Total Hippocampal Volume Research Articles

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer\u2019s Coordinating Center Uniform Data Set

BackgroundLongitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer’s disease, particularly in the early disease stages. This study leveraged the National Alzheimer’s Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition.MethodsThe sample included 465 participants from the National Alzheimer’s Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer’s Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer’s disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD.ResultsOf the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p < 0.01), Digit Symbol Coding (p < 0.01), Logical Memory Immediate Recall (p = 0.02), Trail Making A (p < 0.01), and Semantic Fluency (p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (p < 0.01) and Geriatric Depression Scale-15 scores (p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia.ConclusionsIn this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer’s disease.

C-08 Hippocampal Volume in a Cognitively Healthy Population Scoring Within Normal Limits on Cognitive Tasks

Abstract Objective Our aim was to investigate hippocampal volume in a cognitively healthy aging population that scored within normal limits on neuropsychological testing. Decreased hippocampal volume was expected to predict decreased memory performance, and not expected to predict executive function. Method A cross-sectional design was conducted from archival data at Huntington Medical Research Institutes. The sample consisted of 35 older adults (63-89 years) with college degrees or higher. Hippocampal volume and intracranial volume were obtained via MRI, and neuropsychological assessment measures included Wechsler Memory Scale, 3rd edition (WMS-III), California Verbal Learning Test, 2nd edition (CVLT-II), and the Stroop Color and Word Test. Results Total hippocampal volume was a good predictor of Logical Memory delayed (LM-II) scores (Figure 1), such that a larger hippocampus was associated with poorer LM-II performance (p &lt; .01). Consistent with the above, both left hemisphere (LH) (p = .03), and right hemisphere (RH) hippocampal volume (p &lt; .01), were found to be good predictors of LM-II scores, and a larger RH or LH hippocampus was associated with poorer performance. Neither CVLT-II nor Stroop C Interference sores were significantly related to total hippocampal volume. Conclusion(s) Unexpectedly, participants with a larger hippocampus performed more poorly on the LM-II task. These results might be explained by the effects of neuroinflammation in early Alzheimer’s disease pathology. However, given that the MRI volumes did not account for atrophy or damaged cortical tissue, inference is limited. Future research investigating the early pathology of brain aging in the hippocampus in cognitively healthy individuals is recommended.

Individuals in the prediabetes stage exhibit reduced hippocampal tail volume and executive dysfunction

IntroductionHigh glucose levels are associated with cognitive impairment and total hippocampal volume reductions. However, the effects of the blood glucose level on hippocampal subfield volumes remain unclear, especially in the prediabetes stage.MethodsSixty participants were enrolled in this cross‐sectional study and were divided into the nondiabetes, prediabetes, and diabetes groups according to their medical history and A1c level. A full battery of neuropsychological tests was used to assess the global cognition, executive function, attention, verbal fluency, working memory, immediate memory, and delayed memory. FreeSurfer 6.0 was used for the hippocampus parcellation. Hippocampal subfield volumes were adjusted by intracranial volume. Analyses of covariance, multiple linear regression, and partial correlation analysis were used to explore the relationship between A1c level, cognitive function, and hippocampal subfields volume, in which age, sex, education years, body mass index, history of hypertension, level of cholesterol, and the presence of ApoE4‐positive status were adjusted.ResultsSignificant differences in the total left hippocampal volume (p = 0.046) and left hippocampal tail volume (p = 0.014) were noted among three groups. Significant correlation was identified between the A1c level and the volume of left hippocampal tail (r = −0.334, p = 0.009) after adjusting all the covariants. Increased A1c level was significantly associated with executive dysfunction, as assessed by trail making test B (R = 0.503, p = 0.0016) and Stroop test C (R = 0.506, p = 0.001).ConclusionsOur results support that the left hippocampal tail volume may be served as an early marker of diabetes‐related brain damage, associated with executive dysfunction. Clinicians should pay closer attention to adults in the prediabetes stage to prevent later cognitive impairment.

Abnormalities of hippocampal shape and subfield volumes in medication-free patients with obsessive-compulsive disorder.

