Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer's Disease: A Pilot Study

BACKGROUND: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms. OBJECTIVE: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. METHODS: YKL-40 and neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. RESULTS: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. CONCLUSION: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin

The effects of different familial Alzheimer's disease mutations on APP processing in vivo

BACKGROUND: Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. METHODS:In the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families. RESULTS: We observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations. CONCLUSIONS: These findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology

Large scale analytic calculations in quantum field theories

We present a survey on the mathematical structure of zero- and single scale quantities and the associated calculation methods and function spaces in higher order perturbative calculations in relativistic renormalizable quantum field theories.Comment: 25 pages Latex, 1 style fil

Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment

BACKGROUND: Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD. METHODS: rCBF was investigated in 54 MCI subjects using Tc-99m hexamethylpropyleneamine oxime (HMPAO). An automated analysis software (BRASS) was applied to analyze the relative blood flow (cerebellar ratios) of 24 cortical regions. After the baseline examination, the subjects were followed clinically for an average of two years. 17 subjects progressed to Alzheimer's disease (PMCI) and 37 subjects remained stable (SMCI). The baseline SPECT ratio values were compared between PMCI and SMCI. Receiver operating characteristic (ROC) analysis was applied for the discrimination of the two subgroups at baseline. RESULTS: The conversion rate of MCI to AD was 13.7% per year. PMCI had a significantly decreased rCBF in the left posterior cingulate cortex, as compared to SMCI. Left posterior cingulate rCBF ratios were entered into a logistic regression model for ROC curve calculation. The area under the ROC curve was 74%–76%, which indicates an acceptable discrimination between PMCI and SMCI at baseline. CONCLUSION: A reduced relative blood flow of the posterior cingulate gyrus could be found at least two years before the patients met the clinical diagnostic criteria of AD

Endogenous Galectin-9 Suppresses Apoptosis in Human Rheumatoid Arthritis Synovial Fibroblasts

Galectin-9 (Gal9) has been postulated to have anti-infammatory properties based on the ability of exogenous Gal9 to induce apoptosis in synovial fbroblasts in animal models of rheumatoid arthritis (RA). Here we aimed to assess the potential role of endogenous Galectins, including Gal9, in the infammatory pathology of the RA synovium in humans. Firstly expression of Galectins 1–9 was determined in synovial fbroblasts (RASF) and dermal fbroblasts (DF) isolated from RA patients, the latter representing a non-infamed site. We then further challenged the cells with pro-infammatory TLR agonists and cytokines and assessed Galectin expression. Gal9 was found to be diferentially and abundantly expressed in RASF compared to DF. Agonists of TLR3 and TLR4, along with IFNgamma were also found to induce Gal9 expression in RASF. siRNA was then used to knock-down Gal9 expression in RASF and the efects of this on apoptosis and cell viability were assessed. Increased apoptosis was observed in RASF following Gal9 knock-down. We conclude that, unlike exogenous Gal9, endogenous Gal9 is protective against apoptosis and enhances synovial fbroblast viability suggesting that its role in RA is both pathogenic and pro-infammatory

The accuracy of the MMSE in detecting cognitive impairment when administered by general practitioners: A prospective observational study

<p>Abstract</p> <p>Background</p> <p>The Mini-Mental State Examination (MMSE) has contributed to detecting cognitive impairment, yet few studies have evaluated its accuracy when used by general practitioners (GP) in an actual public-health setting.</p> <p>Objectives</p> <p>We evaluated the accuracy of MMSE scores obtained by GPs by comparing them to scores obtained by Alzheimer's Evaluation Units (UVA).</p> <p>Methods</p> <p>The study was observational in design and involved 59 voluntary GPs who, after having undergone training, administered the MMSE to patients with symptoms of cognitive disturbances. Individuals who scored ≤ 24 (adjusted by age and educational level) were referred to Alzheimer's Evaluation Units (UVA) for diagnosis (including the MMSE). UVAs were unblinded to the MMSE score of the GP. To measure interrater agreement, the weighted Kappa statistic was calculated. To evaluate factors associated with the magnitude of the difference between paired scores, a linear regression model was applied. To quantify the accuracy in discriminating no cognitive impairment from any cognitive impairment and from Alzheimer's disease (AD), the ROC curves (AUC) were calculated.</p> <p>Results</p> <p>For the 317 patients, the mean score obtained by GPs was significantly lower (15.8 vs. 17.4 for the UVAs; p < 0.01). However, overall concordance was good (Kappa = 0.86). Only the diagnosis made by the UVA was associated with the difference between paired scores: the adjusted mean difference was 3.1 for no cognitive impairment and 3.8 for mild cognitive impairment. The AUC of the scores for GPs was 0.80 (95%CI: 0.75–0.86) for discriminating between no impairment and any impairment and 0.89 (95%CI: 0.84–0.94) for distinguishing patients with AD, though the UVA scores discriminated better.</p> <p>Conclusion</p> <p>In a public-health setting involving patients with symptoms of cognitive disturbances, the MMSE used by the GPs was sufficiently accurate to detect patients with cognitive impairment, particularly those with dementia.</p

Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging

Background: White matter hyperintensities (WMH) on MRI scans indicate lesions of the subcortical fiber system. The regional distribution of WMH may be related to their pathophysiology and clinical effect in vascular dementia (VaD), Alzheimer's disease (AD) and healthy aging. Methods: Regional WMH volumes were measured in MRI scans of 20 VaD patients, 25 AD patients and 22 healthy elderly subjects using FLAIR sequences and surface reconstructions from a three-dimensional MRI sequence. Results: The intraclass correlation coefficient for interrater reliability of WMH volume measurements ranged between 0.99 in the frontal and 0.72 in the occipital lobe. For each cerebral lobe, the WMH index, i.e. WMH volume divided by lobar volume, was highest in VaD and lowest in healthy controls. Within each group, the WMH index was higher in frontal and parietal lobes than in occipital and temporal lobes. Total WMH index and WMH indices in the frontal lobe correlated significantly with the MMSE score in VaD. Category fluency correlated with the frontal lobe WMH index in AD, while drawing performance correlated with parietal and temporal lobe WMH indices in VaD. Conclusions: A similar regional distribution of WMH between the three groups suggests a common (vascular) pathogenic factor leading to WMH in patients and controls. Our findings underscore the potential of regional WMH volumetry to determine correlations between subcortical pathology and cognitive impairment. Copyright (C) 2004 S. Karger AG, Basel