Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease

OBJECTIVES: To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration. METHODS: Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD--the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1. RESULTS: There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group. CONCLUSIONS: There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.     

Visual association pathology in preclinical Alzheimer disease

The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD. We found that 52% of the cognitively intact subjects, and all subjects with mild cognitive impairment or dementia, had dense neurofibrillary tangles (NFTs), neuropil threads, and tau-immunoreactive neurites surrounding neuritic plaques (NPs) in visual association cortex Brodmann area 19. All cognitively intact subjects with area 19 NFTs also had dense core NP and beta amyloid (Abeta) angiopathy in area 19. Area 19 pathology was occasionally present in the absence of substantial pathology in the hippocampus or entorhinal cortex and was not correlated with medial temporal lobe pathology. Dense AD pathology in area 19 is present in some cognitively intact subjects with preclinical AD. The unique metabolic, connectional, and vascular features of this region may confer enhanced vulnerability to neurodegeneration.     

Structural changes of the corpus callosum in mild cognitive impairment and Alzheimer's disease

BACKGROUND: Although previous studies demonstrate significant atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD), CC alterations in mild cognitive impairment have not been investigated yet. METHODS: 21 subjects with mild cognitive impairment, 10 with AD and 21 healthy controls were investigated using magnetic resonance imaging. In the mid-sagittal slice the CC was traced manually. Additionally, voxel-based morphometry (VBM) was performed. RESULTS: The CC was significantly smaller in patients with AD compared to healthy controls in both manual tracing and VBM. The atrophy was prominent in rostral parts of the CC. In subjects with mild cognitive impairment, the two rostral CC segments were smaller compared to controls when manually traced. In contrast, VBM revealed no significant difference between subjects with mild cognitive impairment and controls. CONCLUSION: Manual tracing was more sensitive in detecting discrete structural CC changes than VBM. Alterations of the CC in mild cognitive impairment rank in between normal aging and AD, supporting the hypothesis that mild cognitive impairment most often represents a preclinical stage of AD.     

Neurofibrillary tangles,amyloid, and memory in aging and mild cognitive impairment

BACKGROUND: Large numbers of neurofibrillary tangles (NFTs) and amyloid plaques are diagnostic markers for Alzheimer disease (AD), but lesser numbers of these lesions are also seen in nondemented elderly individuals. Much of the existing literature suggests that the NFTs of AD have a closer correlation with cognitive function than do amyloid plaques. Whether a similar relationship exists in normal aging and mild cognitive impairment (MCI), a condition that frequently reflects a preclinical stage of AD, remains unknown. OBJECTIVE: To determine the distribution patterns of beta-amyloid plaques and NFTs and the association of these lesions with memory performance in nondemented individuals. METHODS: We investigated regional distributions and neuropsychological correlates of NFTs and amyloid plaques in cognitively normal elderly persons and subjects with MCI who received neuropsychological testing before death.Subjects Eight nondemented subjects who volunteered to receive annual neuropsychological testing and agreed to brain donation were studied. Five subjects showed no cognitive impairment, and 3 were diagnosed with MCI. RESULTS: Distribution of NFTs followed a rigorous and hierarchical pattern, but distribution of amyloid plaques varied among individuals. Subjects with MCI displayed higher NFT densities than did nonimpaired subjects. In addition, NFT density in the temporal lobe correlated with memory scores, whereas density of amyloid plaques did not. CONCLUSIONS: Neurofibrillary tangles are more numerous in medial temporal lobe regions associated with memory function and show a relationship to performance on memory tests in nondemented individuals. These results suggest that NFTs may constitute a pathological substrate for memory loss not only in AD but also in normal aging and MCI.     

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer''s disease compared to normal controls

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups has smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.     

Oxidative Damage to RNA in Aging and Neurodegenerative Disorders

An age-associated increase in oxidative damage to nucleic acids, predominantly to RNA, has been recently demonstrated in neurons of human and rodent brains, which may play a fundamental role in the development of age-associated neurodegeneration. Indeed, more prominent levels of neuronal RNA oxidation compared to normal aging have been described in neurodegenerative disorders including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Moreover, oxidative damage to RNA has been found also in cellular and animal model of neurodegeneration. Oxidative RNA modification can occur not only in protein-coding RNAs but also in non-coding RNAs that are recently revealed to contribute towards the complexity of the mammalian brain. It has been hypothesized that RNA oxidation causes aberrant expression of microRNAs and proteins and subsequently initiates inappropriate cell fate pathways. While less lethal than mutations in the genome and not inheritable, such sublethal damage to cells might be associated with underlying mechanisms of degeneration, especially age-associated neurodegeneration. Of particular interest, the accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that RNA oxidation is a feature in neurons of aging brain and more prominently observed in vulnerable neurons at early-stage of age-associated neurodegenerative disorders, indicating that RNA oxidation actively contributes to the background, the onset, and the development of the disorders. Further investigations aimed at understanding of the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and lead to better therapeutic strategies.     

