# Connectivity Alterations in Vascular Parkinsonism: A Structural Covariance Study
## 4 Discussion
Recent data reveal that the ventral striatum modulates the hippocampal activity, and this interaction may enable the prefrontal cortex to influence basal ganglia loops during decision-making instances [31]. Interestingly, recent evidence highlighted a strong relationship between limbic dopamine function and salience network functional connectivity in humans. Anatomical and functional overlap between these systems exist and dysfunctions in any one of the network nodes likely produce impairment across both systems [32]. Both the salience and the mesolimbic systems are involved in neurodegenerative and psychiatric disorders [33; 34; 35; 36; 37]. Even though structural covariance results are not a direct measure of connectivity, a correspondence between connectivity and structural covariance has been described [38]. Therefore, we can reasonably interpret our result as the evidence of structural connectivity disruption in VP within the salience and mesolimbic networks, both playing a crucial role in the cognitive frontal and executive control and emotional processing. However, why structural disconnections occur in the brain of our VP patients remains unknown. One possibility is that vascular lesions in the VP brain may produce critical changes within the cortico-striato-pallidal, thalamo-frontal and other loops [39], thus resulting in a progressive disconnection syndrome. The abnormalities within these networks raise some critical questions. First, VP and cognitive impairment. This is an interesting point since unlike PD, cognitive decline in VP patients often occurs early at the presentation of the disease [40]. Thus, in our study, we questioned whether VP patients might have neurocognitive dysfunctions in the core clinical picture. Interestingly, we found that VP patients had worse cognitive abilities than PD and controls. In particular, although these patients had equal/slightly lower MMSE scores, they reported significant impairment in overall neurocognitive performance than those with PD and controls. Of note, compared to PD and controls, significantly lower performances have been observed on FAB, COWAT and MCST tests. In detail, FAB is a neuropsychological battery consisting of six tasks to investigate the frontal lobe functions (abstract reasoning, mental flexibility, motor programming, inhibitory control, sensitivity to interference and environmental autonomy). It is a useful tool widely used in clinical practice for detecting executive dysfunctions with high sensitivity in patients with PD and parkinsonism [41; 42]. COWAT test assesses phonemic verbal fluency, thus evaluating language and executive function domains [43]. Decreased COWAT values are considered a predictor of phenoconversion from normal cognition to preclinical AD [44; 45]. Finally, MCST can assess \"set-shifting\" ability and detect the early change in cognitive function in patients with movement disorders [46]. Thus, the convergently decreased scores on FAB, COWAT and MCST found in our VPpatients could be suggestive of cognitive impairment manifesting as frontal lobe syndrome. However, frontal lobe syndrome is not an expected result in VP since the dementia picture in these patients is characterized by dysevecutive syndrome with impairment of attention, planning, abstract thinking, and verbal fluency, in association with late-onset behavioral disorders [47; 48; 49]. In addition to frontal lobe syndrome, we also found reduced scores on RAVLT R-IR (Immediate Recall) and RAVLT-DR (Delayed Recall) in our VP patients as compared to the controls. This is not surprising since these patients showed a reduced structural covariance alteration between the striatum and hippocampus. RAVLT is a neuropsychological tool widely used for neurocognitive assessment in patients with dementia [43]. It is sensitive to assessing verbal memory deficits [50; 51] and is considered an effective marker for discriminating normal aging subjects from patients with dementia [52].