Search

AIMS In the search for blood-based biomarkers of neurodegenerative diseases, we characterized the concentration of total prion protein (t-PrP) in the plasma of neurodegenerative dementias. We aimed to assess its accuracy in this differential diagnostic context. METHODS Plasma t-PrP was measured in 520 individuals including healthy controls (HC) and patients diagnosed with neurological disease control (ND), Alzheimer's disease (AD), sporadic Creutzfeldt-Jakob disease (sCJD), frontotemporal dementia (FTD), Lewy body dementia (LBD) and vascular dementia (VaD). Additionally, t-PrP was quantified in genetic prion diseases and iatrogenic CJD. The accuracy of t-PrP discriminating the diagnostic groups was evaluated and correlated with demographic, genetic and clinical data in prion diseases. Markers of blood-brain barrier impairment were investigated in sCJD brains. RESULTS Compared to HC and ND, elevated plasma t-PrP concentrations were detected in sCJD, followed by FTD, AD, VaD and LBD. In sCJD, t-PrP was associated neither with age nor sex, but with codon 129 PRNP genotype. Plasma t-PrP concentrations correlated with cerebrospinal fluid (CSF) markers of neuro-axonal damage, but not with CSF t-PrP. In genetic prion diseases, plasma t-PrP was elevated in all type of mutations investigated. In sCJD brain tissue, extravasation of immunoglobulin G and the presence of swollen astrocytic end-feet around the vessels suggested leakage of blood-brain barrier as a potential source of increased plasma t-PrP. CONCLUSIONS Plasma t-PrP is elevated in prion diseases regardless of aetiology. This pilot study opens the possibility to consider plasma t-PrP as a promising blood-based biomarker in the diagnostic of prion disease.

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63, 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61, 0.94)) and AD (HR 0.66 (95% CI 0.51, 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.

Background There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. Objective 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. Methods Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. Results In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. Discussion For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

The cerebrospinal fluid (CSF) biomarkers amyloid-β42 (Aβ42), total Tau, and phospho-181-Tau represent important diagnostic tools to support the clinical diagnosis of Alzheimer's disease (AD). Acquiring CSF by lumbar puncture is considered a moderately invasive procedure, while blood sampling is minimally invasive with calculable risks and can be performed by trained non-medical staff. Thus, the identification of reliable and robust blood biomarkers of AD-related neuropathology would be significantly advantageous in daily practice and would allow more patients to be screened. In this study, we performed a multiplex amyloid-β assay to simultaneously measure Aβ40 and Aβ42. We analyzed how well Aβ40, Aβ42, and the Aβ42 to Aβ40 ratio (Aβ42/40) could differentiate between patients suffering from dementia either due or not due to AD. In addition, we studied different factors affecting Aβ levels in plasma. Plasma Aβ42/40 level was significantly lower in patients with dementia due to AD than in those with dementia due to other causes. Aβ42/40 correlated weakly between plasma and CSF, but did not differ between amyloid-PET positive or negative patients. Furthermore, we found that kidney function influences Aβ40 and Aβ42 plasma levels, but not Aβ42/40 level. Liver function, age, and sex do not affect Aβ levels in plasma.

Cost- and time-effective markers of Alzheimer's disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p

Dementia in general and Alzheimer’s disease in particular is increasingly seen in association with autoimmunity being causatively or supportively involved in the pathogenesis. Besides classic autoantibodies (AABs) present in dementia patients, there is the new autoantibody class called functional autoantibodies, which is directed against G-protein coupled receptors (GPCRs; GPCR-AABs) and are seen as pathogenic players. However, less is known about dementia patients’ burden with functional autoantibodies. We present here for the first time a study analyzing the prevalence of GPCR-AABs in patients with different dementia forms such as unclassified, Lewy body, vascular and Alzheimer’s dementia. We identified the GPCR-AABs’ specific targets on the receptors and introduced a neutralization strategy for GPCR-AABs. Patients with Alzheimer’s and vascular dementia carried GPCR-AABs targeting the first loop of the alpha1- and the second loop of the beta2-adrenergic receptors (α1-AABs; β2-AABs). Nearly all vascular dementia patients also carry autoantibodies targeting the endothelin A receptor (ETA-AABs). The majority of patients with Lewy body dementia lacked any of the GPCR-AABs. In vitro, the function of the dementia-associated GPCR-AABs could be neutralized by the aptamer BC007. Due to the presence of GPCR-AABs in dementia patients mainly in those suffering from Alzheimer’s and vascular dementia, the orchestra of immune players in these dementia forms, so far preferentially represented by the classic autoantibodies, should be supplemented by functional autoantibodies. As dementia-associated functional autoantibodies could be neutralized by the aptamer BC007, the first step was taken for a new in vivo treatment option in dementia patients who were positive for GPCR-AABs.

