Progressive Brain Changes Research Articles

Inhibition of Calcineurin with FK506 Reduces Tau Levels and Attenuates Synaptic Impairment Driven by Tau Oligomers in the Hippocampus of Male Mouse Models.

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and structural brain changes, primarily involving Aβ plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent research highlights the significance of smaller Aβ and Tau oligomeric aggregates (AβO and TauO, respectively) in synaptic dysfunction and disease progression. Calcineurin (CaN), a key calcium/calmodulin-dependent player in regulating synaptic function in the central nervous system (CNS) is implicated in mediating detrimental effects of AβO on synapses and memory function in AD. This study aims to investigate the specific impact of CaN on both exogenous and endogenous TauO through the acute and chronic inhibition of CaN. We previously demonstrated the protective effect against AD of the immunosuppressant CaN inhibitor, FK506, but its influence on TauO remains unclear. In this study, we explored the short-term effects of acute CaN inhibition on TauO phosphorylation and TauO-induced memory deficits and synaptic dysfunction. Mice received FK506 post-TauO intracerebroventricular injection and TauO levels and phosphorylation were assessed, examining their impact on CaN and GSK-3β. The study investigated FK506 preventive/reversal effects on TauO-induced clustering of CaN and GSK-3β. Memory and synaptic function in TauO-injected mice were evaluated with/without FK506. Chronic FK506 treatment in 3xTgAD mice explored its influence on CaN, Aβ, and Tau levels. This study underscores the significant influence of CaN inhibition on TauO and associated AD pathology, suggesting therapeutic potential in targeting CaN for addressing various aspects of AD onset and progression. These findings provide valuable insights for potential interventions in AD, emphasizing the need for further exploration of CaN-targeted strategies.

Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning.

The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1-6.0 points) in all the IQ index scores (p < 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood-brain barrier in order to treat this CNS phenotype.

Twenty Years of Managed Epilepsy for a Stranded Male Guadalupe Fur Seal (Arctocephalus townsendi) Secondary to Suspect Domoic Acid Toxicosis

Many wild otariids (sea lions and fur seals) strand along the California coast annually with seizures following presumed exposure to harmful algal blooms (HABs). This is a long-term case study of a stranded subadult male Guadalupe fur seal (Arctocephalus townsendi) that stranded in 2001 and within days after admission began demonstrating seizure activity. The epilepsy was stabilized with antiepileptic drug (AED) therapy and advanced imaging was performed. Magnetic resonance (MR) scans showed signs of encephalopathy consistent with domoic acid (DA) toxicosis. This fur seal was deemed “non-releasable” and over the following 19 years, he received supportive veterinary care and AED treatment at a permitted facility. In the summer of 2020, the fur seal showed progressive behavioral and functional deterioration whereupon humane euthanasia was performed. Post-mortem MR and diffusion tensor images (DTI) were acquired. A volumetric comparison with historic scans showed evidence of severe progressive unilateral right hippocampal atrophy. Histopathology confirmed severe chronic right and mild left hippocampal atrophy. The progressive degenerative brain changes demonstrate how adaptive brain function can be with neuronal atrophy secondary to DA exposure. This case highlights some considerations and decision-making processes needed for the rehabilitation and placement of wild stranded otariids with acquired epilepsy secondary to DA toxicity.

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

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.

Distinct profiles of functional connectivity density aberrance in Alzheimer's disease and mild cognitive impairment.

Investigating the neuroimaging changes from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is of great significance. However, the details about the distinct functional characteristics of AD and MCI remain unknown. In this study, we investigated distinct profiles of functional connectivity density (FCD) differences between AD and MCI compared with the normal population, aiming to depict the progressive brain changes from MCI to AD. As a data-driven method, FCD measures the profiles of FC for the given voxel at different scales. Resting-state functional magnetic resonance imaging (fMRI) images were obtained from patients with AD and MCI and matched healthy controls (HCs). One-way ANCOVA was used to investigate (global, long-range, and local) FCD differences among the three groups followed by post-hoc analysis controlling age, sex, and head motion. The three groups exhibited significant global FCD differences in the superior frontal gyrus. The post-hoc results further showed that patients with AD had a significant increase in global FCD values than those with MCI and HCs. Patients with MCI exhibited an increased trend compared with HCs. We further identified brain regions contributing to the observed global FCD differences by conducting seed-based FC analysis. We also identified that the observed global FCD differences were the additive effects of altered FC between the superior frontal gyrus and the posterior default model network. These results depicted the global information communication capability impairment in AD and MCI providing a new insight into the progressive brain changes from MCI to AD.

