Cerebrospinal fluid amyloid-β 2-42 is decreased in Alzheimer’s, but not in frontotemporal dementia

Abstract

Alzheimer’s dementia (AD) and frontotemporal dementias (FTD) are common and their clinical differential diagnosis may be complicated by overlapping symptoms, which is why biomarkers may have an important role to play. Cerebrospinal fluids (CSF) Aβ2-42 and 1-42 have been shown to be similarly decreased in AD, but 1-42 did not display sufficient specificity for exclusion of other dementias from AD. The objective of the present study was to clarify the diagnostic value of Aβ2-42 peptides for the differential diagnosis of AD from FTD. For this purpose, 20 non-demented disease controls (NDC), 22 patients with AD and 17 with FTD were comparatively analysed by a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol with subsequent Aβ-SDS-PAGE/immunoblot, allowing the quantification of peptides 1-38ox, 2-40 and 2-42 along with Aβ 1-37, 1-38, 1-39, 1-40, 1-40ox and 1-42. CSF Aβ1-42 was decreased in AD as compared to NDC, but not to FTD. In a subgroup of the patients analyzed, the decrease of Abeta2-42 in AD was evident as compared to both NDC and FTD. Aβ1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Aβ1-42 demonstrated sufficient diagnostic accuracies only when combined with Aβ1-38. Aβ2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Aβ2-42 to Aβ1-38. Aβ2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD.

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

“…Increased levels of Aβ2-42 were detected in AD brains (Wiltfang et al, 2001). This is in line with results showing decreased levels of Aβ2-42 in CSF of AD patients (Bibl et al, 2012). Since BACE-1 is not capable in directly generating this peptide, a suggested model for the emergence of N-terminal truncation is the subsequent cleavage of the N-terminus of BACE generated Aβ1-x by either Aβ degrading enzymes like insulin-degrading enzymes (IDE) or neprilysin or the aminopeptidase A (APA) (Arai et al, 1999; Wiltfang et al, 2001; Wang et al, 2006).…”

Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease

“…Translating these immunohistochemical observations to clinical assays may prove difficult, as levels of tau in CSF are near the lower limits of biologic detection (Hampel et al, 2010) limiting the further identification of a specific subset of tau in the form of a neoepitope; although one group has found promising evidence for diagnostic utility of specific C-truncated isoforms of tau in PSP through immunoprecipitation and western blotting techniques (Borroni et al, 2008, 2009) and others have developed assays to measure 3- and 4R tau in CSF (Luk et al, 2012). Alternatively-truncated forms of Aβ 1−42 may also have diagnostic importance in FTLD (Pijnenburg et al, 2007; Bibl et al, 2011, 2012; Gabelle et al, 2011) and cytoskeletal proteins, such as neurofilament have also been explored (Sjogren et al, 2000b; De Jong et al, 2007). These potential biomarkers warrant further study and validation.…”

Supportive CSF biomarker evidence to enhance the National Institute on Aging-Alzheimer's Association criteria for diagnosis of Alzheimer's type dementia – A study from Southern India

“…Majority of studies demonstrate decreased levels. Low levels are found even in early stages of dementia (Andreasen et al, 1999;Mulder et al, 2002;Hampel et al, 2004;Fagan et al, 2007) Levels were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients and MCI patients who developed other forms of dementia (p < 0.001) (Finehout et al, 2007;Bibl et al, 2012). The present study was undertaken to validate the measurement of biomarkers as a supplement to the latest diagnostic criteria for Alzheimer disease (AD) dementia by National Institute on Aging-Alzheimer's Association (NIA-AA) work group using a sample attending a tertiary care center in Southern India.…”