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimers disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by neurological disorders and misshaped spiky red blood cells (acanthocytes) including Chorea-Acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease-like 2 (HDL 2), pantothenate kinase-associated neurodegeneration (PKAN), abeta- and hypobetalipoproteinemia and aceruloplasminemia. This clinically and genetically heterogeneous group of diseases shares main clinical features presenting most often as a hyperkinetic movement disorder. Even though these are long noted disease conditions, we still know only little on the underlying disease mechanisms. The current review focuses upon ChAc as the core entity of NA syndromes caused by mutations in the VPS13A gene. The support of patient organizations and the ERA-NET initiative yielded to different multidisciplinary efforts with significant progress on our understanding of ChAc. Disturbances in two pathways are currently considered to be significantly involved in the pathophysiology of ChAc, namely elevated Lyn kinase phosphorylation and decreased signaling via Phosphoinositide 3-kinase (PI3K). These recent developments may reveal potential drugable targets for causative therapies of ChAc.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative motor disorder. However, non-motor complications frequently alter the course of the disease. A particularly disabling non-motor symptom is dementia. Methods/Design: The study is designed as a multicentre prospective, observational cohort study of about 700 PD patients aged 45–80 years with or without dementia and PD-mild cognitive impairment (MCI). The patients will be recruited in eight specialized movement disorder clinics and will be followed for 36 months. Information about the patients’ functional status will be assessed at baseline and 6-/12- month intervals. In addition, 120 patients with dementia with Lewy bodies (DLB) will be included. Well-established standardized questionnaires/tests will be applied for detailed neuropsychological assessment. In addition, patients will be asked to participate in modules including volumetric MRI, genetic parameters, and neuropsychology to detect risk factors, early diagnostic biomarkers and predictors for dementia in PD. Results: The study included 604 PD patients by March 2011; 56.3% were classified as having PD alone, with 30.6% of patients suffering from PD-MCI and 13.1% from PD with dementia. The mean age of the cohort was 68.6 ± 7.9 years, with a mean disease duration of 6.8 ± 5.4 years. There was a preponderance of patients in the earlier Hoehn and Yahr stages. Conclusion: The main aim of the study is to characterize the natural progression of cognitive impairment in PD and to identify factors which contribute to the evolution and/or progression of the cognitive impairment. To accomplish this aim we established a large cohort of PD patients without cognitive dysfunction, PD patients with MCI, and PD patients with dementia, to characterize these patients in a standardized manner, using imaging (serial structural MRI), genetic and proteomic methods in order to improve our understanding of the course of the PD process and the development of cognitive dysfunction and dementia in this disease. The inclusion of the DLB patients will start in the second quarter of 2011 in the BMBF-funded follow-up project LANDSCAPE.

Reduced (GSH(R)) but not oxidized glutathione (GSSG) has been shown to be dramatically altered in the substantia nigra (SN) of Lewy body disease (LBD) patients post mortem; but up to now, there is no convincing evidence that these changes can be monitored in vivo. We investigated GSH(R) and GSSG in rapidly processed cerebrospinal fluid (CSF) and plasma samples of 80 LBD and 35 control subjects and detected reduced CSF GSH(R) levels in LBD subjects. The reduction was negatively associated with age but not with disease-associated parameters. Plasma GSH(R), CSF GSSG, and plasma GSSG levels did not significantly differ between the groups. Our findings confirm the results from neuropathologic studies, which demonstrated an alteration of the glutathione system in LBD. We hypothesize that alterations of the glutathione system occur in a very early stage of the disease or may even represent a risk marker for LBD.

Type 2 diabetes mellitus (T2DM) is a risk factor of dementia. The effect of T2DM treatment quality on dementia risk, however, is unclear. 1,342 elderly individuals recruited via general practitioner registries (AgeCoDe cohort) were analyzed. This study analyzed the association between HbA1c level and the incidence of all-cause dementia (ACD) and of Alzheimer's disease dementia (referred to here as AD). HbA1c levels ≥6.5% were associated with 2.8-fold increased risk of incident ACD (p = 0.027) and for AD (p = 0.047). HbA1c levels ≥7% were associated with a five-fold increased risk of incident ACD (p = 0.001) and 4.7-fold increased risk of incident AD (p = 0.004). The T2DM diagnosis per se did not increase the risk of either ACD or AD. Higher levels of HbA1c are associated with increased risk of ACD and AD in an elderly population. T2DM diagnosis was not associated with increased risk if HbA1c levels were below 7%.

Background Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition. Methods Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS. Results Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P

Cardiovascular risk factors are associated with coronary artery disease (CAD) and with cognitive dysfunction. However, the precise pathogenic mechanisms responsible for this association remain elusive. In the present study, CAD patients with cognitive impairment showed significantly higher platelet activation compared with CAD patients without cognitive impairment. In addition, we identified platelet activity to be a significant independent predictor for the severity of cognitive impairment in these patients. We discuss the link between platelet hyperactivity and dementia (including Alzheimer`s disease) based on the literature and our findings. We also discuss the potential mechanisms involved. This link may become a therapeutic option.

Parkinson’s disease (PD) without (non-demented, PDND) and with dementia (PDD), and dementia with Lewy bodies (DLB) are subsumed under the umbrella term Lewy body disorders (LBD). The main component of the underlying pathologic substrate, i.e. Lewy bodies and Lewy neurites, is misfolded alpha-synuclein (Asyn), and - in particular in demented LBD patients - co-occurring misfolded amyloid-beta (Abeta). Lowered blood and cerebrospinal fluid (CSF) levels of transthyretin (TTR) - a clearance protein mainly produced in the liver and, autonomously, in the choroid plexus - are associated with Abeta accumulation in Alzheimer’s disease. In addition, a recent study suggests that TTR is involved in Asyn clearance. We measured TTR protein levels in serum and cerebrospinal fluid of 131 LBD patients (77 PDND, 26 PDD, and 28 DLB) and 72 controls, and compared TTR levels with demographic and clinical data as well as neurodegenerative markers in the CSF. Five single nucleotide polymorphisms of the TTR gene which are considered to influence the ability of the protein to carry its ligands were also analyzed. CSF TTR levels were significantly higher in LBD patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by PDND patients. In addition, CSF TTR levels correlated negatively with CSF Abeta1–42, total tau and phospho-tau levels. Serum TTR levels did not significantly differ among the studied groups. There were no relevant associations between TTR levels and genetic, demographic and clinical data, respectively. These results suggest an involvement of the clearance protein TTR in LBD pathophysiology, and should motivate to elucidate TTR-related mechanisms in LBD in more detail.