Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer’s Disease

Abstract

Background: Differential diagnosis of people presenting with mild cognitive impairment (MCI) that will progress to Alzheimer's disease (AD) remains clinically challenging. Current criteria used to define AD include a series of neuropsychological assessments together with relevant imaging analysis such as magnetic resonance imaging (MRI). The clinical sensitivity and specificity of these assessments would be improved by the concommitant use of novel serum biomarkers. The branched chain aminotransferase proteins (BCAT) are potential candidates as they are significantly elevated in AD brain, correlate with Braak Stage and may have a role in AD pathology. Objective:In this hypothesis-driven project, we aimed to establish if serum BCAT and its metabolites are significantly altered in AD participants and assess their role as markers of disease pathology.Methods: Serum amino acids were measured using a triple quadrupole mass spectrometer for tandem mass spectroscopy together with BCAT levels using Western blot analysis, coupled with neuropsychological assessments and MRI. Results:We present data supporting a substantive mutually correlated system between BCAT and glutamate, neuropsychological tests, and MRI for the diagnosis of AD. These three domains, individually, and in combination, show good utility in discriminating between groups.Our model indicates that BCAT and Glutamate accurately distinguish between control and AD participants and in combination with the neuropsychological assessment, MoCA, improved the overall sensitivity to 1.00 and specificity to 0.978. Conclusion:These finding indicate that BCAT and Glutamate have potential to improve the clinical utility and predictive power of existing methods of AD assessment and hold promise as early indicators of disease pathology.

Alzheimer’s disease: targeting the glutamatergic system

“…However, further studies are required to fully determine the impact of increased BCAT levels in AD brain. More recently, we reported that serum BCAT was also higher in AD individuals relative to healthy agematched controls (Hudd et al 2019). In this study we adopted a combined approach to generate a differential diagnosis of people presenting with MCI that will progress to AD.…”

Mini Nutritional Assessment May Identify a Dual Pattern of Perturbed Plasma Amino Acids in Patients with Alzheimer’s Disease: A Window to Metabolic and Physical Rehabilitation?

“…A recent research study has documented that blood BCAT proteins were increased in patients with AD in comparison to healthy controls [8]. Blood BCAT proteins and glutamate increase the sensitivity and specificity of Montreal Cognitive Assessment in correctly discriminating healthy subjects and subjects with AD, which is useful for an early diagnosis of AD [8].…”

“…A recent research study has documented that blood BCAT proteins were increased in patients with AD in comparison to healthy controls [8]. Blood BCAT proteins and glutamate increase the sensitivity and specificity of Montreal Cognitive Assessment in correctly discriminating healthy subjects and subjects with AD, which is useful for an early diagnosis of AD [8]. The increase in blood BCAT paralleled the increased levels of BCATs found previously in the hippocampus, frontal and temporal cortex, in a post-mortem analysis of AD patients [64].…”

“…Recently, a study documented that levels of blood branched-chain aminotransferase protein (BCAT), the enzyme that regulates Branched Chain AAs (BCAAs) and glutamate metabolism, and glutamate were higher in AD in comparison to healthy controls. This helped to increase the reliability of neurocognitive assessment in distinguishing healthy subjects and subjects with AD [8].…”

Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

“…Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids necessary for protein synthesis, but when found in excess, impact energy homeostasis [13][14][15]. Recent work demonstrated that elevated dietary BCAA intake is associated with obesity and insulin resistance in both humans and rodents [16,17], and plasma BCAA levels are highly predictive of T2D development in normoglycemic individuals [18].…”