Fluid biomarkers for diagnosing dementia: rationale and recommendations for Canadian Physicians

Literature data suggest that plasma amyloid beta (Aβ 1-40/2) peptides are elevated in populations at risk for Alzheimerʼs disease (AD) and progressively decline during the conversion from Mild Cognitive impairment to AD. At present, there is no consensus regarding the optimal methodology for conducting quantification of plasma Aβ 1-40 or Aβ 1-42. Further, there is insufficient evidence supporting clinical applications for plasma Aβ 1-40 or Aβ 1-42 measures. Therefore, they are not recommended either for primary care or specialists, though CSF Aβ 1-42, total tau and p-tau can be considered at the tertiary care level for selected cases to improve diagnosis certainty, particularly in those cases presenting atypical clinical features. CSF biomarkers are not recommended for screening in normal healthy subjects for the purpose of assessing future risk of developing AD. Fluid biomarkers must be sampled using standardized methodology, in a certified, centralized facility, and transported under appropriate conditions. 3 Definitions and abbreviations AD-P: Alzheimer's pathology: Spectrum of brain macroscopic and microscopic pathological features associated with the AD clinical phenotype. Classic features of AD-P are senile neuritic (amyloid) plaques and neurofibrillary tangles, synaptic loss, and vascular amyloid deposits. AP: Amyloid plaques: Extracellular deposits of fibrillary beta-amyloid abundant in the cortex of AD patients. Amyloid plaques are commonly classified as diffuse or dense-core based on their morphology and positive or negative staining with Thioflavin-S or Congo Red. 1 APOE4: An allele of the apolipoprotein E gene (APOE; chromosome 19) associated with a high risk for AD. Biomarker: Characteristic measured as an indicator of biological or pathogenic processes, or of pharmacologic response. ELISA: enzyme-linked immunosorbent assay Molecular probe (imaging agent): Molecular imaging agents are probes used to visualize, characterize, and measure pathological and/or pathophysiological processes in living systems. Both endogenous molecules and exogenous probes can be used as molecular imaging agents. Molecular target: A biological process of interest for quantification with molecular probes. Neurodegeneration: Progressive loss of structure or function of neurons, including neuronal death. Neurofibrillary tangles (NFTs): Hyperphosphorylated and misfolded intraneuronal aggregates of tau protein. PET: Positron Emission Tomography: Imaging technique that utilizes a tracer concentration of short-lived radiopharmaceuticals targeting a biological process of interest. High-resolution PET produces 3D images quantifying a biological process reaching up to pico molar (10-9-10-12 M) concentrations. p-tau-181; phosphorlyated tau (p-tau) in the 181-threonine position Radiopharmaceutical: A radioisotope labelled molecule intended for use in the diagnosis and/or monitoring of a disease in humans. t-tau: concentration of …