Hippocampal Volume Reduction Research Articles

Dynamic study of the hippocampal volume by structural MRI in a rat model of depression.

The reduction of hippocampal volume remains controversial in depression because of the variability among individuals in clinical studies. Here, a reliable experimental rat model of depression, established by chronic unpredictable mild stress (CUMS), was used. Thirty rats were randomly divided into two groups (CUMS group and control group). Hippocampal volume was dynamically measured every 2 weeks in a 56-day chronic stress procedure using structural magnetic resonance imaging, and the correlation between the hippocampal volume and the learning and memory changes was investigated. Our results demonstrated that CUMS rats showed significantly smaller volumes of the bilateral hippocampus compared to that of the controls, changing dramatically with the development of CUMS procedure. The left hippocampal volume was reduced earlier and more markedly than the right one from the 2nd week to the 8th week of the CUMS procedure (on the 8th week: left: approximately 15.3 %; right: approximately 8.4 % reduction). Additionally, the hippocampal volume of CUMS rats was significantly negatively correlated with the learning and memory changes. Of note, it showed that the more obviously the hippocampal volume reduced, the more severely the learning and memory damaged. In conclusion, the hippocampal volume decreased gradually and dynamically and was correlated with the impairment of the learning and memory in depression.

Dysmorphogenic effects of first trimester-equivalent ethanol exposure in mice: a magnetic resonance microscopy-based study.

The first trimester of human development and the equivalent developmental period in animal models is a time when teratogenic ethanol (EtOH) exposure induces the major structural birth defects that fall within fetal alcohol spectrum disorder (FASD). Previous FASD research employing an acute high dose maternal intraperitoneal EtOH treatment paradigm has identified sensitive periods for a number of these defects. Extending this work, this investigation utilized high resolution magnetic resonance microscopy (MRM)-based analyses to examine the dysmorphology resulting from maternal dietary EtOH intake occurring during selected first trimester-equivalent time periods. Female C57Bl/6J mice were acclimated to a liquid 4.8% EtOH (v/v)-containing diet, then bred while on standard chow. Dams were again provided the EtOH-containing liquid diet for a period that extended either from the beginning of gestational day (GD) 7 to the end of GD 11 or from the beginning of GD 12 to the end of GD 16. On GD 17, a subset of fetuses was selected for MRM-based analyses. Group comparisons were made for litter characteristics and gross dysmorphology, as well as whole and regional brain volumes. EtOH-induced stage of exposure-dependent structural brain abnormalities were observed. The GD 7 to 11 EtOH-exposed group presented with a significant decrease in cerebellar volume and an increase in septal volume, while GD 12 to 16 EtOH treatment resulted in a reduction in right hippocampal volume accompanied by enlarged pituitaries. Additionally, the GD 12 to 16 EtOH exposure caused a high incidence of edema/fetal hydrops. These results illustrate the teratogenic impact of maternal dietary EtOH intake occurring at time periods approximately equivalent to weeks 3 through 6 (GD 7 to 11 in mice) and weeks 7 through 12 (GD 12 to 16 in mice) of human gestation, further documenting EtOH's stage of exposure-dependent neuroteratogenic end points and highlighting the vulnerability of selected brain regions during the first trimester. Additionally they suggest that clinical attention should be paid to fetal hydrops as a likely component of FASD.

Neuron Volumes in Hippocampal Subfields in Delayed Poststroke and Aging-Related Dementias

