Functional Neural Correlates of Attentional Deficits in Amnestic Mild Cognitive Impairment

Although amnestic mild cognitive impairment (aMCI; often considered a prodromal phase of Alzheimer’s disease, AD) is most recognized by its implications for decline in memory function, research suggests that deficits in attention are present early in aMCI and may be predictive of progression to AD. The present study used functional magnetic resonance imaging to examine differences in the brain during the attention network test between 8 individuals with aMCI and 8 neurologically healthy, demographically matched controls. While there were no significant behavioral differences between groups for the alerting and orienting functions, patients with aMCI showed more activity in neural regions typically associated with the networks subserving these functions (e.g., temporoparietal junction and posterior parietal regions, respectively). More importantly, there were both behavioral (i.e., greater conflict effect) and corresponding neural deficits in executive control (e.g., less activation in the prefrontal and anterior cingulate cortices). Although based on a small number of patients, our findings suggest that deficits of attention, especially the executive control of attention, may significantly contribute to the behavioral and cognitive deficits of aMCI.     

轻度认知损伤患者的联系记忆损伤特征

遗忘型轻度认知损伤患者(aMCI)在项目记忆和联系记忆上都有损伤．本文通过临床记忆量表中的项目记忆和联系记忆测验,研究aMCI的联系记忆是否比项目记忆有更显著的损伤．另外,通过分析配对联想学习测验,进一步研究aMCI联系记忆损伤的特点．25名aMCI和28名健康老人参与了两个联系记忆测验(配对联想学习测验和联想回忆测验)和两个项目记忆测验(图像自由回忆和无意义图形再认),aMCI患者在联系记忆测验上表现出了更显著的损伤,即使控制了项目记忆的损伤,aMCI的联系记忆仍然比健康老人显著降低．另外,ROC分析表明联系记忆测验比项目记忆测验对aMCI病人有更高的区分度．对配对联想学习测验的分析表明,相对于健康老人,aMCI患者在记忆有语言联系的词对要比记忆无语义联系的词对更为困难．本研究进一步表明aMCI患者的联系记忆比项目记忆有更大的损伤．相对于健康老人,aMCI患者不仅难以在两个无关项目间创建记忆连接,而且在有效利用项目间本身的语义联系方面存在更大的损伤．联系记忆测验比项目记忆测验对aMCI患者有更高的区分度．在神经心理评估中增加联系记忆测验,能更加有效地识别aMCI患者．     

Famous Landmark Identification in Amnestic Mild Cognitive Impairment and Alzheimer's Disease

Background

Identification of famous landmarks (FLI), famous faces (FFI) and recognition of facial emotions (FER) is affected early in the course of Alzheimer''s disease (AD). FFI, FER and FLI may represent domain specific tasks relying on activation of distinct regions of the medial temporal lobe, which are affected successively during the course of AD. However, the data on FFI and FER in MCI are controversial and FLI domain remains almost unexplored.

Objectives

To determine whether and how are these three specific domains impaired in head to head comparison of patients with amnestic MCI (aMCI) single domain (SD-aMCI) and multiple domain (MD-aMCI). We propose that FLI might be most reliable in differentiating SD-aMCI, which is considered to be an earlier stage of AD pathology spread out, from the controls.

Patients and Methods

A total of 114 patients, 13 with single domain (SD–aMCI) and 30 with multiple domains (MD–aMCI), 29 with mild AD and 42 controls underwent standard neurological and neuropsychological evaluations as well as tests of FLI, FER and FFI.

Results

Compared to the control group, AD subjects performed worse on FFI (p = 0.020), FER (p<0.001) and FLI (p<0.001), MD-aMCI group had significantly worse scores only on FLI (p = 0.002) and approached statistical significance on FER (0.053). SD-aMCI group performed significantly worse only on FLI (p = 0.028) compared to controls.

Conclusions

Patients with SD-aMCI had an isolated impairment restricted to FLI, while patients with MD–aMCI showed impairment in FLI as well as in FER. Patients with mild dementia due to AD have more extensive impairment of higher visual perception. The results suggest that FLI testing may contribute to identification of patients at risk of AD. We hypothesize that clinical examination of all three domains might reflect the spread of the disease from transentorhinal cortex, over amygdala to fusiform gyrus.     

