Cortical macro and microstructural correlates of cognitive and neuropsychiatric symptoms in Parkinson’s disease

Neuropsychiatric symptoms and cognitive impairment are among the most relevant non-motor manifestations of Parkinson’s disease (PD). They affect the majority of patients across all stages of the disease and are a major source of reduced quality of life, caregiver burden and distress, and institutionalization [1].

Anxiety, depression and apathy are distinct neuropsychiatric syndromes that are pervasive along the course of PD. They can even be traced back as part of the prodromal manifestations of PD, are common at time of PD diagnosis in drug-naïve subjects, and highly frequent in non-demented PD patients [2]. Although symptoms of anxiety, depression and apathy highly overlap they can be properly identified in PD subjects using appropriate instruments 3, 4.

Cognitive impairment is also pervasive in PD. Subjective cognitive complaints and some degree of mild cognitive impairment (PD-MCI) relative to healthy controls is present at time of diagnosis in most PD patients [5]. Furthermore, within 3 years of follow-up approximately 25% of patients with established PD and normal cognition develop PD-MCI, and 20% of those diagnosed with PD-MCI develop dementia (PDD) [6].

Neuroimaging has been increasingly used to investigate the neural substrates of cognitive and neuropsychiatric impairment in PD 7, 8. Of particular importance in this context is the assessment of structural brain damage, both at the macrostructural or microstructural level, associated with these conditions. This would contribute to elucidate whether these symptoms represent the clinical expression of an inherent cortical neurodegeneration occurring early in PD 9, 10, 11. Depressive symptoms in PD have been notably related to dysfunction of emotion-related circuits connecting cortical and subcortical limbic areas 12, 13. Neuroimaging studies of anxiety symptoms in PD are scarce. However, altered cortico-basal-ganglia-thalamocortical circuits have been suggested as a possible mechanism of anxiety in PD [11]. Regarding brain correlates of cognition, previous studies have reported diffuse cortical changes at the frontal and temporo-parietal level that rely on distributed brain networks depending on the cognitive domain 14, 15, 16. Finally, apathy in PD has been studied mainly as a syndrome. Despite this, different structures belonging to cognitive, premotor or limbic regions have been proposed for the respective cognitive, self-activation and emotional subdomains [4]. Importantly, functional MRI or white-matter DTI metrics do not directly assess the loss of non-projecting cortical neurons.

On the other hand, cortical microstructural alterations can be quantified using DTI-derived mean diffusivity (MD) data in cortical GM regions. Briefly, increases in MD within the cerebral cortex have been recently suggested to detect incipient neuronal death, as water can diffuse more freely in cortical regions with reduced neural density [17]. The added value of this technique was recently reviewed by our group [18]. Cortical microstructural alterations associated with apathy and depression in PD were recently investigated by Prange and colleagues [7]. Nevertheless, the volumetric approach used for characterizing gray matter diffusivity suffered from several drawbacks. First, the voxelwise analyses were restricted to limbic regions, precluding the study of key regions outside this system. Secondly, partial volume correction techniques were not applied to volumetric diffusivity data. Therefore, regional differences in gray matter density could be responsible for apparent diffusivity increases. Finally, gray matter volumetric analyses of diffusivity data suffer from important limitations that can be overcome by using a surface-based approach [19].

In this work we use a surface-based approach to characterize the cortical microstructural correlates of the aforementioned cognitive and behavioral symptoms in PD. Surface-based intracortical diffusivity data has been recently used to assess microstructural damage in a number of neurodegenerative disorders including PD 19, 20, 21, 22, 23. In fact, this metric has shown increased sensitivity than macrostructural cortical thinning for the detection of early cortical damage in PD [20].

We hypothesize that cognitive and behavioral symptoms reflect both macro (cortical thinning) and microstructural (increased intracortical MD) damage in PD patients, reinforcing the clinical impact of the inherent cortical neurodegeneration occurring early in this disorder. Moreover, microstructural alterations may reveal that cortical damage occurs in the absence of macrostructural changes. Identifying early signs of cortical degeneration in PD associated with non-motor symptoms is critical to better delineate the specific brain circuitry or/and neurotransmitter pathways to be targeted in therapeutic settings.

留言 (0)

沒有登入
gif