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Objective: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-β (Aβ) plaques. Lipids affect γ-secretase-dependent amyloid precursor protein (APP) metabolism that generates Aβ in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans., Methods: We examined Aβ in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for Aβ(38), Aβ(40), Aβ(42), α-cleaved soluble APP, β-cleaved soluble APP, total-tau, and phospho-tau., Results: Aβ release was markedly increased in NPC, with a shift toward the Aβ(42) isoform. Levels of α- and β-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower Aβ(42) and total-tau than untreated patients., Conclusion: Increased CSF levels of Aβ(38), Aβ(40), and Aβ(42) and unaltered levels of β-cleaved soluble APP are consistent with increased γ-secretase-dependent Aβ release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates γ-secretase-dependent Aβ production in humans and may be of relevance to AD pathogenesis.

The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) in the progress of the neurodegenerative disorder Alzheimer's disease (AD) and it is now widely accepted that Aβ is related to the pathogenesis of AD. For example, studies have shown that Aβ is neurotoxic and that the neurotoxicity of Aβ is related to its aggregation state. The concentration of the 42 amino acid form of Aβ (Aβ1-42) is reduced in the cerebrospinal fluid (CSF) from AD patients, which is believed to reflect the AD pathology with plaques in the brain acting as sinks. Less well investigated, however, is the ability of other Aβ isoforms to distinguish AD patients from controls and to identify treatment effects in clinical trials. Recently, novel C-truncated forms of Aβ (Aβ1-14, Aβ1-15, and Aβ1-16) were identified in human CSF. The presence of these small peptides is consistent with a catabolic amyloid precursor protein cleavage pathway by β- followed by α-secretase. It has been shown that Aβ1-14, Aβ1-15, and Aβ1-16 increase dose-dependently in response to γ-secretase inhibitor treatment while Aβ1-42 levels are unchanged. Here, we review the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers.

Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.

The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)(1-42), T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer’s disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls(n = 20). CSF was analyzed for Aβ(1-42), T-tau, and P-tau, and PA(X-38), Aβ(X-40), Aβ(X-42), sAβPPα, and sAβPPβ. In multivariate analysis, thecore biomarkers Aβ(1-42), T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93–1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95–1.00, p < 0.0001), this increase mainly mediated by Aβ(X-42). In conclusion, CSF biomarkers Aβ(1-42), T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when astringent analytical protocol is used.

In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.

Background: The clinical utility of identifying pediatric metabolic syndrome (MetS) is controversial. This study sought to determine the status of pediatric MetS as a risk factor for adult subclinical atherosclerosis (carotid intima-media thickness [cIMT]) and type 2 diabetes mellitus (T2DM) and compare and contrast this prediction with its individual components., Methods and Results: Using data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies, we examined the utility of 4 categorical definitions of youth MetS and their components in predicting adult high cIMT and T2DM among 1781 participants aged 9 to 18 years at baseline (1984 to 1988) who were then examined 14 to 27 years later (2001-2007) when aged 24 to 41 years. Youth with MetS were at 2 to 3 times the risk of having high cIMT and T2DM as adults compared with those free of MetS at youth. Risk estimates with the use of high body mass index were similar to those of MetS phenotypes in predicting adult outcomes. Comparisons of area under the receiver operating characteristic curve and net reclassification index suggested that prediction of adult MetS, high cIMT, and T2DM in adulthood with the use of youth MetS was either equivalent or inferior to classification based on high body mass index or overweight and obesity., Conclusions: Youth with MetS are at increased risk of meaningful adult outcomes; however, the simplicity of screening for high BMI or overweight and obesity in the pediatric setting offers a simpler, equally accurate alternative to identifying youth at risk of developing adult MetS, high cIMT, or T2DM.

Hypertriglyceridaemia is an uncommon cause of acute pancreatitis, accounting for 1-4% of cases. In the case of lipoprotein-lipase mutations, lipid levels may rise to extreme levels during acute pancreatitis. In this case a 29-year-old female was hospitalized several times due to acute pancreatitis. She presented with extreme lipid levels and difficulty in blood testing. While the correlation of acute pancreatitis and hyperlipidaemia is known, awareness of its association with defects in lipid metabolism could, in this case, have furthered diagnostic and prevented repeated hospitalizations.

