Amyloid-β-Secondary Structure Distribution in Cerebrospinal Fluid and Blood Measured by an Immuno-Infrared-Sensor: A Biomarker Candidate for Alzheimer’s Disease

Abstract

The misfolding of the Amyloid-beta (Aβ) peptide into β-sheet enriched conformations was proposed as an early event in Alzheimer's Disease (AD). Here, the Aβ peptide secondary structure distribution in cerebrospinal fluid (CSF) and blood plasma of 141 patients was measured with an immuno-infrared-sensor. The sensor detected the amide I band, which reflects the overall secondary structure distribution of all Aβ peptides extracted from the body fluid. We observed a significant downshift of the amide I band frequency of Aβ peptides in Dementia Alzheimer type (DAT) patients, which indicated an overall shift to β-sheet. The secondary structure distribution of all Aβ peptides provides a better marker for DAT detection than a single Aβ misfold or the concentration of a specific oligomer. The discrimination between DAT and disease control patients according to the amide I frequency was in excellent agreement with the clinical diagnosis (accuracy 90% for CSF and 84% for blood). The amide I band maximum above or below the decisive marker frequency appears as a novel spectral biomarker candidate of AD. Additionally, a preliminary proof-of-concept study indicated an amide I band shift below the marker band already in patients with mild cognitive impairment due to AD. The presented immuno-IR-sensor method represents a promising, simple, robust, and label-free diagnostic tool for CSF and blood analysis.

Differential diagnosis of Alzheimer’s disease using spectrochemical analysis of blood

“…A slight increase of the intensity at the Amide I region (1,650-1,630 cm ; P = 0.1069, 95% CI = −0.005, 0.0005), observed in our AD patients, could presumably be caused by increased levels of Aβ plaques. In a recent study, using a more complex setting with a specialized, immuno-IR sensor, it was shown that the structural changes of Aβ peptide from α-helix to β-sheet, seen in AD, can be detectable by a significant downshift at the Amide I region (1,643 cm ), and this further proves the importance of this region (13). Similar results were seen in an another study, which analyzed protein solutions containing soluble and aggregated forms of tau protein (random coil and β-sheet, respectively); in this case, a transition from a maximum peak at 1,650 cm −1 to a peak at 1,630 cm −1 was evident (25).…”

“…A major goal is the detection of AD at a very early stage, even before the patient becomes symptomatic (10,13). Early diagnosis is crucial, as once the patient appears with clinical symptoms, the damage that has occurred in the brain may already be irreversible.…”

“…However, if at-risk individuals are identified early, it may be possible to delay or even prevent additional progression of the disease by administration of drugs that decrease Aβ production or aggregation (preventing plaque formation) or tau protein aggregation (preventing tangle formation) (14). The diagnostic accuracy of existing biomarkers has been previously reported to vary from ∼70 to ∼95% (10,13,15,16); however, most of the current tests cannot be used routinely because of their high cost and laborious sample processing.…”

Screening Younger Individuals in a Primary Care Setting Flags Putative Dementia Cases and Correlates Gastrointestinal Diseases with Poor Cognitive Performance

“…Current biomarkers include neuroimaging and CSF neurochemical diagnosis (Aβ, Tau, and phosphorylated Tau) [11,12], but these diagnostic tools are not available in many primary care units. Cognitive testing is commonly used as a diagnostic tool, including the Clinical Dementia Rating (CDR), which classifies the severity of dementia [13,14].…”

Ligand‐Induced Conformational Changes in HSP90 Monitored Time Resolved and Label Free—Towards a Conformational Activity Screening for Drug Discovery

“…Recently, we established a robust method to specifically immobilize his‐tagged and lipidated proteins on germanium IREs through binding to solid‐supported lipid bilayers9, 10 and to nitrilotriacetic acid (NTA) groups attached to planar surfaces as well as to dextran brushes based on self‐assembled monolayers (SAMs) of silanes or thiols 11, 12, 13, 14. This recent breakthrough allowed us to use ATR‐FTIR spectroscopy as a flow‐through‐based sensor of conformational change to examine the conformational effects of binding resorcinol scaffold inhibitors to the molecular chaperone heat‐shock protein 90 (HSP90).…”