Entorhinal Volume Research Articles

Memory in the aging brain: Doubly dissociating the contribution of the hippocampus and entorhinal cortex

Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity-based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age-related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes.

Hippocampal and entorhinal atrophy in mild cognitive impairment

To evaluate the utility of MRI hippocampal and entorhinal cortex atrophy in predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Baseline brain MRI was performed in 139 patients with MCI, broadly defined, and 63 healthy controls followed for an average of 5 years (range 1 to 9 years). Hippocampal and entorhinal cortex volumes were each largest in controls, intermediate in MCI nonconverters, and smallest in MCI converters to AD (37 of 139 patients converted to AD). In separate Cox proportional hazards models, covarying for intracranial volume, smaller hippocampal volume (risk ratio [RR] 3.62, 95% CI 1.93 to 6.80, p < 0.0001), and entorhinal cortex volume (RR 2.43, 95% CI 1.56 to 3.79, p < 0.0001) each predicted time to conversion to AD. Similar results were obtained for hippocampal and entorhinal cortex volume in patients with MCI with Mini-Mental State Examination (MMSE) scores > or = 27 out of 30 (21% converted to AD) and in the subset of patients with amnestic MCI (35% converted to AD). In the total patient sample, when both hippocampal and entorhinal volume were entered into an age-stratified Cox model with sex, MMSE, education, and intracranial volume, smaller hippocampal volume (RR 2.21, 95% CI 1.14 to 4.29, p < 0.02) and entorhinal cortex volume (RR 2.48, 95% CI 1.54 to 3.97, p < 0.0002) predicted time to conversion to AD. Similar results were obtained in a Cox model that also included Selective Reminding Test (SRT) delayed recall and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol as predictors. Based on logistic regression models in the 3-year follow-up sample, for a fixed specificity of 80%, the sensitivities for MCI conversion to AD were as follows: age 43.3%, MMSE 43.3%, age + MMSE 63.7%, age + MMSE + SRT delayed recall + WAIS-R Digit Symbol 80.6% (79.6% correctly classified), hippocampus + entorhinal cortex 66.7%, age + MMSE + hippocampus + entorhinal cortex 76.7% (85% correctly classified), age + MMSE + SRT delayed recall + WAIS-R Digit Symbol + hippocampus + entorhinal cortex 83.3% (86.8% correctly classified). Smaller hippocampal and entorhinal cortex volumes each contribute to the prediction of conversion to Alzheimer disease. Age and cognitive variables also contribute to prediction, and the added value of hippocampal and entorhinal cortex volumes is small. Nonetheless, combining these MRI volumes with age and cognitive measures leads to high levels of predictive accuracy that may have potential clinical application.

CaMKII Activation in the Entorhinal Cortex Disrupts Previously Encoded Spatial Memory

To investigate the role of the entorhinal cortex in memory at a molecular level, we developed transgenic mice in which transgene expression was inducible and limited to the superficial layers of the medial entorhinal cortex, pre- and parasubiculum. We found that expression of a constitutively active mutant form of CaMKII in these structures disrupted spatial memory formation. Immediate post-training activation of the transgene disrupted previously established memory while transgene activation 3 weeks following the training was ineffective. These results demonstrate that, similar to the hippocampus, the entorhinal cortex plays a time-limited role in spatial memory formation but is not a final cortical repository of long-term memory. Moreover, these results suggest that the indiscriminate activation of CaMKII is able to disrupt preexisting memories, possibly by altering the pattern of synaptic weight changes that are thought to form the basis of the memory trace.

