Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.

BACKGROUND: Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases. METHODS: Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases. RESULTS: APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases. CONCLUSION: These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.

Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment.

OBJECTIVE: To identify oxidatively modified proteins in brains of persons with inherited Alzheimer's disease. METHODS: Redox proteomics was used to identify oxidatively modified brain proteins in persons with mutations in the genes for presenilin-1 (PS-1). RESULTS: An initial redox proteomics assessment of oxidatively modified proteins from brains of individuals with PS-1 mutations was performed. These PS1 mutations, Q222H and M233T, are completely penetrant causing early-onset familial AD as previously reported in these Australian families. We show that oxidative modifications of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), gamma-enolase, actin, and dimethylarginine dimethylaminohydrolase 1 (DMDMAH-1) are present in the brain of familial AD subjects. CONCLUSIONS: These initial results suggest that oxidatively modified proteins are important common features in both familial and sporadic AD.

Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease.

Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer's disease (EOFAD) cases. In this study, we identified two missense mutations in the coding sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Abeta(1-40) and Abeta(1-42), which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.

Transition metal chelator therapy--a potential treatment for Alzheimer's disease?

A defining feature of Alzheimer's disease (AD) pathology is the presence of amyloid beta known as A-beta (Abeta) within neuritic plaques of the hippocampus and neocortex of the brain. While early in vitro studies suggested that Abeta could itself be toxic to neuronal cells, recent studies have indicated that this peptide has both neurotoxic and neuroprotective properties that are modulated by the binding of transition metal ions. Transition metal ion binding was shown to modulate Abeta solubility as well as its hydrogen peroxide production, thereby providing explanations for both its trophic and toxic properties. These findings lead to the suggestion that interference with this interaction may reverse the neurotoxic properties of Abeta. More recently, in vivo and in vitro studies into the effects of transition metal chelator treatments on Abeta solubilisation and neurological function have been published. Such studies have yielded promising results, however the potential side effects of many such metal chelators may prove too great for clinical use. It is widely agreed that the ideal chelator for such interdiction would act only on those transition metals that complex with Abeta, and only at metal ion binding sites that contribute to Abeta aggregation and reactive oxygen species generation. The efficacy of metal chelators in reducing Abeta load in transgenic mouse brains demonstrates that this approach has considerable merit as a research tool and as a stimulus to develop second generation agents that can selectively prevent transition metals from binding to the Abeta peptide itself without perturbing the action of other important metal requiring biomolecules in the brain.