The influence of genetic and environmental factors on brain functional organization in mild cognitive impairment: can a late-life cognitive and physical training combat cognitive decline?

Mild cognitive impairment (MCI) is a clinical condition of the elderly age characterized by a cognitive decline that is more prominent than expected and that, however, does not affect the activities of daily life (Gauthier et al., 2006). More than half of these patients progress to dementia within two years (Geslani et al., 2005) and for this reason MCI can be considered a risk factor for developing dementia, as well as one of the most relevant stages of the normal cognition-to-pathology continuum. Experiment 1: When does cognitive decline become objectifiable? Evidence for the role of functional neuroimaging in dissociating Mild from Subjective Cognitive Impairment In the last decade, promising results coming from structural and functional neuroimaging studies and biochemistry investigations revealed the presence of specific biomarkers that can assist the diagnosis and prognosis of MCI (e.g., Small et al., 2008; Mattsson et al., 2009; Jack et al., 2010). However recent diagnostic guidelines confirmed that neuropsychological assessment should be considered the primary method to diagnose MCI and that imaging techniques and laboratory testing should not be included in the clinical practice (Sachdev et al., 2014). Nevertheless, it should be noted that even when considering specific type of dementia, such as Alzheimer's disease, the diagnostic certainty should be qualified as probable or possible (Sachdev et al., 2014) and for MCI the degree of uncertainty is even greater, since its pathophysiology is more debated and heterogeneous (Gauthier et al., 2006). Thus, the lack of a gold-standard procedure to assess the validity of neuropsychological evaluation is an important issue and should be considered when interpreting specificity and sensitivity of individual tests. On these premises, the in-vivo evaluation of brain activity may represent a complementary tool to the neuropsychological evaluation of cognitive decline and would help to determine, whether or not, patient's complain about his own cognitive status does rely on an objectifiable pathological process (i.e., MCI condition) or depends on a subjective evaluation solely (i.e., Subjective Cognitive Impairment - SCI). For this reason, we conducted a functional magnetic resonance imaging (fMRI) experiment comparing patterns of brain activity elicited by a previously validated visuo-spatial attention task (Bernardi et al., 2013) in twenty-four clinically defined SCI subjects (11F, 72±6 years) and thirty-one MCI patients (17F, 74±5 years). Although the two groups achieved similar task accuracies (p>.05), MCI patients demonstrated dysfunctional activations of the bilateral posterior cingulate cortex and of the right angular gyrus, as compared to SCI participants. In healthy subjects, these brain regions are part of the default mode network (DMN - Raichle et al., 2001) and their activity decreases during an attention demanding-task. Thus our results corroborate the validity of the neuropsychological assessment and designate the medial parietal cortex as an adequate neural marker of MCI