Enlargement Of Lateral Ventricles Research Articles

The plasma fraction GRF6019 slows brain atrophy in mild‐to‐moderate Alzheimer’s disease

AbstractBackgroundThe plasma fraction GRF6019 shows multiple benefits on age‐related changes in the mouse brain, including enhanced synaptic density and neurogenesis. In a trial of GRF6019 in mild‐to‐moderate Alzheimer’s disease (AD), cognition stabilized over a 24‐week period (Hannestad et al., 2020). Here we present the volumetric MRI data from that trial.MethodParticipants were 60‐90 years old with probable AD according to NIA‐AA criteria, and Mini Mental State Examination score 12‐24. They received 1 daily infusion of 100 mL or 250 mL of GRF6019 over 5 consecutive days at Week 1 and Week 13. MRIs were done at baseline at the end of the study using a MP‐RAGE or IR‐SPGR sequence. The 3D T1‐weighted scans were acquired sagittally over approximately 192 slices at a thickness of 1.0‐1.2. Images underwent the Freesurfer pipeline and hand editing to correct over‐ and under‐estimations of hippocampal volumes. Hippocampal and lateral ventricular volumes were extracted and normalized by the estimated total intracranial volume. Fold‐changes between baseline and 6 months were estimated and log2‐transformed to obtain a symmetrical distribution. MRI images from ADNI were analyzed in the same manner.ResultHippocampal volumes decreased from baseline by 2% (p<0.001, one‐sample Wilcoxon test) in ADNI AD participants (n=75), while hippocampal volumes did not significantly change in ADNI control participants (n=82; 0.03%, p>0.05) or in GRF6019‐treated AD trial participants (n=34; 0.3%, p>0.05). Lateral ventricle volumes increased from baseline by 5.2% in ADNI AD but showed smaller increases in ADNI controls (2.7%) and in GRF6019‐treated individuals (3.1%). The difference in change from baseline between GRF6019 AD and ADNI AD was significant in the right lateral ventricle (p<0.005, two‐samples Wilcoxon test) but not in the left lateral ventricle. There was no apparent difference in the change from baseline in MRI volumes between the 100 ml and 250 mL dose of GRF6019.ConclusionIn mild‐to‐moderate AD, the plasma fraction GRF6019 slowed hippocampal atrophy and lateral ventricle enlargement compared to matched individuals with AD in ADNI. The MRI data are consistent with the lack of cognitive worsening observed in these trial participants and supports continued clinical development of GRF6019 in AD.

Active hydrocephalus with aqueduct stenosis to an old woman

Introduction: Aqueduct stenosis (AS) in old people is a rare pathological entity. I report a case of a 66 years old woman with severe ataxia, cognitive deterioration, loss of sphincters control (gatism). Clinical, neuro-radiologic and therapeutic considerations are discussed.
 Case presentation: A 66 years old woman with a 6 months history of mild cerebral trauma by car accident without losing consciousness, present 2 months before hospitalization severe ataxia, cognitive disorders, gatism. At the time of trauma, brain scanner performed in another institution showed minimal fronto-basal cerebral contusions and blood collection around the brain stem. One month after a new unenhanced brain scan all previous lesions are gone. At admission, an abnormal enlargement of lateral and third ventricles are remarked both on unenhanced CT and MRI scan of the brain explained by cerebral aqueductal stenosis. Ventricular open pressure was 350 mm H2O. A ventriculoperitoneal shunt with a variable pressure valve was installed. The surgery went uneventful and the patient recovered as expected. 6-month follow-up visit the patient was symptom-free, with a fine intellectual recovery.

VP Shunt With Recurrent Malfunction in Two Pediatric Patients: Is the Hydrocephalus Truly Idiopathic?

VP Shunt With Recurrent Malfunction in Two Pediatric Patients: Is the Hydrocephalus Truly Idiopathic?