Objective: Aberrations in apolipoprotein (apo) metabolism and increased systemic inflammation associate with the metabolic syndrome (MetS) and may contribute to its atherogenicity. We examined whether the association between carotid atherosclerosis and MetS in a population of young adults is mediated by apoB and apoA-I and/or by inflammatory markers C-reactive protein and type II secretory phospholipase A2., Methods and Results: We used cross-sectional and 6-year prospective data from the cardiovascular risk in young Finns study. In young adults (aged 24 to 39 years), apoB, C-reactive protein, and type II secretory phospholipase A2 enzyme activity were significantly higher and apoA-I lower in subjects with MetS (N=325) than in subjects without MetS (N=1858). In prospective analysis (N=1587), both MetS and high apoB predicted (P<0.0001) incident high carotid intima-media thickness, defined as carotid intima-media thickness >90th percentile and/or plaque. The association between MetS and incident high carotid intima-media thickness was attenuated by approximately 40% after adjustment with apoB. Adjustments with apoA-I, C-reactive protein, or type II secretory phospholipase A2 did not diminish the association., Conclusions: High levels of apoB, C-reactive protein, and type II secretory phospholipase A2 and low levels of apoA-I associate with MetS in young adults. The atherogenicity of MetS in this population assessed by incident high carotid intima-media thickness appears to be substantially mediated by elevated apoB but not inflammatory markers.

Parkinson's disease (PD) and atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a group of neurodegenerative diseases sharing many similar signs and symptoms but distinguished by their particular clinical features, treatment response, prognosis and mortality. The differential diagnosis may be challenging, especially in early disease stages. Considering the importance of an accurate diagnosis both for clinical management and for research, new diagnostic tools are needed. In this study, we investigated 56 PD, 42 MSA, 39 PSP, 9 CBD patients, and 24 healthy controls. After screening the cerebrospinal fluid (CSF) proteome using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), we identified 4 proteins (ubiquitin [mass-to-charge ratio (m/z) 8590], beta2-microglobulin [m/z 11730], and 2 secretogranin 1 [chromogranin B] fragments [m/z 7260 and m/z 6250]) that differentiated healthy controls and PD patients from patients with APD. However, they could not differentiate PD patients from controls. As none of these changes were APD subgroup-specific, they most likely reflect the intensity and/or extent of the neurodegenerative process in general., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Hepatologists assay liver enzymes and cardiologists structural heart proteins in serum to diagnose and monitor their patients. This way of thinking has not quite made it into the memory clinics yet, in spite of the availability of validated cerebrospinal fluid biomarkers for key pathological events in the brain in neurodegeneration. Here, we argue that a spinal tap should be considered in all patients who seek medical advice for memory problems and list the highly relevant clinical questions CSF analyses can address.

Several single-center studies have confirmed the usability of cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD), even in early disease stages. Large scale multicenter studies have principally confirmed this, although such studies have also indicated the presence of significant intercenter and interlaboratory variations in biomarker measurements. Such variations may hamper the development of biomarkers and their introduction into clinical routine practice. Recently a quality control program run by the Alzheimer's Association was started in order to harmonize procedures of laboratories world-wide. This program provides both standardized guide lines and external control CSF samples, and will allow longitudinal evaluation of laboratory performance.

In Alzheimer's disease (AD), pathological processes start in the brain long before clinical dementia. Biomarkers reflecting brain alterations may therefore indicate disease at an early stage, enabling early diagnosis. This raises several ethical questions and the potential benefits of early diagnosis must be weighted against possible disadvantages. Currently, there are few strong arguments favouring early diagnosis, due to the lack of disease modifying therapy. Also, available diagnostic methods risk erroneous classifications, with potentially grave consequences. However, a possible benefit of early diagnosis even without disease modifying therapy is that it may enable early decision making when patients still have full decision competence, avoiding problems of hypothetical consents. It may also help identifying patients with cognitive dysfunction secondary to other diseases that may be responsive to treatment already today.

Background: The metabolism of amyloid precursor protein (APP) and beta-amyloid (Abeta) is widely studied in Alzheimer's disease, where Abeta deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB)., Methods: The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the beta-amyloid peptides Abeta38, Abeta40 and Abeta42, and the amyloid precursor protein (APP) isoforms alpha-sAPP and beta-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers., Results: In the cross-sectional study, LNB patients had lower levels of CSF alpha-sAPP, beta-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF alpha-sAPP, beta-sAPP and P-tau at baseline, which all increased towards normal at follow-up., Conclusions: Amyloid metabolism is altered in LNB. CSF levels of alpha-sAPP, beta-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

Abstract Several drug candidates for Alzheimer's disease are being evaluated in clinical trials, with the goal of finding a drug with disease-modifying effects. When such a drug finally reaches the market, there will be a demand for accurate diagnostic tools useful for early detection of disease and for monitoring biochemical effects. The core cerebrospinal fluid (CSF) biomarkers amyloid peptides (Abeta42), total-tau and phospo-tau are promising in this respect. However, inter-center variation (caused by pre-analytical, analytical and post-analytical factors), and inter-laboratory variation (caused by analytical factors), particularly for CSF Abeta42, lowers their utility in multicenter studies. Here, we discuss the causes of these variations, and present a global quality control program to overcome them.

