amyloid-beta-peptides and Frontotemporal-Lobar-Degeneration

To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.. The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).. Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.. The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Biomarkers; Case-Control Studies; Chemokine CCL2; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Lobar Degeneration; Humans; Hydrocephalus, Normal Pressure; Male; Middle Aged; Multiple System Atrophy; Neurofilament Proteins; Parkinson Disease; Peptide Fragments; Phosphoproteins; Sensitivity and Specificity; Supranuclear Palsy, Progressive; tau Proteins

To investigate amyloid-β (Aβ) in frontotemporal dementia (FTD), cerebrospinal fluid (CSF) Aβ38, Aβ40, and Aβ42 in frontotemporal lobar degeneration (FTLD; N = 18 genetically and/or pathologically confirmed and N = 8 FTD with concomitant amyotrophic lateral sclerosis) were compared with Alzheimer's disease (AD; pathological or Pittsburgh-compound-B Positron-emission-tomography (PIB-PET) positive; N = 25) and controls (N = 24). For all the Aβ subtypes, group difference was seen and post-hoc analysis revealed lower levels in FTLD compared to controls (p≤0.05). Aβ42/40 ratio showed no difference between FTLD and controls; however, a difference was seen between AD versus FTLD (p < 0.01). This is an intriguing finding, suggesting a possible role of Aβ in FTLD pathogenesis.

Topics: Amyloid beta-Peptides; Biomarkers; Case-Control Studies; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged; Peptide Fragments; Pilot Projects; ROC Curve; Sensitivity and Specificity

Biomarkers in the cerebrospinal fluid (CSF) are currently regarded as indispensable indicators for accurate differential diagnosis of neurodegenerative disorders. Although high levels of astrocyte-secreted glial fibrillar acidic protein (GFAP) in the CSF of patients with Alzheimer's disease (AD) have been reported, the levels of GFAP in the CSF have not been fully investigated in other neurological disorders that cause dementia, such as dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). In this study, we determined the levels of GFAP in the CSF of healthy control subjects and AD, DLB, and FTLD patients to address two questions: (i) Do the levels of GFAP differ among these disorders? and (ii) Can GFAP be used as a biomarker for the differential diagnosis of these neurodegenerative disorders? The levels of GFAP in AD, DLB, and FTLD patients were significantly higher than those in the healthy control subjects. Although the levels of GFAP were not significantly different between AD and DLB patients, a higher level of GFAP was observed in FTLD patients than in AD and DLB patients. It is concluded that representative neurological disorders causing dementia were associated with higher levels of GFAP in the CSF. We propose the following mechanism concerning the amount of glial fibrillar acidic protein (GFAP) in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). The increase in the release of GFAP into CSF is considered to reflect the sum of degeneration of astrocytes and astrocytosis. The sum of degeneration and astrocytosis or the GFAP release could be in the order of FTLD > DLB > AD > normal condition.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Female; Frontotemporal Lobar Degeneration; Glial Fibrillary Acidic Protein; Humans; Lewy Body Disease; Male; Mental Status Schedule; Peptide Fragments; tau Proteins

Cerebrospinal fluid (CSF) biomarkers have been increasingly studied for dementia diagnosis, however the accuracy to distinguish between different forms of dementia is still unsatisfactory. In this study, the added value of another CSF Aβ-peptide (Aβ40), along with the core CSF markers t-Tau, p-Tau, and Aβ42, in the discrimination between two large dementia groups of Frontotemporal Lobar Degeneration (FTLD; n=107), Alzheimer's Disease (AD; n=107) and non-demented subjects (n=33) was evaluated. In FTLD, t-Tau and p-Tau were significantly increased in relation to controls, but lower than in AD, while Aβ42 was similar in FTLD and controls, but higher than in AD. Equally reduced Aβ40 levels were seen in both dementia groups, and therefore the combination of Aβ40 with core CSF biomarkers optimally discriminated FTLD and AD patients from controls. Aβ42 and t-Tau were selected as the best biomarker subset to differentiate FTLD from AD, with no added value of Aβ40 to the model. Diagnostic accuracy between FTLD and AD was still sub-optimal, with a significant percentage (23%) of FTLD patients, in particularly women, carrying an ApoE-ε4 allele, showing a CSF-AD biomarkers profile. Although CSF Aβ40 does not appear to have an additional value in the distinction between FTLD and AD, it increases the discrimination between subjects with dementia from controls. A CSF-AD biomarker profile can be seen in patients with a clinical phenotype of FTLD, reinforcing the need for autopsy confirmation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged; Peptide Fragments; Sensitivity and Specificity

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer's disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild-type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer's disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased Aβ42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging and suggest that structural changes in PS1/γ-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.

Topics: Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cells, Cultured; Female; Frontotemporal Lobar Degeneration; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Neurons; Oxidative Stress; Peptide Fragments; Plaque, Amyloid; Presenilin-1; Protein Conformation

To determine the additional value of cerebrospinal fluid (CSF)amyloid-beta1-40 (Abeta40) next to amyloid-beta1-42 (beta42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Abeta40, Abeta42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Abeta42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Abeta42, Tau, and Abeta40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Abeta42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau(cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step,Abeta40 (cut-off 10 ng/ml) was used to differentiate controls (PPV68%). Applying CSF Abeta40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Abeta42 and Tau were used. CSF Abeta40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Abeta40 in differential diagnosis between FTLD, AD, and control subjects.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Frontotemporal Lobar Degeneration; Humans; Logistic Models; Male; Middle Aged; Peptide Fragments; Retrospective Studies; tau Proteins