Cognitive decline in AD and mild cognitive impairment is associated with global brain damage

OBJECTIVE: To investigate the relationships between structural damage in the whole brain, the temporal lobes, and the frontal lobes and cognitive decline at old age. The authors hypothesized that widespread brain damage as quantified using magnetization transfer imaging (MTI) is related to global cognitive decline, whereas regional damage to the temporal lobes is related to memory impairment, and regional damage to the frontal lobes is related to executive dysfunctioning. METHODS: Cognitive function of 22 patients with probable AD, 13 patients with mild cognitive impairment (MCI), and 28 elderly controls was assessed using an extensive neuropsychological test battery. Structural damage in the whole brain, the temporal lobes, and the frontal lobes was estimated using volumetric MTI analysis. Associations between MTI measures and neuropsychological tests were investigated using Pearson correlation analysis. RESULTS: MTI measures of the whole brain, as well as the temporal and the frontal lobes, were strongly associated with global cognitive deterioration and impairment in memory, orientation, language, praxis, gnosis, and executive functioning. However, there were no specific cognitive correlates of regional brain damage to the temporal and frontal lobes. CONCLUSIONS: Using whole brain volumetric magnetization transfer imaging, the authors demonstrated that cognitive decline in patients with mild cognitive impairment and AD is associated with widespread structural brain damage. As there were no specific relationships between regional brain damage and impairment of specific cognitive functions, pathology in AD and mild cognitive impairment is much more generalized than was expected.     

Neuroimaging as a marker of the onset and progression of Alzheimer's disease

Several neuroimaging techniques are promising tools as early markers of brain pathology in Alzheimer's disease (AD). On structural MRI, atrophy of the entorhinal cortex is present already in mild cognitive impairment (MCI). In the autosomal dominant forms of AD, the rate of atrophy of medial temporal structures separates affected from control persons even 3 years before the clinical onset of cognitive impairment. The elevated annual rate of brain atrophy offers a surrogate tool for the evaluation of newer therapies using smaller samples, thereby saving time and resources. On functional MRI, activation paradigms activate a larger area of parieto-temporal association cortex in persons at higher risk for AD, whereas the entorhinal cortex activation is lesser in MCI. Similar findings have been detected with activation procedures and water (H(2)(15)O) PET. Regional metabolism in the entorhinal cortex, studied with FDG PET, seems to predict normal elderly who will deteriorate to MCI or AD. SPECT shows decreased regional perfusion in limbic areas, both in MCI and AD, but with a lower likelihood ratio than PET. Newer PET compounds allow for the determination in AD of microglial activation, regional deposition of amyloid and the evaluation of enzymatic activity in the brain of AD patients.     

Comparison of the memory performance index with standard neuropsychological measures of cognition

The Mild Cognitive Impairment Screen (MCIS) is a computer-based cognitive assessment designed for clinical and research use in detecting amnestic mild cognitive impairment (aMCI). Performance on the MCIS is reported as the Memory Performance Index (MPI). However, the comparability between the MPI and traditional neuropsychological tests in detecting aMCI, and in differentiating it from Alzheimer's disease (AD) and normal aging has not been examined. A cross-sectional study was conducted to assess the validity of the MPI relative to standard neuropsychological measures. Participants included 12 individuals diagnosed with aMCI, 49 with mild AD, and 25 healthy elderly. The MCIS significantly discriminated among aMCI, AD, and healthy elderly controls. The MCIS is effective in detecting aMCI, and in discriminating it from cognitive changes observed in AD and normal aging. The MCIS may be a valuable tool in the identification of elderly at high risk for dementia due to its ease-of-use and brief administration time.     

Oxidative damage in mild cognitive impairment and early Alzheimer's disease

Increasing evidence supports a role for oxidative damage in the pathogenesis of Alzheimer's disease (AD). Multiple studies show significantly increased levels of lipid peroxidation and protein, DNA, and RNA oxidation in vulnerable regions of the brain of patients with late-stage AD (LAD). More recent studies of patients with amnestic mild cognitive impairment (MCI), the earliest clinical manifestation of AD, show similar patterns of oxidative damage. These observations suggest that oxidative damage to critical biomolecules occurs early in the pathogenesis of AD and precedes pronounced neuropathologic alterations. Because oxidative damage begins early in the progress of the disease, it represents a potential therapeutic target for slowing the onset and progression of AD.     

White matter tract integrity in aging and Alzheimer's disease

The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied "tract-based spatial statistics" (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging.     