Long-term brain changes in bipolar disorder

IntroductionThe term “neuroprogression” imply that bipolar disorder (BD) progressively worsens for some patients and accompanying neuroanatomical changes. BD has indeed been associated with cortical and subcortical brain abnormalities. But cross-sectional studies cannot determine whether the observed brain alterations reflect static premorbid traits or whether they result from progressive changes during the course of illness.ObjectivesThe aims of this series of studies were to determine if progressive brain changes occur in bipolar disorder, and if so, what the drivers of these changes are.MethodsWe addressed these questions in the St. Göran cohort – a longitudinal study where patients and controls undergo structural magnetic resonance imaging (MRI) scans at baseline and after 7 years. We have also conducted a longitudinal multicenter study within the ENIGMA consortium including 307 patients and 925 healthy controls scanned at two time points.ResultsWe addressed these questions in the St. Göran cohort – a longitudinal study where patients and controls undergo structural magnetic resonance imaging (MRI) scans at baseline and after 7 years. We have also conducted a longitudinal multicenter study within the ENIGMA consortium including 307 patients and 925 healthy controls scanned at two time points.ConclusionsBD is associated with some (accelerated ventricular enlargement) but not global progressive brain changes (change in cortical structures do not differ from controls). Occurrence of manic episodes is, however, associated with accelerated cortical thinning over time. These results highlight the importance of preventing the potentially toxic effects of manic episodes and might explain why some patients experience worsening cognitive function.DisclosureML has received lecture honoraria (unrelated to this topic) from Lundbeck pharmaceuticals.

Commentary on whether progressive brain change underlies the pathology of schizophrenia: Should this even be debated?

Cortical thinning is a well-known feature in schizophrenia. The considerable variation in the spatial distribution of thickness changes has been used to parse heterogeneity. A ‘cortical impoverishment’ subgroup with a generalized reduction in thickness has been reported. However, it is unclear if this subgroup is recoverable irrespective of illness stage, and if it relates to the glutamate hypothesis of schizophrenia.We applied hierarchical cluster analysis to cortical thickness data from magnetic resonance imaging scans of three datasets in different stages of psychosis (n = 288; 160 patients; 128 healthy controls) and studied the cognitive and symptom profiles of the observed subgroups. In one of the samples, we also studied the subgroup differences in 7-Tesla magnetic resonance spectroscopy glutamate concentration in the dorsal anterior cingulate cortex.Our consensus-based clustering procedure consistently produced 2 subgroups of participants. Patients accounted for 75%–100% of participants in one subgroup that was characterized by significantly lower cortical thickness. Both subgroups were equally symptomatic in clinically unstable stages, but cortical impoverishment indicated a higher symptom burden in a clinically stable sample and higher glutamate levels in the first-episode sample. There were no subgroup differences in cognitive and functional outcome profiles or antipsychotic exposure across all stages.Cortical thinning does not vary with functioning or cognitive impairment, but it is more prevalent among patients, especially those with glutamate excess in early stages and higher residual symptom burden at later stages, providing an important mechanistic clue to one of the several possible pathways to the illness.

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.

Biomarkers of neuroprogression and late staging in bipolar disorder: A systematic review.

Bipolar disorder may undertake a progressive course in a subset of patients, and research efforts have been made to understand the biological basis underlying this process. This systematic review examined the literature available on biological markers associated with illness progression in bipolar disorder. Peer-reviewed articles were assessed using Embase, PsycINFO and PubMed, as well as from external sources. After initial screening, a total of 871 citations from databases and other sources were identified. Participants with a diagnosis of bipolar disorder were included in our systematic review; however, studies with participants younger than 15 or older than 65 were excluded. All studies were assessed using the Newcastle-Ottawa Scale assessment tool, and data pertaining to the results were extracted into tabular form using Google Sheets and Google Documents. The systematic review was registered on PROSPERO international prospective register of systematic reviews (ID Number: CRD42020154305). A total of 35 studies were included in the systematic review. Increased ventricular size and reduction of grey matter volume were the most common brain changes associated with illness progression in bipolar disorder. Among the several biomarkers evaluated in this systematic review, findings also indicate a role of peripheral inflammatory markers in this process. The studies evaluating the biological basis of the illness progression in bipolar disorder are still scarce and heterogeneous. However, current evidence supports the notion of neuroprogression, the pathophysiological process related to progressive brain changes associated with clinical progression in patients with bipolar disorder. The increase in peripheral inflammatory biomarkers and the neuroanatomical changes in bipolar disorder suggest progressive systemic and structural brain alterations, respectively.

