Progressive Structural Brain Changes Research Articles

Antipsychotics and structural brain changes: could treatment adherence explain the discrepant findings?

Progressive structural brain changes are well documented in schizophrenia and have been linked to both illness progression and the extent of antipsychotic treatment exposure. Literature reporting longitudinal changes in brain structure in individuals with schizophrenia is selectively reviewed to assess the roles of illness, antipsychotic treatment, adherence and other factors in the genesis of these changes. This narrative review considers literature investigating longitudinal changes in brain structure in individuals with schizophrenia. The review focusses on structural changes in the cortex, basal ganglia and white matter. It also examines effects of medication non-adherence and relapse on the clinical course of the illness and on structural brain changes. Studies investigating structural magnetic resonance imaging changes in patients treated with long-acting injectable antipsychotics are reviewed. Temporal changes in brain structure in schizophrenia can be divided into those that are associated with antipsychotic treatment and those that are not. Changes associated with treatment include increases in basal ganglia and white matter volumes. Relapse episodes may be a critical factor in illness progression and brain volume reductions. Medication adherence may be an important factor that could explain the findings that brain volume reductions are associated with poor treatment response, higher intensity of antipsychotic treatment exposure and more time spent in relapse. Improved adherence via long-acting injectable antipsychotics and adherence focussed psychosocial interventions could maximize protective effects of antipsychotics against illness progression.

Accelerated Brain Aging in Patients With Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) may be accompanied by an accelerated structural decline of the brain with age compared to healthy controls (HCs); however, this has yet to be proven. To answer this question, we built a brain age prediction model using mean gray matter volumes of each brain region as features, which were obtained by voxel-based morphometry derived from T1-weighted MRI scans. The prediction model was built using two Chinese Han datasets (dataset 1, N = 106 for HCs and N = 90 for patients with OCD; dataset 2, N = 270 for HCs) to evaluate its performance. Then, a new prediction model was trained using data for HCs in dataset 1 and applied to patients with OCD to investigate the brain aging trajectory. The brain-predicted age difference (brain-PAD) scores, defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with matched HCs in dataset 1. It was demonstrated that the prediction model performs consistently across different datasets. Patients with OCD presented higher brain-PAD scores than matched HCs, suggesting that patients with OCD presented accelerated brain aging. In addition, brain-PAD scores were negatively correlated with the duration of illness, suggesting that brain-PAD scores might capture progressive structural brain changes. These results identified accelerated brain aging in patients with OCD for the first time and deepened our understanding of the pathogenesis of OCD.

Longitudinal trajectory of clinical insight and covariation with cortical thickness in first-episode psychosis

Among people with a first-episode of psychosis, those with poorer clinical insight show neuroanatomical abnormalities in frontal, temporal and parietal cortices compared to those with better clinical insight. Whether changes in clinical insight are associated with progressive structural brain changes is unknown. We aimed to evaluate 1) associations between clinical insight and cortical thickness at a baseline assessment, 2) covariation between clinical insight and cortical thickness across baseline, one-year and two-year follow-up assessments, and 3) the predictive value of clinical insight for cortical thickness at one-year and two-year follow-ups. Scale for the assessment of Unawareness of Mental Disorder ratings and magnetic resonance imaging scans were acquired at baseline, one-year, and two-year follow-ups in 128, 74, and 44 individuals with a first-episode psychosis, respectively. Cortical thickness metrics were then computed at baseline, one-year and two-year follow-ups and analyzed with linear mixed models. At baseline, clinical insight was not significantly associated with cortical thickness in any region. Longitudinal mixed effects models showed that a worsening in clinical insight between the one-year and two-year assessments was significantly associated with cortical thinning in dorsal pre-central and post-central gyri. Cortical thinning in left fusiform gyrus at two-years was predicted by poorer clinical insight at baseline. Results suggest that poor clinical insight soon after the onset of a first-episode psychosis may lead to progressive cortical changes in temporal lobe, while changes in clinical insight during the second year covary with cortical thinning in circumscribed dorsal frontal and parietal cortices.

Progressive Structural Brain Changes and NRG1 Gene Variants in First-Episode Nonaffective Psychosis

Background: Structural brain abnormalities are already present during the early phases of psychosis, but factors underlying brain volume changes are still not well understood. The neuregulin 1 gene (NRG1), influencing neurodevelopment and neuroplasticity, has been associated with schizophrenia. Our aim was to examine whether variations in the NRG1 gene (SNP8NRG221132, SNP8NRG6221533 and SNP8NRG243177 polymorphisms) influence longitudinal changes in the brain during a first episode of psychosis (FEP). Methods: A 3-year follow-up magnetic resonance imaging (MRI) study was performed. Fifty-nine minimally medicated patients who were experiencing FEP and 14 healthy control individuals underwent genotyping and structural brain MRI at baseline and at 1- and 3-year follow-up. A comparison of brain volumes, gray matter, white matter (WM), lateral ventricles (LV), cortical cerebrospinal fluid, and thalamus and caudate was made between the groups according to their genotype. Results: In patients, the SNP8NRG6221533 risk C allele was significantly associated with increased LV volume across time. C allele carriers had significantly less WM compared with subjects homozygous for the T allele after the follow-up. No other significant differences were observed among subgroups. No significant changes according to the genotypes were found in healthy individuals. Conclusion: Our findings suggest that variations of neurodevelopment-related genes, such as the NRG1 gene, can contribute to brain abnormalities described in early phases of schizophrenia and progressive changes during the initial years of the illness. To our knowledge, it is the first time that a relation between NRG1 polymorphisms and longitudinal brain changes is reported.