A multimodal approach to the study of children treated for posterior fossa tumor: A review of the literature and a pilot study

ObjectiveThe aims of the present study were: (1) to review the literature on long-lasting cognitive sequelae in children treated for Posterior Fossa Tumor and (2) to investigate anatomic functional relations in a case series of 7 children treated for PFT using magnetic resonance imaging (MRI) post-processing methods. MethodsWe retrospectively analyzed MRIs of children who underwent complete surgical resection of PFT and performed extensive neuropsychological evaluation. Tumor, ventricular volumes, and VPS insertion site were drawn on T1 volumetric MRI scans and normalized to a pediatric template. Children showed worse performances on tasks tapping executive functions, memory, visuo-motor precision, and expressive language. ResultsVolumes of interest related to these functions showed a maximum overlap on the left vermis and the lateral ventricle enlargement, except for impaired narrative fluency –which was associated with left lateral ventricle enlargement– and narrative memory –which was related to the right vermis and the enlarged fourth ventricle. ConclusionResults suggest that anatomic functional relations in children treated for PFT are related to a combination of different pathophysiological factors.

Magnetic resonance imaging in schizophrenia: Luxury or necessity? (Review).

Schizophrenia, one of the most common psychiatric disorders, with a worldwide annual incidence rate of approximately 0.3-0.7%, known to affect the population below 25 years of age, is persistent throughout lifetime and includes people from all layers of society. With recent technological progress that allows better imaging techniques, such as the ones provided by computed tomography and particularly magnetic resonance imaging (MRI), research on schizophrenia imaging has grown considerably. The purpose of this review is to establish the importance of using imaging techniques in the early detection of brain abnormalities in patients diagnosed with schizophrenia. We reviewed all articles which reported on MRI imaging in schizophrenia. In order to do this, we used the PubMed database, using as search words ‘MRI’ and ‘schizophrenia’. MRI studies of first episode patients and chronic patients, suggest reduction of the whole brain volume. Enlargement of lateral ventricles was described as positive in 15 studies out of 19 and was similar to findings in chronic patients. Moreover, for the first episode patients, all data collected point to important changes in medial temporal lobe structures, diminished hippocampal volume, the whole frontal lobe, asymmetry in prefrontal cortex, diminished volume in cingulate, corpus callosum, and cavum septum pellucidum reported abnormalities. MRI is recommended as an important tool in the follow-up process of patients with schizophrenia. Yet, it is still under debate whether the abnormalities described in this condition are able to be used as diagnostic biomarkers.

SEGMENTATION OF BRAIN STRUCTURES IN ALZHEIMER MR IMAGES USING SPATIAL FUZZY CLUSTERING LEVEL SET

Alzheimer’s Disease (AD) is an irreversible neurodegenerative disorder that affects brain structures. Corpus Callosum (CC) atrophy and Lateral ventricle (LV) enlargement are useful structural biomarkers in distinguishing the preclinical stages of AD. The shape of CC appears to be homogeneous from normal controls to AD images and LV shows shape dissimilarity across subjects. Therefore, effective methods to segment CC and LV are essential to characterize the magnitude of morphometric changes. In this study, an attempt has been made to segment CC and LV from MR brain images using the Spatial Fuzzy Clustering based Level Set (SFC-LS) method. For this, T1-weighted MR images of AD, Mild Cognitive Impairment (MCI), and normal controls are obtained from a public database. Spatial fuzzy clustering forms the initial contour for the level set and regularizes the evolution of curve. The segmented images are validated against ground truth using standard measures. Results indicate that SFC-LS is able to segment CC and LV with automated contour initialization. The final contours obtained are sharp and distinct with a high validation performance of accuracy and specificity greater than 97% for normal controls, MCI, and AD. A dice score of 83% and 84% is achieved in segmenting CC and LV respectively. As structural changes in CC and LV have the potential to predict the early stages of AD, the proposed approach seems to be clinically significant.

Effects of Spaceflight Stressors on Brain Volume, Microstructure, and Intracranial Fluid Distribution.

Astronauts are exposed to elevated CO2 levels onboard the International Space Station. Here, we investigated structural brain changes in 11 participants following 30-days of head-down tilt bed rest (HDBR) combined with 0.5% ambient CO2 (HDBR + CO2) as a spaceflight analog. We contrasted brain changes observed in the HDBR + CO2 group with those of a previous HDBR sample not exposed to elevated CO2. Both groups exhibited a global upward shift of the brain and concomitant intracranial free water (FW) redistribution. Greater gray matter changes were seen in the HDBR + CO2 group in some regions. The HDBR + CO2 group showed significantly greater FW decrements in the posterior cerebellum and the cerebrum than the HDBR group. In comparison to the HDBR group, the HDBR + CO2 group exhibited greater diffusivity increases. In half of the participants, the HDBR + CO2 intervention resulted in signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), a constellation of ocular structural and functional changes seen in astronauts. We therefore conducted an exploratory comparison compared between subjects that did and did not develop SANS and found asymmetric lateral ventricle enlargement in the SANS group. These results enhance our understanding of the underlying mechanisms of spaceflight-induced brain changes, which is critical for promoting astronaut health and performance.

