Cognitive and functional neuroimaging correlate for anosognosia in mild cognitive impairment and Alzheimer's disease

OBJECTIVES: To investigate the correlation between anosognosia and behavioural symptoms, performance on executive tests, and frontal cortex regional cerebral blood flow (rCBF) in patients with 'amnestic mild cognitive impairment' (MCI) and mild Alzheimer's disease (AD). METHODS: From a prospective Memory Clinic cohort including consecutively referred patients, age 60 years or above, and with MMSE score 20 or above, 36 patients with AD and 30 with MCI were included in this study. Anosognosia was assessed using a categorical scale and discrepancy scores between patients' and relatives' reports on a 20-item Memory Questionnaire (MQ). Behavioural symptoms were assessed with Frontal Behavioural Inventory (FBI). Executive functions were examined with a range of neuropsychological tests. Tc99m-HMPAO SPECT was obtained in an unselected sample of 55 of the 66 patients, and rCBF was analysed in six cortical frontal regions. RESULTS: Insight was equally impaired in the two patient groups. A significant correlation was found between impaired awareness and dementia severity (MMSE). Discrepancy-scores on the MQ were significantly correlated to scores on FBI and to rCBF in the right inferior frontal gyrus, but not to executive tests. The groups classified by the categorical ratings 'full', 'shallow' and 'no' awareness were not characterized by differences in behavioural symptoms, executive performance or frontal rCBF. CONCLUSIONS: Impaired awareness is associated with behavioural symptoms and may reflect functional impairment in the right inferior frontal cortex.     

Hippocampal volumes among older Indian adults: Comparison with Alzheimer's disease and mild cognitive impairment

Background:Hippocampal volume data from India have recently been reported in younger adults. Data in older adults are unknown. The present paper describes hippocampal volume from India among older adults and compares the same with patients having Alzheimer''s disease (AD) and mild cognitive impairment (MCI).Results:Age and duration of illness in the MCI group were 70.6 ± 8.6 years and 1.9 ± 0.9 years, respectively. In the AD group, age and duration of illness were 72 ± 8.1 years and 3.1 ± 2.2 years, respectively. In cognitively normal subjects, the age range was 45-88 years (66.9 ± 10.32) years. Mean mini–mental status examination (MMSE) score of healthy subjects was 28.28 ± 1.33. In the MCI group, MMSE was 27.05 ± 1.79. In the AD group, MMSE was 13.32 ± 5.6. In the healthy group, the hippocampal volume was 2.73 ± 0.53 cm³ on the left side and 2.77 ± 0.6 cm³ on the right side. Likewise, in MCI, the volume on the left side was 2.35 ± 0.42 cm³ and the volume on the right side was 2.36 ± 0.38 cm³. Similarly, in the AD group, the volume on the right side was 1.64 ± 0.55 cm³ and on the left side it was 1.59 ± 0.55 cm³. Post hoc analysis using Tukey''s honestly significant difference (HSD) showed, using analysis of variance (ANOVA) that there was a statistically significant difference between healthy and AD (P ≤ 0.01), and between healthy and MCI (P ≤ 0.01) subjects. There was a correlation between MMSE score and hippocampal volume in the AD group.Conclusion:The volume of the hippocampus in older Indian adults was 2.77 ± 0. 6 cm³ on the right side and 2.73 ± 0.52 cm³ on the left side. There was a significant hippocampal volume loss in MCI/AD compared to cognitively normal subjects.     

Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment

Alzheimer''s disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with the rate of progression in 822 Caucasian subjects of amnestic mild cognitive impairment (MCI). There was no significant association with disease progress for any of the recently identified disease susceptibility variants in CLU, CR1, PICALM, BIN1, EPHA1, MS4A6A, MS4A4E or CD33 following multiple testing correction. We did, however, identify multiple novel loci that reached genome-wide significance at the 0.01 level. These top variants (rs7840202 at chr8 in UBR5: P=4.27 × 10⁻¹⁴; rs11637611 with a cluster of SNPs at chr15q23 close to the Tay–Sachs disease locus: P=1.07 × 10⁻¹⁵; and rs12752888 at chr1: P=3.08 × 10⁻¹¹) were also associated with a significant decline in cognition as well as the conversion of subjects with MCI to a diagnosis of AD. Taken together, these variants define approximately 16.6% of the MCI sub-population with a faster rate of decline independent of the other known disease risk factors. In addition to providing new insights into protein pathways that may be involved with the progress to AD in MCI subjects, these variants if further validated may enable the identification of a more homogeneous population of subjects at an earlier stage of disease for testing novel hypotheses and/or therapies in the clinical setting.     