Use of a Modified Spatial-Context Memory Test to Detect Amnestic Mild Cognitive Impairment

In this study we sought to differentiate participants with amnestic mild cognitive impairment (a-MCI) from those with mild dementia of Alzheimer’s type (m-DAT) and normal controls by modifying an existing test of spatial context memory (SCMT) designed so as to evaluate the function of brain regions affected in early m-DAT. We found that participants with a-MCI had better total scores on our modified SCMT than those with m-DAT. Furthermore, the locational memory subtest was able to discriminate between those with a-MCI and m-DAT. Additionally, compared with other screening tests, our spatial context memory test showed high sensitivity and specificity in discerning those with a-MCI from the normal population but, was relatively ineffective in discriminating a-MCI patients from those with m-DAT. We conclude that our modified test of SCMT is an effective tool for discriminating a-MCI from m-DAT and does so by detecting differences in locational memory.     

White Matter Changes in Patients with Amnestic Mild Cognitive Impairment Detected by Diffusion Tensor Imaging

Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer’s disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.     

Gray and White Matter Changes in Subjective Cognitive Impairment,Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Voxel-Based Analysis Study

Subjective cognitive impairment may be a very early at-risk period of the continuum of dementia. However, it is difficult to discriminate at-risk states from normal aging. Thus, detection of the early pathological changes in the subjective cognitive impairment period is needed. To elucidate these changes, we employed diffusion tensor imaging and volumetry analysis, and compared subjective cognitive impairment with normal, mild cognitive impairment and Alzheimer''s disease. The subjects in this study were 39 Alzheimer''s disease, 43 mild cognitive impairment, 28 subjective cognitive impairment and 41 normal controls. There were no statistically significant differences between the normal control and subjective cognitive impairment groups in all measures. Alzheimer''s disease and mild cognitive impairment had the same extent of brain atrophy and diffusion changes. These results are consistent with the hypothetical model of the dynamic biomarkers of Alzheimer''s disease.     

Regional Expression of Key Cell Cycle Proteins in Brain from Subjects with Amnestic Mild Cognitive Impairment

Mild cognitive impairment (MCI) is regarded as a transition stage between the cognitive changes of normal aging and the more serious problems caused by Alzheimer’s disease (AD). Previous studies had demonstrated increased expression of cell cycle proteins in AD brain. In the present study, we have analyzed the expression of the cell cycle proteins, CDK2, CDK5 and cyclin G1 in hippocampus and inferior parietal lobule (IPL) in subjects with amnestic mild cognitive impairment and control using Western blot analysis. The expression of CDK2, CDK5 and cyclin G1 were found to be significantly increased in MCI hippocampus as well as in IPL compared to control brain. These results suggest that some cells may have re-entered the cell cycle. However, the expression of CDK2 and CDK5 is greater in MCI hippocampus compared to those of MCI IPL, and hippocampus is a region that is severely affected by AD pathology. Since these proteins are involved directly or indirectly in microtubule destabilization and hyperphosphorylation of tau, and also in APP processing we hypothesize that cell cycle disturbance may be important contributor in the pathogenesis of AD. Special issue dedicated to Dr. John P. Blass.     

Microstructural White Matter Changes,Not Hippocampal Atrophy,Detect Early Amnestic Mild Cognitive Impairment

Background

Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.

Methods

We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.

Results

Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.

Conclusions

Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.     

A Mutual Self- and Informant-Report of Cognitive Complaint Correlates with Neuropathological Outcomes in Mild Cognitive Impairment

Background

This study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer’s disease (AD) neuropathology in elders with mild cognitive impairment (MCI).

Methods

Data were drawn from the National Alzheimer’s Coordinating Center Uniform and Neuropathology Datasets (observational studies) for participants with a clinical diagnosis of MCI and postmortem examination (n = 1843, 74±8 years, 52% female). Cognitive complaint (0.9±0.5 years prior to autopsy) was classified into four mutually exclusive groups: no complaint, self-only, informant-only, or mutual (both self and informant) complaint. Postmortem neuropathological outcomes included amyloid plaques and neurofibrillary tangles. Proportional odds regression related complaint to neuropathology, adjusting for age, sex, race, education, depressed mood, cognition, APOE4 status, and last clinical visit to death interval.