Acute presentation of third ventricular cavernous malformation following COVID-19 infection in a pregnant woman: A case report

BackgroundCerebral cavernous malformation (CCM) in third ventricular area may become symptomatic relatively rarely, secondary to hemorrhage and growth or rupture into the ventricle, causing obstructive hydrocephalus, during third trimester of pregnancy. Case descriptionA 34+4 weeks pregnant (G4P1A2) lady was admitted to one of our satellite hospitals with one-week history of severe headache, blurred vision, nausea, vomiting, and right-sided facial numbness. At presentation, she had sudden decreased level of consciousness with Glasgow Coma Scale (GCS) equal to 4, and bilateral fixed pupils. A brain computed tomography (CT) showed enlargement of both lateral ventricles with 2.5cm sized round hemorrhagic lesion at the right posterior thalamic region. After medical stabilization and placement of an external ventricular drain (EVD), the patient was referred for neurosurgical intervention. Magnetic resonance imaging (MRI) revealed a cavernous hemangioma adjacent to the right posterior wall of the third ventricle. After cesarean section and anterior interhemispheric trans-callosal approach, the mass was removed totally. However, on third postoperative day, she experienced mild hypoxia and dyspnea with fever. Chest CT-scan of the patient showed bilateral consolidation. Thereafter, COVID-19 was confirmed subsequently with positive nasopharyngeal swab testing for RT-PCR. The patient was treated as COVID-19 infection and symptoms improved on day 10 of the treatment and completely recovered. ConclusionsCOVID-19 may promote ICH from CCM leading to obstructive hydrocephalous in our patient.

Abstract 64: Scar-Forming Glial Cells Engulf Synapse and Worsen Stroke Outcome Through Megf10 and Mertk

Objective: Previous studies showed that microglia and astrocytes actively engulf synapse through MEGF10 and MERTK in the developing brain. But whether microglia and astrocytes in ischemic stroke (IS) or hemorrhagic stroke (HS) mice are still phagocytotic and how they affect the outcome of stroke remain unclear. Methods: Microglia or astrocyte-specific MEGF10 or MERTK knockout mice were generated, and subjected to transient middle cerebral artery occlusion (tMCAO), or collagenase-induced intracerebral hemorrhage. Immunostaining, Transmission electron microscope and Western blot were used to evaluate synapse engulfment, and dendritic spines were quantified using Golgi staining. Cresyl violet staining was used to evaluate atrophy volume and lateral ventricle enlargement of stroke mice. Neurobehavioral test including mNSS , rotarod, grid-walking and smart cage were performed to assess neurofunctional recovery. Single-cell RNA sequencing was further conducted to compare gene expression between IS and HS mice. Results: We showed that 14 days after IS, 25% of microglia and 50% of astrocytes were phagocytotic and engulfed synapses in the glial scar. However, in HS, 25% of microglia and 5% of astrocytes were phagocytotic, and only microglia were found to engulf synapses. We further demonstrated that MEGF10 and MERTK were upregulated in both astrocytes and microglia of mice subjected to IS and HS, and knockout of MEGF10 or MERTK in astrocytes or microglia inhibited synapse engulfment, which further increased synaptic density, reduced brain atrophy volume and improved neurobehavioral recovery after IS. However, knockout of MEGF10 or MERTK in microglia but not astrocytes in HS mice resulted in increased synaptic density and neurobehavioral recovery improvement. Single-cell RNA sequencing revealed that phagocytosis-related processes were downregulated in a subtype of astrocytes in HS brain than that in IS brain. Conclusion: Our study revealed a previously unknown role for astrocytes and microglia in engulfing synapse in the glial scar in stroke brain, and showed phagocytic astrocytes and microglia contribute differently to brain function recovery of mice that subjected to IS and HS, opening a new avenue to develop effective strategy for stroke treatment.

