# Connectivity Alterations in Vascular Parkinsonism: A Structural Covariance Study
## 4 Discussion
Moreover, RAVLT Immediate and Delayed are frequently used in the clinical setting, highlighting different aspects of episodic memory (learning and delayed memory, respectively) [43]. On this basis, we can speculate that reduced RAVLT performances observed in our VP patients could reflect verbal episodic memory deficit. We align with previous evidence demonstrating that isolated short-term memory impairment may occur in this vascular disease, especially in the early stages [9]. Moreover, in the an Italian cross-sectional longitudinal observational PRIAMO study [48], attention and memory impairment were found in about 70% of VP with short disease duration. Finally, the disconnection between the striatum and mesolimbic system may be the structural substrate of reduced BDI scores reported in our VP patients. Taken together, our evidence, although preliminary, suggests that our VP patients with reduced structural connectivity between the striatum and several brain regions/structures may have an initial cognitive impairment. Second, imaging and clinical correlations in VP patients are important to mention. Indeed, another important question in this study was to test whether the disruption of structural covariance connectivity in the VP group was in relation to the lower scores in cognitive performances we found in this group. Interestingly, the connectivity between the Right Caudate and Right Insula was modulated by the scores of COWAT, RAVLT-RD, MCST, BDI and HAMA tests. While novel in this particular scenario, our results agree with the vision of the insula as a key player in several cognitive and emotional processes. Indeed, the insula manages the inter-relationship between the salience of the selective attention focused on reaching a task (dorsal attention system) and the salience of arousal established to maintain direction on the significant environmental elements (ventral attention system) [53]. This modulation of the salience might be particularly relevant during tasks requiring attention to identify an effective strategy, such as MCST and COWAT tests, or require the ability to focus on the information recall, such as RAVLT-RD [54]. With regard to laterality, the Right Insula, together with other areas of the region of the right ventrolateral prefrontal cortex and right striatum, has been associated with the self-awareness of memory and other high order cognitive performances, as well as with conscious detection of errors [55]. This pivotal role of monitoring feedback on task execution and self-evaluative processes appears to rely preferentially on the right hemisphere regions [56]. Moreover, regarding the correlation between Right Caudate-Right Insula covariance and BDI and HAMA scores, the central role that the insula plays in the control of emotivity and in the pathophysiology of anxious-depressive disorders is well known [57]. BDI scores also significantly modulated the poor connectivity between the Right Caudate and Left Thalamus, thus confirming the key role of limbic-striatal-thalamic connections in mood disorders [58]. Finally, MCST scores had a significant interaction with Right Putamen-Left Thalamus connectivity, which can be explained by considering the importance that the basal ganglia circuits have in executive functions [59]. Taken together, these findings further strengthened the results of this study, demonstrating that the structural covariance alterations we found in the VP patients are effectively related to their cognitive performances. There were some limitations to the study. Firstly, the sample size of our cohort is small. Thus, the results from the correlation analysis could have only a descriptive nature. However, VP remains a rare and heterogeneous entity that is difficult to diagnose clinically. A large cohort of VP patients is needed to confirm our results. Secondly, in the absence of histopathological data, it is not possible to determine whether there was a vascular or degenerative origin of their parkinsonism in VP patients.