Hippocampal atrophy is widely recognized in Alzheimer disease (AD). Whether neurons within hippocampal subfields are similarly affected in other aging-related dementias, particularly after stroke, remains an open question. We investigated hippocampal CA3 and CA4 pyramidal neuron volumes and densities using 3-dimensional stereologic techniques in postmortem samples from a total of 67 subjects: poststoke demented (PSD; n = 11), nondemented stroke survivors (PSND) and PSD patients from the CogFAST (Cognitive Function After Stroke) cohort (n = 13), elderly controls (n = 12), and subjects diagnosed as having vascular dementia (n = 11), AD (n = 10), and mixed AD and vascular dementia (n = 10). We found that CA3 and CA4 neuron volumes were reduced in PSD samples compared with those in PSND samples. The CA3 and CA4 neuron volumes were positively correlated with poststroke global cognitive function but were not associated with the burden of AD pathology. There were no differences in total neuron densities in either subfield in any of the groups studied. Our results indicate that selective reductions in CA4 and to a lesser extent CA3 neuron volumes may be related to post stroke cognitive impairment and aging-related dementias. These data suggest that CA4 neurons are vulnerable to disease processes and support our previous finding that a reduction in hippocampal neuron volume predominantly reflects vascular mechanisms as contributing to dementia after stroke.

A Longitudinal Study of Alterations of Hippocampal Volumes and Serum BDNF Levels in Association to Atypical Antipsychotics in a Sample of First-Episode Patients with Schizophrenia

BackgroundSchizophrenia is associated with structural and functional abnormalities of the hippocampus, which have been suggested to play an important role in the formation and emergence of schizophrenia syndrome. Patients with schizophrenia exhibit significant bilateral hippocampal volume reduction and progressive hippocampal volume decrease in first-episode patients with schizophrenia has been shown in many neuroimaging studies. Dysfunction of the neurotrophic system has been implicated in the pathophysiology of schizophrenia. The initiation of antipsychotic medication alters the levels of serum Brain Derived Neurotrophic Factor (BDNF) levels. However it is unclear whether treatment with antipsychotics is associated with alterations of hippocampal volume and BDNF levels.MethodsIn the present longitudinal study we investigated the association between serum BDNF levels and hippocampal volumes in a sample of fourteen first-episode drug-naïve patients with schizophrenia (FEP). MRI scans, BDNF and clinical measurements were performed twice: at baseline before the initiation of antipsychotic treatment and 8 months later, while the patients were receiving monotherapy with second generation antipsychotics (SGAs).ResultsWe found that left hippocampal volume was decreased (corrected left HV [t = 2.977, df = 13, p = .011] at follow-up; We also found that the higher the BDNF levels change the higher were the differences of corrected left hippocampus after 8 months of treatment with atypical antipsychotics (Pearson r = 0.597, p = 0.024).ConclusionsThe association of BDNF with hippocampal volume alterations in schizophrenia merits further investigation and replication in larger longitudinal studies.

Volumetric changes in hippocampal subregions and their relation to memory in pediatric nonlesional localization‐related epilepsy

Developmental differences in structure and function have been reported along the hippocampal subregions. The aims of this study were to determine if there were volumetric differences in hippocampal head (HH), body (HB), tail (HT), and total hippocampus (TotH)) in children with nonlesional localization-related epilepsy relative to controls, and the relation between hippocampal subregions with episodic memory and clinical parameters. Forty-eight children with nonlesional localization-related epilepsy, consisting of 29 left-sided and 19 right-sided epilepsy, and 27 healthy controls were recruited. All patients and controls underwent volumetric T1-weighted imaging, and verbal and nonverbal memory testing. The volume of hippocampal subregions was compared between patients and controls. The associations between left hippocampal subregions with verbal memory; right hippocampal subregions with nonverbal memory; and hippocampal subregions with age, age at seizure onset, and seizure frequency were assessed. Patients with left-sided epilepsy had smaller left HH (p=0.003) and HB (p=0.012), right HB (p=0.021) and HT (p=0.015), and right TotH (p=0.020) volumes. Those with right-sided epilepsy had smaller right HT (p=0.018) volume. There were no statistically significant differences between verbal and nonverbal memory in left-sided and right-sided epilepsy relative to controls (all p>0.025). In left-sided epilepsy, there was a significant association between left HH volume with verbal memory (β=0.492, p=0.001). There was no significant association between left and right hippocampal subregions with verbal and nonverbal memory, respectively, in right-sided epilepsy and controls (all p>0.002). In left-sided and right-sided epilepsy, there was no significant association between hippocampal subregions with age, age at seizure onset, and seizure frequency (all p>0.002). We have found hippocampal volume reduction, but did not identify a gradient in the severity of volume reduction along the hippocampal axis in children with localization-related epilepsy. Further study is needed to clarify if there are volumetric changes within the cornu ammonis subfields and dentate gyrus. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Hippocampus, caudate nucleus and entorhinal cortex volumetric MRI measurements in discrimination between Alzheimer’s disease, mild cognitive impairment, and normal aging