Iatrogenic Hypothalamus Injury After Resection of Subependymoma Within the Left Brain Ventricle

Damage to the hypothalamus may result from direct surgical injury or from hemorrhage and ischemia caused by the procedure. Patients with hypothalamus damage can be comatose and exhibit hyperthermia. Here, we present a patient whose hypothalamus was directly damaged by a drainage catheter. His clinical manifestations included diabetes insipidus, hyperthermia and adrenocorticotropic hormone (ACTH) deficiency. The patient was a 48-year-old male and had a body weight of 95 kg. He was admitted to the hospital on August 31, 2019 for memory impairment and nonspecific dizziness that persisted for four months. A magnetic resonance image of the head showed an intraventricular mass attached to the anterior third of the septum pellucidum and Monro's foramen and enlargement of the left lateral ventricle. This intraventricular cystic tumor was 1.9 cm in diameter, without gadolinium enhancement. The tumor resection was performed without complications and with less bleeding than expected. The patient developed central diabetes insipidus within just two hours after the operation and presented with hyperthermia within six hours after the operation. ACTH deficiency was evident on day 1 after surgery. After we removed the catheter 19 hours after the operation, the patient never developed polyuria or high fever again. Two months later, his ACTH level was normal and never needed to take prednisone again. This unusual complication should be taken into account in patients who need external ventricular drains. Much attention should be paid to ensure that the length of the drainage catheter beneath the brain surface does not exceed 5 cm.

Male with Altered Mental Status.

Case PresentationA 62-year-old male presented to the emergency department with altered mental status and fever. Computed tomography of the head showed enlargement of the left lateral ventricle. Magnetic resonance imaging demonstrated debris and purulence in the ventricle along with edema and transependymal flow of cerebrospinal fluid surrounding both ventricles.DiscussionThe patient was diagnosed with ventriculitis. Ventriculitis is an uncommon but serious disease. Early recognition and treatment are essential.

Liraglutide, 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model

Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5–8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.

Dyke-Davidoff-Masson syndrome.

We are presenting a case of 15-year old male patient presented with weakness of right upper and lower limbs, difficulty lifting objects with the right hand. He was born full term to non- consanguineous parents with no significant antenatal or perinatal history. On examination there was hemi-atrophy of the right side of the body with simultaneous involuntary movements of contralateral hand accompanying voluntary movement of the ipsilateral side. Neurological examination reveals right side spastic hemiparesis with upper limb more affected than lower limb. Tendon reflexes were brisk on affected side with extensor plantar response. Mini mental status examination score was 26/30 suggestive of mild cognitive impairment. Other systemic examinations were within normal limits. Plain and contrast MRI of brain findings reveal left cerebral hemi-atrophy with thinning of the ipsilateral grey matter cortex, reduced volume of the underlying white matter, enlargement of the left lateral ventricle and reduced size of ipsilateral left cerebral peduncle is noted. Along with slight compensatory thickening of the ipsilateral skull vault is seen. Findings confirm diagnosis of Dyke-Davidoff-Masson Syndrome. He was under medical management along with physiotherapy rehabilitation focussing majorly on hand rehabilitation.

Relationship between cerebral microbleeds, ventricular enlargement and white matter hyperintensities in Alzheimer’s disease

AbstractBackgroundTo investigate whether the number of cerebral microbleeds (CMB) could be a useful indicator to predict glymphatic system dysfunction in Alzheimer’s disease (AD) patients, by comparing the degree of cerebral spinal fluid (CSF) and interstitial fluid (ISF) stasis.MethodForty probable AD patients were included, with those exhibiting two or more CMB were included in the multiple CMB group (mCMB, n = 21, mean = 11.1), and none or one CMB included in the non‐multiple CMB group (nmCMB, n = 19, mean = 0.84). CMB were defined in axial gradient recalled echo (GRE) T2*‐weighted images. Evans index (EI) was calculated to measure lateral ventricle enlargement, Voxel‐based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) software was used to determine the extent of gray and white matter atrophy, and Fazekas scale (FS) was used to determine white matter hyperintensities (WMH).ResultEI was significantly larger in mCMB than in nmCMB, while the gray and white matter volume was not different between groups. Thus, the difference in lateral ventricle enlargement between AD with and without multiple CMB reflects a combination of the degree of brain atrophy and the extent of CSF stasis. FS was higher in mCMB than in the nmCMB, suggesting the failure of ISF elimination was more severe in mCMB cases.ConclusionThe difference in lateral ventricle enlargement and WMH between AD with or without multiple CMB may reflect a difference in the degree of CSF/ISF stagnation.