In this study, we sought to identify alterations of hippocampal shape and subfield volumes in a relatively large sample of medication-free obsessive-compulsive disorder (OCD) patients without comorbid depression. 3D T1-weighted Magnetic Resonance Imaging scans were collected from 81 medication-free OCD patients and 95 age- and sex-matched healthy controls (HC). Total hippocampal volume and volume of eight bilateral subfields were measured using FreeSurfer software. Subregional shape deformity was examined via FSL software. Volumetric and shape differences between groups and correlations with OCD symptoms were examined. The volume of right hippocampus was significantly reduced in OCD patients (p = .001, η2 = 0.065). Follow-up analysis of right hemisphere subfields showed reduced volume in right subiculum (p < .001, η2 = 0.081), presubiculum (p < .001, η2 = 0.125), CA2/3 (p = .001, η2 = 0.06), and hippocampal tail (p < 0.001, η2 = 0.105), while the volume of right fimbria was increased (p = .001, η2 = 0.058). Shape analysis revealed a bilateral outward bending in the hippocampal body related to a lateral displacement of hippocampus from the body to the tail. Symptom severity was correlated with volumes of presubiculum (with compulsions, r = -0.25, p = .024) and fimbria (with obsessions, r = -0.28, p = .012), and with the lateral shift of middle and posterior hippocampus (with obsessions). Alterations across hippocampal subfields and overall shape may contribute to the distinctive cognitive and affective abnormalities associated with OCD.

Memory-guided attention: bilateral hippocampal volume positively predicts implicit contextual learning.

Several studies have begun to demonstrate that contextual memories constitute an important mechanism to guide our attention. Although there is general consensus that the hippocampus is involved in the encoding of contextual memories, it is controversial whether this structure can support implicit forms of contextual memory. Here, we combine automated segmentation of structural MRI with neurobehavioral assessment of implicit contextual memory-guided attention to test the hypothesis that hippocampal volume would predict the magnitude of implicit contextual learning. Forty healthy subjects underwent 3T magnetic resonance imaging brain scanning with subsequent automatic measurement of the total brain and hippocampal (right and left) volumes. Implicit learning of contextual information was measured using the contextual cueing task. We found that both left and right hippocampal volumes positively predicted the magnitude of implicit contextual learning. Larger hippocampal volume was associated with superior implicit contextual memory performance. This study provides compelling evidence that implicit contextual memory-guided attention is hippocampus-dependent.

Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer's Disease Associates with Increased Odds for Brain Infarcts.

Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer's disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998-2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoproteinɛ4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.

Bilateral volume reduction in posterior hippocampus in psychosis of epilepsy

ObjectivePsychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is...

Automated Subfield Volumetric Analysis of Hippocampus in Patients with Drug-Naïve Nondementia Parkinson's Disease.

Several studies used automated segmentation of hippocampal subfield (ASHS) for detailed measurements of anatomic subregions of the hippocampus, especially in the field of neurodegenerative disorders. In this study, we investigated the hippocampal subfield volume of patients with early-stage nondementia PD compared with normal healthy subjects using the ASHS method. A total of 32 subjects were enrolled in this study (sixteen patients with drug naive nondementia PD and sixteen healthy controls). All subjects were scanned with a 1.5 tesla MRI. The volumes of the seven subfields were calculated separately, and then, the whole hippocampal volume was calculated by the summing of CA1, CA2-3, CA4-DG, subiculum, presubiculum, and fimbria, excluding the hippocampal fissure. There were significant diagnosis-by-hemisphere interactive effects on the total hippocampal volume (F = 5.197; p=0.031) and the subfield volume of CA2-3 (F = 7.586; p=0.010) and CA4-DG (F = 7.403; p=0.011). The volumes of CA2-3 (F = 19.911; p < 0.001), CA4-DG (F = 20.273; p < 0.001), and total hippocampus (F = 10.573; p=0.005) in the left hemisphere were reduced compared to the right hemisphere. We suggest that the hippocampal volume asymmetry, especially in CA4-DG and CA2-3, could be observed in drug-naïve PD patients even in the early stage of the disease.

