Entorhinal Cortex Volume Research Articles

Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer's Disease.

Prevention of dementia due to Alzheimer’s disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of “normal” aging. A different approach involves testing of “central auditory processing” (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOE ɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

Disconnection of hippocampal networks contributes to memory dysfunction in individuals with temporal lobe epilepsy.

A deficit in declarative memory function is common among individuals with temporal lobe epilepsy. The purpose of this study is to evaluate the relationship between the volume of the hippocampus, entorhinal cortex along with the surrounding parahippocampal white matter and memory performance in those with temporal lobe epilepsy. T1 weighted MRI scans were acquired using a 3-D pulse sequence in 50 individuals with temporal lobe epilepsy. Hippocampal and entorhinal cortex volumes were derived by manually tracing consecutive coronal slices aligned perpendicular to the long axis of the hippocampus. In addition, parahippocampal white matter volumes were determined using voxel based morphometry. Finally, declarative memory was assessed using immediate and delayed verbal and visual memory tests from the Wechsler Memory Scale third edition. Significant correlations were seen between right and left hippocampal volumes and delayed verbal memory test scores. In addition, left parahippocampal white matter showed positive correlations with immediate and delayed verbal and visual recall. Furthermore, regression models found that the right hippocampus and left parahippocampal white matter were the best predictors of immediate and delayed verbal and visual memory performance. These results show that a decrease in white matter fibers projecting to the hippocampus may cause a disruption of incoming multi-modal sensory information, contributing to the memory decline seen in individuals with temporal lobe epilepsy.

Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study

The rise in incidence of Alzheimer's disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas. Three different memory measures were examined relative to volumetric loss and cortical thickness among 45participants with amnestic mild cognitive impairment. frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed. Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis

We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimer's disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total gray/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging scans, whereas hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume—the same region in which Alzheimer's pathology originates—was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in undiagnosed community-dwelling older adults.

Anterolateral Entorhinal Cortex Volume Predicted by Altered Intra-Item Configural Processing.

Recent functional imaging studies have proposed that the human entorhinal cortex (ERC) is subdivided into functionally distinct anterolateral (alERC) and posteromedial (pmERC) subregions. The alERC overlaps with regions that are affected earliest by Alzheimer's disease pathology, yet its cognitive function remains poorly understood. Previous human fMRI studies have focused on its role in object memory, but rodent studies on the putatively homologous lateral entorhinal cortex suggest that it also plays an important role in representing spatial properties of objects. To investigate the cognitive effects of human alERC volume differences, we developed an eye-tracking-based task to evaluate intra-item configural processing (i.e., processing the arrangement of an object's features) and used manual segmentation based on a recently developed protocol to delineate the alERC/pmERC and other medial temporal lobe (MTL) subregions. In a group of older adult men and women at varying stages of brain atrophy and cognitive decline, we found that intra-item configural processing, regardless of an object's novelty, was strongly predicted by alERC volume, but not by the volume of any other MTL subregion. These results provide the first evidence that the human alERC plays a role in supporting a distinct aspect of object processing, namely attending to the arrangement of an object's component features.SIGNIFICANCE STATEMENT Alzheimer's disease pathology appears earliest in brain regions that overlap with the anterolateral entorhinal cortex (alERC). However, the cognitive role of the alERC is poorly understood. Previous human studies treat the alERC as an extension of the neighboring perirhinal cortex, supporting object memory. Animal studies suggest that the alERC may support the spatial properties of objects. In a group of older adult humans at the earliest stages of cognitive decline, we show here that alERC volume selectively predicted configural processing (attention to the spatial arrangement of an object's parts). This is the first study to demonstrate a cognitive role related to alERC volume in humans. This task can be adapted to serve as an early detection method for Alzheimer's disease pathology.

Structural MRI and Amyloid PET Imaging for Prediction of Conversion to Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Meta-Analysis.

ObjectiveThe aim of this study was to explore the prognostic values of biomarkers of neurodegeneration as measured by magnetic resonance imaging (MRI) and amyloid burden as measured by amyloid positron emission tomography (PET) in predicting conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI).MethodsPubMed and EMBASE databases were searched for structural MRI or amyloid PET imaging studies published between January 2000 and July 2014 that reported conversion to AD in patients with MCI. Means and standard deviations or individual numbers of biomarkers with positive or negative status at baseline and corresponding numbers of patients who had progressed to AD at follow-up were retrieved from each study. The effect size of each biomarker was expressed as Hedges's g.ResultsTwenty-four MRI studies and 8 amyloid PET imaging studies were retrieved. 674 of the 1741 participants (39%) developed AD. The effect size for predicting conversion to AD was 0.770 [95% confidence interval (CI) 0.607–0.934] for across MRI and 1.316 (95% CI 0.920–1.412) for amyloid PET imaging (p<0.001). The effect size was 1.256 (95% CI 0.902–1.609) for entorhinal cortex volume from MRI.ConclusionOur study suggests that volumetric MRI measurement may be useful for the early detection of AD.

Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

To evaluate the impact of obstructive sleep apnea (OSA) on neurocognitive function and brain morphology in older adults with depression and cognitive impairment. We prospectively screened OSA with the STOP-Bang questionnaire in the last 25 patients enrolled into the Donepezil Treatment of Cognitive Impairment and Depression (DOTCODE) trial. High and low probability of OSA were defined as a STOP-Bang score of ≥5 (h-OSA) and of <5 (l-OSA), respectively. Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial. After 16 weeks of antidepressant treatment, the h-OSA group performed significantly worse on the Selective Reminding Test delayed recall task than the l-OSA group, controlling for baseline performance (F = 19.1, df = 1,22, p < 0.001). In 19 of 25 participants who underwent brain MRI, the h-OSA group had significantly greater volumes of MRI hyperintensities in deep white matter, periventricular white matter, and subcortical gray matter compared with the l-OSA group. There was no significant association between OSA and hippocampal or entorhinal cortex volumes in our sample, even after controlling for intracranial volume. OSA is associated with impaired verbal episodic memory and microvascular damage in older adults with depression and cognitive impairment. One possibility is that by contributing to cerebral microvascular damage, OSA may exacerbate progressive memory decline.

Perceived Stress Is Differentially Related to Hippocampal Subfield Volumes among Older Adults.

IntroductionChronic exposure to stress has been shown to impact a wide range of health-related outcomes in older adults. Despite extensive animal literature revealing deleterious effects of biological markers of stress on the dentate gyrus subfield of the hippocampus, links between hippocampal subfields and psychological stress have not been studied in humans.This study examined the relationship between perceived stress and hippocampal subfield volumes among racially/ethnically diverse older adults.Methods and MaterialsBetween July 2011 and March 2014, 116 nondemented participants were consecutively drawn from the Einstein Aging Study, an ongoing community-based sample of individuals over the age of 70 residing in Bronx, New York. All participants completed the Perceived Stress Scale, Geriatric Depression Scale, and underwent 3.0 T MRI. FreeSurfer was used to derive total hippocampal volume, hippocampal subfield volumes (CA1, CA2/CA3, CA4/Dentate Gyrus (CA4/DG), and subiculum), entorhinal cortex volume, whole brain volume, and total intracranial volume.ResultsLinear regression analyses revealed that higher levels of perceived stress were associated with smaller total hippocampal volume (β = -0.20, t = -2.40, p = 0.02), smaller CA2/CA3 volumes (β = -0.18, t = -2.24, p = 0.03) and smaller CA4/DG volumes (β = -0.19, t = -2.28, p = 0.03) after controlling for total intracranial volume, age, gender, and race. These findings remained unchanged after removal of individuals with clinically significant symptoms of depression.DiscussionOur findings provide evidence of a relationship between a direct indicator of psychological stress and specific hippocampal subfield volumes in elderly individuals. These results highlight the importance of clinical screening for chronic stress in otherwise healthy older adults.

Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy.

To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with magnetic resonance imaging (MRI)-guided stereotactic laser interstitial thermal therapy (LiTT). We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug-resistant mTLE who underwent MRI-guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volume-based analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure-free and not seizure-free groups. Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval [CI] 30.1-75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9-88.4%) at 2-year follow-up. Median follow-up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure-free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure-free and non-seizure-free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted. We conclude that MRI-guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.

Hippocampal volume and cingulum bundle fractional anisotropy are independently associated with verbal memory in older adults.

The objective of this study was to investigate the relationship of medial temporal lobe and posterior cingulate cortex (PCC) volumetrics as well as fractional anisotropy of the cingulum angular bundle (CAB) and the cingulum cingulate gyrus (CCG) bundle to performance on measures of verbal memory in non-demented older adults. The participants were 100 non-demented adults over the age of 70years from the Einstein Aging Study. Volumetric data were estimated from T1-weighted images. The entire cingulum was reconstructed using diffusion tensor MRI and probabilistic tractography. Association between verbal episodic memory and MRI measures including volume of hippocampus (HIP), entorhinal cortex (ERC), PCC and fractional anisotropy of CAB and CCG bundle were modeled using linear regression. Relationships between atrophy of these structures and regional cingulum fractional anisotropy were also explored. Decreased HIP volume on the left and decreased fractional anisotropy of left CAB were associated with lower memory performance. Volume changes in ERC, PCC and CCG disruption were not associated with memory performance. In regression models, left HIP volume and left CAB-FA were each independently associated with episodic memory. The results suggest that microstructural changes in the left CAB and decreased left HIP volume independently influence episodic memory performance in older adults without dementia. The importance of these findings in age and illness-related memory decline require additional exploration.

