Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment

OBJECTIVE: To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. DESIGN: A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. SETTING: Referral dementia clinic. SUBJECTS: Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. MAIN OUTCOME MEASURES: Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. RESULTS: The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. CONCLUSION: These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.     

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

Background:  Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned.
Methods:  We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls.
Results:  Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices.
Discussion:  We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD.     

Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps

BACKGROUND: While most patients with mild cognitive impairment (MCI) transition to Alzheimer disease (AD), others develop non-AD dementia, remain in the MCI state, or improve. OBJECTIVE: To test the following hypotheses: smaller hippocampal volumes predict conversion of MCI to AD, whereas larger hippocampal volumes predict cognitive stability and/or improvement; and patients with MCI who convert to AD have greater atrophy in the CA1 hippocampal subfield and subiculum. DESIGN: Prospective longitudinal cohort study. SETTING: University of California-Los Angeles Alzheimer's Disease Research Center. PATIENTS: We followed up 20 MCI subjects clinically and neuropsychologically for 3 years. MAIN OUTCOME MEASURE: Baseline regional hippocampal atrophy was analyzed with region-of-interest and 3-dimensional hippocampal mapping techniques. RESULTS: During the 3-year study, 6 patients developed AD (MCI-c), 7 remained stable (MCI-nc), and 7 improved (MCI-i). Patients with MCI-c had 9% smaller left and 13% smaller right mean hippocampal volumes compared with MCI-nc patients. Radial atrophy maps showed greater atrophy of the CA1 subregion in MCI-c. Patients with MCI-c had significantly smaller hippocampi than MCI-i patients (left, 24%; right, 27%). Volumetric analyses showed a trend for greater hippocampal atrophy in MCI-nc relative to MCI-i patients (eg, 16% volume loss). After permutation tests corrected for multiple comparison, the atrophy maps showed a significant difference on the right. Subicular differences were seen between MCI-c and MCI-i patients, and MCI-nc and MCI-i patients. Multiple linear regression analysis confirmed the group effect to be highly significant and independent of age, hemisphere, and Mini-Mental State Examination scores at baseline. CONCLUSIONS: Smaller hippocampi and specifically CA1 and subicular involvement are associated with increased risk for conversion from MCI to AD. Patients with MCI-i tend to have larger hippocampal volumes and relative preservation of both the subiculum and CA1.     

Profile of memory impairment and gray matter loss in amnestic mild cognitive impairment

The present study assessed the patterns of cortical gray matter (GM) loss in patients with amnestic mild cognitive impairment (aMCI) with distinct profiles of memory impairment, i.e. aMCI patients failing on both recall and recognition memory vs. aMCI patients showing impaired recall but preserved recognition memory. This distinction is usually not taken into account in studies on aMCI and the aim of the present study was to assess whether this distinction is useful. Twenty-eight aMCI patients and 28 matched controls subjects were included. All aMCI patients failed a recall memory task (inclusion criteria). All underwent a visual recognition memory task (DMS48). However, 12 succeeded on this task while 16 failed. Relative gray matter (GM) loss was measured using voxel-based morphometry. When comparing aMCI patients to controls regardless of the profile of memory impairment, GM loss was found in temporal, parietal and frontal areas. However, in aMCI patients with preserved recognition (but impaired recall), GM loss was confined to frontal areas. This contrasted with GM loss in the right medial temporal lobe and bilateral temporo-parietal regions in aMCI patients with impaired recall and recognition memory, a pattern of GM loss usually described in early AD. We conclude that different profiles of memory impairment in aMCI patients are associated with distinct patterns of GM loss.     

Gray matter atrophy patterns of mild cognitive impairment subtypes

Mild cognitive impairment (MCI) is a heterogeneous neurocognitive disorder that can be classified into various subtypes. The present study aims to examine the gray matter (GM) atrophy patterns of MCI subtypes in comparison with a cognitively healthy group. Participants, including 135 MCI subjects and 120 cognitively healthy controls, were drawn from the Sydney Memory and Ageing Study. The MCI subjects were first categorized into amnestic (aMCI) and non-amnestic (naMCI) subtypes, which were then divided into single-domain (aMCI-SD and naMCI-SD) and multiple-domain subtypes (aMCI-MD and naMCI-MD). Furthermore, naMCI-SD was divided into three subgroups (language, processing speed, and executive function) according to individual cognitive impairment. Voxel-wise GM volumes were then compared between MCI subtypes and controls. The aMCI group had significantly lower GM volumes in the bilateral hippocampi and temporal cortices than the controls. This was mainly due to GM reduction of aMCI-MD but not aMCI-SD, as the latter did not show any significant GM reduction. GM reduction of naMCI and its two subdivisions was shown in widespread brain regions compared to controls. GM volumes of the multiple-domain subtypes (aMCI-MD and naMCI-MD) were lower than their single-domain counterparts (aMCI-SD and naMCI-SD) in the frontal and temporal lobes, respectively. Moreover, the language subgroup of naMCI-SD showed GM reduction in the frontal and temporal lobes compared to controls. MCI subtypes displayed specific patterns of GM atrophy that appear to be related to their various clinical presentations, which implies that underlying mechanisms of MCI subtypes are different.     

Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment

We used voxel-based morphometry to comprehensively and objectively map gray matter loss in 22 patients with amnestic mild cognitive impairment, defined as progressive isolated episodic memory decline. Compared with 22 age-matched healthy controls, patients had highly significant gray matter loss predominantly affecting the hippocampal region and cingulate gyri (posterior and subcallosal part of the anterior), and extending into the temporal neocortex. Compared with 16 age-matched patients with mild Alzheimer's disease, gray matter density was significantly preserved in mild cognitive impairment in the posterior association cortex. This pattern of gray matter loss in mild cognitive impairment agrees with but considerably expands upon previous region-of-interest based MRI studies, and is highly consistent with the course of neurofibrillary tangles across aging and Alzheimer's disease.     

DTI评价轻度认知障碍及轻中度阿尔茨海默病脑白质微细结构损害的研究

目的应用磁共振弥散张量成像(DTI)技术研究轻度认知障碍(MCI)及轻中度阿尔茨海默病(AD)患者脑白质微细结构的改变。方法对MCI患者、轻中度AD患者各12例及健康老年人12名(对照组)行常规MRI及DTI检查,测量其胼胝体压部、额叶、顶叶、颞叶、枕叶、内囊前肢及内囊后肢白质区部分各向异性分数(FA)和平均弥散率(MD)。将3组的FA、MD值进行比较,并与MMSE评分、单词回忆及单词再认评分进行相关性分析。结果 (1)MCI患者顶叶白质FA值为0.489±0.079,与对照组(0.558±0.079)相比下降(P0.05)。(2)AD患者额叶、顶叶及颞叶FA值分别为0.405±0.072、0.454±0.069和0.363±0.056,与对照组(分别为0.499±0.081、0.558±0.079和0.440±0.061)比较差异均有统计学意义(P0.05)。AD患者胼胝体压部、额叶及顶叶MD值分别为0.978±0.082、0.920±0.054和0.81 7±0.045,均高于对照组(分别为0.801±0.093、0.820±0.084、0.712±0.096)(P0.05)。AD、MCI两组内囊前、后肢及枕叶FA及MD值分别与健康对照组比较均无统计学差异(P0.05)。(3)3组顶叶、颞叶FA值与MMSE、单词回忆及单词再认评分均有相关性(分别r=0.869、-0.621、-0.759,均P0.01;r=0.446、-0.486、-0.361,均P0.05),胼胝体压部FA值与单词再认评分有相关性(r=-0.343,P0.05);3组胼胝体压部及顶叶MD值与MMSE、单词回忆及单词再认评分均有相关性(分别r=-0.612、0.547、0.586,均P0.01;r=-0.576、0.499、0.519,均P0.01),内囊前肢MD值与MMSE评分相关(r=-0.340,P0.05)。结论 MCI及轻中度AD患者存在脑白质选择性微细结构损害,且该损害出现在与高级皮层功能相关的脑区,而与初级功能相关的区域未见明显受损。     

Diffusion tensor imaging in Alzheimer disease and mild cognitive impairment

A wide range of imaging studies provides growing support for the potential role of diffusion tensor imaging (DTI) in evaluating microstructural white matter integrity in Alzheimer disease (AD) and mild cognitive impairment (MCI). Our review aims to present DTI principles, post-processing and analysis frameworks and to report the results of particular studies.The distribution of AD-related white matter abnormalities is widely discussed in the light of deteriorated connectivity within certain tracts due to secondary white matter degeneration; primary alterations are also assumed to contribute to the pattern. The question whether it is more effective to assess the whole-brain diffusion or to directly concentrate on specific regions remains an interesting issue. Assessing white matter microstructure alterations, as evaluated by group-level differences of tensor-derived parameters, may be a promising neuroimaging tool for differential diagnosis between AD, MCI and other cognitive disorders, as well as being particularly helpful in the interpretation of underlying pathological processes.     

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.     

Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease

BACKGROUND: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). OBJECTIVE: To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. PATIENTS: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. DESIGN: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. RESULTS: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. CONCLUSIONS: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.     

Olfactory tau pathology in Alzheimer disease and mild cognitive impairment

OBJECTIVE: To examine the occurrence of tau pathology in the olfactory system in aged subjects and its relation to the severity of Alzheimer disease (AD) pathology. MATERIAL AND METHODS: 273 autopsy cases (167 female, 106 male, aged 61-102, mean 83.2+/-4.5 SD years) underwent a standard neuropathological assessment with immuno-histochemical study of tau and Abeta amyloid in the olfactory bulb and nerve, and diagnosis of AD using established consensus criteria including Braak staging of neuritic AD pathology. RESULTS: All cases of definite AD (Braak stages 5 and 6, n = 96) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 50%, and neuritic plaques only in two cases. Braak stage 4 (n = 73) was associated with tau pathology in the olfactory system in 90.4 and amyloid deposits in 9%, Braak stage 3 (n = 56) with mainly mild to moderate olfactory tau lesions in 44.6 and Abeta deposits in 9%. Braak stage 2 (n = 22) showed olfactory tau pathology in 36.4% without amyloid deposits, whereas Braak stages 0 and 1 (n = 25) were all negative. Olfactory tau pathology showed highly significant correlation with neuritic Braak staging in the brain, while both scores showed significant but low correlation with age. CONCLUSIONS: These data confirm previous studies demonstrating considerable tau pathology in the olfactory system in all definite AD cases, in more than 2/3 of limbic AD and in more than 1/3 of elderly individuals with or without mild cognitive impairment associated with Braak stage 2. Clinical dementia correlated with both Braak and olfactory tau scores, indicating that both are associated with a high risk of cognitive decline.     