Brain imaging evidence of preclinical Alzheimer's disease in normal aging

This study was designed to test the hypothesis that baseline glucose metabolism and medial temporal lobe brain volumes are predictive of cognitive decline in normal older people. We performed positron emission tomography using [18F]fluorodeoxyglucose and structural magnetic resonance imaging at baseline in 60 cognitively normal community-dwelling older subjects who were part of a longitudinal cohort study. Subjects were followed for a mean of 3.8 years, with approximately annual evaluation of global cognition (the Modified Mini-Mental State Examination) and episodic memory (delayed recall). Baseline brain volumes and glucose metabolism were evaluated in relation to the rate of change in cognitive test scores. Six subjects developed incident dementia or cognitive impairment (converters). Baseline positron emission tomography scans showed regions in left and right angular gyrus, left mid-temporal gyrus, and left middle frontal gyrus that predicted the rate of change on the Modified Mini-Mental State Examination (p < 0.001). The left hemisphere temporal and parietal regions remained significant when converters were excluded. Both hippocampal (p = 0.03) and entorhinal cortical volumes (p = 0.01) predicted decline on delayed recall over time, and entorhinal cortical volumes remained significant when converters were excluded (p = 0.02). These brain volumes did not predict Modified Mini-Mental State Examination decline. These results indicate that temporal and parietal glucose metabolism predict decline in global cognitive function, and medial temporal brain volumes predict memory decline in normal older people. The anatomical location of these findings suggests detection of preclinical Alzheimer's disease pathology.

Temporal Lobe Epilepsy: More than Hippocampal Pathology

Voxel-based Morphometry of the Thalamus in Patients with Refractory Medial Temporal Lobe EpilepsyBonilha L, Rorden C, Castellano G, Cendes F, Li LMNeuroimage 2005;25:1016–1021Previous research has ...

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual's structural MRI, and fMRI activation was quantified within each region. Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE epsilon4 allele than in the 16 noncarriers. The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

Apolipoprotein E isoform does not predict hipporcampal or entorhinal volume atrophy in nondemented older adults

and stimulated (eg. sublingual 0.4 mg nitroglycerin) brain perfusion (eg. IV Tc-99m-HMPAO) studies to detect the low metabolism-preserved perfusion pattern characteristic of early neurodegeneration and the inverse pattern of early vascular disease. For either coincident or sequential studies the thyroid probe multichannel analyzer allows correction for F-18 downscatter into the Tc-99m window. We used doses 5 MBq to test system sensitivity and 370 MBq to validate RBU with dual-isotope brain SPECT. Average cortical brain activity with RBU or SPECT is normally within 30% of peak activity. Low tracer doses ( 5 MBq) detect abnormal (p 0.01) regions typically 50% peak brain activity within a 1 min acquisition with net cortical counts 10,000. Background, estimated to equal thigh counts, was typically 30% net cortical counts at 1 hr after dosing. Conclusions: Cortical Radioactive Brain Uptake (CRBU) uses readily available equipment. With both metabolism and perfusion tracers, about 10 acquisitions of 1 min each are simple to perform and relatively inexpensive ( $100). CRBU has potential for widespread use in screening patients with cognitive symptoms, especially due to Alzheimer’s disease whose metabolic-perfusion signature both identifies it and distinguishes the typically associated cerebrovascular disease.

MRI predictors of risk of incident Alzheimer disease

To determine if baseline entorhinal and hippocampal volumes and their rate of atrophy could predict the risk of incident Alzheimer disease (AD). The authors used proportional odds models to assess the relationship between entorhinal and hippocampal size and risk of incident AD among 58 nondemented elderly people. All participants were followed with annual clinical evaluations and structural MRI scans for up to 5 years (baseline and 5 years of follow-up). At baseline, 23 of 58 participants received a diagnosis of amnestic mild cognitive impairment (MCI) and 35 of 58 were healthy control subjects with no cognitive impairment. Structural MRI scans were acquired with a T1-weighted three-dimensional spoiled gradient-recalled echo pulse sequence in a 1.5 T scanner. Entorhinal and hippocampal volumes were derived from 1.6-mm gapless coronal images reformatted to be perpendicular to the long axis of the hippocampus and were normalized by dividing with intracranial volume. Fourteen of 58 nondemented participants developed AD during the follow-up period. Initial diagnosis of MCI was a significant predictor of incident AD. In addition, both baseline entorhinal volume and its slope of decline were independent predictors of incident AD, but initial hippocampal size and its rate of decline were not, after controlling for entorhinal volume. In nondemented individuals, entorhinal cortex atrophy is associated with risk of Alzheimer disease.