Age differences in hippocampal subfield volumes from childhood to late adulthood.

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1-CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown. Here, we used a high-resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8-82 yrs. The magnitude of age differences in volume varied among the regions. Combined CA1-2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3-DG and the entorhinal cortex were negative in mid-childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age. The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan. © 2015 Wiley Periodicals, Inc.

Temporal Lobe and Frontal-Subcortical Dissociations in Non-Demented Parkinson's Disease with Verbal Memory Impairment.

ObjectiveThe current investigation examined verbal memory in idiopathic non-dementia Parkinson’s disease and the significance of the left entorhinal cortex and left entorhinal-retrosplenial region connections (via temporal cingulum) on memory impairment in Parkinson’s disease.MethodsForty non-demented Parkinson’s disease patients and forty non-Parkinson’s disease controls completed two verbal memory tests – a wordlist measure (Philadelphia repeatable Verbal Memory Test) and a story measure (Logical Memory). All participants received T1-weighted and diffusion magnetic resonance imaging (3T; Siemens) sequences. Left entorhinal volume and left entorhinal-retrosplenial connectivity (temporal cingulum edge weight) were the primary imaging variables of interest with frontal lobe thickness and subcortical structure volumes as dissociating variables.ResultsIndividuals with Parkinson’s disease showed worse verbal memory, smaller entorhinal volumes, but did not differ in entorhinal-retrosplenial connectivity. For Parkinson’s disease entorhinal-retrosplenial edge weight had the strongest associations with verbal memory. A subset of Parkinson’s disease patients (23%) had deficits (z-scores < -1.5) across both memory measures. Relative to non-impaired Parkinson’s peers, this memory-impaired group had smaller entorhinal volumes.DiscussionAlthough entorhinal cortex volume was significantly reduced in Parkinson’s disease patients relative to non-Parkinson’s peers, only white matter connections associated with the entorhinal cortex were significantly associated with verbal memory performance in our sample. There was also no suggestion of contribution from frontal-subcortical gray or frontal white matter regions. These findings argue for additional investigation into medial temporal lobe gray and white matter connectivity for understanding memory in Parkinson’s disease.

Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n=195), and regional brain volumes (n=34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q<0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

Relationship of medial temporal lobe atrophy, APOE genotype, and cognitive reserve in preclinical Alzheimer's disease

This study evaluated the utility of baseline and longitudinal magnetic resonance imaging (MRI) measures of medial temporal lobe brain regions collected when participants were cognitively normal and largely in middle age (mean age 57 years) to predict the time to onset of clinical symptoms associated with mild cognitive impairment (MCI). Furthermore, we examined whether the relationship between MRI measures and clinical symptom onset was modified by apolipoprotein E (ApoE) genotype and level of cognitive reserve (CR). MRI scans and measures of CR were obtained at baseline from 245 participants who had been followed for up to 18 years (mean follow-up 11 years). A composite score based on reading, vocabulary, and years of education was used as an index of CR. Cox regression models showed that lower baseline volume of the right hippocampus and smaller baseline thickness of the right entorhinal cortex predicted the time to symptom onset independently of CR and ApoE-ɛ4 genotype, which also predicted the onset of symptoms. The atrophy rates of bilateral entorhinal cortex and amygdala volumes were also associated with time to symptom onset, independent of CR, ApoE genotype, and baseline volume. Only one measure, the left entorhinal cortex baseline volume, interacted with CR, such that smaller volumes predicted symptom onset only in individuals with lower CR. These results suggest that MRI measures of medial temporal atrophy, ApoE-ɛ4 genotype, and the protective effects of higher CR all predict the time to onset of symptoms associated with MCI in a largely independent, additive manner during the preclinical phase of Alzheimer's disease.

Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study.

In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus &CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (β = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD.

Changes in Search Path Complexity and Length During Learning of a Virtual Water Maze: Age Differences and Differential Associations with Hippocampal Subfield Volumes.