Vitamin D deficiency is associated with decreased cognition independent from the disease status and AD morphology

AbstractBackground25(OH)D deficiency was associated with cognitive impairment and altered brain volumes, namely reduction in white matter and medial temporal lobe and enlargement of lateral ventricles. 25(OH)D deficiency was also associated with the development of Alzheimer's disease (AD). In this study, we aimed to investigate whether 25(OH)D levels are independently associated with cognitive performance and AD‐associated morphology in a mixed sample.MethodThe study was conducted at Hacettepe University Faculty of Medicine, Ankara, Turkey. The participants were chosen from our dementia research database.Demographic variables, 25(OH)D levels, standardized Modified Mini Mental Test (3MS) z‐scores, 1.5 T brain MRI, the data for comorbid medical conditions and current prescription drugs were used as pertinent variables. FreeSurfer v.6.0 was used for automated structural neuroimaging analysis. Based on the previous literature, AD cortical signature, predictive cortical thickness, medial temporal lobe gray matter and mean hippocampal volumes were calculated and used independently to assess AD‐related morphological changes. Cut‐off for 25(OH)D deficiency was accepted as 20 ng/ml. Statistical analyses were conducted using IBM SPSS Statistics 23 for Windows. To assess the predictive power of 25(OH)D, regression models were used with standardized 3MS scores and AD‐related areas as dependent variables. Statistical assumptions were met for all models presented. Funded by TUBITAK 214S048 and Hacettepe University THD 2018‐17363.ResultA total of 210 patients over 55 years of age (47 AD, 15 nonAD dementia, 74 Mild and Subjective Cognitive Impairment, 74 cognitively intact) were included. Mean 25(OH) level was 22.48 ±15.8 ng/ml. 108 participants (51.4%) had 25(OH)D deficiency (AD 57%, nonAD Dementia 60%, SCI/MCI 51%, Control 46%, p>0.5). 25(OH)D deficiency was significantly associated with 3MS scores (χ2 =5.608,df=1,p=0.018). The association was also marginally significant when adjusted for age, diagnosis and medial temporal lobe gray matter volume (Exp(β): 2.472, p=0.05). 25(OH)D levels were not associated with AD‐related morphological changes on multivariate analyses.ConclusionPlasma 25(OH)D levels are associated with cognitive performance regardless of the diagnosis. The effect seems to be independent of AD‐related brain morphological changes. Our results suggest an independent effect of 25(OH)D levels on cognition.

Paroxysmal Lower Limb Tremor as a Rare Presentation of Colloid Cyst of the Third Ventricle: A Case Report and Literature Review

Objective: Colloid cysts of the third ventricle are benign intracranial tumors. They are most commonly presented with signs of intracranial hypertension due to obstructive hydrocephalus, including headache, nausea/vomiting and vision disturbances, whereas extrapyramidal symptoms such as tremor are very rare. Sudden death, due to abruptly developed hydrocephalus, can be also observed. Although paroxysmal symptomatology attributed to the intermittent obstruction of the foramen of Monro is considered the “classical” clinical presentation, it is rather the exception in clinical practice. Case Report: A 42-year-old woman with no medical history was admitted to the neurology department as suffering from a potential demyelinating disease due to episodes of paroxysmal tremor of her right lower limb and persistent mild gait instability, which presented 15 days prior to her arrival. She also complained of episodes of partially position-dependent bilateral headache over the last 10 years, as well as episodes of vertigo over the last 4 years. On arrival, her gait was shuffling and mildly wide-based and an intermittent tremor of her right lower limb was observed in supine and sitting positions, but not in a prone position. Brain magnetic resonance imaging (MRI) demonstrated a round cystic lesion of the third ventricle, accompanied by hydrocephalus with enlargement of lateral ventricles. MRI findings were highly indicative of a colloid cyst. The patient underwent resection of the mass and the tremor resolved after surgery. Conclusion: Given the greatly heterogeneous clinical presentation of colloid cysts, our case highlights the significance of the prompt diagnosis of this rare but potentially fatal cause of paroxysmal limb tremor.