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.

     

Subclinical epileptiform activity during sleep in Alzheimer's disease and mild cognitive impairment

ObjectiveRecent findings suggested that subclinical epileptiform activity is prevalent during sleep in a significant proportion of Alzheimer’s Disease (AD) patients. The aims of our study were: (A) comparing the frequency of subclinical epileptiform activity during the sleep in a sample diagnosed with ‘probable’ AD and Mild Cognitive Impairment (MCI) due to AD, and in healthy subjects; (B) evaluating epileptiform EEG activity as a function of different sleep stages within a well-controlled polysomnographic setting.MethodsWe prospectively enrolled 50 ‘probable’ AD patients (73 ± 7.0 years) and 50 subjects with MCI due to AD (72 ± 6.7 years) without history of seizures, comparing them with 50 controls (69 ± 6.7 years). Patients underwent to a full-night video-PSG.ResultsSubclinical epileptiform activity was detected in 6.38% of ‘probable’ AD patients, 11.63% of MCI due to AD subjects and 4.54% of controls (p = 0.43). The comparisons between the three groups for the frequency of epileptiform activity did not reach statistically significant differences neither for total sleep nor for any sleep period considered.ConclusionsOur study shows that, when controlling for sleep stages and the influence of psychoactive drugs, AD patients and MCI due to AD subjects do not exhibit a higher frequency of epileptiform discharges during sleep compared to healthy subjects.SignificanceSubclinical epileptiform activity during sleep does not discriminate ‘probable’ AD from MCI due to AD and healthy controls.     

A point-based tool to predict conversion from mild cognitive impairment to probable Alzheimer's disease

BackgroundOur objective in this study was to develop a point-based tool to predict conversion from amnestic mild cognitive impairment (MCI) to probable Alzheimer's disease (AD).MethodsSubjects were participants in the first part of the Alzheimer's Disease Neuroimaging Initiative. Cox proportional hazards models were used to identify factors associated with development of AD, and a point score was created from predictors in the final model.ResultsThe final point score could range from 0 to 9 (mean 4.8) and included: the Functional Assessment Questionnaire (2‒3 points); magnetic resonance imaging (MRI) middle temporal cortical thinning (1 point); MRI hippocampal subcortical volume (1 point); Alzheimer's Disease Cognitive Scale—cognitive subscale (2‒3 points); and the Clock Test (1 point). Prognostic accuracy was good (Harrell's c = 0.78; 95% CI 0.75, 0.81); 3-year conversion rates were 6% (0‒3 points), 53% (4‒6 points), and 91% (7‒9 points).ConclusionsA point-based risk score combining functional dependence, cerebral MRI measures, and neuropsychological test scores provided good accuracy for prediction of conversion from amnestic MCI to AD.     

Behavioral regulation: factor analysis and application of the Behavioral Dyscontrol Scale in dementia and mild cognitive impairment

BACKGROUND: Executive dysfunction is a hallmark of both Dementia of the Alzheimer's Type (AD) and Vascular Dementia (VaD). A complete neuropsychological battery contains measures of executive function, but the focus tends to be on cognitive processes with verbal or written output. The Behavioral Dyscontrol Scale (BDS) is purported to be a measure of executive function that addresses control over voluntary motor behavior. Previous factor analyses revealed three-factor solutions using a variety of patient populations. Our goals were to examine the factor structure in a sample of geriatric outpatients and to apply that factor structure to detect possible differences between AD, VaD, amnestic Mild Cognitive Impairment (MCI), non-amnestic MCI, and normal controls. METHODS: An exploratory factor analysis was performed on 260 outpatient evaluations from 2002-2006. Only the seven items requiring motor responses were included. RESULTS: A two-factor solution emerged. We named the factors Motor Problem-Solving and Simple Motor Repetitive Behaviors. For the first factor, the AD and VaD groups differed from the MCI groups and normal controls, but did not differ from each other. There were no differences between the control, amnestic MCI, and non-amnestic MCI groups. There were no differences between the groups for the second factor. CONCLUSION: It was concluded that voluntary control of behavior that requires problem-solving for complex tasks may help differentiate dementia from mild cognitive impairment and normal aging.     

