with definite MS using enzyme linked immunosorbent assay. RESULTS: There were no differences in apoE allele frequencies in MS or herpes zoster patients compared to the allele frequencies of controls. The levels of serum or CSF apoE did not differ from those of age-matched controls, nor did they correlate with the disease activity. CONCLUSION: We conclude that apoE does not contribute to the activity of MS or the outcome of herpes zoster.

Putting the individual back into individual growth curves.

Scaling of time (age) in latent growth curve (LGC) models has important implications for studies of development. When participants begin a study at different ages, sample means and covariance-based structural equation modeling (SEM) approaches produce biased estimates of the variance of the intercept and the covariance between the Intercept and Slope factors. However, individual data vector-based SEM approaches produce proper estimates of these parameters that are identical to those produced by multilevel modeling (MLM). Scaling of the time variable also raises issues regarding the interpretation of within- and between-persons effects of time that parallel those associated with centering of predictor variables in MLM. A numerical example is used to illustrate these issues, and an Mx script for fitting individual data vector-based LGC models is provided.