BackgroundStructural neuroimaging MR volumetric changes can predict progression of MCI to AD. Early effective treatment of MCI has been shown to delay institutionalization and improve cognition and behavioral symptoms. Aim of the workTo evaluate the role of volumetric MRI to identify a pattern of regional atrophy characteristic in differentiation between Alzheimer’s disease, Mild Cognitive Impairment, and Normal elderly control. Material and methodsThe regional ethics committee approved the study and written informed consent was obtained from all participants. Between April 2012 and May 2013, prospective study was conducted on 25 patients (18 males and 7 females) and 15 healthy elderly controls (9 males and 6 females) referred to the Radiodiagnosis Department from the Neuropsychiatry Department that had clinical manifestations of suspected cognitive impairment, we used the Mini Mental State Examination (MMSE) as a measure of general cognitive function and the total learning from the Auditory Verbal Total Learning Test (AVTOT) as a measure of memory performance. One year follow up of patients was done to assess the disease progress. ResultsTwenty-five patients were included in this study {Alzheimer disease (10 cases), MCI (15 cases)} and 15 healthy elderly controls. Mean MMSE scores were significantly lower in patients with Alzheimer’s disease compared with MCI and control cases (P<0.001). Positive correlation (except left caudate nucleus) between gray matter volume reduction in MCI and AD in relation to elderly control and MMSE score was observed. The Auditory Verbal Learning Test (AVTOT) was significantly lower in patients with Alzheimer’s disease compared with MCI and control cases (P<0.001). No significant differences were found between groups as regards age, sex, education or dominant hand. Significant gray matter volume reductions were found in both AD and MCI compared to healthy elderly control however no significant differences were found among MCI patients or AD patients. Sensitivity, specificity, PPV and NPV of caudate nucleus and hippocampal volume reduction in AD and MCI in relation to elderly control were higher than entorhinal cortex. ConclusionSemi-automated MR volumetric measurements can be used to determine atrophy in hippocampus, caudate nucleus and entorhinal cortex which aided in discrimination of healthy elderly control subjects from subjects with AD and MCI and predict clinical decline of MCI leading to increase the efficiency of clinical treatments, delay institutionalization and improve cognition and behavioral symptoms.

Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer's disease: a preliminary study.

ObjectiveCross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer’s disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ.MethodsThirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments.ResultsIn individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = −0.35, p = .401).ConclusionsAlthough preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD.

In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy

PurposeImbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE.MethodsDynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data.Key FindingsThe PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding.SignificanceAlterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.

Cognitive and clinical correlates of hippocampus volume, an MRI 2-year follow-up study

