The Alzheimer variant of Lewy body disease: A pathologically confirmed case-control study

The objective of the study was to identify clinical features that distinguish patients with dementia with Lewy bodies (DLB), who were classified as Alzheimer's disease ( AD) patients, from patients with AD. We examined a group of 27 patients from our memory clinic, originally diagnosed with AD, of whom 6 were postmortem found to have DLB. For the present study, we compared cognitive, noncognitive and neurological symptoms between the two groups. We found that there were no differences on ratings of dementia and scales for activities of daily living. Patients with DLB performed better on the MMSE and the memory subtest of the CAMCOG, but there was no difference in any other cognitive domain. Furthermore, genetic risk factors, including family history of dementia or allele frequency of the apolipoprotein epsilon 4, did not discriminate between the two groups, and there were no differences on CCT scans. Taken together, our findings suggest that Lewy body pathology may be present in patients who do not show the typical clinical features which distinguish DLB from AD. Copyright (C) 2005 S. Karger AG, Basel

Gaussian Mixture Models and Model Selection for [18F] Fluorodeoxyglucose Positron Emission Tomography Classification in Alzheimer’s Disease

We present a method to discover discriminative brain metabolism patterns in [18F] fluorodeoxyglucose positron emission tomography (PET) scans, facilitating the clinical diagnosis of Alzheimer’s disease. In the work, the term “pattern” stands for a certain brain region that characterizes a target group of patients and can be used for a classification as well as interpretation purposes. Thus, it can be understood as a so-called “region of interest (ROI)”. In the literature, an ROI is often found by a given brain atlas that defines a number of brain regions, which corresponds to an anatomical approach. The present work introduces a semi-data-driven approach that is based on learning the characteristics of the given data, given some prior anatomical knowledge. A Gaussian Mixture Model (GMM) and model selection are combined to return a clustering of voxels that may serve for the definition of ROIs. Experiments on both an in-house dataset and data of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) suggest that the proposed approach arrives at a better diagnosis than a merely anatomical approach or conventional statistical hypothesis testing

Validation of the German Revised Addenbrooke's Cognitive Examination for Detecting Mild Cognitive Impairment, Mild Dementia in Alzheimer's Disease and Frontotemporal Lobar Degeneration

Background/Aims: The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. Methods: The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. Results: The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD {[}area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. Conclusion: The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia. Copyright (C) 2010 S. Karger AG, Base

Multivariate and Univariate Neuroimaging Biomarkers of Alzheimer's Disease

We performed univariate and multivariate discriminant analysis of FDG-PET scans to evaluate their ability to identify Alzheimer's disease (AD). FDG-PET scans came from two sources: 17 AD patients and 33 healthy elderly controls were scanned at the University of Michigan; 102 early AD patients and 20 healthy elderly controls were scanned at the Technical University of Munich, Germany. We selected a derivation sample of 20 AD patients and 20 healthy controls matched on age with the remainder divided into 5 replication samples. The sensitivity and specificity of diagnostic AD-markers and threshold criteria from the derivation sample were determined in the replication samples. Although both univariate and multivariate analyses produced markers with high classification accuracy in the derivation sample, the multivariate marker's diagnostic performance in the replication samples was superior. Further, supplementary analysis showed its performance to be unaffected by the loss of key regions. Multivariate measures of AD utilize the covariance structure of imaging data and provide complementary, clinically relevant information that may be superior to univariate measures

Association of chronic pain with biomarkers of neurodegeneration, microglial activation and inflammation in the CSF and impaired cognitive function

ObjectivesDebate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsParticipants were classified using the ATN classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, ANCOVA models identified differences in CSF levels of Aβ1‐42, ptau181, t‐tau, sTREM2 and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analysed. Linear mixed‐effect models examined longitudinal changes.ResultsThe study included 995 individuals with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non‐Alzheimer's pathophysiology (SNAP) and chronic pain showed increased CSF levels of t‐tau and sTREM2. Chronic pain was associated with increased TNF‐α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid positive and neurodegeneration negative chronic pain patients showed higher memory function cross‐sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.Interpretationour study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm those findings.This article is protected by copyright. All rights reserved.</jats:sec

Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults

BackgroundIdentifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD).ObjkectivesInvestigate the use of miRNA as early blood-biomarker of cognitive decline in older adults.DesignCross-sectional.SettingTwo observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)).Participants830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI.MeasurementsqPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-& beta;42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets.ResultsSix miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-& beta;42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression.Conclusionssix miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD

Early and Differential Diagnosis of Dementia and Mild Cognitive Impairment Design and Cohort Baseline Characteristics of the German Dementia Competence Network

Background: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. Methods: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. Results: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. Conclusion: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD. Copyright (C) 2009 S. Karger AG, Base

temporary implementation and testing of a confocal sr μxrf system for bone analysis at the x ray fluorescence beamline at elettra

Abstract The confocal μ XRF spectrometer of Atominstitut (ATI) was transported and set up at the X-ray Fluorescence beamline at Elettra - Sincrotrone Trieste. It was successfully adjusted to the incoming beam (9.2 keV). Test measurements on a free-standing Cu wire were performed to determine the size of the focused micro-beam (non-confocal mode, 56 × 35 μ m 2 ) and the size of the confocal volume (confocal mode, 41 × 24 × 34 μ m 2 ) for the Cu–K α emission. In order to test the setup's capabilities, two areas on different human bone samples were measured in confocal scanning mode. For one of the samples the comparison with a previous μ XRF measurement, obtained with a low power X-ray tube in the lab, is presented

Development of a short version of the German subjective cognitive decline questionnaire (SCD-Q17): a principal component analysis approach to item reduction

Since it was shown that Alzheimer’s disease (AD) begins many years before the onset of symptoms with subjective cognitive decline (SCD), there has been increasing interest in the early clinical stages where disease-modifying drugs are expected to have the greatest benefit. However, at this early stage cognitive testing may yield unremarkable results, it is necessary to find a tool that can provide a simple and reliable indication of SCD as a part of a screening tool for AD in the general population. The German version of the 24-item Subjective Cognitive Decline Questionnaire (SCD-Q) with a dichotomous answer scale was tested, which then revealed some challenges. For this reason, an adaptation of the questionnaire was necessary. 360 participants completed the SCD-Q, all of whom were outpatients at a memory clinic. The most relevant subitems were identified by principal component analysis. This analysis focused on the self-perceived perspective of the decline. Results of the principal component analysis, consultations with experts and feedback from respondents were integrated into a short version of the SCD-Q with 17 items and a Likert scale – the SCD-Q17. The SCD-Q17 was sent to 100 participants of the original questionnaire for re-completion and, a new cut-off value was calculated by receiver operator characteristic (ROC) curves. The SCD-Q17 is a useful tool for the reliable detection of subjective symptoms, and thus may prompt more in-depth assessments of the underlying etiology. CogScreen has been retrospectively registered at clinical trials (NCT06191952)

Impact of pre‐analytical sample handling factors on plasma biomarkers of Alzheimer's disease

An unmet need exists for reliable plasma biomarkers of amyloid pathology, in the clinical laboratory setting, to streamline diagnosis of Alzheimer's disease (AD). For routine clinical use, a biomarker must provide robust and reliable results under pre-analytical sample handling conditions. We investigated the impact of different pre-analytical sample handling procedures on the levels of seven plasma biomarkers in development for potential routine use in AD. Using (1) fresh (never frozen) and (2) previously frozen plasma, we evaluated the effects of (A) storage time and temperature, (B) freeze/thaw (F/T) cycles, (C) anticoagulants, (D) tube transfer, and (E) plastic tube types. Blood samples were prospectively collected from patients with cognitive impairment undergoing investigation in a memory clinic. β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), apolipoprotein E4, glial fibrillary acidic protein, neurofilament light chain, phosphorylated-tau (phospho-tau) 181, and phospho-tau-217 were measured using Elecsys® plasma prototype immunoassays. Recovery signals for each plasma biomarker and sample handling parameter were calculated. For all plasma biomarkers measured, pre-analytical effects were comparable between fresh (never frozen) and previously frozen samples. All plasma biomarkers tested were stable for ≤24 h at 4°C when stored as whole blood and ethylenediaminetetraacetic acid (EDTA) plasma. Recovery signals were acceptable for up to five tube transfers, or two F/T cycles, and in both polypropylene and low-density polyethylene tubes. For all plasma biomarkers except Aβ42 and Aβ40, analyte levels were largely comparable between EDTA, lithium heparin, and sodium citrate tubes. Aβ42 and Aβ40 were most sensitive to pre-analytical handling, and the effects could only be partially compensated by the Aβ42/Aβ40 ratio. We provide recommendations for an optimal sample handling protocol for analysis of plasma biomarkers for amyloid pathology AD, to improve the reproducibility of future studies on plasma biomarkers assays and for potential use in routine clinical practice