Associations among Cognitive Functions, Plasma DNA, and White Matter Integrity in Patients with Early-Onset Parkinson's Disease

Abstract

Early-onset Parkinson's disease (EOPD) patients are symptomatic at a relatively young age, and the impacts of the disease on both the patients and their caregivers are dramatic. Few studies have reported on the cognitive impairments seen in EOPD, and the results of these studies have been diverse. Furthermore, it is still unclear what microstructural white matter (WM) changes are present in EOPD patients. As such, we conducted this study to investigate the microstructural WM changes experienced by EOPD patients and their association with cognitive function and plasma DNA levels. We enrolled 24 EOPD patients and 33 sex- and age-matched healthy volunteers who underwent complete neuro-psychological testing (NPT) to evaluate their cognitive function and diffusion tensor imaging (DTI) scanning to determine their fiber integrity. The plasma DNA measurements included measurements of nuclear and mitochondrial DNA levels. Fractional anisotropy (FA) maps were compared using voxel-based statistics to determine differences between the two groups. The differences in DTI indices and NPT scores were correlated after adjusting for age, sex, and education. Our results demonstrate that patients with EOPD have elevated nuclear DNA levels and wide spectrums of impairments in NPT, especially in the executive function and visuospatial function domains. Exploratory group-wise comparisons of the DTI indices revealed that the patients with EOPD exhibited lower DTI parameters in several brain locations. These poorer DTI parameters were associated with worse cognitive performances and elevated plasma nuclear DNA levels, especially in the anterior thalamic radiation region. Our findings suggest that the thalamus and its adjacent anterior thalamic radiation may be important in the pathogenesis of EOPD, as they appear to become involved in the disease process at an early stage.

Diffusion Tensor Imaging in Parkinson's Disease and Parkinsonian Syndrome: A Systematic Review

“…-Low FA of primarily the frontal and parietal regions correlated with executive, visuospatial dysfunctions (20)(21)(22)(23)(24).…”

White matter damage and systemic inflammation in Parkinson’s disease

“…The association between WM damages and systemic inflammation was demonstrated in current and previous studies [50, 51]. The result of linear regression analysis, controlling confounding effects, emphasized the major impacts of systemic inflammation including granulocyte apoptosis, lymphocyte apoptosis, LFA-1, and P-selectin.…”

Interaction of systemic oxidative stress and mesial temporal network degeneration in Parkinson’s disease with and without cognitive impairment

“…Increased apoptosis of lymphocytes and monocytes and increased expression of LFA-1 might support the view that there is only one primary pathophysiology of PD: abnormal systemic oxidative stress and the acceleration of peripheral immune cell infiltration into the brain. Neurodegeneration in PD associated with systemic inflammation via various pathways has been thoroughly discussed [ 12 , 13 , 16 – 18 , 24 , 25 ]. Several previous studies showed that higher percentages of peripheral apoptotic lymphocytes [ 32 ] and the CNS infiltration of lymphocytes and monocytes contribute to neurodegeneration [ 22 , 33 , 34 ].…”

“…This association has been further been demonstrated by the increased peripheral leukocyte apoptosis with striatal dopamine neuron loss [ 16 ] and white matter alteration observed through the use of diffusion tensor imaging [ 17 ]. In addition, increased oxidative stress has been found to be associated with cognitive function status even in the early stage of the disease in young PD patients [ 18 ]. The accumulating evidence has shown an association between inflammation and cognitive impairment not only in PD [ 19 ] but also in other neurodegenerative diseases such as AD [ 20 ] and even in changes due to normal aging [ 21 ].…”

“…Although the peripheral immune cells are associated with the initial pathogenesis of PD [ 22 ], it is still not known whether this association is widely spread in a non-specific manner to all brain tissues or if it is only focused on particular regions, i.e., the so-called vulnerable areas. Some recent studies have demonstrated the correlational relationships between structural alterations of various areas and different peripheral oxidative stress markers [ 17 , 18 , 23 ]. Moreover, two mediation studies by our team revealed the interactions between altered brain structures and elevated serum oxidative stress [ 24 , 25 ].…”