Animal studies suggest that phosphorylation of microtubule-associated protein tau is a physiological way of destabilizing axons in the developing brain, promoting synaptic plasticity, while in the adult human brain tau phosphorylation is a specific sign of Alzheimer's disease. We here show, for the first time, that newborn human infants have extremely high levels of phosphorylated tau in their cerebrospinal fluid, and that these levels decrease during the first years of life. Tau phosphorylation in Alzheimer's disease may be a physiological response to Alzheimer-associated synaptotoxicity.

This article summarizes how biochemical markers may aid in the development of novel treatments that interfere with fundamental pathogenic processes in Alzheimer's disease. Details are given on the potential use of biomarkers in Alzheimer's disease clinical trials as additional inclusion criteria to enrich study populations with participants who really suffer from the disease, as a means to stratify study participants into meaningful subgroups that may benefit differently from the treatment, and as tools to detect desired biochemical effects and undesired side effects of the drug.

Much is unknown regarding the regulation of Alzheimer-related amyloid-beta protein precursor (AbetaPP)-processing in the human central nervous system. It has been hypothesized that amyloidogenic AbetaPP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of AbetaPP-derived molecules in cerebrospinal fluid (CSF) with chromogranin (Cg) derived peptides, representing the regulated secretion. Patients with Alzheimer's disease (AD, N=32), multiple sclerosis (MS, N=50), and healthy controls (N= 70) were enrolled. CSF was analyzed for the amyloid peptides Abeta1-42, Abetax-42, Abetax-40, Abetax-38, alpha-cleaved soluble AbetaPP (sAbetaPPalpha), beta-cleaved soluble AbetaPP (sAbetaPPbeta), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes AbetaPP into Abeta, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. CSF Cg levels correlated to sAbetaPP and Abeta peptides in AD, MS, and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. These results suggest that a large part of AbetaPP in the human central nervous system is processed in the regulated secretory pathway of neurons.

Intense research during the last decades has resulted in an unprecedented accumulation of knowledge regarding the pathogenesis of Alzheimer's disease. Primarily, the focus has been directed toward amyloid and tau pathology and their relations to synaptic and neuronal loss. However, as the complexity of the disease becomes increasingly evident, the importance of other factors, such as inflammation, oxidative stress, and mitochondrial dysfunction, grow apparent. Here, we review available CSF biomarkers for these pathological processes. We also consider their usability in clinical practice and in clinical trials.

Context: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted., Objective: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI., Design, Setting, and Participants: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia., Main Outcome Measures: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD., Results: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%., Conclusions: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Background: Conventional risk factors and metabolic syndrome (MetS) are cross-sectionally associated with subclinical atherosclerosis in young adults. We evaluated the relations of conventional risk factors and MetS to the 6-year progression of carotid intima-media thickness (IMT) in a population of young adults., Results and Methods: The study included 1809 subjects (aged 32+/-5 years) who had IMT measured in 2001 and 2007. Risk factor measurements included low-density lipoprotein cholesterol, body mass index, C-reactive protein, smoking, and family history of coronary disease in addition to MetS components. We used European Group for the Study of Insulin Resistance, revised National Cholesterol Education Program, and International Diabetes Federation definitions to diagnose MetS in 2001. Waist circumference (P<0.0001), low-density lipoprotein cholesterol (P=0.01), and insulin (P=0.003) were directly associated with IMT progression in a multivariable model adjusted for age, sex, and baseline IMT (model R(2)=24%). When the MetS/European Group for the Study of Insulin Resistance definition was included in the model, it was directly associated with IMT progression (P=0.03), but its inclusion did not improve the model's predictive value. IMT increased 79+/-7 mum (mean+/-SEM) in subjects with MetS according to the MetS/European Group for the Study of Insulin Resistance definition and 42+/-2 mum in subjects without MetS (P<0.0001). In addition, the number of MetS components was linearly associated with IMT progression (P<0.0001). Similar results were seen with MetS/revised National Cholesterol Education Program and MetS/International Diabetes Federation definitions., Conclusions: Obesity, high low-density lipoprotein cholesterol, and high insulin level predicted IMT progression in young adults. All MetS definitions identified young adults with accelerated IMT progression, but we found no evidence that MetS would predict IMT progression more than expected from the sum of its risk components.

