Long-Term Response to Cholinesterase Inhibitor Treatment Is Related to Functional MRI Response in Alzheimer's Disease.

BACKGROUND: Treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEI) enhances cholinergic activity and alleviates clinical symptoms. However, there is variation in the clinical response as well as system level changes revealed by functional MRI (fMRI) studies. METHODS: We investigated 18 newly diagnosed mild AD patients with fMRI using a face recognition task after a single oral dose of rivastigmine, a single dose of placebo and 1-month treatment with rivastigmine. The clinical follow-up took place at 6 and 12 months. RESULTS: MMSE score difference between baseline and the follow-ups showed a positive correlation with fMRI activation difference between treatment and placebo in the right prefrontal cortex. A negative correlation was found for the left prefrontal cortex and the left fusiform gyrus. In addition, greater signal intensity in the right versus the left fusiform gyrus predicted a response to ChEI with increasing MMSE scores during the follow-up with 77.8% sensitivity and 77.8% specificity. CONCLUSIONS: The increased fMRI activation by cholinergic stimulation in brain areas associated with the processing of the visual task reveals still functioning brain networks and a subsequent positive effect of ChEI on cognition. Thus, fMRI may be useful for identifying AD patients most likely to respond to treatment with ChEI.

Structure and function of medial temporal and posteromedial cortices in early Alzheimer's disease.

Medial temporal lobe (MTL) atrophy and posteromedial cortical hypometabolism are consistent imaging findings in Alzheimer's disease (AD). As the MTL memory structures are affected early in the course of AD by neurofibrillary tangle pathology, the posteromedial metabolic abnormalities have been postulated to represent remote effects of MTL alterations. In this study, we investigated with functional MRI (fMRI) the structure-function relationship between the MTL and posteromedial regions, including the retrosplenial, posterior cingulate and precuneal cortices, in 21 older controls (OCs), 18 subjects with amnestic mild cognitive impairment (MCI) and 16 AD patients during a word list learning task. In the voxel-based morphometric and volumetric analyses, the MCI subjects showed smaller entorhinal volume than OCs (P = 0.0001), whereas there was no difference in the hippocampal or posteromedial volume. AD patients, as compared with MCI patients, showed pronounced loss of volume in the entorhinal (P = 0.0001), hippocampal (P = 0.01) and posteromedial (P = 0.001) regions. The normal pattern of posteromedial fMRI task-induced deactivation during active encoding of words was observed bilaterally in the OCs, but only in restricted unilateral left posteromedial areas in the MCI and AD patients. Across all subjects, more extensive impairment of the retrosplenial and posterior cingulate function was significantly related to smaller entorhinal (P = 0.001) and hippocampal (P = 0.0002) volume. These findings demonstrate that entorhinal atrophy and posteromedial cortical dysfunction are early characteristics of prodromal AD, and precede and/or overwhelm atrophy of the hippocampus and posteromedial cortices. Disturbances in posteromedial cortical function are associated with morphological changes in the MTL across the continuum from normal aging to clinical AD.

Effect of cholinergic stimulation in early Alzheimer's disease - functional imaging during a recognition memory task.

Treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (AChEI) enhances cholinergic activity and alleviates clinical symptoms. In the present functional magnetic resonance imaging (fMRI) study, we investigated the effect of the AChEI rivastigmine on cognitive function and brain activation patterns during a face recognition memory task. Twenty patients with newly-diagnosed mild AD were administered a single oral dose of placebo, a single dose of rivastigmine (acute), and twice-daily treatment with rivastigmine for 4 weeks (chronic). After each treatment, the patients underwent a facial recognition task during fMRI. The prefrontal areas known to be involved in face recognition memory processing demonstrated greater fMRI activity in both the acute and chronic rivastigmine conditions compared to the placebo condition. In the same brain areas, differences in both fMRI activation at the map level and regional fMRI signal intensity measures between the placebo and chronic treatment conditions correlated negatively with the Mini- Mental State Examination score. In the chronic rivastigmine condition, patients with better preserved cognitive abilities demonstrated less enhanced prefrontal activity, whereas patients with poorer cognition showed greater prefrontal activity. These findings suggest that the prefrontal attention/working memory systems are already impaired in the early stages of AD and that the effect of cholinergic medication in the brain areas involved in recognition memory, i.e., increased or decreased fMRI activation patterns, depends on the severity of the disease. These findings also suggest the importance of early AChEI treatment in the course of AD, at the point when there is still some cognitive reserve available and the therapy has the highest potential efficacy.