Assessment of Racial Disparities in Biomarkers for Alzheimer Disease

ImportanceRacial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms.ObjectiveTo ascertain whether there are racial disparities in molecular biomarkers for Alzheimer disease.Design, Setting, and ParticipantsA total of 1255 participants (173 African Americans) were enrolled from January 1, 2004, through December 31, 2015, in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University and completed a magnetic resonance imaging study of the brain and/or positron emission tomography of the brain with Pittsburgh compound B (radioligand for aggregated amyloid-β) and/or cerebrospinal fluid (CSF) assays for the concentrations of amyloid-β42, total tau, and phosphorylated tau181. Independent cross-sectional analyses were conducted from April 22, 2016, to August 27, 2018, for each biomarker modality with an analysis of variance or analysis of covariance including age, sex, educational level, race, apolipoprotein E (APOE) ε4 allele status, and clinical status (normal cognition or dementia). All biomarker assessments were conducted without knowledge of the clinical status of the participants.Main Outcomes and MeasuresThe primary outcomes were hippocampal volumes adjusted for differences in intracranial volumes, global cerebral amyloid burden as transformed into standardized uptake value ratios (partial volume corrected), and CSF concentrations of amyloid-β42, total tau, and phosphorylated tau181.ResultsOf the 1255 participants (707 women and 548 men; mean [SD] age, 70.8 [9.9] years), 116 of 173 African American participants (67.1%) and 724 of 1082 non-Hispanic white participants (66.9%) had normal cognition. There were no racial differences in the frequency of cerebral ischemic lesions noted on results of brain magnetic resonance imaging, mean cortical standardized uptake value ratios for Pittsburgh compound B, or for amyloid-β42 concentrations in CSF. However, in individuals with a reported family history of dementia, mean (SE) total hippocampal volumes were lower for African American participants than for white participants (6418.26 [138.97] vs 6990.50 [44.10] mm3). Mean (SE) CSF concentrations of total tau were lower in African American participants than in white participants (293.65 [34.61] vs 443.28 [18.20] pg/mL; P < .001), as were mean (SE) concentrations of phosphorylated tau181 (53.18 [4.91] vs 70.73 [2.46] pg/mL; P < .001). There was a significant race by APOE ε4 interaction for both CSF total tau and phosphorylated tau181 such that only APOE ε4–positive participants showed the racial differences.Conclusions and RelevanceThe results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.

Hippocampal subfield CA2+3 exhibits accelerated aging in Alcohol Use Disorder: A preliminary study.

The profile of brain structural dysmorphology of individuals with Alcohol Use Disorders (AUD) involves disruption of the limbic system. In vivo imaging studies report hippocampal volume loss in AUD relative to controls, but only recently has it been possible to articulate different regions of this complex structure. Volumetric analysis of hippocampal regions rather than total hippocampal volume may augment differentiation of disease processes. For example, damage to hippocampal subfield cornu ammonis 1 (CA1) is often reported in Alzheimer's disease (AD), whereas deficits in CA4/dentate gyrus are described in response to stress and trauma. Two previous studies explored the effects of chronic alcohol use on hippocampal subfields: one reported smaller volume of the CA2+3 in alcohol-dependent subjects relative to controls, associated with years of alcohol consumption; the other, smaller volumes of presubiculum, subiculum, and fimbria in alcohol-dependent relative to control men.The current study, conducted in 24 adults with DSM5-diagnosed AUD (7 women, 53.7 ± 8.8) and 20 controls (7 women, 54.1 ± 9.3), is the first to use FreeSurfer 6.0, which provides state-of-the art hippocampal parcellation, to explore the sensitivity of hippocampal sufields to alcoholism. T1- and T2- images were collected on a GE MR750 system with a 32-channel Nova head coil. FreeSurfer 6.0 hippocampal subfield analysis produced 12 subfields: parasubiculum; presubiculum; subiculum; CA1; CA2+3; CA4; GC-ML-DG (Granule Cell (GC) and Molecular Layer (ML) of the Dentate Gyrus (DG)); molecular layer; hippocampus-amygdala-transition-area (HATA); fimbria; hippocampal tail; hippocampal fissure; and whole volume for left and right hippocampi. A comprehensive battery of neuropsychological tests comprising attention, memory and learning, visuospatial abilities, and executive functions was administered.Multiple regression analyses of raw volumetric data for each subfields by group, age, sex, hemisphere, and supratentorial volume (svol) showed significant effects of svol (p < .04) on nearly all structures (excluding tail and fissure). Volumes corrected for svol showed effects of age (fimbria, fissure) and group (subiculum, CA1, CA4, GC-ML-DG, HATA, fimbria); CA2+3 showed a diagnosis-by-age interaction indicating older AUD individuals had a smaller volume than would be expected for their age. There were no selective relations between hippocampal subfields and performance on neuropsychological tests, likely due to lack of statistical power.The current results concur with the previous study identifying CA2+3 as sensitive to alcoholism, extend them by identifying an alcoholism-age interaction, and suggest an imaging phenotype distinguishing AUD from AD and stress/trauma.

