Estudio de las anormalidades en la corteza cerebral y sus asociaciones con variables clínicas y cognitivas en enfermedades neuropsiquiátricascortical /abnormalities and their clinical and cognitive associations in neuropsychiatric disorders

Resum

Background Overlap in genetic risk has been reported in patients with schizophrenia, bipolar disorder and interictal psychosis and these conditions also share similarities in their structural brain abnormalities, in particular cortical abnormalities. Structural neuroimaging studies using Voxel-Based Morphometry (VBM) and Magnetization Transfer Imaging (MTI) have identified cortical abnormalities in fronto-temporal regions in patients with first-episode psychosis and similar, albeit less extensive changes, have also been reported in patients with bipolar disorder, and in those with temporal lobe epilepsy and interictal psychosis. However, the association between genes and cortical abnormalities remains to be determined. In Alzheimer¿s disease the presence of the Apolipoprotein E (APOE) ¿4 allele is one of the most important genetic risk factors for developing the condition and the structural brain abnormalities characteristic of Alzheimer¿s disease have been well documented, but it remains to be determined whether the APOE genotype may influence on the pattern of cortical brain atrophy in these patients. Attention, executive function, and severity of symptoms have been found to correlate with cortical abnormalities in patients with first-episode schizophrenia, but less is known about such correlations in patients with bipolar disorder and interictal psychosis, and the same applies to the influence of the APOE ¿4 genotype on the associations between cognitive and clinical phenotypes and the pattern of atrophy in patients with Alzheimer¿s disease. Surface-Based Morphometry (SBM) techniques allow the measurement of thickness, area and volume of the cortex. SBM has only been used to study neuropsychiatric diseases in recent years. Available SBM studies have reported reduction in fronto-temporal cortical thickness in patients with chronic schizophrenia, first-episode schizophrenia, and in those with bipolar disorder. Most of these studies have only measured cortical thickness without exploring in detail the association of cortical abnormalities with cognitive impairment and clinical symptoms. In this Thesis, SBM has been used to measure independently the thickness, area and volume of the cortex in patients with psychosis of presumed developmental origin (first-episode schizophrenia and bipolar disorder), in patients with psychosis associated with temporal lobe epilepsy, in whom neurodevelopmental abnormalities and neurodegeneration may interact, and in patients with Alzheimer¿s disease, a progressive neurodegenerative disease. This Thesis also explores the associations of cortical abnormalities in these conditions with clinical features and cognitive performance. Aims The studies presented in this Thesis investigate cortical parameters (thickness, area and volume) in different psychotic disorders, i.e. first-episode psychosis, bipolar disorder and interictal psychosis, and in Alzheimer¿s disease. The general objectives are: 1) To study changes in cortical parameters in these conditions; 2) To explore the associations between cortical parameters and clinical variables; 3) To explore the associations between cortical parameters and cognitive measures; 4) To determine whether cortical abnormalities in patients with psychotic disorder are similar to those seen in patients with Alzheimer¿s disease. Methodology Subjects. In the first-episode psychosis study 37 patients (mean age = 26.8 years; 25 males) were compared to 38 healthy controls (mean age = 25.0 years; 22 males). In the bipolar study 25 patients with bipolar disorder type I (mean age = 37.4 years; 10 males) were compared to 11 with bipolar disorder type II (mean age = 42.8 years; 3 males). In the interictal psychosis study 22 patients with temporal lobe epilepsy and interictal psychosis (mean age = 38.9; 9 males), 23 temporal lobe epilepsy without psychosis (mean age = 38.7 years; 11 males) matched for duration of epilepsy, and 21 healthy controls (mean age = 36.0 years; 11 males) participated. In the Alzheimer¿s disease study 38 patients [9 APOE ¿4 non-carriers (mean age = 68.5 years; 6 males); 23 heterozygous APOE ¿4 carriers (mean age = 70.7 years; 6 males); 6 homozygous APOE ¿4 carriers (mean age = 67.5 years; 3 males)] and 23 healthy controls (mean age = 69.7 years; 12 males) participated. Imaging was performed on an MRI 1.5T scanner. Cortical parameters (thickness, area and volume) were measured using an SBM method (Freesurfer). Subjects underwent clinical and neuropsychological assessment that included measures of premorbid and current IQ, verbal and visual memory and executive function. In each study ¿vertex-by-vertex¿ analysis was used to estimate the differences in cortical thickness between groups and linear mixed models were used to estimate differences in all cortical parameters between groups and the associations of these cortical parameters with clinical and cognitive variables. Results In the first-episode psychosis study reductions in the area of the superior temporal gyrus, without changes in cortical thickness were seen in patients compared to controls and premorbid and current IQ at disease onset were associated with area, but not with thickness, of the fronto-temporal cortex. In the bipolar disorder study no differences in cortical parameters were present between patients with bipolar disorder type I and II, but the associations between current IQ and temporal cortical area were stronger in patients with bipolar disorder type II than in those with the type I disorder. Premorbid IQ was associated with frontal cortical area and volume in patients with bipolar disorder when type I and II were considered together. In the interictal psychosis study thinning in the inferior frontal cortex was present in patients with temporal lobe epilepsy and interictal psychosis, and current IQ was associated with fronto-temporal cortical area only in those with interictal psychosis. Clinical variables were not associated with cortical parameters in any of these studies. In the Alzheimer¿s disease study_greater thinning of the medial temporal cortex accompanied by specific volume loss in the hippocampus, and greater memory impairment were present in Alzheimer¿s disease patients with increasing numbers of APOE ¿4 alleles. Conclusions In patients with firts episode psychosis,_the observed pattern of reductions in the area of the superior temporal gyrus without concomitant changes in cortical thickness, suggest a possible disruption of corticogenesis during early development, although the stronger association of fronto-temporal cortical area with current than with premorbid IQ suggest that factors (genetic or environmental) operating during the transition to psychosis may also be relevant. The pattern of cortico-cognitive associations observed in patients with bipolar diosrder considered as a whole is similar to that observed in schizophrenia and the possible differences between those with type I and II disorder merits further consideration in a larger study that includes a healthy control population. In patients with temporal lobe epilepsy and intercictal psychosis, thinning in the inferior frontal cortex may reflect the interplay of the cumulative effects of seizure activity and psychosis-related genetic factors. APOE genotype may influence the pattern of cortical thinning, hippocampal atrophy and neuropsychometric profile in patients with Alzheimer¿s disease. The pattern of cortical abnormalities seen in patients with psychosis with predominant reductions in cortical area is different to that seen in degenerative conditions i.e. in Alzheimer¿s disease.