Failure of repetition suppression and memory encoding in aging and Alzheimer's disease.

The suppression of neural activity in the medial temporal lobe (MTL) has been suggested as a marker of successful recognition of familiarity in healthy subjects, but to be impaired in patients with Alzheimer's disease (AD). In this study, we investigated whether the ability to suppress MTL activity during repeated exposure to face-name pairs was related to the ability to successfully encode novel associations in 90 individuals ranging from healthy young and older subjects to mildly impaired elderly and AD patients. Activity in the anterior MTL during Repeated stimuli was inversely related to performance in post-scan associative recognition for the Novel face-name pairs. In a subset (n=60) of subjects undergoing more detailed neuropsychological testing, greater MTL Repeated activity was correlated with worse word-list delayed recall performance. Failure of response suppression to familiar information may be a sensitive marker of MTL dysfunction and memory impairment in aging and prodromal AD.

Intrinsic connectivity between the hippocampus and posteromedial cortex predicts memory performance in cognitively intact older individuals.

Coherent fluctuations of spontaneous brain activity are present in distinct functional-anatomic brain systems during undirected wakefulness. However, the behavioral significance of this spontaneous activity has only begun to be investigated. Our previous studies have demonstrated that successful memory formation requires coordinated neural activity in a distributed memory network including the hippocampus and posteromedial cortices, specifically the precuneus and posterior cingulate (PPC), thought to be integral nodes of the default network. In this study, we examined whether intrinsic connectivity during the resting state between the hippocampus and PPC can predict individual differences in the performance of an associative memory task among cognitively intact older individuals. The intrinsic connectivity, between regions within the hippocampus and PPC that were maximally engaged during a subsequent memory fMRI task, was measured during a period of rest prior to the performance of the memory paradigm. Stronger connectivity between the hippocampal and posteromedial regions during rest predicted better performance on the memory task. Furthermore, hippocampal-PPC intrinsic connectivity was also significantly correlated with episodic memory measures on neuropsychological tests, but not with performance in non-memory domains. Whole-brain exploratory analyses further confirmed the spatial specificity of the relationship between hippocampal-default network posteromedial cortical connectivity and memory performance in older subjects. Our findings provide support for the hypothesis that one of the functions of this large-scale brain network is to subserve episodic memory processes. Research is ongoing to determine if impaired connectivity between these regions may serve as a predictor of memory decline related to early Alzheimer's disease.

Functional alterations in memory networks in early Alzheimer's disease.

The hallmark clinical symptom of early Alzheimer's disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.

Evidence of altered posteromedial cortical FMRI activity in subjects at risk for Alzheimer disease.

The posteromedial cortices and other regions of the "default network" are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed functional magnetic resonance imaging (fMRI) to investigate whether the presence of apolipoprotein E (APOE) epsilon allele and degree of memory impairment were associated with the dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into epsilon carriers and noncarriers, underwent fMRI during a memory-encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the epsilon carriers relative to noncarriers. Even among cognitively normal subjects, epsilon carriers demonstrated reduced posteromedial deactivation compared with the noncarriers in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE epsilon and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD.

Differences in cortical thickness in healthy controls, subjects with mild cognitive impairment, and Alzheimer's disease patients: a longitudinal study.

In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum followup time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical surface model. Compared to HC group (n = 26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype.