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Background:

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Methods:

Ninety‐one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high‐resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1‐CA2 transition zone (CA1‐2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.

Results:

Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1‐2, and total hippocampal volumes. MCI had smaller CA1‐2 volumes. Discriminant analysis and power analysis showed that CA1‐2 was superior to total hippocampal volume for distinction between controls and MCI.

Conclusion:

The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

     

Grey matter atrophy of basal forebrain and hippocampus in mild cognitive impairment

The basal forebrain area (BFA) is closely connected to the hippocampus by virtue of cholinergic neuronal projections. Structural neuroimaging studies have shown reduced volumes of both structures in Alzheimer's disease and its prodromal stage mild cognitive impairment (MCI), but generally not in the same investigation. By combining voxel based morphometry and region of interest methods, we measured the grey matter (GM) volumes of the two brain regions with the goal of elucidating their contributions to MCI and its two subtypes (amnestic MCI and non-amnestic MCI) in an elderly epidemiological sample. The results replicated previous findings that the atrophies of both brain regions were associated with an increased likelihood of MCI and its two subtypes. However, in a regression model for the prediction of MCI with GM volumes for both regions used as predictors, only hippocampal atrophy remained significant. Two possible interpretations for this pattern of results were discussed. One is that the observed correlation between BFA atrophy and MCI is spurious and due to the hippocampal atrophy correlated with both. Alternatively, our observation is consistent with the possibility that BFA atrophy has a causal effect on MCI, which is mediated via its influence on hippocampal atrophy. Furthermore, we found that the left hippocampal atrophy had a stronger effect than the right hippocampus and bilateral BFA in the prediction of amnestic MCI occurrence when the four unilateral areas were entered into one regression model. In addition, a slight but statistically significant difference was found in the left hippocampal volume between APOE ε4 allele carriers and non-carriers, consistent with prior studies.     

Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease

Nerve growth factor (NGF) is critical for the regulation, differentiation, and survival of basal forebrain cholinergic neurons that degenerate in the late stage of Alzheimer disease (AD). The precursor of NGF (proNGF) is the predominant form of NGF in brain and is increased in end stage AD. To determine whether this increase in proNGF is an early or late change during the progression of cognitive decline, we used Western blotting to measure the relative amounts of proNGF protein in the parietal cortex from subjects clinically classified with no cognitive impairment (NCI; n = 20), mild cognitive impairment (MCI; n = 20), or mild to moderate AD (n = 19). We found that proNGF increased during the prodromal stage of AD. The amount of proNGF protein was 1.4-fold greater in the MCI group as compared to NCI, and was 1.6-fold greater in mild-moderate AD as compared to NCI, similar to our previous findings of a 2-fold increase in end stage AD. There was a negative correlation between proNGF levels and Mini Mental Status Examination (MMSE) score, demonstrating that the accumulation of proNGF is correlated with loss of cognitive function. These findings demonstrate that proNGF levels increase during the preclinical stage of AD and may reflect an early biological marker for the onset of AD.     

Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment

Cellular mechanisms conferring neuroprotection in the brains of patients with Alzheimer disease (AD) remain incompletely understood. Erythropoietin (Epo) and the erythropoietin receptor (EpoR) are expressed in neural tissues and protect against oxidative and other stressors in various models of brain injury and disease. Our objective in this study was to determine whether EpoR is upregulated in the brains of persons with sporadic AD and mild cognitive impairment (MCI). Postmortem hippocampus and temporal cortex from subjects with AD, MCI, and no cognitive impairment (NCI) were procured from the Religious Orders Study. Total immunoreactive EpoR protein was determined by Western blotting. Astrocytes expressing immunoreactive EpoR were quantified in 4 temporal and 6 hippocampal regions, and correlated with clinical, neuropsychologic, and neuropathologic indices. Total immunoreactive EpoR protein was markedly increased in AD and MCI temporal cortex versus NCI tissues. Composite measures of glial EpoR expression in temporal cortex layers I to IV were significantly greater in the MCI group compared with the NCI and AD groups. Hippocampal EpoR scores were increased in persons with MCI and AD relative to those with NCI. There was substantial subregional heterogeneity in disease-related EpoR expression patterns in AD and MCI temporal cortex and hippocampus. There was no association of EpoR-positive astrocytes with summary measures of global cognition or AD pathology. We conclude that upregulation of EpoR in temporal cortical and hippocampal astrocytes is an early, potentially neuroprotective, event in the pathogenesis of sporadic AD.