De neurobiologie van motorische symptomen bij depressie op latere leeftijd.

Psychomotor dysfunction (PMD) is a symptom dimension of major depressive disorder that is particularly common in late life depression (LLD) and leads to falls. Its neurobiology remains unresolved. Accelerated aging or neurodegeneration in the brain's motor regions could explain the severity of motor symptoms in LLD. Recently developed PET imaging techniques allow to study the brain's neuronal synaptic density, which is typically affected in key brain regions involved in common neurodegenerative diseases. Grey and white matter alterations that are naturally seen in healthy aging can be studied with advanced automated methods for the analysis of MR imaging. This doctoral project investigated the neurobiology of PMD was in LLD, following a stepwise approach. First, historical clinical descriptions and interpretations of motor symptoms were explored in melancholia, the predecessor of major depressive disorder (chapter 1). This confirmed the multifocal involvement and the diagnostic importance of motor symptoms within depressive syndromes. It became clear that over time, physicians and scientists gave different affective, motivational and cognitive interpretations to psychomotor retardation and agitation. These interpretations were further explored in a study of 34 patients with LLD and 41 healthy older persons, by investigating relationships between motor scales and experimental measures of fine, gross motor function, gait and balance with scales measuring mood, motivational and cognitive function (chapter 3). This study confirmed the multifocal pattern of PMD and showed how its severity was not significantly explained by affective, motivational or cognitive dysfunction nor antipsychotic drug use. A digital tablet task revealed that patient's fine movement execution was more impaired than initiation, in comparison to healthy older persons an independently of task complexity. Their initiation speed normalized in the presence of visual start cues, which hints at a deficit at the level of the basal ganglia. As a second step, brain imaging changes associated with PMD were investigated by conducting a scoping review (chapter 4). This review revealed four replicated key imaging findings associated with (more extensive) PMD: lower dopamine availability in the striatum, widespread changes of white matter structural integrity, lower blood flow to the frontal cortex, and altered functional connectivity in the frontal, cingulate cortex and the basal ganglia. The review lay bare the need for a stricter sample selection with exclusion of relevant neuropsychiatric diseases, and a consensus on motor measures that are less influenced by affective, motivational, cognitive or observer bias. To study the specific role of brain aging or neurodegeneration in the motor symptoms of LLD, associations of synaptic density (using an SV2A- PET tracer) in the brain and mild motor signs (using the MDS-UPDRSIII score) were investigated in a sample of 68 healthy older persons (chapter 5). This study revealed how a widespread symmetrical pattern of lower synaptic density in the cortex and subcortical structures related to more pronounced motor symptoms in healthy aging, independent of a white matter hyperintensity rating or grey matter volume. The same investigation was consecutively performed in the group of 34 patients with LLD of the Leuven Late Life Depression study, though with an increased set of motor measures including assessments of fine motor function and gait. No widespread pattern of lower synaptic density was seen, but instead, a localized change in synaptic density of the globus pallidus as well as grey matter volume reductions in the thalamus, globus pallidus and putamen was observed that related to more severe fine and gross motor dysfunction. Capitalizing on these imaging findings, our third and last step was the investigation of basal ganglia grey matter volume changes of 66 older LLD patients over a course of electroconvulsive therapy (ECT), a rapid acting antidepressant therapy. In parallel with large scale studies, a volume increase was observed in the caudate, putamen and accumbens nucleus upon depression remission after ECT. This volume increase however did not correlate with the improvement of PMD (measured with the CORE scale). Though no overall significant volume change was noticed for the globus pallidus, volumetric changes of this structure correlated with the CORE agitation improvement after ECT. In conclusion, PMD appears to be an independent motor dimension of LLD with specific clinical characteristics and brain imaging findings that point to a dysfunction within the basal ganglia-thalamic circuit. These localized findings were fundamentally different from brain changes related to mild motor signs in healthy older persons, suggesting that the higher prevalence of PMD in LLD is not explained by brain aging effect alone.