# Connectivity Alterations in Vascular Parkinsonism: A Structural Covariance Study
## 1 Introduction  
Vascular parkinsonism (VP) is a heterogeneous condition presenting the clinical picture of a multifaceted parkinsonian syndrome, characterized by a neuroimaging spectrum of lesions visually appreciable on conventional magnetic resonance imaging (MRI) scans. Brain lesions may include extensive white matter lesions (WML), multiple cerebral infarctions in basal ganglia, or both [1]. In particular, WM damage is crucial in VP for both the development of specific clinical features and the severity of the disease [1, 2]. Moreover, it has also been reported that normal-appearing white matter (NAWM) damage may occur inthese patients but not in patients with Parkinson's disease (PD). Finally, NAWM alterations may be related to the clinical picture and it has been suggested that non-clearly visible WM alterations may contribute to the pathophysiology of this vascular disease [3]. Not only structural but also functional alterations have been described in VP patients. Nuclear medicine techniques such as dopamine transporter single-photon emission computed tomography (DAT-SPECT) have been tested to investigate the integrity of presynaptic dopaminergic neurons. DAT-SPECT may be abnormal or normal in VP patients, thus identifying different clinical subtypes [4].  
In recent years, emerging neuroimaging techniques have been developed. It is the case of structural covariance, a recent MRI analysis approach that allows investigating the anatomic organization of the brain in terms of co-variation of gray matter morphology between brain regions [5]. This approach is based on the presumption that regions with related atrophy are part of the same functional network, and consequently, it provides information on structural brain connectivity. Investigations of structural covariance patterns have primarily focused on neurodegenerative diseases, demonstrating abnormal structural connections of brain areas potentially liable to the clinical manifestations of these diseases [5]. In PD patients, structural covariance studies have demonstrated extensive alterations in cortical connectivity in many brain regions in the mid-stage of the disease [6], and structural changes occurring in the corticolimbic network represent an early predictive biomarker of cognitive impairment [7]. Moreover, the structural covariance analyses were applied to the basal ganglia circuitry, identifying abnormalities in the caudate-associated network and demonstrating the interactions between basal ganglia atrophy and progressive structural network alterations [8].  
To date, no study has investigated structural covariance in patients with VP. We hypothesized that the structural covariance analysis might highlight peculiar characteristics of the cerebral topographical organization in VP, different from idiopathic PD. In particular, VP patients with the status cribosus of basal ganglia and the dopaminergic striatal deficit could have altered structural connections between the striatum and the brain. Thus, in the current study, using a neuroimaging approach, we performed a structural covariance analysis to investigate brain connectivity between corpus striatum and overall brain regions in patients with VP compared to those with PD and controls. Furthermore, we tested the hypothesis that altered brain connectivity may be related to the clinical features of our patients.