Rudie Kortekaas

Many factors are involved in the pathogenesis of depression. This article provides an overview of the results given in the thesis entitled 'Linking Depression', in which some putative underlying neurobiological and genetic mechanisms of depression are examined. To gain more insight in brain activity as endophenotype for depression. As part of the Netherlands Study of Depression and Anxiety (nesda), 301 people, including patients with depression and/or anxiety and healthy volunteers, underwent functional magnetic resonance imaging (fmri) and genotyping. During the processing of negative emotions, patients with depression showed a pattern of heightened limbic activation but less prefrontal activation. The same pattern, but in reverse, was seen during the processing of positive emotions. We showed that the disc1, comt and npy genes were associated with brain activation patterns comparable to those seen in patients with depression. In addition, in cases of depression, there was ...

Genetic variation in the catechol-O-methyltransferase (COMT) Val158Met polymorphism has been shown to influence performance on cognitive and emotional tasks. Specifically, it has been suggested that the Met allele might be less advantageous than the Val allele with respect to emotional processing. This study addresses the question whether the presence of the Met allele is directly related to both lower emotional verbalizing proficiency and differences in brain activation during emotional processing. Specifically, we investigated whether COMT genotype would be associated with differences in activation in cortical midline structures during valence evaluation of words. Forty participants ranging from low to high on the verbalizing subscale of the Bermond-Vorst Alexithymia Questionnaire (BVAQ) were genotyped for the COMT Val158Met polymorphism. During fMRI, they evaluated the valence of emotional words. Met homozygotes reported more difficulties in verbalizing their feelings. In additio...

While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. As a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blo...

E very organism that is alive today is a direct descendant of one or two ancestors: one in the case of asexual reproduction and two in the case of sexual reproduction. This self-evident truth tells us two things about those ancestors: (i) they reached sexual maturity in a su ciently healthy state and (ii) they actually replicated. These two achieve-ments, individual survival and species survival, are essential for the continuity of life and, as a result, any trait that increases the ability to execute them is favored by natural selection. It is tempting to call these achievements the goals of life, but apparent goals is a safer term to use. Dawkins (1976) remarked that the two apparent goals of life can easily be simpli ed by regarding the gene as the "atom" of natural selection and replication. Two seemingly rivaling apparent goals of life now become one: individual survival and species survival can both be seen as two di erent expression forms of the conservation of an o...

Neuropeptide Y (NPY) has been associated with stress reactivity in affective disorders and is most densely expressed in the amygdala. An important stressor associated with affective disorders is the experience of childhood emotional maltreatment (CEM). We investigated whether the interaction of NPY risk genotype and CEM would affect brain activation. From The Netherlands Study of Depression and Anxiety, 33 healthy controls and 85 patients with affective disorders were scanned with functional magnetic resonance imaging while making gender decisions of emotional facial expressions. Results showed interactions between genotype and CEM, within carriers of the risk genotype, CEM was associated with higher amygdala activation, whereas CEM did not influence activation in non-risk carriers. In the posterior cingulate cortex (PCC), less activation was seen in those with CEM and the risk genotype, whereas genotype did not influence PCC activation in those without CEM. In addition, those carrying the risk genotype and with experience of CEM made a faster gender decision than those without CEM. Thus, the combined effect of carrying NPY risk genotype and a history of CEM affected amygdala and PCC reactivity, areas related to emotion, self-relevance processing and autobiographical memory. These results are consistent with the notion that the combination of risk genotype and CEM may cause hypervigilance.