Cortical thickness analysis to detect progressive mild cognitive impairment: a reference to Alzheimer's disease.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) is associated with an increased risk of Alzheimer's disease (AD). It would be advantageous to be able to distinguish the characteristics of those MCI patients with a high probability to progress to AD if one wishes to monitor the disease development and treatment. METHODS: We assessed the baseline MRI and maximum of 7 years clinical follow-up data of 60 MCI subjects in order to examine differences in cortical thickness (CTH) between the progressive MCI (P-MCI) and stable MCI (S-MCI) subjects. CTH was measured using an automatic computational surface-based method. During the follow-up, 15 MCI subjects converted to AD on average 1.9 +/- 1.3 years after the baseline examination, while 45 MCI subjects remained stable. RESULTS: The P-MCI group displayed significantly reduced CTH bilaterally in the superior and middle frontal, superior, middle and inferior temporal, fusiform and parahippocampal regions as well as the cingulate and retrosplenial cortices and also in the right precuneal and paracentral regions compared to S-MCI subjects. CONCLUSIONS: Analysis of CTH could be used in conjunction with neuropsychological testing to identify those subjects with imminent conversion from MCI to AD several years before dementia diagnosis.

Functional MRI assessment of task-induced deactivation of the default mode network in Alzheimer's disease and at-risk older individuals.

Alzheimer's disease (AD) is the most common form of dementia in old age, and is characterized by prominent impairment of episodic memory. Recent functional imaging studies in AD have demonstrated alterations in a distributed network of brain regions supporting memory function, including regions of the default mode network. Previous positron emission tomography studies of older individuals at risk for AD have revealed hypometabolism of association cortical regions similar to the metabolic abnormalities seen in AD patients. In recent functional magnetic resonance imaging (fMRI) studies of AD, corresponding brain default mode regions have also been found to demonstrate an abnormal fMRI task-induced deactivation response pattern. That is, the relative decreases in fMRI signal normally observed in the default mode regions in healthy subjects performing a cognitive task are not seen in AD patients, or may even be reversed to a paradoxical activation response. Our recent studies have revealed alterations in the pattern of deactivation also in elderly individuals at risk for AD by virtue of their APOE e4 genotype, or evidence of mild cognitive impairment (MCI). In agreement with recent reports from other groups, these studies demonstrate that the pattern of fMRI task-induced deactivation is progressively disrupted along the continuum from normal aging to MCI and to clinical AD and more impaired in e4 carriers compared to non-carriers. These findings will be discussed in the context of current literature regarding functional imaging of the default network in AD and at-risk populations.

Amyloid deposition is associated with impaired default network function in older persons without dementia.

Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Structural and functional MRI in mild cognitive impairment.

Mild cognitive impairment (MCI), and the amnestic subtype of MCI in particular, is the most recent concept used to describe the intermediary state between healthy aging and Alzheimer's disease (AD). It is hoped that research focusing on MCI would yield markers for early identification of individuals with prodromal AD at such a pre-dementia stage when potential disease modifying therapies would be most efficacious. Magnetic resonance imaging (MRI) combined with various data analysis methods provides tools to investigate alterations in brain structure and function in vivo. Structurally, MCI is characterized by atrophy of the medial temporal lobe (MTL) structures such as the hippocampus and entorhinal cortex, and the amount of atrophy in MCI is intermediate between healthy aging and AD. Additionally, atrophy of the posteromedial cortices such as the posterior cingulum and precuneus as well as of the lateral temporal cortices has been reported. The pattern of atrophy appears to vary according to the subtype of MCI. Functional MRI studies in MCI, compared to healthy aging and AD, have demonstrated both increased and decreased MTL activity during encoding novel visually presented material. Differences in the MTL activation pattern in MCI subjects may relate to differences in the severity of cognitive decline. There is some evidence that increased MTL activity observed during encoding may be compensatory due to incipient atrophy in the MTL structures. The resting state (or, "default mode") network, and the posteromedial cortical regions in particular, appear to malfunction in MCI. It is suggested that both altered MTL and posteromedial cortical function may be indicative of future cognitive decline from MCI to clinical AD.

Discriminating accuracy of medial temporal lobe volumetry and fMRI in mild cognitive impairment.