Pathophysiology of neuronal energy crisis in Alzheimer's disease

A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.     

Greater nucleic acids oxidation in the temporal lobe than the frontal lobe in SAMP8

Our previous studies have shown that substantial amounts of 8-oxoguanine are present in the DNA and RNA in the hippocampi of old senescence-accelerated mice (SAMP8); however, oxidative damage to DNA and RNA in the other regions of the brain from a month after birth to the onset of aging has not been examined completely. In this study, we analyzed the amount of 8-oxoguanine in DNA and RNA in the temporal and frontal lobes of SAMP8 during aging by the immunohistochemical method. Compared with age-matched control acceleration-resistant mice (SAMR1), 8- and 12-month-old SAMP8 had increased amounts of 8-oxoguanine in the DNA and RNA in the frontal lobe, whereas in the temporal lobe, this trend began to appear as early as 4 months. The levels of 8-oxoguanine in the temporal lobe were significantly higher than those in the frontal lobe. These results indicate that nucleic acid oxidative damage occurs as an age-associated phenomenon, and can occur more easily in the temporal lobe than in the frontal lobe of SAMP8.     

轻度认知障碍老年人情节记忆功能的磁共振成像研究

目的 运用核磁共振(MRI)技术探讨轻度认知障碍(MCI)老人与健康老人脑结构和功能的异同.方法 对14例MCI老人(MCI组)和15名健康老人(正常对照组)进行神经心理学检查,并应用基于体素的形态测量方法 ,测定两组的灰质体积,并用事件相关功能MRI技术,测定两组在执行情节记忆提取任务时相关脑区的功能变化.结果 (1)神经心理学:MCI组听觉词语记忆测试[(2.1±1.7)分]和画钟试验[(7.8±1.2)分]成绩差于正常对照组[分别为(9.2±1.3)分和(9.2±0.8)分;P＜0.05].(2)结构影像:MCI组的灰质体积小于正常对照组,主要位于情节记忆相关脑区(P＜0.001).(3)功能影像:MCI组与正常对照组任务正确率和反应时间的差别无统计学意义;MCI组激活降低的脑区主要是海马旁回,而增强激活的脑区主要是前额叶前侧、背外侧、右侧颞上回、右侧颞下回、枕叶皮层(P＜0.005).结论 MCI组内侧颞叶记忆系统结构萎缩、功能下降,在任务难度适当的情节记忆提取任务中,MCI组动员额外脑区激活,以代偿颞叶内侧记忆系统的损害.     

Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment

Alterations in synaptic protein stoichiometry may contribute to neocortical synaptic dysfunction in Alzheimer disease (AD). Whether perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remain unclear. We examined protein levels of synaptophysin (SYP), synaptotagmin (SYT), and drebrin (DRB) in 5 neocortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual) of people clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Normalized SYP levels were decreased approximately 35% in the superior temporal and inferior parietal cortex in severe AD compared with NCI. SYT levels were unchanged across clinical diagnosis in the cortical regions. Levels of DRB, a dendritic spine plasticity marker, were reduced approximately 40% to 60% in all cortical regions in AD compared with NCI. DRB protein was also reduced approximately 35% in the superior temporal cortex of MCI subjects, and DRB and SYP levels in the superior temporal cortex correlated with Mini-Mental State Examination and Braak scores. In contrast, DRB levels in the superior frontal cortex increased approximately 30% in MCI subjects. The differential changes in DRB expression in the frontal and temporal cortex in MCI suggest a disparity of dendritic plasticity within these regions that may contribute to the early impairment of temporal cortical functions subserving memory and language compared with the relative preservation of frontal cortical executive function during the initial stages of cognitive decline.     

Evidence of neurodegeneration in obstructive sleep apnea: Relationship between obstructive sleep apnea and cognitive dysfunction in the elderly

The incidence of dementia and obstructive sleep apnea (OSA) increases with age. Late‐onset Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the elderly characterized by amyloid β (Aβ) plaques and neurofibrillary tangles. The disease involves widespread synaptic loss in the neocortex and the hippocampus. Rodent and clinical studies suggest that OSA impairs the structural integrity of several brain regions, including the medial temporal lobe. Indeed, hypoxia, hypertension, hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress noted in OSA patients also occur in AD patients. This Review highlights pathological commonality, showing that OSA upregulates Aβ, tau hyperphosphorylation, and synaptic dysfunction. Indeed, OSA and hypertension trigger hypoperfusion and hypometabolism of brain regions, including cortex and hippocampus. Several studies show that hypertension‐driven brain damage and pathogenic mechanisms lead to an Aβ increase. The pathophysiological mechanism by which OSA enhances hypertension may be linked to sympathoexcitation, oxidative stress, and endothelial dysfunction. Strong pathophysiological similarities that exist between OSA and AD are underscored here. For example, the hippocampus is negatively impacted in both OSA and AD. OSA promotes hippocampal atrophy, which is associated with memory impairment. Cognitive impairment, even in the absence of manifest dementia, is an important independent predictor of mortality. However, several pathophysiological mechanisms in OSA are reversible with appropriate therapy. OSA, therefore, is a modifiable risk factor of cognitive dysfunction, and treating OSA prior to mild cognitive impairment may be an effective prevention strategy to reduce risk for cognitive decline and AD in middle‐aged persons and the elderly. © 2015 Wiley Periodicals, Inc.     