Relating Medial Temporal Lobe Volume to Frontal fMRI Activation for Memory Encoding in Older Adults

Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.

MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD

With high-resolution quantitative magnetic resonance imaging (MRI) techniques, it is possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer’s disease (AD). In the present study, 27 patients diagnosed with mild cognitive impairment (MCI) received a high-resolution MRI scan at baseline and were followed with yearly clinical evaluations. Ten of the 27 patients converted to AD during a 36-month period following the baseline clinical evaluation. Hippocampal and entorhinal cortex volumes derived from the baseline scan were compared to determine which of these two regions, known to be pathologically involved very early in the course of AD, could best differentiate MCI converters from non-converters. Although both entorhinal and hippocampal volumes were found to be independent predictors of the likelihood of conversion to AD, it was the right hemisphere entorhinal volume that best predicted conversion with a concordance rate of 93.5%.

Differential associations between entorhinal and hippocampal volumes and memory performance in older adults.

Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r= .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r= .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.

A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naive schizophrenia

Background: Imaging studies have frequently reported volume loss of limbic structures in schizophrenia, yet there appears to be no quantitative data on entorhinal cortex volumes in patients with neuroleptic naive first-episode schizophrenia. Methods: The volume of the entorhinal cortices of 22 control subjects and 18 patients with neuroleptic-naı̈ve first-episode schizophrenia were measured from magnetic resonance images (MRI) scans using recently designed anatomic criteria for MRI anatomy of the entorhinal cortex. Results: Smaller entorhinal volumes were found bilaterally in the schizophrenic patients. This volume loss did not correlate with items on the Positive and Negative Syndrome Scale. Conclusions: These data suggest early involvement of the entorhinal cortex in schizophrenia.

MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.

Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.

Quantitative MRI volumetry of the entorhinal cortex in temporal lobe epilepsy

The entorhinal cortex (Brodmann’s area 28) is located at the anterior aspect of the parahippocampal gyrus ventral to the amygdala and the hippocampus. It is reciprocally interconnected with the hippocampus via glutamatergic pathways. We investigated whether the entorhinal cortex is damaged in human temporal lobe epilepsy (TLE). The volume of the entorhinal cortex was measured using magnetic resonance imaging (MRI) in 36 patients with cryptogenic TLE and in 21 controls. The mean volumes of the entorhinal cortex on the focal side did not differ from controls. In 11 of 36 patients, however, the entorhinal cortex volume was reduced by 25%. Entorhinal volume correlated with hippocampal volume in TLE (ipsilaterally, r= 0.454, P< 0.01; contralaterally, r= 0.340, P< 0.05). Further, 64% of patients with 25% entorhinal cortex damage had ipsilateral hippocampal atrophy. On the other hand, right focal TLE patients with hippocampal atrophy had a 19% volume reduction of the ipsilateral entorhinal cortex (P< 0.05). The volume of the entorhinal cortex correlated with the duration of TLE (r= −0.335, P< 0.05). The present study indicates that the entorhinal cortex might be damaged in a subpopulation of patients with cryptogenic TLE. In most cases, volume reduction was associated with hippocampal damage. These data suggest that entorhinal damage contributes to the symptomatology in TLE.

Volumes of the Entorhinal and Perirhinal Cortices in Alzheimer’s Disease

We measured the volumes of the entorhinal, perirhinal, and temporopolar cortices on magnetic resonance images by using a recently designed histology-based protocol in 30 patients with early Alzheimer’s disease (AD) and 32 healthy control subjects. Compared to the controls, all of these cortical regions were significantly atrophied in AD patients ( p < 0.0001). However, the entorhinal cortex was the most severely involved brain region studied, with 40% volume loss, and this region provided the highest discriminative accuracy (92%) in separating patients with AD from healthy control subjects. Importantly, the entorhinal volume loss was evident already in mild AD. In addition, the volume of the entorhinal cortex was not dependent on age, but it did correlate significantly with the severity of the disease. Because it assesses the major site of initial neuropathological changes in AD, magnetic resonance imaging volumetric measurement of the entorhinal cortex can offer a tool for distinguishing AD patients even in the very early stages of the disease from healthy aged subjects.