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.     

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimer's disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.     

White matter lesions are associated with cortical atrophy more than entorhinal and hippocampal atrophy

The goal of this study was to examine the relationship between subcortical vascular disease and brain atrophy in patients with Alzheimer's disease (AD) and mixed dementia (i.e., AD and subcortical vascular disease together). MRI was performed on 77 cognitively normal (CN) subjects, 50 AD and 13 mixed dementia patients. Subcortical vascular disease was determined by white matter hyperintensities (WMH) volume and presence of subcortical lacunes. Brain atrophy was measured using total brain cortical gray matter (CGM), entorhinal cortex (ERC) and hippocampal volumes. CGM volume, but not ERC or hippocampal volume was inversely related to WMH volume in patients and controls. In contrast, no relationship was detected between CGM, ERC, or hippocampal volumes and subcortical lacunes. Furthermore, no interaction was found between WMH and diagnosis on cortical atrophy, implying that WMH affect cortical atrophy indifferently of group. These results suggest that subcortical vascular disease, manifested as WMH, may affect cortical atrophy more than ERC and hippocampal atrophy. Further, AD pathology and subcortical vascular disease may independently affect cortical atrophy.     

Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders

In this paper, we review the evidence indicating that the common disturbance in recent memory associated with aging is a consequence of functional and structural impairment in the hippocampal formation. In the Fischer 344 rat, an experimental model of the human age-related memory disorder was developed. The majority of aged rats of this strain show impaired performance in the 8-arm radial maze in a manner typical of young rats with bilateral hippocampal lesions. Aged animals also exhibit rapid decay of LTP and slower kindling of the perforant path-dentate synapse. Furthermore, quantitative morphometric analysis of the hippocampal synaptic architecture revealed that aged, memory-impaired rats had a specific loss of perforated axospinous synapses in the middle third of the dentate gyrus molecular layer; the extent of loss was directly related to the degree of memory dysfunction. Most important was the fact that the electrophysiological and morphological abnormalities did not appear in equally old animals with good memory.     

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.     

Increased hippocampal atrophy rates in AD over 6 months using serial MR imaging

We measured hippocampi on baseline-, 6- and 12-month scans in a group of AD (n = 36) and control subjects (n = 20). We found that mean annualised atrophy rates using 6-month intervals were comparable at a group level to those generated from a 12-month interval. Higher variance was seen using shorter intervals, although this was only significant in the control group. This has implications where shorter inter-scan intervals may be advantageous, such as rapid diagnosis, and tracking of disease progression including in a clinical trial.     

Absent gender differences of hippocampal atrophy in amnestic type mild cognitive impairment

Hippocampus displayed progressively gender-associated damage in Alzheimer's disease. However, gender effects have been largely neglected in studies of amnestic type mild cognitive impairment (aMCI) patients who were believed to represent an early stage of this disease. The goal of this study was to use in vivo neuroimaging techniques to determine whether there were any evidences of gender differences in hippocampal atrophy in aMCI. A region of interest-based magnetic resonance imaging approach was used to compare hippocampal volume between aMCI patients (22 male, 17 female) and normal aging controls (12 male, 11 female). Independent of group, male hippocampal volumes were larger than female volumes and right hippocampal volumes were typically smaller than left volumes. Hippocampal volumes were significantly reduced in the clinical group but no gender differences were noted in terms of degree of atrophy present. However, female patients showed more impaired cognitive function than male patients despite this apparent equivalence in atrophy. The absence of a gender difference suggested that early neuropathological progression might be independent of gender. However, the data also suggested female aMCI patients had an increased vulnerability to cognitive impairment earlier in the illness course.     

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.     

Abnormal white matter independent of hippocampal atrophy in amnestic type mild cognitive impairment

Hippocampal atrophy is the key marker in the pathogenesis of Alzheimer's disease (AD), which is associated with white matter (WM) disruption. This type of WM disruption could partly explain AD-related pathology. However, relatively little attention has been directed toward WM disruption which may be independent of these fundamental gray matter (GM) changes in amnestic mild cognitive impairment (aMCI) which is associated with high risk of AD. To evaluate the differences of WM integrity between aMCI patients (N = 32) and healthy controls (N = 31), whole-brain voxel-based methods were applied to diffusion tensor imaging. To explore the possible independence of WM changes from GM loss, an index of hippocampal atrophy was used to partial out GM effects. aMCI patients showed WM disruption in frontal lobe, temporal lobe, internal capsule, cingulate gyrus and precuneus. The findings supported the evidence of independent patterns of degeneration in WM tracts which may co-act in the WM pathological process of aMCI patients. As aMCI is a putatively prodromal syndrome to AD, these data may assist with a better understanding of WM pathological change associated with the development of AD.     