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

S170. PROGRESSIVE SUBCORTICAL VOLUME LOSS IN TREATMENT-RESISTANT SCHIZOPHRENIA PATIENTS AFTER COMMENCING CLOZAPINE TREATMENT

BackgroundThe association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. Early studies investigating a switch from first generation antipsychotic to clozapine have steadily shown a decrease of caudate volume over time; however nowadays most patients are already on second generation antipsychotic medications prior to clozapine commencement and it remains unclear whether switching to clozapine in such circumstances would have any such effect on the basal ganglia. In this study we aimed to comprehensively investigate whether after 6 months of switching to clozapine, subcortical structures demonstrate any progressively neuroanatomical changes in patients with treatment-resistant schizophrenia compared to healthy controls, and whether any such changes are related to clinical variables including treatment response and amount of clozapine taken.MethodsMRI images were acquired for all participants at baseline and after 6 months at University Hospital Galway in a 1.5 T scanner. The longitudinal pipeline of Freesurfer v.5.3.0, based on an unbiased within-subject anatomical template, was employed to segment eight subcortical regions-of-interest: lateral ventricle, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala and nucleus accumbens. Subcortical volumes were bilaterally extracted following quality check of raw data and segmentation. Clinical assessments included the Positive and Negative Syndrome Scale (PANSS), The Scale for the Assessment of Positive Symptoms (SAPS), The Scale for the Assessment of Negative Symptoms (SANS) and Global Assessment Functioning Score (GAF). Two-way repeated ANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Change in volume was expressed using the following formula: (Follow Up -Baseline)/Baseline x 100.Results33 patients with treatment-resistant schizophrenia (TRS) and 31 healthy volunteers (HC) matched for sex and age were successfully recruited at both baseline prior to clozapine treatment and after 6 months. There was a significant effect of time on subcortical brain volumes between TRS and controls (F(7,143)= 52.54, p<0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59)= 48.89; p<0.001) and reduction of thalamus (F(1,59)= 34.85; p<0.001), caudate (F(1,59)= 59.35; p<0.001), putamen (F(1,59)= 87.20; p<0.001) and hippocampus (F(1,59)= 14.49; p<0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r=0.42; p=0.021, r=0.39; p=0.033), SANS (r=0.36; p=0.049, r=0.40; p=0.027) and GAF (r=-0.39; p=0.038, r=-0.42; p=0.024). Reduced thalamic volume over time was associated with increased serum level at follow-up (r=-0.44; p=0.010). There was no significant overall effect of time on subcortical brain structures between patients responding to clozapine compared to patients non-responding to clozapine (F(7,20)=0.50; p=0.834).DiscussionThis study demonstrates that, despite the clinical and functional improvement of most patients with schizophrenia who are switched to clozapine, there is a counterintuitive progressive volume reduction in several subcortical structures over time. Furthermore, patients who have the greatest symptomatic improvement display the largest thalamo-putaminal reductions, indicating that volume reduction reflects an adaptive response associated with symptom improvement rather than a harmful or neurotoxic process in these patients.

Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.

Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment.

The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. This study investigated subcortical morphometric changes 6 months after switching treatment to clozapine in patients with treatment-resistant schizophrenia compared with healthy volunteers, and the relationships between longitudinal volume changes and clinical variables. In total, 1.5T MRI images were acquired at baseline before commencing clozapine and again after 6 months of treatment for 33 patients with treatment-resistant schizophrenia and 31 controls, and processed using the longitudinal pipeline of Freesurfer v.5.3.0. Two-way repeated MANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Whereas no significant subcortical volume differences were found between patients and controls at baseline (F(8,52) = 1.79; p = 0.101), there was a significant interaction between time, group and structure (F(7,143) = 52.54; p < 0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59) = 48.89; p < 0.001) and reduction of thalamus (F(1,59) = 34.85; p < 0.001), caudate (F(1,59) = 59.35; p < 0.001), putamen (F(1,59) = 87.20; p < 0.001) and hippocampus (F(1,59) = 14.49; p < 0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r = 0.42; p = 0.021, r = 0.39; p = 0.033), SANS (r = 0.36; p = 0.049, r = 0.40; p = 0.027) and GAF (r = -0.39; p = 0.038, r = -0.42; p = 0.024) scores. Reduced thalamic volume over time was associated with increased serum clozapine level at follow-up (r = -0.44; p = 0.010). Patients with treatment-resistant schizophrenia display progressive subcortical volume deficits after switching to clozapine despite experiencing symptomatic improvement. Thalamo-striatal progressive volumetric deficit associated with symptomatic improvement after clozapine exposure may reflect an adaptive response related to improved outcome rather than a harmful process.