In‐out‐test and inverse translational medicine: When a new clinical paradigm is needed to find new biomarker perspectives

Abstract

AbstractBackgroundPROA project is based in the Neurology Service and the Investigation Unit at the Hospital Dr. Negrin (Canary Islands, Spain). PROA aims to find new ways to a better understanding of cognitive and biological mechanisms of normal aging and Alzheimer's disease (AD). This study shows previous, preliminary and ongoing PROA project data about the relationship between clinical assessment and biomarkers in Alzheimer’s disease research. It is considered the contribution of In‐out test, a paradigm hypothesized to avoid reliance on executive function, which may compensate damaged memory networks. Unlike other tests using the hippocampal amnesia paradigm, that assess memory after effective encoding of information, the In‐out‐test provokes an interference during encoding by means of a simultaneous executive task. According to this model the memory deficit in prodromal AD can be unmasked when those compensatory networks are saturated by an executive activity without being able to compensate the already damaged mnemonic activity.MethodNeuropsychological assessment: Neuropsychological battery: episodic (Free and cued Selective Reminding Test‐ FCSRT), shot‐term, visual memory, visuospacial and constructive praxis; executive functions; Daily living and instrumental activities. In‐out‐test: Assesses episodic memory after the patient performs a categorization task and memorizes 6 words simultaneously. The time taken to complete this test was 5 to 12 minutes.ResultCross‐sectional study: ICC (Intraclass correlation) between the In‐out‐test and FCSRT r= 0.87 (p=0.001). ICC between the In‐out‐test and Aβ42 and P‐tau/Aβ42 for controls: 0.73 and 0.75 respectively; P‐tau for MCI: 0.77 and total sample: 0.70; Aβ42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤ 0.264. Sensitivity: 0.93; specificity: 0.77. Predictive value for In‐out‐tet, Positive:0.89; negative: 0.83. Conversion study: Agreement (Kappa): In‐out‐test: 0.67/0.61 (memory/learning); FCSRT: 0.57; P‐tau/Aβ42: 0.126. P‐tau(50ng/ml): 0.40. Aβ42 (500 ng/ml): 0.07ConclusionCompensatory mechanisms in prodromal AD might be a confounding factor in the early detection by classical hippocampal amnesia paradigm and even by csf biomarkers. In‐out‐test may play a roll unmasking the memory deficit in the early stages of AD. In orfer to find new reliable biomarkers for aging and AD, PROA project will focused on new targets such as oxidative stress, phosphorilation, microbiota and telomers.