Objective: To test the hypothesis that the arachodinic acid metabolites prostaglandin E2 (PGE2) and 15-(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in cerebrospinal fluid (CSF) are elevated and reflect neuroinflammation and degenerative changes in multiple sclerosis (MS)., Patients and Methods: We measured PGE2 and 15(S)-HETE concentrations, as well as markers of axonal and astroglial injury in CSF from 46 MS patients, 46 healthy siblings and 50 controls., Results: We found elevated levels of both PGE2 and 15(S)-HETE in MS compared with the control and sibling groups. Siblings had lower PGE2 levels and higher 15(S)-HETE levels than controls. There were no correlations between either PGE2 or 15(S)-HETE and clinical scores of MS severity or biochemical markers of axonal or astroglial injury., Conclusion: These data suggest no direct involvement of PGE2 and 15(S)-HETE in the MS disease process. Rather, the elevated levels reflect a general up-regulation of arachidonic acid metabolism and neuroinflammation.

Aims: Heart rate variability (HRV) can be used to estimate autonomic nervous control of the cardiovascular system. In middle-aged subjects, the metabolic syndrome (MetS) is associated with lower HRV. We hypothesized that alterations in autonomic balance are already present in young adults with the MetS, and analysed the association of short-term HRV with the MetS (using the National Cholesterol Education Program definition), in 1889 subjects aged 24-39 years., Methods: Short-term (3 min) HRV analysis included high-frequency (HF), low-frequency (LF) and total (TP) spectral components of HRV and LF/HF ratio., Results: The presence of the MetS was associated with lower HF, LF and TP in men and women, and with higher LF/HF ratio in women. In men, waist circumference was the strongest individual MetS component that associated with HRV. After adjustments for age and heart rate, MetS was associated with lower HF and higher LF/HF ratio in women, but only with a lower TP in men (all P < 0.05)., Conclusions: MetS is associated with lower HRV in young adults. The individual components of MetS are differentially associated with HRV in men and in women. Our results are consistent with lower vagal activity and a possible increase in sympathetic predominance in women with the MetS. This sex difference in vagal activity and sympathovagal balance may partly explain the greater increase in cardiovascular risk associated with MetS in women than in men.

Background: Cell and animal experiments have shown that beta-site APP-cleaving enzyme 1 (BACE1) may be involved in myelination., Objective: Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS)., Methods: BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-beta (Abeta) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. Patients with systemic lupus erythematosus (SLE), 26 with and 41 without cerebral engagement, were also included to enable comparisons with regards to another autoimmune disease. A subset of patients with MS and controls underwent a second lumbar puncture after 10 years., Results: MS patients had lower CSF BACE1 activity than controls (P = 0.03) and patients with cerebral SLE (P < 0.001). Patients with cerebral SLE had higher BACE1 activity than any other group (P < 0.05 for all comparisons). BACE1 activity correlated with the different amyloid markers in all study groups. BACE1 activity decreased over 10 years in the MS group (P = 0.039) and correlated weakly with clinical disease severity scores in an inverse manner., Conclusions: These results suggest an involvement of BACE1 in the MS disease process.

Objective: To examine the reciprocal associations between depressive symptoms and clinical definitions of the metabolic syndrome in childhood and adulthood., Design: Population-based prospective cohort study of 921 participants (538 women and 383 men) in Finland. The components of the metabolic syndrome were measured in childhood (mean age 12 years) and again in adulthood (mean age 33 years). A revised version of the Beck Depression Inventory was used to assess depressive symptoms at the mean ages of 24 and 33., Main Outcome Measures: Metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP), the European Group for the Study of Insulin Resistance, and the International Diabetes Federation criteria., Results: In women, depressive symptoms were associated with increased risk of the metabolic syndrome in adulthood (odds ratio for NCEP metabolic syndrome per 1 SD increase in depressive symptoms 1.40, 95% confidence interval 1.05-1.85). The metabolic syndrome in childhood, in turn, predicted higher levels of depressive symptoms in adulthood (p = .03). In men, no associations were found between depressive symptoms and the clinical definitions of the metabolic syndrome., Conclusion: The process linking depressive symptoms with the metabolic syndrome may go into both directions and may begin early in life., ((c) 2009 APA, all rights reserved.)