Neither perirhinal/entorhinal nor hippocampal lesions impair short-term auditory recognition memory in dogs.

Visual, tactile, and olfactory recognition memory in animals is mediated in part by the perirhinal/entorhinal (or rhinal) cortices and, possibly, the hippocampus. To examine the role of these structures in auditory memory, we performed rhinal, hippocampal, and combined lesions in groups of dogs trained in auditory delayed matching-to-sample with trial-unique sounds. The sample sound was presented through a central speaker and, after a delay, the sample sound and a different sound were played alternately through speakers placed on either side of the animal; the animal was rewarded for responding to the side emitting the sample sound. None of the lesion groups showed significant impairment in comparison either to their own preoperative performance or to the performance of intact control dogs. This was the case both for relearning the delayed matching rule at a delay of 1.5 s and for task performance at variable delays ranging from 10 to 90 s.From these findings we suggest that the tissue critical for auditory recognition memory is located outside both the perirhinal/entorhinal cortices and the hippocampus.     

Dissociating entorhinal and hippocampal involvement in latent inhibition

This study used anatomical cues to suggest a functional dissociation between the roles of the entorhinal cortex and the hippocampus in learning. The authors proposed that the highly convergent inputs to the entorhinal cortex indicate this region may be particularly important for selecting or compressing information. This hypothesis was tested in rabbits (Oryctolagus cunniculus) trained on an associative learning task that is a common index of stimulus selection. In this task, known as latent inhibition, preexposure to a stimulus (such as a tone) leads to slowed learning when the same tone is subsequently paired with an outcome (such as an airpuff to the eye). As hypothesized, rabbits with neurotoxic lesions of the entorhinal cortex failed to show slowed learning following preexposure (no latent inhibition) and learned the association faster than control rabbits. In contrast, hippocampal-lesioned animals showed normal (slowed) learning.     

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis

Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimer's disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.     

Electrophysiological analysis of the hippocampal projections to the entorhinal area

Responses evoked in the entorhinal area by impulse volleys originating in the ipsilateral hippocampus were analysed in the guinea-pig by means of field potential analysis. Perforant path volleys, synaptically elicited by stimulation of the dorsal psalterium of one side, were used to activate the hippocampal lamellar circuit of the same side and, through interhippocampal impulses, the hippocampal pyramidal neurons of the contralateral side. Discharge of the hippocampal pyramidal neurons was followed by a response, a fast negative deflection preceded and followed by slow waves, in the dorsal third of the ipsilateral entorhinal area. Laminar distribution of the fast negative deflection and of the time-locked unit activity suggested that excitatory synaptic effects followed by neuron discharge were generated in neurons of layers VI-II of the entorhinal area. The increasing latency of the fast negative deflection and of unit firing over the cortical depth suggested that these synaptic effects were generated in temporal sequence, going from layer VI to layer II. The entorhinal response disappeared after a lesion at the caudal border of the hippocampus interrupting the caudally-directed hippocampal efferents. The anatomy of the hippocampal and subicular projections to the entorhinal area in the guinea-pig, together with electrophysiological data obtained in recordings from the ipsilateral subiculum, suggested that the hippocampal impulses were relayed to layers VI-V of the entorhinal area by the subiculum. The delayed activation of layers IV-II was possibly mediated by intracortical connections. Double-shock experiments showed that impulses of hippocampal origin inhibited the response to dorsal psalterium volleys of entorhinal neurons giving origin to perforant path fibers. The data show that the hippocampal output activates the deep layers of the entorhinal area from which it is possibly relayed to numerous cortical and subcortical regions. Moreover, the inhibitory effects exerted on neurons originating perforant path fibers give evidence of a negative feedback control system operating in the hippocampal region.     

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%.     

Age effects on atrophy rates of entorhinal cortex and hippocampus

The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04+/-0.02% per year for ERC and 0.05+/-0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE epsilon4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.     