The Correlation of P100 Latency and P100 Amplitude in Patients with Schizophrenia and Migraine Headache Using Visual Evoked Potentials (VEPS)

Background: The VEPs provide an objective measure of brain function, analyzing integrity of visual processing. With patients affected with schizophrenia, the changes with the implementation of VEP are evident, such as symmetrical deceleration of the impulse (reduction of the amplitude) and the continuance of latency, which points to a degenerative illness, suggesting the presence of optical neuritis or hemianopsia conjoined with mentioned intracranial illness. Objective: The aim of the study was to determine the correlation of l P100 latency and P100 amplitude (µV) between patients with schizophrenia and patients with migraine headache. Visual evoked potentials (VEPs) were applied. Methods: The sample included 80 subjects: a) S group- 40 patients with schizophrenia (21 males; 19 females), b) H group-40 healthy subjects with migraine headache (10 males; 30 females). The study was conducted at the Department of Psychiatry, Neurology and Radiology, University Clinical Center Sarajevo. Results: Our research revealed positive correlations were registered in P100 latency in left view field of both eyes and in P100 amplitude in the region of right eye (p=0.01) in comparison with left eye region (p=0.05) in patients with schizophrenia. Conclusion: Results imply that the cognitive impairment seen in schizophrenia is not just due to deficits in higher order aspects of cognition but also encompasses significant deficits in early sensory processing. Our study is useful to initiate new questions and recommendations for further studies, specifically on changes in the occipital lobe in the schizophrenic patient’s brain. Changes in the volume in the occipital lobe are quite evident and further studies are required to better understand how the progressive brain changes affect the structural, functional, and metabolic activities of the occipital lobe in schizophrenia.

Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

BackgroundCharacterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. MethodsCapitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. ResultsWe show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. ConclusionsHD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

Structural and Functional Alterations of the Temporal lobe in Schizophrenia: A Literature Review.

Schizophrenia is a severe chronic mental illness leading to social and occupational dysfunction. Our primary focus in this review article was to analyze further the structural and functional alterations of the temporal lobe in patients with schizophrenia, which might contribute to the associated manifestations we often see in this illness. Our goal was to see if there was any correlation between temporal lobe abnormalities, more specifically, alterations in brain volume and specific symptoms such as auditory and language processing, etc. There is a positive correlation between volume alterations and thoughts disorders in the temporal lobe in the majority of studies. However, superior temporal gyrus volume has also been correlated negatively with the severity of hallucinations and thought disorders in some studies. We utilized Medical Subject Heading (MeSH) search strategy via PubMed database in our articles search yielding 241 papers. After the application of specific inclusion and exclusion criteria, a final number of 30 was reviewed. The involvement of the temporal lobe and its gray and white matter volume alterations in schizophrenia is quite apparent from our research; however, the exact mechanism of the underlying biological process is not thoroughly studied yet. Therefore, further research on larger cohorts combining different imaging modalities including volumetry, diffusion tensor, and functional imaging is required to explain how the progressive brain changes affect the various structural, functional, and metabolic activities of the temporal lobe in schizophrenia.

T155. PROGRESSION OF NEUROANATOMICAL ABNORMALITIES AFTER FIRST-EPISODE OF PSYCHOSIS: A 3-YEAR LONGITUDINAL STRUCTURAL MRI STUDY