Background Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode psychosis. Many studies examining brain structure changes in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether reduction in hippocampal volume is a morphological trait in such a group of patients in an attempt to find its clinical and cognitive correlates for patients with different diagnoses of first-episode psychosis both at their first contact and at short-term follow-up. Patients and methods We obtained high-resolution three-dimensional T-weighed MRI scans of the hippocampus for 90 patients with first-episode psychosis (49 patients with schizophrenia, 21 patients with bipolar psychoses, and 20 patients with depressive psychosis) as well as 23 healthy controls both at the baseline and after 2 years of assessment. Assessment of the clinical picture was carried out using the structured SCID interviews, HDRS, YMRS, and PANSS. Cognitive function and intellectual abilities were examined using WMS-III, the Trail Making Test, and WAIS. Results A greater reduction in hippocampal volume was evident in the schizophrenia group than the bipolar and depressive psychosis groups compared with the healthy controls both at baseline and after 2 years, indicative of being a morphological trait for such patients. Negative symptoms were related to hippocampal volume reduction in the schizophrenia group. The initial assessment of untreated patients revealed reduction in their hippocampus volume which correlated with the longer duration of untreatment. After 2 years of follow-up, recurrent hospitalization was found to be related to further volume reduction. Impaired working memory, verbal memory, and baseline intellectual abilities were related positively to structural hippocampal changes. Cognitive and clinical correlation with a reduction in hippocampal size was less evident in the bipolar psychosis group, which may highlight different structural changes in other areas in the striatum. Conclusion and recommendation Hippocampal volume reduction may be considered as morphological traits for some patients with first-episode psychosis, and linked to some clinical and cognitive impairment. Study of the shape, localized regions of the hippocampus as well as other brain areas may help to clarify the circuits shared in the pathophysiology of psychoses of different types. Early detection of structural changes with the study of high-risk patients may aid effective treatment and improve outcomes.

EPA-1037 – Cytokine abnormalities, inflammation and psychosis in the northern finland 1966 birth cohort

Cytokines are regulators of inflammation that exert effects in the periphery and the brain. Interleukin-6 (IL-6) is a cytokine produced by leukocytes, and CNS microglia and astrocytes. Converging evidence suggests that IL-6 may play a role in the pathophysiology of schizophrenia. Previous studies have found that IL-6 levels have been associated with smaller left hippocampal volume and greater cognitive impairment in patients with schizophrenia. We will perform a case-control study of blood IL-6 levels, and longitudinal changes in cognition and hippocampal volume in subjects from the Northern Finland 1966 Birth Cohort. In n=33 patients with schizophrenia and =71 controls, blood IL-6 levels were measured at age 31, and MRI scans and cognitive assessments were completed at ages 34 and 43. We will test hypotheses that 1) at age 31, patients with schizophrenia have higher blood IL-6 levels than controls, controlling for multiple potential confounding factors, and 2) within schizophrenia, a) higher IL-6 levels at age 31 are associated with greater impairments in verbal learning and memory and smaller hippocampal gray matter volume at age 34, and b) higher IL-6 levels predict greater cognitive decline and reduction in hippocampal volumes over follow-up from age 34 to 43. Schizophrenia is also associated with impaired cognition, which persists despite current treatments, and is an important determinant of quality of life and overall function. This study will improve our understanding of the complex interactions between the immune system and the brain, including a core dimension of psychopathology for which available pharmacologic treatments are inadequate.

Integration of multimodal MRI data via PCA to explain language performance.

Objective/methodsNeuroimaging research has predominantly focused on exploring how cortical or subcortical brain abnormalities are related to language dysfunction in patients with neurological disease through the use of single modality imaging. Still, limited knowledge exists on how various MRI measures relate to each other and to patients' language performance. In this study, we explored the relationship between measures of regional cortical thickness, gray–white matter contrast (GWMC), white matter diffusivity [mean diffusivity (MD) and fractional anisotropy (FA)] and the relative contributions of these MRI measures to predicting language function across patients with temporal lobe epilepsy (TLE) and healthy controls. T1- and diffusion-weighted MRI data were collected from 56 healthy controls and 52 patients with TLE. By focusing on frontotemporal regions implicated in language function, we reduced each domain of MRI data to its principal component (PC) and quantified the correlations among these PCs and the ability of these PCs to explain the variation in vocabulary, naming and fluency. We followed up our significant findings by assessing the predictive power of the implicated PCs with respect to language impairment in our sample.ResultsWe found significant positive associations between PCs representing cortical thickness, GWMC and FA that appeared to be partially mediated by changes in total brain volume. We also found a significant association between reduced FA and increased MD after controlling for confounding factors (e.g., age, field strength, total brain volume). Reduced FA was significantly associated with reductions in visual naming while increased MD was associated with reductions in auditory naming scores, even after controlling for the variability explained by reductions in hippocampal volumes. Inclusion of FA and MD PCs in predictive models of language impairment resulted in significant improvements in sensitivity and specificity of the predictions.ConclusionsQuantitative MRI measures from T1 and diffusion-weighted scans are unlikely to represent perfectly orthogonal vectors of disease in individuals with epilepsy. On the contrary, they exhibit highly intercorrelated PCs in their factor structures, which is consistent with an underlying pathological process that affects both the cortical and the subcortical structures simultaneously. In addition to hippocampal volume, the PCs of diffusion weighted measures (FA and MD) increase the sensitivity and specificity for determining naming impairment in patients with TLE. These findings underline the importance of combining multimodal imaging measures to better predict language performance in TLE that could extend to other patients with prominent language impairments.

EPA-0482 – Exploring genetic and environmental determinants of brain volumes in schizophrenia

Schizophrenia is an aetiologically complex disorder associated with significant familial risk. It is marked also by reductions in whole brain, grey and possibly white matter volumes. How these pathological abnormalities are influenced by schizophrenia's genetic and environmental risk remains uncertain. We investigated the relationship between familial and environmental risk on brain volume in twin pairs varying in their zygosity and concordance for schizophrenia, and healthy control twins, using a variety of complementary imaging strategies. These included region of interest and automated tissue segmentation volumes and voxel based morphometry. We found that whole brain, grey, white, frontal and right hippocampal volumes were smaller in probands with schizophrenia compared to healthy controls. Well co-twins from MZ discordant pairs showed a trend towards lower white matter volume compared to the healthy controls. Well co-twins from DZ discordant pairs had smaller hippocampal volumes compared to the healthy controls. The patients with schizophrenia and their well co-twins from MZ discordant pairs differed in the superior frontal cortex using both region of interest and VBM techniques. Lower birth weight and hypoxia were both associated with lower whole brain volumes, and with lower white and grey matter volumes respectively. Our data suggest that total brain and grey matter volume reductions in schizophrenia, possibly focused in part in the frontal cortex, are related primarily to unique environmental factors, including perinatal complications. The white matter and local hippocampal volume reductions suggest an additional vulnerability to genetic risk effects.

Ginseng extract attenuates early MRI changes after status epilepticus and decreases subsequent reduction of hippocampal volume in the rat brain

Prolonged epileptic seizures during status epilepticus (SE) are known to cause neuronal death and lead to brain damage. Lesions in various brain regions can result in memory and cognitive impairment, thus searching of new neuroprotective drugs is important. We evaluated effects of single and chronic administration of ginseng extract on early and late changes in MRI measurements in the rat brain after lithium-pilocarpine SE. Butanol extract of ginseng root cell culture DAN-25 was administered after termination of SE. MRI study of the rat brain was performed 2, 7, and 30 days after SE. High-resolution T2-weighed images and T2-maps were obtained, and total damaged area, hippocampal volume, and T2 relaxation time in several brain structures were calculated. Single administration of ginseng extract attenuated early changes in brain structures found on day 2 after SE. Both single and chronic treatment with ginseng extract decreased brain damage on day 7 after SE. An increase in T2-relaxation time in the hippocampus on day 2 after SE was less prominent in ginseng-treated rats than in saline-treated rats. 30 days after SE, the reduction of hippocampal volume was found both in saline-treated and ginseng-treated rats; however, it was less pronounced in ginseng-treated rats. We conclude that administration of ginseng extract after SE termination reduced brain damage caused by prolonged seizures. Ginseng extract was effective during early period after SE and had a specific protective effect on the hippocampus.

Hippocampal Volume and Memory Performance in Children With Perinatal Stroke

BackgroundPediatric neurologists and neonatologists often are asked to predict cognitive outcome after perinatal brain injury (including likely memory and learning outcomes). However, relatively few data exist on how accurate predictions can be made. Furthermore, although the consequences of brain injury on hippocampal volume and memory performance have been studied extensively in adults, little work has been done in children. MethodsWe measured the volume of the hippocampus in 27 children with perinatal stroke and 19 controls, and measured their performance on standardized verbal and non-verbal memory tests. ResultsWe discovered the following: (1) As a group, children with perinatal stroke had smaller left and right hippocampi compared with control children. (2) Individually, children with perinatal stroke demonstrated 1 of 3 findings: no hippocampal loss, unilateral hippocampal loss, or bilateral hippocampal volume loss compared with control children. (3) Hippocampal volume inversely correlated with memory test performance in the perinatal stroke group, with smaller left and right hippocampal volumes related to poorer verbal and non-verbal memory test performance, respectively. (4) Seizures played a significant role in determining memory deficit and extent of hippocampal volume reduction in patients with perinatal stroke. ConclusionsThese findings support the view that, in the developing brain, the left and right hippocampi preferentially support verbal and nonverbal memory respectively, a consistent finding in the adult literature but a subject of debate in the pediatric literature. This is the first work to report that children with focal brain injury incurred from perinatal stroke have volume reduction in the hippocampus and impairments in certain aspects of declarative memory.

Hippocampal correlates of depression in healthy elderly adults

Mixed findings have been reported on the relationship between hippocampal integrity and major depression in clinical populations. Few neuroimaging studies have investigated associations between hippocampal measures and depressive symptoms in nondemented older adults. Here, we address this issue by imaging 36 nondemented adults over age 70 from the Einstein Aging Study, a community-based sample from the Bronx, NY. Depressive symptoms were assessed using the 15-item Geriatric Depression scale (GDS). Clinically significant depression was defined using a cut-off score of 5 or greater. Hippocampal data included MRI-derived volume data normalized to midsagittal area and MRS-derived N-acetylaspartate to creatine ratios (NAA/Cr). Our result indicates that smaller total hippocampal volume was associated with higher GDS scores, but there were no significant association between hippocampal NAA/Cr and GDS score. These effects were consistent after controlling for age, education, and gender. Reduction in hippocampal volume could represent a risk factor or a consequence of depression in older adults. Further studies are needed to better understand the role of the hippocampus in the development and experience of depression in older adults.

Hippocampal Volume Reduction Correlates With Apathy in Traumatic Brain Injury, But Not Schizophrenia

Apathy commonly accompanies both traumatic brain injury (TBI) and deficit syndrome schizophrenia (DSZ), despite unclear neurological bases. The authors examined differences in cortical thickness and subcortical/cerebellar regional volumes between adult TBI survivors, patients with DSZ, and healthy-control subjects by use of 3-D magnetic resonance imaging (MRI), and correlated imaging findings with clinical ratings of apathy and selected cognitive test scores. Imaging findings revealed specific areas of volume reduction in TBI survivors and areas of cortical thinning among patients with DSZ. The severity of apathy symptoms was similar across patient groups; however, severity of apathy was only correlated with imaging findings in TBI survivors.