Depression has been associated with limbic hyperactivation and frontal hypoactivation in response to negative facial stimuli. Anxiety disorders have also been associated with increased activation of emotional structures such as the amygdala and insula. This study examined to what extent activation of brain regions involved in perception of emotional faces is specific to depression and anxiety disorders in a large community-based sample of out-patients. An event-related functional magnetic resonance imaging (fMRI) paradigm was used including angry, fearful, sad, happy and neutral facial expressions. One hundred and eighty-two out-patients (59 depressed, 57 anxiety and 66 co-morbid depression-anxiety) and 56 healthy controls selected from the Netherlands Study of Depression and Anxiety (NESDA) were included in the present study. Whole-brain analyses were conducted. The temporal profile of amygdala activation was also investigated. Facial expressions activated the amygdala and fusiform gyrus in depressed patients with or without anxiety and in healthy controls, relative to scrambled faces, but this was less evident in patients with anxiety disorders. The response shape of the amygdala did not differ between groups. Depressed patients showed dorsolateral prefrontal cortex (PFC) hyperactivation in response to happy faces compared to healthy controls. We suggest that stronger frontal activation to happy faces in depressed patients may reflect increased demands on effortful emotion regulation processes triggered by mood-incongruent stimuli. The lack of strong differences in neural activation to negative emotional faces, relative to healthy controls, may be characteristic of the mild-to-moderate severity of illness in this sample and may be indicative of a certain cognitive-emotional processing reserve.

Lipofuscin accumulation is a characteristic feature of senescent postmitotic neuronal cells but estrogen may have protecting effects by inhibiting its formation. In the present ultrastructural study, lipofuscin accumulation was studied in 2 estrogen-α-receptive brainstem areas: nucleus pararetroambiguus (NPRA) and the commissural part of the solitary tract nucleus/A2 catecholaminergic group (NTScom/A2) and compared with the estrogen-insensitive medial tegmental field (mtf), in young (23 weeks) and aged (95 weeks) female hamsters. In the aged animals, extensive intracytoplasmic lipofuscin accumulation was observed. A total number of 6450 neurons were classified in 4 categories. Levels were significantly elevated in each of the brain areas studied. Lipofuscin accumulation was strongest in the mtf, less in NPRA, and remarkably less in the area of NTScom/A2. In conclusion, the observed differences in lipofuscin accumulation suggest: (1) considerable regional differences in the degree of neuronal vulnerability; and (2) a possible neuroprotective role for estrogen, because the degree of accumulation is inversely related to the density of the estrogen receptors, varying from nonreceptive (mtf) to NPRA and NTScom/A2 (most receptive).

P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a wide range of substrates from the brain. This is important for maintaining loco-regional homeostasis and for protecting the brain against blood-borne toxic substances. Altered P-gp function seems to be involved in the pathophysiology of neurodegenerative disease and various neurological and psychiatric disorders. Positron emission tomography (PET) with the radiotracer (11)C-verapamil (VPM-PET) is a validated technique allowing measurement of P-gp function at the human BBB. In this review, we highlight changes of P-gp function, as measured with VPM-PET, in aging and in the pathogenesis and progression of neurodegenerative disease, as well as their role in depressive disorders.

Structural neuronal plasticity is present in the nucleus para-retroambiguus (NPRA) and the commissural nucleus of the solitary tract/A2 group (NTScom/A2) in female hamsters. Both brainstem nuclei play a role in estrous cycle related autonomic adaptations. We investigated how aging affects the capillary condition in these adaptive brainstem regions. Senescent female hamsters (+/-95 weeks) were tested weekly for their 4-day estrous cycle. Subsequently morphological changes of NPRA and NTScom/A2 were compared with those of young (+/-20 weeks) females in an ultrastructural study. The medial tegmental field served as control area. In 841 capillaries (n=319 capillaries, young females (N=3); n=522 capillaries, aged females (N=4)) vascular aberrations were classified into 3 categories: endothelial and tight junction, basement membrane and pericyte aberrations. In old animals, capillaries showed marked endothelial changes, disrupted tight junctions, and thickening and splitting of basement membranes. Aberrations were found in 40-60% of all capillaries. About 70% of the pericytes contained degenerative inclusions. Despite this generalized vascular degeneration, the reproductive cycle of female hamsters was unaffected by vascular senescence. Perivascular fibrosis as reported in aging rats was never observed, which suggests the existence of species differences.