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.

Background: Alzheimer's disease is a neurodegenerative disease with unknown cause, being the first cause of dementia affecting 24 million people, which is set to double by 2040. Periodontitis is a multifactorial, inflammatory and chronic disease that causes the loss of the tooth's support system; being the number one cause of tooth loss in adults. Both diseases are highly prevalent, making them an important public health issue. New studies have shown that there might be a relation between them.Method: Systematic review and comparative analysis of studies through a bibliographic search that included clinical trials, case-control and cohort studies in humans, with objective tests for the diagnosis of both diseases. Excluding: descriptive studies or studies that didn't focus on Alzheimer's; studies that didn't diagnose periodontitis clinically; sigle case studies; based on patients with syndromes; or evaluated exclusively the quality of life of the patients. From the 473 articles found only 9 fulfilled the inclusion and exclusion criteria.Result: Out of the 9 articles selected, 7 found a statistically significant difference between people with Alzheimer's and without it in relation to periodontitis (Choi S et al, Ide M et al, de Suza T et al, Martande SS et al, Holmer J et al, Cestari JA at al, Aragón F et al). Chen CK et al didn't find a statistical significance at the beginning (p=0.0547) but did in the 10 years follow-up (p=0.00264). Tiisanoja A et al didn't find a statistic significance (RR=1.54; IC=0.52-4.56). However, when subjecting the article's results to CI for the proportion analysis we discovered that only one study found this difference significant out of the 6 included. Conclusion:The most common oral problems in patients with Alzheimer's were gingivitis, periodontitis, tooth loss, candidiasis, calculus. Although there seems to be a relationship between the two, further studies with larger populations and a better screening process for participants, are needed in order to truly assess whether there is a causal relationship between the two pathologies or not. One of the greatest limitations we encountered was the lack of homogeneity between the studies statistical tools, making it impossible to do a meta-analysis.

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Despite advances in the detection of biomarkers and in the design of drugs that can slow the progression of Alzheimer’s disease (AD), the underlying primary mechanisms have not been elucidated. The diagnosis of AD has notably improved with the development of neuroimaging techniques and cerebrospinal fluid biomarkers which have provided new information not available in the past. Although the diagnosis has advanced, there is a consensus among experts that, when making the diagnosis in a specific patient, many years have probably passed since the onset of the underlying processes, and it is very likely that the biomarkers in use and their cutoffs do not reflect the true critical points for establishing the precise stage of the ongoing disease. In this context, frequent disparities between current biomarkers and cognitive and functional performance in clinical practice constitute a major drawback in translational neurology. To our knowledge, the In-Out-test is the only neuropsychological test developed with the idea that compensatory brain mechanisms exist in the early stages of AD, and whose positive effects on conventional tests performance can be reduced in assessing episodic memory in the context of a dual-task, through which the executive auxiliary networks are ‘distracted’, thus uncover the real memory deficit. Furthermore, as additional traits, age and formal education have no impact on the performance of the In-Out-test.

Background PROA 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. Method Neuropsychological 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. Result Cross‐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): 0.07 Conclusion Compensatory 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.