Neuronal hypertrophy in asymptomatic Alzheimer disease

The pathologic changes of Alzheimer disease (AD) evolve very gradually over decades before the disease becomes clinically manifest. Thus, it is not uncommon to find substantial numbers of Abeta plaques and neurofibrillary tangles in autopsy brains of older subjects with documented normal cognition, a state that we define as asymptomatic AD (ASYMAD). The goal of this study is to understand the morphometric substrate of ASYMAD subjects compared with mild cognitive impairment and definite AD cases. We used designed-based stereology to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in 4 cerebral regions: anterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex, and CA1 of hippocampus. We examined and compared autopsy brains from 4 groups (n = 15 each) of participants in the Baltimore Longitudinal Study of Aging: ASYMAD, mild cognitive impairment, AD, and age-matched controls. We found significant hypertrophy of the neuronal cell bodies, nuclei, and nucleoli of CA1 of hippocampus and anterior cingulate gyrus neurons in ASYMAD subjects compared with control and mild cognitive impairment cases. In the posterior cingulate gyrus and primary visual cortex, the hypertrophy was limited to the nuclei and nucleoli. The hypertrophy of cortical neurons and their nuclei and nucleoli in ASYMAD may represent an early reaction to the presence of neurotoxic Abeta or tau, or a compensatory mechanism that prevents the progression of the disease into dementia.     

Absence of cognitive impairment or decline in preclinical Alzheimer's disease

OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.     

Oxidatively modified RNA in mild cognitive impairment

Studies show increased oxidative damage in the brains of subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI). To determine if RNA oxidation occurs in MCI, sections of hippocampus/parahippocampal gyrus (HPG) from 5 MCI, 5 late stage AD (LAD) and 5 age-matched normal control (NC) subjects were subjected to immunohistochemistry using antibodies against 8-hydroxyguanine (8-OHG) and 1-N2-propanodeoxyguanosine (NPrG). Confocal microscopy showed 8-OHG and NPrG immunostaining was significantly (p<0.05) elevated in MCI and LAD HPG compared with NC subjects and was predominately associated with neurons identified using the MC-1 antibody that recognizes conformational alterations of tau, which are associated with early neurofibrillary tangle formation. Pretreating sections with RNase or DNase-I showed immunostaining for both adducts was primarily associated with RNA. In addition, levels of both adducts in MCI were comparable to those measured in LAD, suggesting RNA oxidation may be an early event in the pathogenesis of neuron degeneration in AD.     

Accelerated hippocampal atrophy rates in stable and progressive amnestic mild cognitive impairment

Studies suggest that smaller hippocampal volume predicts Alzheimer's disease (AD) in mild cognitive impairment (MCI). However, few studies have demonstrated decline rates in cognition and hippocampal volume in MCI subjects with stable clinical presentation. Furthermore, the effects of apolipoprotein E (ApoE) on the change rates of medial temporal structures and cognition in MCI are rarely investigated. Fifty-eight subjects with amnestic MCI and 20 normal aging elderly controls received annual neuropsychological and magnetic resonance imaging (MRI) assessments. Annual decline rates in neuropsychological test scores, hippocampal and amygdalar volumes were calculated. ApoE genotypes were examined. Nineteen (32.7%) MCI subjects converted to AD during an average 22.5-month follow-up period. The annual hippocampal atrophy rate was correlated with a decline in memory test scores. The presence of the ApoE ?4 allele did not affect the change rates in neuropsychological test scores and medial temporal structures volume. Compared to subjects with stable MCI (MCI-S) and normal aging, progressive MCI (MCI-P) had the highest annual decline rates in cognition and hippocampal volume. Logistic regression analysis showed that higher annual decline rates in hippocampal volume and global cognitive test scores were associated with conversion to AD. Furthermore, although MCI-S subjects had little cognitive decline, their hippocampal atrophy rates were higher than those of normal aging controls. Therefore, accelerated hippocampal atrophy rates may be an early and important presentation in MCI subjects.