Results

Mutual complaint related to increased likelihood of meeting NIA/Reagan Institute (OR = 6.58, p = 0.004) and Consortium to Establish a Registry for Alzheimer’s Disease criteria (OR = 5.82, p = 0.03), and increased neurofibrillary tangles (OR = 3.70, p = 0.03), neuritic plaques (OR = 3.52, p = 0.03), and diffuse plaques (OR = 4.35, p = 0.02). Informant-only and self-only complaint was not associated with any neuropathological outcome (all p-values>0.12).

Conclusions

In MCI, mutual cognitive complaint relates to AD pathology whereas self-only or informant-only complaint shows no relation to pathology. Findings support cognitive complaint as a marker of unhealthy brain aging and highlight the importance of obtaining informant corroboration to increase confidence of underlying pathological processes.     

Protein Levels and Activity of Some Antioxidant Enzymes in Hippocampus of Subjects with Amnestic Mild Cognitive Impairment

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive aging and early dementia or clinically probable Alzheimer’s disease (AD). Most individuals with amnestic MCI eventually develop AD, which suggests that MCI may be the earliest phase of AD. Oxidative stress is observed in brain from subjects with both AD and MCI. Among others, two possibilities for elevated oxidataive stress are decreased activity or elevated expression of antioxidant enzymes, the latter as a response to the former. Accordingly, in the current study, the protein levels and activity of some antioxidant enzymes in the hippocampus of control and MCI brain were measured using Western blot analysis and spectrophotometric methods, respectively. Alterations in the levels and activity of a number of antioxidant enzymes in MCI brain compared to age-matched controls were found. These results are consistent with the hypothesis that oxidative stress may be an early event in the progression of amnestic MCI to AD. Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.     

A Longitudinal Study of Atrophy in Amnestic Mild Cognitive Impairment and Normal Aging Revealed by Cortical Thickness

In recent years, amnestic mild cognitive impairment (aMCI) has attracted significant attention as an indicator of high risk for Alzheimer''s disease. An understanding of the pathology of aMCI may benefit the development of effective clinical treatments for dementia. In this work, we measured the cortical thickness of 109 aMCI subjects and 99 normal controls (NC) twice over two years. The longitudinal changes and the cross-sectional differences between the two types of participants were explored using the vertex thickness values. The thickness of the cortex in aMCI was found significantly reduced in both longitudinal and between-group comparisons, mainly in the temporal lobe, superolateral parietal lobe and some regions of the frontal cortices. Compared to NC, the aMCI showed a significantly high atrophy rate in the left lateral temporal lobe and left parahippocampal gyrus over two years. Additionally, a significant positive correlation between brain atrophy and the decline of Mini-Mental State Examination (MMSE) scores was also found in the left superior and left middle temporal gyrus in aMCI. These findings demonstrated specific longitudinal spatial patterns of cortical atrophy in aMCI and NC. The higher atrophy rate in aMCI might be responsible for the accelerated functional decline in the aMCI progression process.     

EEG and Cognitive Biomarkers Based Mild Cognitive Impairment Diagnosis

Objective

Recently, Electroencephalogram (EEG) shows potential in the diagnosis of Alzheimer's disease and other dementia. We aim to investigate whether EEG and selected cognitive biomarkers can classify mild cognitive impairment (MCI), dementia and healthy subjects using support vector machine classifier in Indian cohort.

Short-Term Delayed Recall of Auditory Verbal Learning Test Is Equivalent to Long-Term Delayed Recall for Identifying Amnestic Mild Cognitive Impairment

Delayed recall of words in a verbal learning test is a sensitive measure for the diagnosis of amnestic mild cognitive impairment (aMCI) and early Alzheimer’s disease (AD). The relative validity of different retention intervals of delayed recall has not been well characterized. Using the Auditory Verbal Learning Test–Huashan version, we compared the differentiating value of short-term delayed recall (AVL-SR, that is, a 3- to 5-minute delay time) and long-term delayed recall (AVL-LR, that is, a 20-minute delay time) in distinguishing patients with aMCI (n = 897) and mild AD (n = 530) from the healthy elderly (n = 1215). In patients with aMCI, the correlation between AVL-SR and AVL-LR was very high (r = 0.94), and the difference between the two indicators was less than 0.5 points. There was no difference between AVL-SR and AVL-LR in the frequency of zero scores. In the receiver operating characteristic curves analysis, although the area under the curve (AUC) of AVL-SR and AVL-LR for diagnosing aMCI was significantly different, the cut-off scores of the two indicators were identical. In the subgroup of ages 80 to 89, the AUC of the two indicators showed no significant difference. Therefore, we concluded that AVL-SR could substitute for AVL-LR in identifying aMCI, especially for the oldest patients.     

