Discussion
neuronal damage, MCI, atrophy, atrophy-, atrophy-like
DISEASE, ATROPHY
The core result of this study was that individuals with MCI show differential responses to donepezil treatment depending on their MRI patterns at baseline. This finding emphasizes the role of biological heterogeneity when it comes to evaluating the response to AChE-Is treatments. Overall, our data showed that MCI individuals with an MRI pattern indicative of minimal atrophy- or a more hippocampal-sparing-like subtype have a reduced rate of atrophy in MRI outcome measures after 1 year of donepezil treatment. Furthermore, as hypothesized, assessing MRI subtypes in the form of continuous severity and typicality dimensions was more sensitive to these differences in the response to donepezil compared to the conventional categorical subtyping approach.Our findings highlight that the differential response to donepezil was better captured by a continuous characterization of subtyping dimensions than by a conventional categorical subtyping approach. Although most previous studies have used the conventional categorical subtyping approach [In the current cohort, the continuous subtyping approach revealed two predominant MRI patterns. The first pattern was characterized by a low severity and low typicality (i.e. towards a minimal atrophy-like MRI pattern). The second pattern was characterized by high severity but low typicality (i.e. towards a limbic-predominant-like MRI pattern). As a validation, we found the same patterns when we classified the individuals using the conventional categorical approach (52% minimal atrophy and 38% limbic-predominant). These frequency values are consistent with a previous report using visual rating scales to classify MCI individuals from the ADNI cohort into MRI subtypes [We found that, compared to placebo, MCI individuals showed a slower rate of atrophy in cortical regions that conform the AD cortical thickness signature. A previous study on the same cohort had already shown promising results that indicate a significant impact of donepezil treatment in preserving cortical thickness in individual with MCI [Our study also adds evidence suggesting that the effect of donepezil on stabilizing AD signature cortical thickness depends on baseline MRI pattern of atrophy. Using the continuous subtyping approach, we found that those MRI individuals with minimal atrophy- or hippocampal-sparing-like MRI patterns had a slower rate of atrophy in the AD cortical thickness signature. In contrast, MCI individuals with MRI patterns including substantial atrophy in medial temporal structures (towards typical AD or limbic-predominant-like MRI patterns) showed rates of atrophy comparable to the placebo group. A better response to donepezil observed in individuals with minimal atrophy was expected but has not been demonstrated before. This finding is in line with previous reports that encourage to treat patients at early stages of the disease since the neuronal damage at those stages is still mild and treatment may effectively compensate functional deficits [Interestingly, individuals with the hippocampal-sparing-like MRI pattern also showed better response to donepezil in the current study. Firstly, this suggests that severity and typicality dimensions are independent in the prediction of effects to donepezil. Secondly, this finding is consistent with a previous study on individuals with AD undergoing a cholinergic treatment based on encapsulated cell bio-delivery of nerve growth factor (NGF) to the basal forebrain [Consistently with a previous study in this cohort [This study has some limitations. The sample size is relatively small, which could compromise statistical power. This limitation mostly affected statistical testing when using the categorical subtyping approach. The classification of individuals into four categorical smaller groups increases the number of comparisons and reduces statistical power. However, we demonstrated that the characterization of subtypes using continuous dimensions can overcome this limitation, which can be an important step forward in the implementation of the current framework for biological subtypes in clinical trials [