Hippocampal volume alteration in medication-naive depression patients in comparison to healthy individuals: An Indian perspective

Context: Depression is the most common mental health problem in all the age groups. However, the exact pathophysiology of this devastating disorder remains an enigma. Many hitherto conflicting studies have focused on volumetric measurement of the hippocampus using magnetic resonance imaging (MRI), but few studies have been conducted in our country. Thus, our study envisages comparing hippocampal volumes of medication-naive depressed individuals against healthy controls. Materials and Methods: This study was conducted both on patients admitted to the hospital and those attending outdoor clinic fulfilling inclusion/exclusion criteria in a tertiary care hospital. The sample consisted of 25 patients freshly diagnosed as Depressive Episode as per the International Classification of Diseases (ICD-10) and 25 healthy controls. Sociodemographic and clinical history pro forma and Hamilton Rating Scale for Depression were administered on all individuals before obtaining the volumetric measurements of the hippocampi of all individuals using a 1.5 Tesla MRI scanner. Results: Our study indicated right hippocampal volumes (RHVs) of depressed individuals were significantly reduced more so with advancing age. It hinted to the lesser effect of severity of depression on RHVs than in the left hippocampal volumes (LHVs). We found that female patients are more predisposed to RHV loss. However, our study did not reveal any significant difference in LHVs or total hippocampal volumes between depressed individuals and healthy controls. Conclusions: It is one of the exclusive studies which have attempted to shed light on the pathophysiology of depression in relation to its severity and hippocampal volumes in the Indian context.

Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients.

In patients with temporal lobe epilepsy (TLE), presurgical magnetic resonance imaging (MRI) often reveals hippocampal atrophy, while neuropathological assessment indicates the different types of hippocampal sclerosis (HS). Different HS types are not discriminated in MRI so far. We aimed to define the volume of each hippocampal subfield on MRI manually and to compare automatic and manual segmentations for the discrimination of HS types. The T2-weighted images from 14 formalin-fixed age-matched control hippocampi were obtained with 4.7T MRI to evaluate the volume of each subfield at the anatomical level of the hippocampal head, body, and tail. Formalin-fixed coronal sections at the level of the body of 14 control cases, as well as tissue samples from 24 TLE patients, were imaged with a similar high-resolution sequence at 3T. Presurgical three-dimensional (3D) T1-weighted images from TLE went through a FreeSurfer 6.0 hippocampal subfield automatic assessment. The manual delineation with the 4.7T MRI was identified using Luxol Fast Blue stained 10-μm-thin microscopy slides, collected at every millimeter. An additional section at the level of the body from controls and TLE cases was submitted to NeuN immunohistochemistry for neuronal density estimation. All TLE cases were classified according to the International League Against Epilepsy's (ILAE's) HS classification. Manual volumetry in controls revealed that the dentate gyrus (DG)+CA4 region, CA1, and subiculum accounted for almost 90% of the hippocampal volume. The manual 3T volumetry showed that all TLE patients with type 1 HS (TLE-HS1) had lower volumes for DG+CA4, CA2, and CA1, whereas those TLE patients with HS type 2 (TLE-HS2) had lower volumes only in CA1 (p ≤ 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 (p ≤ 0.003). In addition, TLE-HS2 had a higher volume (p = 0.016) and higher neuronal density (p < 0.001) than the TLE-HS1 in DG + CA4. Automatic segmentation failed to match the manual or histological findings and was unable to differentiate TLE-HS1 from TLE-HS2. Total hippocampal volume correlated with DG+CA4 and CA1 volumes and neuronal density. For the first time, we also identified subfield-specific pathology patterns in the manual evaluation of volumetric MRI scans, showing the importance of manual segmentation to assess subfield-specific pathology patterns.

