Early limbic microstructural alterations in apathy and depression in de novo Parkinson's disease

Abstract

A BS TRACT: Background: Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction. Methods: We compared the morphological and microstructural architecture in gray matter using voxel-based morphometry and diffusion tensor imaging coupled with white matter tract-based spatial statistics in a multimodal imaging case-control study enrolling 14 apathetic and 13 nonapathetic patients with de novo Parkinson's disease and 15 agematched healthy controls, paired with PET imaging of the presynaptic dopaminergic and serotonergic systems. Results: De novo parkinsonian patients with apathy had bilateral microstructural alterations in the medial corticostriatal limbic system, exhibiting decreased fractional anisotropy and increased mean diffusivity in the anterior striatum and pregenual anterior cingulate cortex in conjunction with serotonergic dysfunction. Furthermore, microstructural alterations extended to the medial frontal cortex, the subgenual anterior cingulate cortex and subcallosal gyrus, the medial thalamus, and the caudal midbrain, suggesting disruption of long-range nondopaminergic projections originating in the brainstem, in addition to microstructural alterations in callosal interhemispheric connections and frontostriatal association tracts early in the disease course. In addition, microstructural abnormalities related to depressive symptoms in apathetic and nonapathetic patients revealed a distinct, mainly right-sided limbic subnetwork involving limbic and frontal association tracts. Conclusions: Early limbic microstructural alterations specifically related to apathy and depression emphasize the role of early disruption of ascending nondopaminergic projections and related corticocortical and corticosubcortical networks which underpin the variable expression of nonmotor and neuropsychiatric symptoms in Parkinson's disease.

Neuropsychiatric Disorders in Parkinson’s Disease: What Do We Know About the Role of Dopaminergic and Non-dopaminergic Systems?

“…As already mentioned, we found a prominent role of serotonergic degeneration in the occurrence of apathy at early stage of the disease (Maillet et al, 2016). This was confirmed by a complementary study by Prange et al (2019) showing microstructural changes specifically associated with apathy in the limbic system in de novo patients with apathy compared with non-apathetic patients and healthy controls. These changes overlapped with the functional alteration of the serotoninergic terminals but not with the dopaminergic abnormalities (Prange et al, 2019).…”

“…This was confirmed by a complementary study by Prange et al (2019) showing microstructural changes specifically associated with apathy in the limbic system in de novo patients with apathy compared with non-apathetic patients and healthy controls. These changes overlapped with the functional alteration of the serotoninergic terminals but not with the dopaminergic abnormalities (Prange et al, 2019). Given the links between apathy and cognitive decline in PD patients, a role of cholinergic denervation is also possible.…”

Assessing White Matter Pathology in Early-Stage Parkinson Disease Using Diffusion MRI: A Systematic Review

“…Several authors have also used DTI together with VBM, which can detect subtle brain volumetric changes using structural images, to investigate the relationship between WM tracts, GM volume and PD. These studies found reduced WM microstructural integrity and reduction of GM volume in PD subjects in several regions, such as cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, striatum, and the frontal, temporal, limbic, and paralimbic areas (27,45,52,55,62,65,107).…”

“…However, connectivity analysis revealed significant network changes associated with PD patients with depression (59). Parkinson disease with apathy has also been associated with bilateral microstructural alterations in the medial corticostriatal limbic system; more specifically, decreased FA and increased MD were observed in the anterior striatum and pregenual anterior cingulate cortex, along with concomitant serotonergic dysfunction (62).…”

Pharmacologic Approaches for the Management of Apathy in Neurodegenerative Disorders

“…On a more clinical point of view, apathy is sharing several overlapping symptoms with depression that could lead to inappropriate diagnoses, and thus consequently to an inappropriate treatment prescribing. Despite distinct neural pathways (Murakami et al, 2013;Eyre et al, 2017;Prange et al, 2019), apathy and depression are sharing similar symptoms such as diminished interests, psychomotor retardation, diminished decision making and initiatives. Apathy is frequently misdiagnosed with depression leading to antidepressant prescribing.…”