We investigated structural and functional changes in the medial temporal lobe (MTL) using magnetic resonance imaging (MRI) and compared the discriminative power of these measures with neuropsychological testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Functional MRI (fMRI) was performed in 21 elderly controls, 14 MCI subjects, and 15 mild AD patients during encoding and cued retrieval of word-picture pairs. A region-of-interest-based approach in SPM2 was used to extract the extent of hippocampal activation. The volumes of the hippocampus and entorhinal cortex (EC) were manually outlined from anatomical MR images. Discriminant analyses were conducted to assess the ability of hippocampal fMRI, MTL volumetry, and neuropsychological measures to classify subjects into clinical groups. Entorhinal but not hippocampal volumes differed significantly between the control and MCI subjects. Both entorhinal and hippocampal volumes differed between MCI and AD patients. There were no significant differences in the extent of hippocampal fMRI activation during encoding or retrieval between the groups. Entorhinal volume was the best discriminator with a discriminating accuracy of 85.7% between controls and MCI, 86.2% between MCI and AD, and 97.2% between controls and AD. Delayed recall of a wordlist classified the subjects, second best, with a discriminating accuracy of 81.8% between controls and MCI, 75% between MCI and AD and 93.5% between controls and AD. The accuracy of hippocampal volumetry ranged from 42.9 to 69.4%, and hippocampal fMRI activation during encoding and retrieval had a classification accuracy of only 41.4-57.7% between the groups. Our results suggest that evaluation of entorhinal atrophy, in addition to the prevailing diagnostic criteria, seems promising in the identification of prodromal AD. Future technical improvements may improve the utilization of hippocampal fMRI for early diagnostic purposes.

Impaired medial temporal repetition suppression is related to failure of parietal deactivation in Alzheimer disease.

OBJECTIVES: Neural networks supporting encoding of new information are affected early in the course of Alzheimer disease (AD). Functional magnetic resonance imaging (fMRI) studies in AD have reported decreased medial temporal lobe (MTL) activation when comparing novel versus repeated stimuli. It is, however, unclear whether this finding is related to a failure of normal suppression of MTL activity to repeated stimuli in AD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Twenty-nine healthy older subjects comprising a comparison group (OC) and 15 mild AD patients underwent fMRI during an associative memory paradigm in an academic medical center. The task consisted of blocks of Novel and Repeated face-name pairs and visual Fixation. To reveal neural correlates of processing repeatedly presented stimuli, Repeated blocks were contrasted to Fixation. RESULTS: AD patients demonstrated greater activation during Repeated stimuli in the MTL and in prefrontal and superior parietal cortices, compared with OC. In contrast, OC showed greater parietal task-induced deactivation than AD. Increased MTL activity during Repeated was correlated with more impaired parietal deactivation and poorer performance of the postscan recognition memory test of encoding the face-name pairs. CONCLUSION: Reduction of MTL activity to repeated stimuli, which become highly familiarized to healthy OC, was impaired in AD. This abnormal increased MTL activation was related to disrupted parietal deactivation and to poor recognition memory performance. These preliminary results suggest that the typical episodic memory impairment seen in mild AD may manifest as a failure of normal repetition suppression and loss of "beneficial" deactivation in the MTL-parietal memory networks.

Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation.

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face-name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions.

MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study.

The concept of mild cognitive impairment (MCI) has been proposed to represent a transitional stage between normal aging and dementia. We studied the predictive value of the MRI-derived volumes of medial temporal lobe (MTL) structures, white matter lesions (WML), neuropsychological tests, and Apolipoprotein E (APOE) genotype on conversion of MCI to dementia and AD. The study included 60 subjects with MCI identified from population cohorts. During the mean follow-up period of 34 months, 13 patients had progressed to dementia (9 to Alzheimer's disease (AD)). In Cox regression analysis the baseline volumes of the right hippocampus, the right entorhinal cortex and CDR sum of boxes predicted the progression of MCI to dementia during the follow-up. In a bivariate analysis, only the baseline volumes of entorhinal cortex predicted conversion of MCI to AD. The Mini-Mental State Examination (MMSE) score at baseline, WML load, or APOE genotype were not significant predictors of progression. The MTL volumetry helps in identifying among the MCI subjects a group, which is at high risk for developing AD.

