This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified by medial temporal atrophy, MTA) and macroscopic white matter lesions (WMLs) in delaying the conversion from amnestic mild cognitive impairment to Alzheimer's disease (AD). Forty-two amnestic mild cognitive impairment patients were consecutively recruited. They underwent magnetic resonance imaging and a comprehensive questionnaire to classify them as individuals with low or high CR. Patients were then clinically followed-up for 2 years. The patients' risk for conversion to AD because of CR was estimated by controlling for cognitive efficiency, MTA, and WMLs at baseline. Global cognition was the best predictor of conversion to AD in low CR patients. Conversely, in high CR patients only, WMLs (but not MTA) highly contributed in increasing the risk for conversion to AD. In conclusion, CR interacts with both patients' cognitive features and WMLs in modulating the impact of AD pathology. This seems relevant for clinical prognosis and therapeutic strategies.
The “cognitive reserve hypothesis” (CR) explains the differences among individuals in their ability to cope with physiological or pathologic cognitive decline (Stern, 2009 and Stern, 2012). CR has been conceptualized as based on an active model that postulates the existence of compensatory brain mechanisms able to cope with the cerebral damage (Stern, 2009 and Stern, 2012). An alternative passive model (brain reserve, BR) has also been proposed, which is based on quantifying brain size, neuronal amount, and number of synapses (Stern, 2009 and Stern, 2012). Both models have been postulated in the past to account for brain resilience to pathologic damage.
Alzheimer's disease (AD), in its most typical presentation, is characterized by memory deficits followed by a progressive increase of cognitive disabilities, until conversion to dementia (Nelson et al., 2009). Accordingly, in AD brains a typical pattern of tissue damage has been identified, with an earlier involvement of the medial temporal lobe structures (Braak and Braak, 1996), followed by a spread of pathology to the lateral temporal, parietal, and frontal cortex (Braak and Braak, 1996). At an individual level, there is no univocal relationship between brain damage and cognitive impairment, and it has been hypothesized that BR and/or CR may modulate the clinical onset of AD (Stern, 2009 and Stern, 2012). Indeed, because AD results from a progressive accumulation of neuropathologic lesions within a long period of time during which the clinical symptoms are still silent (Elias et al., 2000 and Small et al., 2000), it is reasonable to hypothesize that a higher CR and/or BR may contribute in postponing the time point of inflection toward dementia. In fact, participants with a higher CR and/or BR require a more severe extent of AD pathology to manifest symptoms of cognitive decline (Fratiglioni and Wang, 2007 and Stern, 2009). We recently demonstrated (Serra et al., 2011) in a cross-sectional neuroimaging study that patients at different stages of AD with a higher CR, compared with AD patients with a lower CR, showed more reduced gray matter (GM) volumes in regions typically affected by AD pathology (specifically in the entorhinal cortices and temporal lobes). By contrast, increased GM volume was present in the supramarginal gyrus, posterior cingulate cortex, and precuneus, suggesting that CR modulates selective GM changes that contribute to mitigate the clinical impact of AD (Serra et al., 2011). Other studies support the contention that CR has a protective effect against the clinical occurrence, or at least the detection, of AD (Garibotto et al., 2008, Koepsell et al., 2008 and Roe et al., 2008). These studies assessed the relationship between different levels of CR and brain abnormalities involving not only GM but also white matter (WM).
As demonstrated in previous studies based on animal models (Nichol et al., 2009 and Petrosini et al., 2009), the development of BR and CR is highly correlated with the extent of environmental enrichment to which the animals are exposed. In the case of humans, we can argue that several cognitive, social, and physical activities can be considered as important factors for developing CR and BR (Stern, 2009 and Stern, 2012). However, the interaction between CR proxies and abnormalities in the GM and WM still remains unclear.
Aims of the present study were to investigate, for the first time in a longitudinal study, whether different levels of CR: (1) modulate the rate of conversion to AD in patients with amnestic mild cognitive impairment (a-MCI); (2) interact with cognitive functions, contributing to reduce the risk of conversion, and thus postponing the time point of inflection toward dementia; and (3) interact with brain abnormalities to reduce the risk of progression to AD.
Importantly, we decided to use semiquantitative measures of brain abnormalities readily available in clinical settings and not requiring sophisticated and time-consuming image analysis.