Much effort has been made to identify and verify diagnostic biomarkers for early stage Alzheimer's disease (AD). The need for this is often advocated by possible future disease-modifying treatments, likely to be most effective if initiated early in the disease process. Since the neurodegenerative process probably starts many years before the first onset of symptoms, such future drugs are likely to invoke a need for screening presymptomatic individuals. Here, we speculate on the performance of currently available AD biomarkers in hypothetical screening programs of different designs. We note that many diagnostic tests will have an excellent ability to exclude upcoming AD. However, even the best tests will suffer from poor positive predictive values given the relatively low disease prevalence in populations with no or very few symptomatic individuals, also when taking future converters to AD into account. The magnitude of this problem, which is common among most screening programs, will depend on the efficacy, safety and cost of the future anti-AD drugs. A number of tentative solutions to the problem, apart from better tests, are discussed., (2009 S. Karger AG, Basel)

Frontotemporal dementia (FTD) is a heterogeneous disease with substantial interpersonal variance in aggressiveness. Novel biomarkers for rapidly progressive FTD could improve diagnosis and provide clues regarding its pathogenesis. In this study, surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) was used to analyze peptide profiles in cerebrospinal fluid (CSF) from 24 FTD patients. Thirteen patients had rapidly progressive FTD with distinct pathology in a brain MRI after less than 3 years of disease duration. Eleven patients had slowly progressive FTD with a normal brain MRI, but had abnormal findings in SPECT/PET after more than 5 years of disease duration. The axonal damage marker CSF neurofilament light-chain (NF-L) was measured in all subjects to evaluate the amount of axonal degeneration. A CSF NF-L level of 150 ng/l was used as a cut-off point for high NF-L expression. SELDI-TOF analysis of peptides in the range of 2000-20000 m/z revealed one peak with m/z of 6378 that was expressed at a significantly different level (p<0.01) when rapidly versus slowly progressive cases of FTD were compared. Eleven peaks were expressed at different levels when high versus low CSF NF-L were compared. Using chromatographic purification followed by tandem mass spectrometric analysis, five of these peaks were identified as follows: C-terminal fragment of neuroendocrine protein 7B2 (3512.84 Da), C-terminal fragment of osteopontin (7658.19 Da) as well as its mono- and diphosphorylated forms (7738.16 Da and 7818.13 Da, respectively) and pancreatic ribonuclease (14566.33 Da). The peak intensity of pancreatic ribonuclease was higher in patients with low NF-L expression, while the other peptides had a lower peak intensity in this group. Altered levels of these peptides have also been described in other neurodegenerative diseases. Taken together, these data suggest that differentially-expressed peptides are general markers of axonal degeneration. Further studies are needed to verify their prognostic value in FTD.

Purpose: To examine the relationship of physical activity and its changes over a 9-yr follow-up to the prevalence of metabolic syndrome (MetS) in 2060 young adults (24-39 yr) enrolled in the Cardiovascular Risk in Young Finns Study., Methods: Leisure-time physical activity (LTPA) was assessed using a self-report questionnaire completed in connection with a medical examination at two consecutive measurements in 1992 and 2001. By summing the LTPA items, a physical activity index (PAI) was formed for both measurement points according to which the participants were divided into tracking groups: persistently active, increasingly active, decreasingly active, and persistently inactive. MetS in 2001 was defined by the guidelines of the European Group for the Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), and the International Diabetes Federation (IDF). A continuous metabolic risk score was also calculated by summing the z-scores for the metabolic risk factors., Results: There was a significant linear relationship between MetS and LTPA at baseline in men and at follow-up in both sexes according to all three definitions. Persistent physical activity during 9 yr was associated with a lower prevalence of MetS than persistent physical inactivity on all definitions (all P < 0.05). Similar results were found for increasingly active women (all P < 0.05). All of these associations remained significant after adjustment for potential confounders. In both men and women, the 9-yr change in LTPA was related to the metabolic risk score after adjustments for baseline LTPA, age, smoking, and education., Conclusions: A physically active lifestyle across the lifespan may prevent or delay the onset of metabolic syndrome in young male and female adults.

