In-Out-Test: A New Paradigm for Sorting the Wheat from the Chaff in Prodromal Alzheimer’s Disease

Abstract

Background: Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks. Objective: To assess the validity of the In-out-test in identifying prodromal Alzheimer’s disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers. Methods: A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture. Results: Internal consistency was demonstrated using Cronbach Alpha ( r = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r = 0.57 ( p = 0.57). ICC between the In-out-test and FCSRT r = 0.87 ( p = 0.001). ICC between the In-out-test and Aβ 42 and P-tau/Aβ 42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ 42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44. Conclusions: The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD.

Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

“…Finally, we have assessed the potential relationship of CSF multivariate outcomes with the neuropsychological evaluation of this cohort. Statistically significant results were obtained for in–out test, which assesses episodic memory (Torrealba et al, 2019 ), FCSRT which assess episodic verbal memory (Buschke, 1984 ; Peña-Casanova et al, 2009a ), ROCF3 and ROCF30 (Rey-Osterrieth Complex Figure 3 and 30 min), which evaluates visual memory and visuoperceptual function (Peña-Casanova et al, 2009a ). The in–out test is a recent neurocognitive test particularly interesting since it may detect prodromal AD with a higher degree of accuracy than conventional hippocampal-based memory tests, though avoiding reliance on executive function, which may compensate for damaged memory networks.…”

“…The in–out test is a recent neurocognitive test particularly interesting since it may detect prodromal AD with a higher degree of accuracy than conventional hippocampal-based memory tests, though avoiding reliance on executive function, which may compensate for damaged memory networks. Further, this new paradigm has a high predicting capacity in which patients with MCI will go on to develop AD (Torrealba et al, 2019 ).…”

“…We found that in–out test, FCSRT and ROCF30 punctuations were all negatively related to principal component 1 for CSF proteins. These results are outstanding as they indicate that CSF variables included in PC1 associate with cognitive alterations, specifically in episodic memory, and more interestingly, in predicting conversion to dementia (Torrealba et al, 2019 ).…”

Compensatory Mechanisms in Early Alzheimer’s Disease and Clinical Setting: The Need for Novel Neuropsychological Strategies

“…Other that FCSRT is conditioned by large intersubjects variability, which dampens its accuracy value [90].…”

“…On the other hand, the null correlation in the range 50-80 pg/ml gap reflect a high interindividual variability, which may be interpreted as resulting from MCI and AD patients with different degrees of neuronal loss and reduced compensatory mechanisms typical of aging and others due to AD [90].…”