Dispersed white matter damage has been reported in several diffusion imaging studies in Parkinson's disease (PD). The association of these white matter alteration has been unclear with motor severity of drug_naïve PD. We studied the relationship between local connectome alterations obtained by connectometry approach and motor severity of elderly PD as measured with Unified Parkinson's disease 3. Diffusion MRI connectometry is a new approach to map local connectome to detect tracks with connectivity change. In connectometry, the density of diffusing spins were calculated at various orientations and regressed against PD with UPDRS3 rate by using a multiple regression. Our findings demonstrate the fornix and cingulium fibers in limbic system have association with motor severity in elderly PD patients in onset.Participants involved in this research were recruited from Parkinson's Progression Markers Initiative (PPMI)[1]. DWI images were obtained for 18 patients (7 F 11M, mean age 73.33) and 23 controls (9F 14M, mean age 71.50). Participants were tested and confirmed negative for any neurological disorders apart from PD. The participants' PD status was confirmed by Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the loss of dopaminergic neurons were observed in DaTscans. Every participant involved in this research has signed informed written consents in order to share their unidentified clinical data to investigators. Data used in the preparation of this paper was obtained from Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data/) [9]. This dataset was acquired on a 3 Tesla Siemens scanner, producing 64 DWI (repetition time = 7748 ms, echo time = 86 ms; voxel size: 2.0×2.0×2.0 mm3; field of view = 224×224 mm) at b = 1000 s/mm2 and one b0 image along with a 3D T1-weighted structural scan (repetition time = 8.2 ms, echo time = 3.7 ms; flip angle = 8˚, voxel size: 1.0×1.0×1.0 mm3; field of view = 240mm, acquisition matrix = 240 ×240). The diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function[2] . A diffusion sampling length ratio of 1.25 was used, and the output resolution was 1 mm[3]. The controls data was used to construct atlas data for connectometry. Diffusion MRI connectometry was conducted in a total of 18 subjects using a multiple regression model considering UPDRS3[4]. A percentage threshold of 50 % was used to select local connectomes correlated with updrs3. A deterministic fiber tracking algorithm was conducted to connect the selected local connectomes. A length threshold of 45 mm were used to select tracks. The seeding density was 20 seeds per mm3. To estimate the false discovery rate, a total of 3000 randomized permutations were applied to the group label to obtain the null distribution of the track length.

The analysis results showed tracks with decreased anisotropy related to UPDRS3 with an FDR of 0.0271953 (Figure 1), however there is no track with significantly increased anisotropy related to UPDRS3.The main tracts which are associated are : 1) corticospinal tract, 2) cingulium, 3) Fornix and 4) corpus callosum ( Figure 2).

The cingulate gyrus and fornix are both functionally and structurally disturbed in PD, as a functional part of the limbic system. The cingulate and fornix are critical to emotion formation and autonomic function; while playing a key role in response initiation, planning memory, predominant executive dysfunction [5] and visuospatial skills, which are all impaired in early stages of PD [6]. Decreased FA is observed in cingulium of PD patients in both demented and early-stage non-demented patients [7- 9] and an extensive decrease in functional connectivity of the posterior cingulium occurs in these patients [10]. Functional connectivity between posterior cingulate gyrus and middle temporal lobe is a predictor of cognitive decline in PD while exhibiting a significant decrease even in early-stage, undemented patients [11]. Contrary to FA, an increase in mean diffusivity in early stages of PD is associated with better performance in semantic fluency and other cognitive tasks in newly diagnosed PD patients [5, 6]. Moreover UPDRS3 is also negatively associated with anisotropy in some areas of cortiospinal tract, probably the initial portions of the nigrostriatal fibers, which are considered the primary site of Lewy body pathology in PD (Figure 2). These pathological changes spread to the dorsal vagal nucleus and anterior olfactory nucleus and then involve the limbic system and cingulium at stage 5 of pathological changes and finally reach the neocortex [12].