Aims: To study the relations between the metabolic syndrome (MS) and subclinical atherosclerosis in young adults., Methods and Results: International Diabetes Federation (msIDF), National Institute of Health Adult Treatment Panel III (msNCEP), and European Group for the Study of Insulin Resistance (msEGIR) definitions of MS were related to carotid artery intima-media thickness (cIMT), brachial flow-mediated dilatation (FMD), and carotid artery compliance (CAC) in 2163 Finnish adults (aged 32 +/- 5years). All definitions associated with increased cIMT and decreased CAC in both sexes. The cIMT values (mean+/-SD) were 0.576 +/- 0.088 mm in subjects without the syndrome, 0.615 +/- 0.102 mm in msIDF, 0.617 +/- 0.104 mm in msNCEP, and 0.607 +/- 0.097 mm in msEGIR (P < 0.0001). Corresponding CAC values were 2.26 +/- 0.72, 1.76 +/- 0.66, 1.73 +/- 0.66, 1.72 +/- 0.66%/10 mmHg (P < 0.001). Impaired brachial FMD was not related to MS but it modified the relations between MS and cIMT: MS correlated with increased cIMT in subjects with an impaired FMD response (P = 0.003) but not in subjects with an enhanced FMD response (P = 0.75)., Conclusion: All current definitions of MS identify a population of young adults with evidence of increased subclinical atherosclerosis. Impaired brachial endothelial response is not a hallmark of MS in young adults, but the status of endothelial function modifies the association between metabolic risk factors and atherosclerosis.

Background: Obese youths may be susceptible to develop the metabolic syndrome (MS) later in life., Aim: To study childhood predictors of MS in adulthood., Method: Prospective cohort study including 2,195 subjects, aged 3-18 years at base-line in 1980, who were re-examined in 1983, 1986, and 2001., Results: In adults (aged 24-39 years) in 2001, the prevalence of MS (using the International Diabetes Federation criteria) was 19% in men and 12% in women. Multivariable logistic regression model selected obesity, male sex, high triglycerides, high insulin, high C-reactive protein (CRP), and family history of hypertension and type 2 diabetes, as independent predictors of adult MS. Youth obesity (body mass index (BMI)>80th age- and sex-specific percentile) was the strongest risk factor for MS. During the 21-year follow-up, there was an increasing trend in BMI, insulin, systolic blood pressure, and triglycerides, and a decreasing trend in high-density lipoprotein cholesterol in obese subjects who developed MS in adulthood compared to those obese subjects who did not develop MS., Conclusions: Youth determinants of adult MS included obesity, high triglycerides, high insulin, high CRP, and family history of hypertension and type 2 diabetes. Identifying these risk factors at an early stage could help identifying children and adolescence at greater risk of developing MS later in life.

Novel biomarkers for multiple sclerosis (MS) could improve diagnosis and provide clues to pathogenesis. In this study surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to analyze protein expression in CSF from 46 MS patients, 46 healthy siblings to the patients, and 50 unrelated healthy controls. Twenty-four proteins in the mass range 2-10 kDa were expressed at significantly different levels (p < 0.01) in a robust manner when comparing the three groups. Identities of three proteins were determined using biochemical purification followed by tandem mass spectrometric analysis. Immunoprecipitation experiments confirmed the identities for two peptides derived from chromogranin B (m/z 6252) and from secretogranin II (m/z 3679). These peptides were all decreased in MS when compared with siblings or controls. Radioimmunoassays specific for each peptide confirmed these differences. The lowered concentrations did not correlate to the axonal damage marker neurofilament light protein and may thus reflect functional changes rather than neurodegeneration. Further studies will investigate the involvement of these peptides in MS pathogenesis.

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

Lipid peroxidation has been implicated in the pathogenesis of multiple sclerosis (MS). Isoprostanes, isomers of prostaglandins, are produced by free radical-mediated peroxidation of fatty acids in vivo and can be quantified in biological fluids. This study examines the levels of cerebrospinal fluid (CSF) F2-isoprostanes (F2-iPs) in MS patients (n=46), their healthy siblings (n=46) and unrelated controls (n=50). The median CSF F2-iP concentration (range) was significantly higher in siblings of MS patients, as compared to healthy controls (40.0 [7.1-68.7] and 29.1 [6.4-60.3] pg/mL, respectively, p=0.031). MS patients demonstrated F2-iP levels intermediate between siblings and controls. F2-iP levels in MS patients and siblings correlated significantly (R=0.360, p=0.012). These results suggest that siblings of MS patients have an increased oxidative stress response to environmental and/or genetic factors that may be involved in MS pathogenesis.