BackgroundThe extent and location of longitudinal morphometric changes after first-episode of psychosis (FEP) remains unclear. We investigated the progressive profile of ventricular and cortico-subcortical regions over a 3-year period in FEP patients compared with healthy controls (HC), and whether any progressive neuroanatomical changes were related to clinical factors.MethodsHigh resolution 1.5T T1-weighted MR images were obtained from 28 FEP patients and 28 HCs shortly after presentation to services and again after 3-year follow-up. The longitudinal FreeSurfer pipeline (v.5.3.0) was used for regional volumetric and cortical reconstruction image analyses. Repeated-measures ANCOVA and vertex-wise linear regression analyses were used to compare progressive changes in relation to subcortical structures/ventricles and thickness across the cortical mantle, respectively, between groups. Partial correlations were used to determine associations of progressive neuroanatomical change with clinical and functional characteristics.ResultsCompared with controls, patients displayed progressively reduced volume of the caudate [F(1,51)=5.86, p=0.02, Hedges’ g=0.66], putamen [F(1,51)=6.06, p=0.02, g=0.67] and thalamus [F(1,51)=6.99, p=0.01, g=0.72], with a trend for increased lateral ventricular volume [F(1,51)=3.37, p=0.07, g=0.50] more prominent on the right [F(1, 51)=4.03, p=0.05], and significantly increased rate of cortical thinning [F(1,52)=5.11, p=0.028)] at a mean difference of 0.844% [95% CI (0.095, 1.593)] in the left lateral orbitofrontal region (LLOFR) over the 3-year period. In FEP individuals, greater reduction in putamen volume over time was associated with low cumulative antipsychotic medication dose (r=0.49, p=0.01), and increasing lateral ventricular volume over time was associated with worsening negative symptoms (r=0.41, p=0.04) and poorer global assessment of functioning (r=-0.41, p=0.04).DiscussionOur results demonstrate existence of localised progressive structural disturbance in the subnetwork of the cortico-striato-thalamo-cortical circuitry after the onset of psychosis. Furthermore, increasing ventricular volume is a neuroanatomical marker of poorer clinical and functional outcome. These findings lend weight to the evidence of early progressive brain changes in psychotic disorders and thus, this knowledge could potentially contribute to the identification of imaging biomarkers for timely intervention.

Progressive brain changes in Parkinson’s disease: A meta-analysis of structural magnetic resonance imaging studies

The progressive changes of brain structure in patients with Parkinson’s disease (PD) remain controversial. To identify this controversy, a systematic review and meta-analysis of longitudinal magnetic resonance imaging studies in brain volume was performed. The percentage of volume change over time between patients with PD and healthy subjects of each brain region of interest was obtained. In total, 11 studies, comprising 833 cases (463 patients with PD and 370 healthy control subjects), were included for systematic review and meta-analysis. Ten brain regions were involved. Patients with PD in comparison with healthy controls showed significant progressive reductions in whole gray matter and caudate, putamen, accumbens, and amygdala volumes. Significant whole-brain atrophy from PD was also associated with cognitive dysfunction. The annual percentage of volume loss was −1.04% in whole-brain volume with cognitive decline, −1.16% in whole-brain volume in PD compared to PD with cognitive decline, −0.29% for whole gray matter, −0.62% for caudate, −0.97% for putamen, −3.55% for amygdala, and −5.40% for accumbens in patients with PD versus control subjects. Overall, our findings suggest that PD is related to progressive, regional brain atrophy, mainly affecting gray matter. However, due to existing confounding factors, the limited number of included studies, significant heterogeneity, and defective study design, the results should be interpreted with caution. Further confirmation is required by more studies with strict design, large samples, and unified paradigm.

Longitudinal Cortical Thickness Changes in Bipolar Disorder and the Relationship to Genetic Risk, Mania, and Lithium Use

BackgroundBipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. MethodsPatients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables. ResultsPatients showed abnormal cortical thinning of temporal cortices and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients who experienced hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II. ConclusionsIn the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors, and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

Are structural brain changes in schizophrenia related to antipsychotic medication? A narrative review of the evidence from a clinical perspective.

Some observational studies and literature reviews suggest that antipsychotic drug use is associated with loss of grey or white matter in patients with schizophrenia, whereas others have contradicted this finding. Here, I summarize and critique the available evidence and put it in the context of clinical practice. This narrative review pools evidence from observational and experimental studies in humans and animals on the relationship between antipsychotic medication use and brain structure and function in patients with schizophrenia. To summarize, the observational evidence in patients with schizophrenia and the experimental evidence in animals suggest that antipsychotic drugs can cause reductions in brain volume, but differ as to where those effects are manifest. The experimental evidence in patients is inconclusive. There is stronger and more consistent evidence that other factors, such as alcohol and cannabis use, are likely causes of progressive brain changes in schizophrenia. Overall, I argue the case against antipsychotics is not proven and the jury is out on any significance of putative antipsychotic-induced brain changes. Taken in the context of strong evidence from clinical trials that antipsychotic drugs have beneficial effects on symptoms, function, relapse and cognition, and observational evidence that treatment normalizes other imaging indices and reduces mortality, the balance of probabilities is that antipsychotic drugs do not cause adverse structural brain changes in schizophrenia.