Genetic architecture of hippocampal subfields on standard resolution MRI: How the parts relate to the whole.

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.

Anterior hippocampus volume loss in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a lifelong disease resulting from the loss of hypocretin neurons in the hypothalamus; structural changes are not, however, limited only to the hypothalamus. We previously revealed an overall hippocampal volume loss in narcolepsy with cataplexy. The aim of this study is to describe the volume reduction of the anterior and posterior parts of the hippocampus in patients with narcolepsy with cataplexy in comparison with a control group. The anterior hippocampus is more involved in episodic memory and imagination, and the posterior hippocampus in spatial memory. Manual magnetic resonance imaging hippocampal volumetry was performed in 48 patients with narcolepsy with cataplexy and in 37 controls using the manual delineation technique in the ScanView program. All participants were examined on the same 1.5 T MR scanner; measurement was carried out as T1W 3D image with a slice thickness of 1.0/0 mm. There was a significant absolute loss of the total volume of the anterior hippocampus (sum of left and right) in patients with narcolepsy with cataplexy as compared with the controls (10.5%, p = .03 ANCOVA after correcting for total brain volume and multiple testing). We found a negative correlation between the total anterior hippocampus volume and the duration of the disease (R = -0.4036, p = .016-corrected for multiple testing).

Educational Attainment Moderates the Association Between Hippocampal Volumes and Memory Performances in Healthy Older Adults

Objective: To examine whether educational attainment, as a proxy of cognitive reserve, moderated the association between hippocampal volumes and episodic verbal memory performances in healthy older adults.Methods: Data from 76 community dwelling older adults were included in the present study. Measures of hippocampal volumes (total, left, and right) were obtained using FreeSurfer software. Immediate and delayed verbal recall scores were derived from performances on the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale- Third Edition. Educational attainment was defined by years of education. Linear regression analyses were performed using immediate and delayed recall as dependent variables and hippocampal volumes, years of education, and their interaction terms as independent variables. All analyses were controlled for age, sex, depression, and health status.Results: Total and left Hippocampal volumes had a positive main effect on delayed recall only. Additionally, the interaction between total, left, and right hippocampal volumes and education was a significant predictor for delayed recall performance but not for immediate recall performance. The positive association between hippocampal volumes and delayed recall was greatest in those with more years of education.Conclusion: Larger hippocampal volumes were associated with better delayed verbal recall and the effect on delayed recall was greatest in those with more years of education. Having higher levels of education, or cognitive reserve, may enable individuals to capitalize on greater structural integrity in the hippocampus to support delayed recall in old age. However, longitudinal research is needed to investigate the directionality of these associations.

Hippocampal subfields in adolescent anorexia nervosa

Patients with anorexia nervosa (AN) exhibit volume reduction in cerebral gray matter (GM), and several studies report reduced hippocampus volume. The hippocampal subfields (HS) are functionally and structurally distinct, and appear to respond differently to neuropathology. The aim of this study was to investigate HS volumes in adolescent females with restrictive AN compared to a healthy age-matched control group (HC). The FreeSurfer v6.0 package was used to extract brain volumes, and segment HS in 58 female adolescents (AN = 30, HC = 28). We investigated group differences in GM, white matter (WM), whole hippocampus and 12 HS volumes. AN patients had significantly lower total GM and total hippocampal volume. No group difference was found in WM. Volume reduction was found in 11 of the 12 HS, and most results remained significant when adjusting for global brain volume reduction. Investigations of clinical covariates revealed statistically significant relationships between the whole hippocampus, several HS and scores on depression and anxiety scales in AN. Results from this study show that young AN patients exhibit reduced volume in most subfields of the hippocampus, and that this reduction may be more extensive than the observed global cerebral volume loss.