Reliable change scores and their relation to perceived change in memory: implications for the diagnosis of mild cognitive impairment.

The relation between the subjective report of memory problems and objective evidence of the same has been debated with mixed results appearing in the literature. Less is known about the relation between objective change in test performance and the perceptions of cognitive change from family members/friends and trained clinicians. These relations were explored using 5-year longitudinal data from the population-based Canadian Study of Health and Aging. Statistically reliable deterioration in memory test performance was determined using a standardized regression-based (SRB) approach and a Reliable Change Index (RCI) that accounts for aging and practice effects. Among a subsample of persons with no cognitive impairment (NCI) at baseline, there was a moderate relation between reliable test score decline and ratings made by clinicians and informants. No relation, however, was found with the subjective reports of memory difficulties. These findings hold implications for current mild cognitive impairment (MCI) criteria which include subjective, informant and/or clinician ratings of cognitive decline.     

旱莲草对老年痴呆模型大鼠空间学习记忆及海马神经元突触可塑性的影响

目的:观察旱莲草对D-半乳糖联合β-淀粉样蛋白25-35(Aβ25-35)致老年痴呆(Alzheimer’s disease,AD)模型大鼠空间学习记忆及海马神经元突触可塑性的影响。方法:选用健康成年SD大鼠,随机分为对照组、模型组、药物低剂量组、高剂量组,每组11只。采用皮下注射D-半乳糖联合双侧海马注射Aβ25-35构建痴呆模型大鼠,同时每天给予低剂量(8 g/kg)或高剂量(24 g/kg)的旱莲草水提物灌胃治疗8周。用药结束后,用Morris水迷宫测试大鼠空间学习记忆功能,采用高频刺激(HFS)Schaffer侧支,在同侧海马CA1区诱导长时程增强(LTP)的方法检测大鼠海马神经元突触可塑性的变化。结果:Morris水迷宫实验结果显示:与对照组相比,模型组大鼠的逃避潜伏期(EL)明显延长(P<0.01)、平台所在象限的距离百分比明显减低(P<0.01);药物低剂量组、高剂量组的EL与模型组相比有明显缩短(P<0.05),平台所在象限的距离百分比明显增多(P<0.01);药物高剂量组的EL较低剂量组缩短(P<0.05),平台所在象限的距离百分比增多(P<0.05)。模型组与对照组相比海马CA1区LTP幅度显著降低(P<0.01);药物低剂量组与模型组比较,PS幅度差异不明显(P>0.05);而药物高剂量组PS幅度明显高于模型组和低剂量组,能减轻D-半乳糖联合Aβ25-35对海马CA1区LTP的抑制作用,改善突触功能的可塑性(P<0.01)。结论:旱莲草对老年痴呆模型大鼠空间学习记忆功能具有改善作用,其机制之一可能与提高大鼠海马CA1区的LTP,明显改善突触的可塑性有关。     

Electrophysiological analysis of the dorsal hippocampal commissure projections to the entorhinal area

Synaptic effects evoked in the entorhinal area by dorsal hippocampal commissure (dorsal psalterium) projections were analysed in anesthetized adult guinea-pigs by means of a field potential analysis. Stimuli applied to the caudal part of the dorsal psalterium evoked a complex response in the dorsal third of the entorhinal area. The early part of the entorhinal response consisted of a slow wave interrupted by a spike potential. The electrophysiological characteristics and the laminar distribution of the slow wave and of the spike potential, together with the presence of time-locked unit activity, suggested that dorsal psalterium projections evoke monosynaptic excitatory postsynaptic potentials leading to cellular discharge in radially oriented neurons of layers II and III. The commissural fibers responsible for these effects originate in the contralateral presubiculum. The early part of the entorhinal response was followed by three waves in close temporal sequence. These waves were polysynaptically generated and associated with excitatory and inhibitory synaptic effects. Inhibition was demonstrated for the monosynaptically generated spike potential. Whether these effects were mediated by intracortical circuits and/or extrinsic projections cannot be stated from the present results. Causal relations were observed between the entorhinal monosynaptic response and that evoked by dorsal psalterium stimulation in the ipsilateral dentate gyrus, previously shown to be relayed by perforant path fibers. The results indicate that presubicular commissural projections to the entorhinal area monosynaptically activate neurons of the perforant pathway, whose discharge brings about activation of the ipsilateral dentate gyrus.     

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.