Modulation of beta-amyloid-related cognitive decline by brain-derived neurotrophic factor Val66Met polymorphism in preclinical Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine whether BDNF Val66Met moderates A β amyloid-related cognitive decline, reduction in hippocampal volume, and A β amyloid accumulation in healthy older adults. Healthy older adults (n=165) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent positron emission tomography (PET) neuroimaging for Aβ amyloid using Pittsburgh Compound B (PiB), BDNF genotyping, and cognitive assessment at baseline, 18- and 36-months. Linear mixed models determined rates of change in cognition, hippocampal volume and A β amyloid accumulation over 36 months. In healthy older adults with high Aβ amyloid, Met carriers showed significant and moderate-to-large decline in episodic memory, executive function, and language, and greater reductions in hippocampal volume over 36 months compared to Val/Val homozygotes. BDNF Val66Met was unrelated to rates of change in cognition or hippocampal volume in participants with low Aβ amyloid. BDNF Val66Met was not associated with levels of Aβ amyloid in participants with high or low Aβ amyloid levels at baseline. Similarly, BDNF Val66Met was not associated with rates of Aβ amyloid accumulation in participants with high or low Aβ amyloid levels at baseline. BDNF Val66Met moderated the association between high A β amyloid and cognitive decline and hippocampal atrophy in healthy older adults. High A β amyloid levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippocampal degeneration in individuals in the preclinical stage of AD.

Is hippocampal volume a good marker to differentiate Alzheimer's disease from frontotemporal dementia?

Background: Previous studies analyzed the ability of hippocampal volumes (HV) to differentiate Alzheimer's disease (AD) from frontotemporal dementia (FTD). However, these studies did not include patients selected according to clinico-biological criteria, using pathophysiological biomarkers. Objective: To analyze the effectiveness of hippocampal volumetric measures to distinguish AD from behavioral variant FTD (bvFTD), using strict inclusion criteria based on clinical and pathophysiological markers. Methods: Seventy-two participants were included: 31 AD patients with predominant and progressive episodic memory deficits associated with typical AD cerebrospinal fluid (CSF) profile and/or positive amyloid imaging (PET with 11C-labeled Pittsburgh Compound B [PiB]), 26 bvFTD patients diagnosed according to consensual clinical criteria and with no AD CSF profile, and 15 healthy controls without amyloid retention on PiB-PET exam. HV were segmented with an automated method and were normalized to total intracranial volume (nHV). Results: Significant reductions in HV were found in both AD and bvFTD patients compared with controls, but there were no significant difference between AD and bvFTD patients. Mean nHV distinguished normal controls from either AD or bvFTD with high sensitivity (80.6% and 76.9%, respectively) and specificity (93.3% for both), but it was inefficient in differentiating AD from bvFTD (9.7% specificity). There was no difference in the clinical and neuropsychological profiles according to HV in bvFTD and AD patients. Conclusions: When considered alone, measures of HV are not good markers to differentiate AD from bvFTD. Hippocampal sclerosis associated with FTD may explain the high degree of overlap in nHV between both groups.

A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10−6 and 8.3×10−7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.

Sex differences in resilience to childhood maltreatment: Effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults

Recent data suggests that a history of childhood maltreatment is associated with reductions in hippocampal volume in healthy adults. Because this association is also evident in adults with psychiatric illness, it has been suggested that reductions in hippocampal volume associated with childhood maltreatment may be a risk factor for psychiatric illness. Such an interpretation suggests that healthy adults with a history of childhood maltreatment are more resilient to the effects of maltreatment. Current models of resilience suggest, however, that resiliency should be measured across multiple domains of functioning. The present study sought to investigate childhood maltreatment in relationship to hippocampal volumes in healthy adults and to address the question of whether the putative resiliency extends to other domains of functioning. Sixty-seven healthy Caucasian adults were assessed for a history of childhood emotional abuse, emotional neglect and physical abuse and received high resolution structural MR imaging scans. Participants with and without histories of abuse or neglect were compared on measures of total hippocampal volume, general cognitive ability and subclinical psychopathology. Our results suggest that childhood emotional abuse is associated with reduced hippocampus volume in males, but not in females. However, emotional abuse was associated with higher levels of subclinical psychopathology in both males and females. These data suggest that while females may be more resilient to the neurological effects of childhood maltreatment, they are not more resilient to the psychiatric symptoms associated with childhood maltreatment. Further research is needed to elucidate the mechanisms involved in these different levels of resilience.