Early chronic exposure to low-level lead alters total hippocampal microglia in pre-adolescent mice

Developmental lead (Pb) exposure alters brain function through mechanisms that are not yet understood. A previous study showed that early lead exposure reduced microglia number in the dentate gyrus region of the hippocampus. Given the critical role of microglia in brain development, it is important to determine whether these differences are unique to the dentate gyrus, or occur throughout the hippocampus. Unbiased stereology was used to quantify microglia mean cell body number in total hippocampus, and compare the proportion of microglia in the ventral vs. dorsal regions. Total hippocampal volume was also measured and compared. The study included brain tissue from 30 pre-adolescent C57BL/6 J mice, exposed to 30 ppm Pb acetate (n = 10, mean BLL 3.4 μg/dL at sacrifice), 330 ppm Pb acetate (n = 10, mean BLL 14.1 μg/dL at sacrifice), or 0 ppm Pb acetate (n = 10, negative controls). In lead exposed animals, microglia mean cell body number was reduced in total hippocampus; total hippocampal volume was reduced. Importantly, effects in low- and high-dose exposure groups did not differ. Contrary to study hypotheses, the distribution of hippocampal microglia in the ventral vs. dorsal hippocampal regions did not differ. Overall, lowest and higher levels of lead exposure during development had strikingly similar disruptive effects in the neuroimmune system. Studies are needed to determine the immune and other mechanisms responsible for these effects. Future studies would benefit from larger samples to determine whether in fact there is a group by sex interaction driving the effects of early lead exposure on microglia.

Smaller hippocampal CA1 subfield volume in posttraumatic stress disorder.

Smaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features. Case-control cross-sectional studies of U.S. military veterans (n=282) from the Iraq and Afghanistan era were grouped into PTSD (n=142) and trauma-exposed controls (n=140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model. Significantly lower subfield volumes were associated with PTSD in left CA1 (P=0.01; d=0.21; uncorrected), CA3 (P=0.04; d=0.08; uncorrected), and right CA3 (P=0.02; d=0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD (F4, 221 =3.32, P=0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD-associated differences in global hippocampal shape were nonsignificant. The present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.

Vitamin D deficiency is associated with reduced hippocampal volume and disrupted structural connectivity in patients with mild cognitive impairment.

Vitamin D deficiency may exacerbate adverse neurocognitive outcomes in the progression of diseases such as Parkinson's, Alzheimer's, and other dementias. Mild cognitive impairment (MCI) is prodromal for these neurocognitive disorders and neuroimaging studies suggest that, in the elderly, this cognitive impairment is associated with a reduction in hippocampal volume and white matter structural integrity. To test whether vitamin D is associated with neuroanatomical correlates of MCI, we analyzed an existing structural and diffusion MRI dataset of elderly patients with MCI. Based on serum 25-OHD levels, patients were categorized into serum 25-OHD deficient (<12 ng/mL, n = 27) or not-deficient (>12 ng/mL, n = 29). Freesurfer 6.0 was used to parcellate the whole brain into 164 structures and segment the hippocampal subfields. Whole-brain structural connectomes were generated using probabilistic tractography with MRtrix. The network-based statistic (NBS) was used to identify subnetworks of connections that significantly differed between the groups. We found a significant reduction in total hippocampal volume in the serum 25-OHD deficient group especially in the CA1, molecular layer, dentate gyrus, and fimbria. We observed a connection deficit in 13 regions with the right hippocampus at the center of the disrupted network. Our results demonstrate that low vitamin D is associated with reduced volumes of hippocampal subfields and connection deficits in elderly people with MCI, which may exacerbate neurocognitive outcomes. Longitudinal studies are now required to determine if vitamin D can serve as a biomarker for Alzheimer's disease and if intervention can prevent the progression from MCI to major cognitive disorders.

Common Variant in PLD3 Influencing Cerebrospinal Fluid Total Tau Levels and Hippocampal Volumes in Mild Cognitive Impairment Patients from the ADNI Cohort

Recent studies found the variants in Alzheimer's disease (AD) risk gene PLD3 were associated with cognitive function, but its detailed mechanism before typical AD onset was unknown. Our current study examined the impact of PLD3 common variant rs11667768 on cerebrospinal fluid (CSF) total-tau and phosphorylated-tau levels and structural MRI from the ADNI database. We found rs11667768 was significantly associated with CSF total-tau levels and hippocampal volumes at baseline and six-year follow-up in the total non-demented elderly group and the mild cognitive impairment subgroup, indicating a potential role of PLD3 common variants in influencing cognitive function through changing CSF total-tau levels and hippocampal volumes.