Objectives: The prevalence of the metabolic syndrome is increasing worldwide. We studied its prevalence in Finnish young adults. Three definitions were applied: National Cholesterol Education Program (NCEP), European Group for the Study of Insulin Resistance (EGIR) and International Diabetes Federation (IDF) criteria. We also investigated the secular trend in the metabolic syndrome amongst 24-year-old adults from 1986 to 2001., Design: Population-based follow-up study., Subjects: 2182 healthy young adults (1007 men; 1175 women) aged 24-39 years., Main Outcome Measures: Metabolic syndrome and its components., Results: The prevalence of the metabolic syndrome was 13.0% with NCEP criteria, 9.8% with EGIR criteria and 14.3% with IDF criteria. With NCEP and IDF criteria, the prevalence increased with age in both sexes, but more dramatically in men. There was over sixfold increase in the metabolic syndrome from 4.0% to 25.2% (P < 0.0001) in men between ages 24 and 39 years using the IDF criteria. Increases in obesity and serum triglycerides accounted much for the increase in the prevalence by age. The significant secular trend was seen between years 1986 and 2001 in 24-year-old subjects. The prevalence of the metabolic syndrome increased significantly from 1.0% to 7.5% (P < 0.0001) in 15 years., Conclusions: There is a substantial increase in the prevalence of the metabolic syndrome in healthy young adults between ages 24 and 39 driven mostly by the increase in obesity. The prevalence of the metabolic syndrome is higher amongst Finnish young adult men compared with women. The secular trend between 1986 and 2001 suggest a dramatic increase in the prevalence of the metabolic syndrome in 24-year-old young adults. Condensed abstract The prevalence of the metabolic syndrome may be increasing in young people. We studied the prevalence of the metabolic syndrome in 2182 young Finnish adults aged 24-39 years using NCEP, EGIR and IDF criteria. The prevalence of the metabolic syndrome was higher amongst Finnish men than women and increased dramatically with age. There was also a dramatic increase in the prevalence of the metabolic syndrome in 24-year-old adults between 1986 and 2001.

Background: This study was undertaken to evaluate the quality of ultrasound estimation of fetal weight when performed by midwives experienced in ultrasound examinations. We also examined whether the accuracy was affected by fetal presentation, twin pregnancy or birth weight category. The results of 5 different formulas were compared to determine which was most accurate in our study population., Methods: The study population consisted of 620 fetuses in 607 pregnancies, on whom fetal weight estimations had been performed within 3 days prior to delivery. The group of twins (n=27) was analysed separately. Results achieved by Hadlock 2 formula used in our unit were compared with 4 other widely used formulas for estimation of fetal weight., Results: With Hadlock 2 formula, mean absolute percent error was 6.2% and SD of error was 7.6% of mean birth weight. A total of 81% of estimates were within 10% of the actual birth weight. All the formulas tended to overestimate the weight of twins and fetuses weighing <2,500 g, and underestimate the weight of fetuses >4,000 g. Presentation of the fetus did not significantly influence the accuracy. The formula Hadlock 2, using 3 parameters (biparietal diameter, abdominal circumference and femur length) gave the highest ICC of 0.910., Conclusions: Ultrasound estimation of fetal weight performed by midwives is feasible and of similar accuracy as in the original studies. Major errors may occur both in small and large birth weight groups.

Background: The proportion of proton pump inhibitor users on long-term therapy who can discontinue proton pump inhibitor (PPI) medication without developing symptoms is unknown., Aim: To determine the proportion of patients on long-term PPI therapy who are able to discontinue PPIs without developing symptoms., Methods: Patients on long-term PPIs, without a history of peptic ulcer or esophagitis underwent upper endoscopy. Patients were randomized double-blindly to taper down or continue a constant dosage of omeprazole for three weeks. Thereafter, all patients discontinued PPIs., Results: Of the 97 patients enrolled, had used PPIs for 48 months, 78% had GERD. A total of 27% did not use PPIs during the year after discontinuation, 31% of the patients randomized to tapering discontinued PPIs and 22% of those who did not could discontinue therapy (NS). Gastro-oesophageal reflux disease (GERD) patients were more prone to continue PPIs than non-GERD patients. Only 16 (21%) of GERD patients were off PPIs vs. 48% of patients without GERD (p < 0.05). Serum gastrin was higher at baseline in GERD patients who resumed PPIs versus non-resumers (p < 0.05). GERD and serum gastrin were independent predictors of PPI requirement., Conclusions: Discontinuation of PPI was successful in 27% of long-term PPI users. GERD patients had more difficulty discontinuing PPIs than non-GERD patients.

Similar to murine models with compromised CD22/SHP-1 function, flaky skin (fsn) mutant mice exhibit lymphocyte hyperactivation and an autoimmune phenotype characterized by circulating autoantibodies to dsDNA and glomerulonephritis. Immunophenotyping of fsn/fsn splenic B cells was performed to determine if abnormalities in CD22 expression contributed to the phenotype. We identified an expansion of an IgM(bright) CD22lo population consistent with immature B-lymphocytes. While normal B-lymphocytes require IL-4 to achieve down-modulation of CD22 expression in response to BCR cross-linking, culture with anti-IgM alone led to reduced CD22 expression in fsn/fsn mice. Furthermore, when IL-4 was added to fsn/fsn cultures, no further reduction in CD22 expression was observed. This suggested that fsn/fsn B cells were pre-activated in vivo by chronic IL-4 exposure. A portion of these CD22lo cells expressed the B-1 surface marker CD11b. We contend that decreased activation thresholds among CD22lo B-lymphocytes contributes to the expansion of immature and B-1 B cell populations and to the development of autoimmune pathology in fsn/fsn mice.

This article reviews iron and vitamin B12 malabsorption due to the use of proton pump inhibitors (PPI) and infection with Helicobacter pylori. The bacterium is in some studies associated with low serum values of both ferritin and cobalamin and has in several cases been shown to cause reversible deficiency of these nutrients. PPI depresses absorption of vitamin B12, but only one case of deficiency has been reported in standard reflux therapy. Case reports exist of PPI-related iron deficiency, but studies have not confirmed these risks. General substitution with iron or B12 supplements in PPI therapy can't be advocated. The safety of long-term use of PPI is well documented, but it is still unclear whether PPI accelerates the development of atrophic corpus gastritis in the presence of H pylori.

The K(bm1) and K(bm8) natural mutants of the murine MHC class I molecule H-2K(b) were originally identified by allograft rejection. They also bind viral peptides VSV8 and SEV9 with high affinity, but their peptide complexes have substantially decreased thermostability, and the K(bm1) complexes do not elicit alloreactive T cell responses. Crystal structures of the four mutant complexes at 1.7-1.9 A resolution are similar to the corresponding wild-type K(b) structures, except in the vicinity of the mutated residues, which alter the electrostatic potential, topology, hydrogen bonding, and local water structure of the peptide binding groove. Thus, these natural K(b) mutations define the minimal perturbations in the peptide environment that alter antigen presentation to T cells and abolish alloreactivity.

The majority of cell surface receptors involved in antigen recognition by T cells and in the orchestration of the subsequent cell signalling events are glycoproteins. The length of a typical N-linked sugar is comparable with that of an immunoglobulin domain (30 A). Thus, by virtue of their size alone, oligosaccharides may be expected to play a significant role in the functions and properties of the cell surface proteins to which they are attached. A databank of oligosaccharide structures has been constructed from NMR and crystallographic data to aid in the interpretation of crystal structures of glycoproteins. As unambiguous electron density can usually only be assigned to the glycan cores, the remainder of the sugar is then modelled into the crystal lattice by superimposing the appropriate oligosaccharide from the database. This approach provides insights into the roles that glycosylation might play in cell surface receptors, by providing models that delineate potential close packing interactions on the cell surface. It has been proposed that the specific recognition of antigen by T cells results in the formation of an immunological synapse between the T cell and the antigen-presenting cell. The cell adhesion glycoproteins, such as CD2 and CD48, help to form a cell junction, providing a molecular spacer between opposing cells. The oligosaccharides located on the membrane proximal domains of CD2 and CD48 provide a scaffold to orient the binding faces, which leads to increased affinity. In the next step, recruitment of the peptide major histocompatibility complex (pMHC) by the T-cell receptors (TCRs) requires mobility on the membrane surface. The TCR sugars are located such that they could prevent non-specific aggregation. Importantly, the sugars limit the possible geometry and spacing of TCR/MHC clusters which precede cell signalling. We postulate that, in the final stage, the sugars could play a general role in controlling the assembly and stabilisation of the complexes in the synapse and in protecting them from proteolysis during prolonged T-cell engagement., (Copyright 1999 Academic Press.)

In an attempt to replicate the factor structure of symptom distress re- ported by Mattsson et al. in their study of 404 anxious neurotic outpatients, the same 68-item pretreatment self-report Symptom Check List was administered to an independent but clinically similar sample of 1,116 patients. Using an identical factor-analytic procedure, five useful factors were extracted: Neurotic Feelings, Somatization, Performance Difficulty, Fear-Anxiety, and Depression. Four of these factors were almost identical to those reported by Mattsson e t al. while the fifth factor, Depression, seemed to represent a composite of the two small Depression factors (Anxious and Somatic) found in the earlier study. This minor discrepancy was discussed and the future research potential of these factors was indicated.