This study shows that patients with MCI due to AD and cerebral amyloid deposition have a high amount of amyloid plaques in brain cortical structures, not only in the temporal lobes. This feature could explain some of MCI clinical manifestations that may be attributable not only to the disturbance of memory. MCI could affect different cognitive domains and the global brain involvement demonstrated by amyloid-PET is associated with the impairment of several higher brain activities, and in particular executive functions, attention, memory and praxis.
These findings support recent data showing that pathological amyloid deposition could be present at least several years before the appearance of clinical manifestation of the AD [26]. Amyloid-PET could be used together with anamnestic, clinical and objective neuropsychological tests for early diagnosis of MCI due to AD [27], even if MMSE expression of global cognitive function is normal [28]. Our results are in accordance with previous studies showing that executive functions, evaluated by CDT [28] or Montreal Cognitive Assessment (MoCA) tests [28], could identify persons at risk of developing AD.
Another interesting aspect emerging from our results is that CDT correlates with amyloid pathology within almost normal MMSE values and this could be explained by the fact that CDT requires activation of various neuro-psychological functions, such as auditory perception, auditory memory, abstraction ability, visual memory, visual perception, visual-spatial functions, planning capacity, visual motor and executive functions [29–30]. This association could be related to the globality of the amyloid deposition in the central nervous system and supports the evidence that the cerebral amyloid angiopathy (CCA) could be the result of a deficit of the protein clearance pathways [31]. Recently, Morris et al. [32] proposed that an impairment of the cerebral vascular basement membranes by which fluid passes into and out of the brain explain the accumulation of the amyloid in the central nervous system with an imbalance between production and its clearance.
Our data also suggest that if amyloid deposit if present, the amount of deposition should be relevant for being detected clinically and the process could influence different brain area and not only the medial temporal lobe where important memory related circuits are located. This aspect is in line with other studies [33]. In fact, the hierarchical amyloid deposition in the brain had already been suggested in the past by Thal and Braak [34] from pathological studies, suggesting that the onset of aggregates of β-amyloid initially cared areas of the neocortex as the frontal, parietal and temporal area and only in more advanced stages the hippocampus would be affected by the amyloid pathology. It could be speculated that in the early phase of the disease the deposition of amyloid should involve globally the cortex, and this process could require several years. Recently, a longitudinal study realized in cognitively normal older persons, showed that higher amyloid beta burden was associated with increasing anxious-depressive symptoms over time [35], and these results are consistent with our data showing that amyloid brain deposition produces a behavior modification, particularly evident in the atypical forms of dementia.
Then, probably only when the amount of amyloid is high enough, Tau deposits are produced from amyloid in areas such as the medial temporal lobe, with clinical picture of loss of long-term memory. This hypothesis is in accordance with recent results reported by Donohue et al. [36], showing that there is a time window of at least five years between the initial deposition of amyloid and a clear reduction of cognitive performance detected by MMSE. More recently, even findings reported by Sepulcre J et al. [37] confirm this hierarchical organization of Tau and Amyloid deposits in the cerebral cortex. In particular, these authors suggest that several years before AD dementia manifestations, abnormal accumulations of tau and Aβ insoluble proteins are visible in the temporal lobe and association cortex. Tau and Aβ deposits show some degree of spatial specificity as well as some overlapping in convergent zones [38].
To date, research in the field of AD "causal" therapy is increasingly directed to identify subjects with AD in the pre-clinical stage, when amyloid deposits in the cortex are scarce and cognitive function not compromised. Hence, the possibility of having AD biomarkers in pre-clinical phase appears increasingly important and understanding the progression from MCI to dementia, identifying cluster of markers that intercept patients’ candidate for prescription of future drugs will be fundamental. Among these biomarkers of AD, the amyloid PET, could be useful for really identifying pre-mortem patients with high probability to be affected by AD. Our results support this hypothesis especially when the amyloid deposition is plentiful, as in our study, and higher than 3 times amount in age-matched older persons, it should not be considered as the “normal” effect of aging. Conversely, the presence of high amyloid burden with global diffusion in the cerebral cortex is associated with an increased risk of developing AD blown over time [39–40].
Supporting this evidence, more recently, a dose-response relationship between amyloid deposition and cognitive performance has been suggested [41]. The authors found that the magnitude of amyloid burden at baseline was associated with the rate of cognitive decline over 4-year follow-up period, suggesting a potential link between these two phenomena. Our findings may have important implications also for projecting clinical outcomes on amyloid-PET scan basis, as well as for understanding the effect of amyloid in preclinical AD.
The clinical significance of these results in the routine evaluation of AD patients is confirmed by a recent PET study which showed that, in almost a quarter of selected patients, [18F] flutemetamol PET changed the clinical diagnosis and altered the patient management plan. The authors concluded that amyloid-PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis, providing evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice [41–43].
The main limitation of our study is the small number of patients that should be considered to draw definitive conclusions. Furthermore, selection of older persons with MCI could produce a significant "ceiling effect" reducing diagnostic accuracy of cognitive impairment. Despite these limits, this study supports the idea that even MCI due to AD is a multidomain disease that affects the cognitive sphere, neuropsychiatric and functional aspects of the persons affected with loss of autonomy initially in performing instrumental activities of daily living. All these aspects could be of importance in the initial evaluation of the patients. Through this study, we reinforce the hypothesis of a hierarchical deposition of amyloid aggregates, and the role of major cortical involvement of amyloid pathology in determining greater cognitive and functional impairment.