Increased fMRI responses during encoding in mild cognitive impairment.

Structural and functional magnetic resonance imaging (fMRI) was performed on 21 healthy elderly controls, 14 subjects with mild cognitive impairment (MCI) and 15 patients with mild Alzheimer's disease (AD) to investigate changes in fMRI activation in relation to underlying structural atrophy. The fMRI paradigm consisted of associative encoding of novel picture-word pairs. Structural analysis of the brain was performed using voxel-based morphometry (VBM) and hippocampal volumetry. Compared to controls, the MCI subjects exhibited increased fMRI responses in the posterior hippocampal, parahippocampal and fusiform regions, while VBM revealed more atrophy in MCI in the anterior parts of the left hippocampus. Furthermore, the hippocampal volume and parahippocampal activation were negatively correlated in MCI, but not in controls or in AD. We suggest that the increased fMRI activation in MCI in the posterior medial temporal and closely connected fusiform regions is compensatory due to the incipient atrophy in the anterior medial temporal lobe.

Distinct and overlapping fMRI activation networks for processing of novel identities and locations of objects.

The ventral visual stream processes information about the identity of objects ('what'), whereas the dorsal stream processes the spatial locations of objects ('where'). There is a corresponding, although disputed, distinction for the ventrolateral and dorsolateral prefrontal areas. Furthermore, there seems to be a distinction between the anterior and posterior medial temporal lobe (MTL) structures in the processing of novel items and new spatial arrangements, respectively. Functional differentiation of the intermediary mid-line cortical and temporal neocortical structures that communicate with the occipitotemporal, occipitoparietal, prefrontal, and MTL structures, however, is unclear. Therefore, in the present functional magnetic resonance imaging (fMRI) study, we examined whether the distinction among the MTL structures extends to these closely connected cortical areas. The most striking difference in the fMRI responses during visual presentation of changes in either items or their locations was the bilateral activation of the temporal lobe and ventrolateral prefrontal cortical areas for novel object identification in contrast to wide parietal and dorsolateral prefrontal activation for the novel locations of objects. An anterior-posterior distinction of fMRI responses similar to the MTL was observed in the cingulate/retrosplenial, and superior and middle temporal cortices. In addition to the distinct areas of activation, certain frontal, parietal, and temporo-occipital areas responded to both object and spatial novelty, suggesting a common attentional network for both types of changes in the visual environment. These findings offer new insights to the functional roles and intrinsic specialization of the cingulate/retrosplenial, and lateral temporal cortical areas in visuospatial cognition.

Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans.

A number of studies in rodents and monkeys report a distinction between the contributions of the hippocampus and perirhinal cortex to memory, such that the hippocampus is crucial for spatial memory whereas the perirhinal cortex has a pivotal role in perception and memory for visual objects. To determine if there is such a distinction in humans, we conducted a functional magnetic resonance imaging study to compare the medial temporal lobe responses to changes in object identity and spatial configurations of objects. We found evidence for the predicted distinction between hippocampal and perirhinal cortical activations, although part of the hippocampus was also activated by identification of novel objects. Additionally, an anterior-posterior activation gradient emerged inside the hippocampus and parahippocampal cortex. The anterior hippocampus, perirhinal cortex and anterior parahippocampal cortex are involved in perception of contextually novel objects, whereas the posterior hippocampus and posterior parahippocampal cortex are involved in processing of novel arrangements of familiar objects. These results demonstrate that there is a functional dissociation between processing of novel object identities and new spatial locations of objects among the subregions of medial temporal lobe structures in humans also.

Encoding of novel picture pairs activates the perirhinal cortex: an fMRI study.

It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding. In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory. Little is known, however, regarding the function of the rhinal cortex in humans in vivo. To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects. The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 0.00001). In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 0.05). The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus. The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions. During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval. The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons. The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex. To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD.