Morphometric correlates and predictors of impaired gait and balance in PD

Based on the predominant motor phenotype, Parkinson`s Disease (PD) is often sub-classified into tremor-dominant and akineto-rigid subtypes. More recently, a motor pattern dominated by postural instability and gait disorder (PIGD subtype) has attracted clinical interest, because of its association with more rapid disease progression and faster rate of cognitive decline. This is believed to result from more widespread brainstem and cortical/subcortical degeneration involving the substantia nigra, extranigral nuclei like the locus coeruleus and pedunculopontine nucleus as well as striato-frontal connections. However, the underlying patterns of neurodegeneration producing gait and balance problems in PD are not fully understood. In this project, multimodal MRI sensitive to complementary tissue characteristics, i.e. volume atrophy via whole-brain T1-weighted MRI, iron deposition via MR relaxometry and microstructural damage via DTI will be employed (i) to assess changes occurring in patients with PD compared to healthy controls, (ii) to discriminate patients with PD from healthy controls, (iii) to assess changes occurring in patients with the PIGD subtype of PD compared to PD patients presenting with a non-PIGD subtype and (iv) to determine progression of multimodal MR-indices. Another approach for elucidating the problem discussed above is the comparison of neuronal connectivity. In the last ten years, a new insight to the recording of blood oxygen dependent (BOLD) signal has been grown. During resting state of volunteers, the spontaneous oscillation of BOLD signals, suspected to reflect neuronal activity, can be acquired during an fMRI session without paradigm. The spontaneous oscillation reaches the same level in areas, which are supposed to be closely connected. Therefore, the evaluation of different levels of spontaneous oscillation depicts neuronal networks. In our project we will prospectively study 80 patients with PD and a group of 20 healthy controls matched for gender and age. All participants will undergo a detailed standardised clinical assessment including several well established measures on gait and balance function as well as a standardised MRI protocol including coronal T1-weighted MPRAGE, transversal turbospinecho PD/T2-weighted sequence, coronal TIRM sequence with dark fluid preparation, transversal diffusion-weighted echoplanar imaging (EPI) sequence with 12 diffusion- sensitized gradient directions (for DTI), transversal multi-echo gradient-echo sequence (for MR relaxometry) and contrast-enhanced MRI (for exclusion of cerebral masses). The so-called resting state fMRI comprises a T2*- weighted echoplanar imaging (EPI) sequence, which covers the whole brain and is repeatedly performed over a period of 8 minutes. Over a follow-up period of at least 12 months the clinical and MRI protocols will be repeated.

Based on the predominant motor phenotype, Parkinsons Disease (PD) is often sub-classified as tremor-dominant (TD) or akineto-rigid subtypes. More recently, a motor pattern dominated by postural instability and gait disorder has attracted clinical interest, because of its association with more rapid disease progression and faster rate of cognitive decline. This is believed to result from more widespread degeneration within the brain, however the underlying neuropathological patterns producing gait and balance problems in PD are yet not fully understood. In this project high-resolution magnetic resonance imaging (MRI), with a field strength of 3.0 Tesla, has been employed to assess cerebral changes occurring in patients with PD compared to healthy controls, to discriminate patients with PD from healthy controls, to assess changes occurring in patients with the PIGD-subtype compared to those without PIGD symptoms and to determine progression of atrophy patterns in the brain. For this reason several MRI sequences have been applied in about 100 patients with PD and 40 healthy controls: T1 weighted volumetry to assess atrophy patterns, iron-sensitive scans to study tissue iron deposition, diffusion-weighted imaging (DWI) with diffusion-tensor imaging (DTI) to study microstructure disorganization and resting state functional MRI (rs-fMRI) to study on how different regions and networks are communicating (i.e. functional connectivity). We also have applied several clinical tests, scales and questionnaires to better characterize the patients. PD patients with the PIGD-subtype were overall more disabled and had a poorer quality of life compared to those PD patients without PIGD symptoms, although age and disease duration were comparable between the two groups. We were able to demonstrate the absence of the dorsolateral nigral hyperintensity (DNH) within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra in patients with neurodegenerative parkinsonism including PD using high-field susceptibility-weighted imaging (SWI, a iron-sensitive MRI sequence), thus allowing good discrimination between patients with PD and healthy controls. Moreover, a signal loss of DNH was found in at least two thirds of subjects with idiopathic REM sleep behavior disorder (iRBD), a harbinger of PD, suggesting that this sign may assist in the identification of prodromal degenerative parkinsonism. The objective voxel-based analyses of the structural images (i.e. volumetry, iron-sensitive sequences and DWI) revealed cerebellar cortical atrophy in the PD patients compared to controls, while there were no structural changes between the PD patients with the PIGD-subtype compared to those with a TD-subtype. Interestingly, rs-fMRI revealed that there were several brain network changes, which progressed over time. The most differing network between the PD patients with a PIGD-subtype and those with a TD-subtype were changes in the salience network (which has been implicated in the facilitation of attentional orientation to internal or external stimuli) in PD patients with the PIGD-subtype. The alteration in the communication of salience network with the somatomotor network and VN could help to understand differences in motor symptoms between PD patients with PIGD-and TD-subtypes. Summarizing, the results of this project should consolidate the role of novel MRI markers for the diagnosis and progression of PD.