Relative stability of neurocognitive deficits in early onset schizophrenia spectrum patients

In contrast to the findings of progressive structural brain changes in adolescence, longitudinal studies of patients with early onset schizophrenia spectrum disorders (EOS) indicate that neurocognitive deficits are relatively stable over the first years. The aim of this study is to assess neurocognitive functions longitudinally in patients with EOS compared to healthy controls (HC) using the MATRICS Cognitive Consensus Battery (MCCB). MethodsTwenty patients with EOS and 41 HC were tested with the MCCB at baseline (T1) and after one (T2) and two years (T3). The mean age for the EOS group was 15.6 (SD=1.8) years, while the mean duration of illness was 1.7 (SD=1.4) years at T1. ResultsThe EOS group's neurocognitive performances indicate a stable deficit on most measures. Both the EOS and HC groups showed improved neurocognitive functioning over time on all measures except for the verbal learning domain. There was an interaction between the EOS and HC groups' performance over time on the Trail Making Test A (TMA), a subtest on the processing speed domain. ConclusionThe longitudinal neurocognitive performances measured by the MCCB confirm previous findings of stable deficits in patients with EOS. It is premature to conclude whether the increases in neurocognitive performance reflect developmental processes in adolescence or may be explained by learning effects, or both. As opposed to the other tests in this domain, a stagnation in processing speed as measured by the TMA suggests that the TMA is a particularly sensitive measure of neurodevelopmental deviance in EOS.

BDNF Val66Met variants and brain volume changes in non-affective psychosis patients and healthy controls: A 3year follow-up study

Functional gene polymorphisms modulating neuroplasticity might mediate brain longitudinal structural changes in schizophrenia. The present study aimed to explore possible effects of BDNF Val66Met polymorphism variations on progressive structural brain changes after 3 years from the first episode of psychosis. Patients were part of a large epidemiological and longitudinal intervention program of first-episode psychosis, carried out at the University Hospital Marqués de Valdecilla, Cantabria, Spain. Eighty first-episode patients and 54 healthy controls were included in the final analyses. Brain magnetic resonance imaging (baseline and 3-year follow-up) and BDNF genotype, and clinical and functional outcome were investigated. We did not detect significant association between brain changes and BDNF Val66Met polymorphism variations in patients and controls (all p>0.060). At baseline, there were no significant associations between brain anomalies and BDNF genotype. Functional deficits were similar in Met-carrier and Val homozygote patients after 3-year follow-up (X(2) = 0.66; p = 0.564); there was no relationship between significant volume change across time and functional outcome. Otherwise, Met-carrier controls had significant high rates of alcohol-consumption (p = 0.019) compared to Val homozygote controls. Our findings do not support the notion that BDNF genotype variations may mediate brain macroscopic morphological changes across time.

Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder

Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.

Putative neuroprotective agents in neuropsychiatric disorders

In many individuals with major neuropsychiatric disorders including depression, bipolar disorder and schizophrenia, their disease characteristics are consistent with a neuroprogressive illness. This includes progressive structural brain changes, cognitive and functional decline, poorer treatment response and an increasing vulnerability to relapse with chronicity. The underlying molecular mechanisms of neuroprogression are thought to include neurotrophins and regulation of neurogenesis and apoptosis, neurotransmitters, inflammatory, oxidative and nitrosative stress, mitochondrial dysfunction, cortisol and the hypothalamic-pituitary-adrenal axis, and epigenetic influences. Knowledge of the involvement of each of these pathways implies that specific agents that act on some or multiple of these pathways may thus block this cascade and have neuroprotective properties. This paper reviews the potential of the most promising of these agents, including lithium and other known psychotropics, aspirin, minocycline, statins, N-acetylcysteine, leptin and melatonin. These agents are putative neuroprotective agents for schizophrenia and mood disorders.

Progressive Structural Brain Changes During Development of Psychosis

Ultra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood. Rate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35). UHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto-occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use. The development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis.

Longitudinal MRI study in schizophrenia patients and their healthy siblings

To investigate whether genetic and/or disease-related factors are involved in progressive structural brain changes in schizophrenia, magnetic resonance imaging scans with a 5-year scan interval were acquired in patients, their same-gender siblings and matched healthy controls. Structural equation modelling was applied to assess disease and familial effects. Whole brain and cerebral grey matter volumes decreased excessively in patients compared with their siblings and the controls, suggesting that the progressive brain loss in schizophrenia may be related to the disease process.

Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic resonance imaging study.

It is not clear how far brain abnormalities in early-onset schizophrenia result from progressive neurodevelopmental or neurodegenerative processes. Aims To investigate the hypothesis that structural brain abnormalities in adolescent-onset schizophrenia are progressive in the early phase of the illness. A magnetic resonance imaging case-control study of 16 adolescents with schizophrenia (mean age 16.6 years, s.d.=1.9 years) with a mean time of 2.7 years (s.d.=1.7 years) between measurements and 16 matched controls (average age 16.0 years, s.d.=2.0 years) with a mean time of 1.7 years (s.d.=0.5 years) between measurements. There was no evidence of progressive structural brain changes during late adolescence. Significant ventricular enlargement (greater in males) and left-sided temporal lobe changes were evident from the outset of the illness. Neurodevelopmental brain abnormalities are non-progressive during late adolescence.