Structural, Functional Brain Alterations May Explain Clinical Heterogeneity in PD

Striatal dopamine depletion patterns are associated with the structural connectivity of brain networks, which may contribute to the clinical heterogeneity of PD.

Patterns of striatal dopamine depletion in the brain and their variations in connectivity with cortical networks can explain the clinical differences in cognitive function in patients with Parkinson disease (PD), according to study findings published in Neurology.

Researchers analyzed patterns of striatal dopamine loss in 240 newly diagnosed patients with PD who are drug-naïve between January 2015 and April 2018 at the outpatient clinic at Yonsei Parkinson Center at Severance Hospital in Seoul, South Korea. The average age of PD onset was 69.1 years and average disease duration totaled 17.9 months.  

They used [18F] N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4- iodophenyl) nortropane positron emission tomography (18F-FP-CIT PET) scans and brain magnetic resonance imaging (MRI) scans that underwent analysis using diffusion tensor imaging (DTI). This measured the uptake of the 18F-FP-CIT tracer into 4 different striatal regions of the brain — the caudate, the anterior putamen, and either the “more” or “less” affected sensorimotor striata in terms of dopamine depletion, resulting in composite scores for each of the 4 regions.

They analyzed the networks that formed between these striatal subregions and white matter in the cortex of the brain by measuring white matter hyperintensity and how dopamine depletion clinically affected these cortico-striatal networks.

These findings suggest that clinical heterogeneity according to the striatal dopamine depletion pattern can be explained not only in the functional aspect, but also in the aspect of WM structural connectivity in patients with PD.

The researchers especially focused on the impact of dopamine depletion on these cortico-striatal networks as it corresponded to 4 cognitive domains, including frontal/executive function, verbal memory, attention/working memory/language function, and visual memory/visuospatial function. Additionally, they analyzed its effects on motor function, olfaction, and depression.

They found that different patterns of striatal dopamine depletion, specifically located in the caudate, correlated strongly with alterations in specific white matter structures.

Patients with PD with relatively preserved dopaminergic function within the caudate (as represented by higher composite scores in this striatal subregion) demonstrated strong network connections between the left caudate and left middle frontal gyri. However, patients with PD with selective, severe dopamine loss in the caudate demonstrated strong network connections with the left insula, thalamus, anterior cingulum, putamen, pallidum, cerebellum, and inferior frontal gyrus.

In contrast to the white matter connections found within the caudate, the researchers did not observe any connections between dopamine depletion in the anterior putamen, the more-affected sensorimotor striatum, and the less-affected sensorimotor striatum and alterations of white matter structures.

Clinically, dopamine depletion in caudate strongly impacted frontal/executive function directly or indirectly.

The researchers noted their findings highlight the different patterns of striatal dopamine depletion are closely linked with WM structural alterations, potentially contributing to the “heterogeneous cognitive profiles in individuals with PD.”

“These findings suggest that clinical heterogeneity according to the striatal dopamine depletion pattern can be explained not only in the functional aspect, but also in the aspect of WM structural connectivity in patients with PD,” they concluded.

Study limitations included lack of ideal measurement of dopamine depletion and dopaminergic nerve terminal density, variability in ways to derive equations to estimate composite scores for each striatal subregion or cognitive function domains, technological limitations related to automated parcellation of the brain, potential bias since only two-thirds of the participants underwent neuropsychological testing, and lack of comprehensive examinations of non-motor symptoms other than cognitive dysfunction.

References:

Chung SJ, Kim YJ, Kim YJ, et al. Association between white matter networks and the pattern of striatal dopamine depletion in patients with Parkinson disease. Neurology. Published online October 4, 2022. doi:10.1212/WNL.0000000000201269