Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD.
Objective: It has been shown in normal subjects that opening the eyes in darkness without external visual stimulation increases activity in the ocular motor and attentional systems. By contrast, closing the eyes causes a relative signal increase in multiple sensory areas such as the visual, somatosensory, vestibular, auditory, and gustatory cortical areas. These two states of „resting“ activity of the human brain in complete darkness, which can be imaged using fMRI, were termed the „exteroceptive“ state (contrast OPEN>CLOSED) and the „interoceptive“ state (contrast CLOSED>OPEN). In the present study we investigated whether similar brain activity states can be found in blind subjects when opening and closing their eyes.
Objective: It was the aim of this study to identify genetic variants, which are differentially associated with four distinct clinical Parkinson’s disease (PD) subtypes. Background: Due to the clinical heterogeneity of PD, patients with PD are commonly classified into distinct clinical subtypes. Studies investigating differential associations of genetic risk variants with PD subtypes are extremely limited and mostly analysed variants in only one gene (e.g., SNCA, LRRK2, MAPT, GBA ). We performed association studies on multiple risk loci as identified in genome wide association studies (GWAS) for PD and on variants associated with cognitive impairment in a large cohort of patients with PD; patients were classified into distinct clinical subtypes. Design/Methods: We included 862 Caucasian patients with PD in the study. All patients had demographic and detailed clinical data on motor and non-motor signs available. The classification into one of four subtypes was primarily based on motor signs. Genotyping for 33 independent risk variants for PD and cognitive impairment was performed. Frequencies of variants were compared for PD subtypes, clinical signs and outcome measures (e.g., rate of progression, survival, early cognitive decline, psychosis). Results: 862 patients who fulfilled PD criteria (550 male, mean age at PD onset: 64 yrs) were classified into four subtypes: “tremor dominant” (43%), “akinetic rigid” (28%), “mixed” (18%), and “gait difficulty” (10%). The strongest evidence for differential variant frequencies between the subtypes was observed in the genes RIT2, INPP5F, GBA/SYT11, and SIPA1L2 . We further found differential variant frequencies in patients with early cognitive decline. Conclusions: We present for the first time genetic association data for GWAS risk loci associated with PD and for risk variants associated with cognitive impairment in four PD subtypes. Studies on associations of genetic variants and clinical features including cognitive decline can provide a better understanding for the heterogeneity seen in PD. Disclosure: Dr. Deutschlander has nothing to disclose. Dr. Konno has nothing to disclose. Dr. Soto-Ortolaza has nothing to disclose. Dr. Ossi has nothing to disclose. Dr. Strongosky has nothing to disclose. Dr. Heckman has nothing to disclose. Dr. Uitti has nothing to disclose. Dr. Van Gerpen has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Elsevier - Parkinsonism & Related Disorders, and Wiley - European Journal of Neurology. Dr. Wszolek has received royalty, license fees, or contractual rights payments from Mayo Clinic and I have a financial interest in technologies entitled, “Identification of Mutations in PARK8, a Locus for Familial Parkinson’s Disease” and “Identification of a Novel LRRK2 Mutation, 6055G>A (G2019S), Linked to Autosomal Dominant Par.
A previous functional magnetic resonance imaging (fMRI) study in sighted individuals showed deactivations of multisensory vestibular cortex areas in the posterior insula and adjacent temporal sites during locomotor imagery. These vestibular deactivations were suggested to reflect the suppression of vestibular signals during locomotion in order to prevent potentially adverse interactions of these inputs with the optimized automated locomotion pattern. In this fMRI experiment, 10 totally blind subjects and 10 age‐ and gender‐matched sighted controls imagined several locomotor tasks in a first‐person perspective (kinesthetic imagery of standing, walking, and running). As opposed to their sighted controls, totally blind individuals activated multisensory vestibular areas in the posterior insula and superior temporal gyrus, with right‐sided preponderance during locomotor imagery. These results plausibly suggest that blind subjects rely more on vestibular feedback for locomotor control than do sighted subjects. Thus, this fMRI study provides neuroimaging evidence for distinct cortical processing in the multisensory vestibular system in the blind during locomotor control.
The hippocampal formation, including the parahippocampal gyrus, is known to be involved in different aspects of navigation and spatial orientation. Recently, bilateral parahippocampal activation during mental imagery of walking and running was demonstrated in fMRI. For the current study the question was whether distinct functional regions within the hippocampal formation could be defined from the analysis of brain activity during imagery of stance and locomotion in healthy, blind, and vestibular‐loss subjects. Using the same experimental paradigm in all groups (fMRI during mental imagery of stance and locomotion after training of actual performance, regions of interest [ROI] analysis), activations were found in the hippocampal formation, predominantly on the right side, in all subjects. In healthy subjects, standing was associated with anterior hippocampal activation; during locomotion widespread activity was found in the right parahippocampal gyrus. Compared to healthy controls, blind subjects showed less activity in the right dorsal parahippocampal region, whereas vestibular‐loss subjects had less activity in the anterior hippocampal formation. The findings show that the hippocampal formation in humans processes visual and vestibular signals in different regions. The data support the assumption that the anterior hippocampus and the entorhinal cortex in the parahippocampal region are input areas for vestibular and somatosensory signals. Posterior parahippocampal and fusiform gyri, which are connected to visual cortical areas, are more important for visually guided locomotion and landmark recognition during navigation. The right‐sided dominance reflects the importance of the right hemisphere for spatial orientation.