F161. BRAIN VOLUME CHANGE IN PATIENTS WITH SCHIZOPHRENIA AND ITS RELATION WITH ANTIPSYCHOTIC DRUG USE

BackgroundSchizophrenia is a chronic severe mental illness affecting 0.4% of the society with its early age of onset (generally between 15–25 years) which can be seen in people from all social strata, has recurrent episodes or relapses, and causes disability by deteriorating interpersonal and occupational functioning. Critical behavioral findings accelerated the efforts on understanding the neurobiology of this complex disorder. Although the nature of progressive structural brain change is not understood completely, identifying the role of antipsychotic drugs is important to comprehend how much of the progressive brain volume change is the result of schizophrenia.The purpose of the study is to perform the volumetric brain magnetic resonance imaging (MRI) from patients with schizophrenia, to repeat the MRI after one year regular follow-up, to investigate whether brain volume-brain structures’ volume change by time and reveal its relationship with the type and dosage of antipsychotic drug (APD). This study is considered that would contribute to the discussions about the disease process of schizophrenia and the effect of APD use on structural changes in brain.MethodsFifty-two patients diagnosed with schizophrenia according to DSM IV was participated to the study. Patients are followed for approximately 14 months. In the first interview, patients were applied to a sociodemographic form, The Structured Clinical Interview for DSM-IV (SCID-I), Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI). After the first interviews, the patients who performed brain MR were arranged control meetings by the same doctor regularly (monthly, bimonthly, or when needed) until the second MR. In control meetings, patients were applied to clinical interview form, PANSS, GAF, and CGI. Drugs were recorded regularly by making sure that they took the drugs precisely with the help of their families. Chlorpromazine equivalent doses of APDs were calculated as milligram (mg) and turned into dose-year unit. Second MRIs were performed approximately after 14 months. In SPM program, paired sample t test was used to compare two MRIs and see whether gray matter volume was changed regardless the type of drugs the person used. Also, ANOVA was used to identify the relationship between the type of the drug taken between two MRIs and the volume change in gray matter by choosing the drug type as covariant. SPSS 22 was used to examine the relationship between the sociodemographic features of the patients and their brain volume findings.ResultsFrom the patients participated in our study, 19 of them were female and 33 were male, mean age was 36.5, the level of education was 11 years, the mean onset of the disease was 24 and duration of the illness was 11 years. On the first MRI analyses, gray matter was negatively correlated with the age of the patients (r= -0,473, p<0,001) and the duration of the illness (r=-0,316, p<0,05), and positively correlated with the onset of the disease (r= 0,281, p<0,05) and the level of education (r= 0,321, p<0,05); while white matter positively correlated only with the level of education (r= 0,321, p<0,05). Throughout 14 months, no significant difference was found in brain volume change analysis with 95% confidence. Gray matter was not significantly correlated with APD dose, atypical antipsychotic drug (AAPD) use, and typical antipsychotic drug (TAPD) use.DiscussionIt can be concluded that throughout 14 months period, brain volume of the patients with schizophrenia was not change significantly and the type and dose of APD used during this process did not have any effects on volume change.

White matter alterations in Parkinson's disease with normal cognition precede grey matter atrophy.

IntroductionWhile progressive MRI brain changes characterize advanced Parkinson’s disease (PD), little has been discovered about structural alterations in the earliest phase of the disease, i.e. in patients with motor symptoms and with normal cognition. Our study aimed to detect grey matter (GM) and white matter (WM) changes in PD patients without cognitive impairment.MethodsTwenty PD patients and twenty-one healthy controls (HC) were tested for attention, executive function, working memory, and visuospatial and language domains. High-resolution T1-weighted and 60 directional diffusion-weighted 3T MRI images were acquired. The cortical, deep GM and WM volumes and density, as well as the diffusion properties of WM, were calculated. Analyses were repeated on data flipped to the side of the disease origin.ResultsPD patients did not show any significant differences from HC in cognitive functioning or in brain volumes. Decreased GM intensity was found in the left superior parietal lobe in the right (p<0.02) and left (p<0.01) flipped data. The analysis of original, un-flipped data demonstrated elevated axial diffusivity (p<0.01) in the superior and anterior corona radiata, internal capsule, and external capsule in the left hemisphere of PD relative to HC, while higher mean and radial diffusivity were discovered in the right (p<0.02 and p<0.03, respectively) and left (p<0.02 and p<0.02, respectively) in the fronto-temporal WM utilizing flipped data.ConclusionsPD patients without cognitive impairment and GM atrophy demonstrated widespread alterations of WM microstructure. Thus, WM impairment in PD might be a sensitive sign preceding the neuronal loss in associated GM regions.