Changes in Thalamic Connectivity in the Early and Late Stages of Amnestic Mild Cognitive Impairment: A Resting-State Functional Magnetic Resonance Study from ADNI

We used resting-state functional magnetic resonance imaging (fMRI) to investigate changes in the thalamus functional connectivity in early and late stages of amnestic mild cognitive impairment. Data of 25 late stages of amnestic mild cognitive impairment (LMCI) patients, 30 early stages of amnestic mild cognitive impairment (EMCI) patients and 30 well-matched healthy controls (HC) were analyzed from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We focused on the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. Compared to healthy controls, we found functional connectivity between the left/right thalamus and a set of brain areas was decreased in LMCI and/or EMCI including right fusiform gyrus (FG), left and right superior temporal gyrus, left medial frontal gyrus extending into supplementary motor area, right insula, left middle temporal gyrus (MTG) extending into middle occipital gyrus (MOG). We also observed increased functional connectivity between the left/right thalamus and several regions in LMCI and/or EMCI including left FG, right MOG, left and right precuneus, right MTG and left inferior temporal gyrus. In the direct comparison between the LMCI and EMCI groups, we obtained several brain regions showed thalamus-seeded functional connectivity differences such as the precentral gyrus, hippocampus, FG and MTG. Briefly, these brain regions mentioned above were mainly located in the thalamo-related networks including thalamo-hippocampus, thalamo-temporal, thalamo-visual, and thalamo-default mode network. The decreased functional connectivity of the thalamus might suggest reduced functional integrity of thalamo-related networks and increased functional connectivity indicated that aMCI patients could use additional brain resources to compensate for the loss of cognitive function. Our study provided a new sight to understand the two important states of aMCI and revealed resting-state fMRI is an appropriate method for exploring pathophysiological changes in aMCI.     

Regional Amyloid Deposition in Amnestic Mild Cognitive Impairment and Alzheimer's Disease Evaluated by [18F]AV-45 Positron Emission Tomography in Chinese Population

Background

To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer''s disease (AD) subjects with [¹⁸F]AV-45 positron emission tomography (PET).

Materials and Methods

[¹⁸F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [¹⁸F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed.

Results

The global cortical [¹⁸F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment.

Conclusions

Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [¹⁸F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [¹⁸F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.     

Monocyte Activation in HIV/HCV Coinfection Correlates with Cognitive Impairment

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects’ GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.     

Application and Revision of Montreal Cognitive Assessment in China's Military Retirees with Mild Cognitive Impairment

ObjectiveIn an effort to accommodate MOCA to better fit for the Chinese context, this study was designed to employ the MOCA criteria to screen mild cognitive impairment (MCI) and analyze associated risk factors in military retirees.MethodsThree hundred and four retired military cadres were recruited using a random cluster sampling technique with information collected including personal, prevalence, MOCA scale, and related neuropsychiatry scale. Thirty retirees were randomly chosen to be further analyzed one month later using the revised MOCA scale.Results①Our data indicated an incidence rate of 64.8% for mild cognitive impairment in retired military cadres. The incidence rate for MCI was significantly higher in those aged 80 or above compared with those 80 years of age or younger (P<0.05). The incidence rate of MCI was significantly higher in those with fewer than 6 years of education compared with those with over 7 years of education (P<0.05). The MCI incidence was higher for those with little exercise than those taking regular exercise (P<0.01). Moreover, the MCI incidence was higher in stroke patients than those who never had a stroke episode (P<0.05). ②There was a significant correlation between MOCA and MMSE scale scores (r = 0.81). MOCA scale scores were negatively correlated with ADL and CES-D scores (although not PSQI scores). ③ MOCA recension Cronbach’s alpha value was 0.862. The related coefficient of MOCA and MOCA recension was 0.878(P<0.01). When the Score of cut-off -point of the MOCA recension was 28, the area in ROC curve analyses was 0.859, as well as the largest area.ConclusionRetired cadres exhibited a greater incidence of MCI (than general population), which was closely associated with age, level of education and physical exercise and cerebral apoplexy. Revised MOCA scale displays a better validity and reaction degree of reliability and is more suitable for screening and diagnosis of MCI in the elderly in China.