Impairment of hippocampus-dependent cognitive processes has been proposed to underlie age-related deficits in navigation. Animal studies suggest a differential role of hippocampal subfields in various aspects of navigation, but that hypothesis has not been tested in humans. In this study, we examined the association between volume of hippocampal subfields and age differences in virtual spatial navigation. In a sample of 65 healthy adults (age 19-75 years), advanced age was associated with a slower rate of improvement operationalized as shortening of the search path over 25 learning trials on a virtual Morris water maze task. The deficits were partially explained by greater complexity of older adults' search paths. Larger subiculum and entorhinal cortex volumes were associated with a faster decrease in search path complexity, which in turn explained faster shortening of search distance. Larger Cornu Ammonis (CA)1-2 volume was associated with faster distance shortening, but not in path complexity reduction. Age differences in regional volumes collectively accounted for 23% of the age-related variance in navigation learning. Independent of subfield volumes, advanced age was associated with poorer performance across all trials, even after reaching the asymptote. Thus, subiculum and CA1-2 volumes were associated with speed of acquisition, but not magnitude of gains in virtual maze navigation.

Presurgical entorhinal cortex volume and postoperative seizure outcome in temporal lobe epilepsy

BackgroundAlthough temporal lobe surgery is an effective treatment for patients with intractable mesial temporal lobe epilepsy (mTLE), a third of patients will continue to experience seizures at 2 years after surgery. The reasons are unknown. One suggestion is that patients with abnormalities of the entorhinal cortex might have a subtype of mTLE that is resistant to surgery. We investigated the association between presurgical entorhinal cortex volume and postoperative outcome in patients with mTLE. Methods78 patients with intractable mTLE and unilateral hippocampal sclerosis underwent comprehensive presurgical evaluation at the Department of Epileptology, University Hospital Bonn, Germany. Patients and 76 age-matched healthy controls received an MP-RAGE T1-weighted MRI. We determined left and right entorhinal cortex volume, masked to participant identity, using rigorous manual techniques. All patients had complex partial seizures, underwent amygdalohippocampectomy, and received postoperative outcome assessment. FindingsThere was a significant effect of group (controls, left mTLE, right mTLE) on the volume of the left (univariate ANOVA F=29·6, p<0·001) and right (F=8·3, p<0·001) entorhinal cortex, and entorhinal asymmetry (F=92·6, p<0·001). Post-hoc analysis with Bonferroni correction revealed that patients with left (p<0·001) and right (p=0·01) mTLE had significantly reduced volume of the ipsilateral entorhinal cortex relative to controls, and patients with right mTLE also had volume reduction of the contralateral entorhinal cortex (p=0·01). We found no significant differences in entorhinal cortex volumes and clinical data between patients (n=48, 62%) surgically rendered seizure free (ILAE I-II) and patients (n=30, 38%) with persistent seizures (ILAE III-VI). InterpretationThese data indicate that gross atrophy of the entorhinal cortex is not a predictor of postoperative outcome in patients with intractable mTLE. We are evaluating whether alterations in entorhinal cortex connectivity and extent of resection are related to postoperative outcome in our series of patients. FundingThis work was supported by a UK Medical Research Council grant awarded to SSK.

Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 tesla MRI: The PREDICT-MR study

IntroductionSmaller hippocampal volumes have been associated with major depressive disorder (MDD). The hippocampus consists of several subfields that may be differentially related to MDD. We investigated the association of occurrence of major depressive episodes (MDEs), assessed five times over seven years, with hippocampal subfield and entorhinal cortex volumes at 7 tesla MRI. MethodsIn this prospective study of randomly selected general practice attendees, MDEs according to DSM-IV-R criteria were assessed at baseline and after 6, 12, 39 and 84 months follow-up. At the last follow-up, a T2 (0.7mm3) 7 tesla MRI scan was obtained in 47 participants (60±10 years). The subiculum, cornu ammonis (CA) 1 to 3, dentate gyrus&CA4 and entorhinal cortex volumes were manually segmented according a published protocol. ResultsOf the 47 participants, 13 had one MDE and 5 had multiple MDEs. ANCOVAs, adjusted for age, sex, education and intracranial volume, revealed no significant differences in hippocampal subfield or entorhinal cortex volumes between participants with and without an MDE in the preceding 84 months. Multiple episodes were associated with smaller subiculum volumes (B=−0.03mL/episode; 95% CI −0.06; −0.003), but not with the other hippocampal subfield volumes, entorhinal cortex, or total hippocampal volume. LimitationsA limitation of this study is the small sample size which makes replication necessary. ConclusionsIn this exploratory study, we found that an increasing number of major depressive episodes was associated with smaller subiculum volumes in middle-aged and older persons, but not with smaller volumes in other hippocampal subfields or the entorhinal cortex.

Two Alzheimer's disease risk genes increase entorhinal cortex volume in young adults.

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root.

Predicting aggressive decline in mild cognitive impairment: the importance of white matter hyperintensities.

Although white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease. To examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration. The Alzheimer's Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct. A decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status. Greater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001). White matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.