O2‐03‐03: Beta‐amyloid oligomer detection in cerebrospinal fluid and brain tissue

CSF in Alzheimer's Disease

“…Walsh et al showed that soluble oligomers of Ab inhibit hippocampal longterm potentiation in rats [126], and others have found that they can lead to abnormal phosphorylation of tau as well as neuritic dystrophy [127][128][129]. Comparing AD with controls, studies have shown that the former have higher levels of oligomers in their brains [130,131]. Several studies have tried to replicate these findings in CSF, but results have been inconsistent.…”

“…Some studies have found elevated CSF Ab oligomer in AD [132][133][134][135][136] or in cognitively normal older adults with an AD-like biomarker profile [137], while others have not found this relationship [130,138]. The term "oligomer" includes species from dimers to much larger protofibrils, and this may be an explanation to the diverging results, since most studies have not used methods that enable a precise characterization of the measurand.…”

Cerebrospinal fluid biomarkers for pathological processes in Alzheimer's disease

“…Attempts to measure oligomers in CSF have successfully been made with several methods. Elevated levels have been found in AD patients compared with controls by using ELISA [56], an ultrasensitive bio-barcode assay [57] and fluorescence correlation spectroscopy [58]. One study using ELISA [54] and another using flow cytometry [59] found no statistically significant differences between AD and control, although a trend toward higher CSF oligomer levels in the AD group could be seen in the latter study.…”

How many biomarkers to discriminate neurodegenerative dementia?

“…Although several methods have been recently developed in the attempt to analyze diffusible oligomers in the CSF, results on the normal levels and range are controversial. Some studies reported increased levels of Ab-derived diffusible ligands (ADDLs; molecular weights between 17 and 42 kDa) 148 and of the high molecular weight (HMW) oligomer Ab 42 (MW: 45-90 kDa) 149 , whereas other studies showed that oligomer Ab 42 levels in AD largely overlap with those in different diseases [150][151][152] and are decreased in comparison with control subjects 153 . Actually, Ab oligomers are heterogeneous compounds of different molecular weights, so it is hard to estimate the whole spectrum of oligomers with low, medium and high molecular weight, explaining the different results using different techniques 154 .…”

“…Indeed, it is worth noting that the variability of the results is very high among the many studies on oligomeric aggregates in CSF. Actually, in the majority of these studies, Ab and aSyn oligomers have been measured using immunometric or cytofluorimetric assay, which can give false positive results 152,159 due to the presence of interfering factors, such as heterophilic antibodies 160 , or the presence of RIPA buffer 151,153 . Therefore, the search for CSF oligomers may be very promising for the diagnosis and the comprehension of pathological pathways of neurodegenerative diseases, but a great effort is required to validate a reliable method of analysis.…”