Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets

Multi-modal Imaging and Cognitive Profiles in de novo Parkinson’s Disease

The overall aim of my PhD was to study the correlations between cognitive functions, neurodegeneration and functional alterations in diffuse projection systems. To this aim we plan to combine formal neuropsychological testing, structural and functional imaging and in-vivo quantitative assessments of the dopaminergic, serotonergic and cholinergic systems. Through a multi-modal imaging approach, we had the chance to deeply understand neuroanatomical and neurochemical basis of cognition in its whole, in a large cohort of de novo Parkinson’s Disease (PD) patients. Our study cohort ranges from 30 to 96 of de novo PD patients, who underwent 18F- fluorodeoxyglucose Positron Emission Tomography ([18F]FDG-PET), used as a marker of regional neurodegeneration; [123I]Ioflupane Single Photon Emission Computed Tomography ([123I]FP-CIT-SPECT, as a marker of dopaminergic impairment in the basal ganglia and in the cortex as well as a proxy marker of serotonergic deafferentation in the thalamus; and quantitative electroencephalography (qEEG) recordings, used instead as a marker of cholinergic deafferentation. We combined these imaging methods with formal neuropsychological testing, a social cognition test and multiple clinical variables. In this work we aim to answer to three main scientific questions: i) Does social cognition in de novo PD patients have a specific cortical and neurochemical signature? ii) Is there a mediated effect between diffuse projection systems degeneration and cortical metabolism as well as on regional expression of monoaminergic transmission in the deep grey matter? iii) Are specific cognitive domains impaired in de novo PD patients and are they differently affected by regional metabolism and diffuse projection systems degeneration? In Chapter 3 we investigated the topographical and neurochemical bases of Theory of Mind (ToM), which refers to the ability to attribute mental states to others and to predict, describe, and explain behaviour based on such mental states, using multi-tracer molecular imaging and quantitative electroencephalography in a group of 30 drug-naïve, de novo PD patients. ToM was assessed using the “Reading the Mind in the Eyes Task” (RMET), while general cognition with the Mini Menta State examination (MMSE). We found that PD patients performed significantly worse at RMET compared to 60 healthy controls, as well as a significant positive correlation between RMET performance and regional metabolism in the superior temporal gyrus and the insula, and an inverse correlation with [123I]FP-CIT thalamic specific binding ratio values, as expression of serotonin deafferentation. On the other hand, MMSE correlated with qEEG posterior Theta/Alpha power, confirming its independency from social cognition. In Chapter 4, using multi-tracer molecular imaging, we assessed in a cohort of 96 drug-naïve, de novo PD patients the association between cortical metabolism and dopaminergic and serotonergic systems deafferentation of either striatum or thalamus, and whether this association was mediated by either striatum or thalamus metabolism. We found that the impact of deep grey matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in this population. We showed a significant direct correlation between bilateral temporo-parietal metabolism and caudate dopaminergic innervation, as well as a significant correlation between prefrontal metabolism and thalamus serotonergic innervation, which were, respectively, mediated by striatal and thalamic metabolism. In Chapter 5, we evaluate the association between neurotransmitter impairment, brain metabolism and cognition in a cohort of 95 drug-naïve, de novo PD patients, using [18F]FDG-PET images as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT for dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological tests battery. We found positive correlations between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic expression and working memory, (iii) qEEG slowing in the posterior leads and both memory and visuo-spatial functions