Prediction of Alzheimer's disease and mild cognitive impairment using cortical morphological patterns

This article describes a novel approach to extract cortical morphological abnormality patterns from structural magnetic resonance imaging (MRI) data to improve the prediction accuracy of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Conventional approaches extract cortical morphological information, such as regional mean cortical thickness and regional cortical volumes, independently at different regions of interest (ROIs) without considering the relationship between these regions. Our approach involves constructing a similarity map where every element in the map represents the correlation of regional mean cortical thickness between a pair of ROIs. We will demonstrate in this article that this correlative morphological information gives significant improvement in classification performance when compared with ROI‐based morphological information. Classification performance is further improved by integrating the correlative information with ROI‐based information via multi‐kernel support vector machines. This integrated framework achieves an accuracy of 92.35% for AD classification with an area of 0.9744 under the receiver operating characteristic (ROC) curve, and an accuracy of 83.75% for MCI classification with an area of 0.9233. In differentiating MCI subjects who converted to AD within 36 months from non‐converters, an accuracy of 75.05% with an area of 0.8426 under ROC curve was achieved, indicating excellent diagnostic power and generalizability. The current work provides an alternative approach to extraction of high‐order cortical information from structural MRI data for prediction of neurodegenerative diseases such as AD. Hum Brain Mapp 34:3411–3425, 2013. © 2012 Wiley Periodicals, Inc.     

Differentiation between amnestic‐mild cognitive impairment and early‐stage Alzheimer's disease using the Frontal Assessment Battery test

Background: Previous research has described the executive dysfunction that occurs in patients with amnestic‐mild cognitive impairments (A‐MCI) and early‐stage Alzheimer's disease (EAD), which are comparatively similar stages of dementia. The aim of the present cross‐sectional study is to evaluate executive dysfunction using the Frontal Assessment Battery (FAB) screening test in two groups and to investigate the interaction with other cognitive impairments. Methods: Among 170 consecutive patients with Alzheimer's disease or A‐MCI, we recruited 48 subjects who were under 75 years of age and had been diagnosed as having either A‐MCI or EAD. We then compared the total and the subtest scores of the mini‐mental state examination (MMSE) and the FAB between the two groups. Moreover, we investigated the statistical interactive associations of the FAB subtest scores with the influential MMSE subtest scores or the diagnosis (A‐MCI or EAD). Results: No significant differences in the age, sex ratio, duration of illness, and education years were observed between the two groups. However, significant differences in the FAB total and subtest scores (conflicting instructions and go/no‐go) were found between the two groups. Furthermore, significant differences in the MMSE total and subtest scores (orientation, memory delayed recall, and attention and calculation) were also noted between the two groups. In a generalized linear model analysis, only two FAB subtest scores (conflicting instructions and go/no‐go) were significantly influenced by the diagnosis (A‐MCI or EAD) in a manner that was independent of the interaction with the orientation or memory delayed recall. Conclusion: The present findings suggest that the FAB total score and subtest scores reflecting interference performances (conflicting instructions and go/no‐go) significantly declined in patients with EAD, independent of the disorientation and memory disorder. Such characteristics of neuropsychological screening test scores may be useful to clinicians for differentiating EAD and A‐MCI at bedside.     

Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study

Activity and reactivity of the default mode network in the brain was studied using functional magnetic resonance imaging (fMRI) in 28 nondemented individuals with mild cognitive impairment (MCI), 18 patients with mild Alzheimer's disease (AD), and 41 healthy elderly controls (HC). The default mode network was interrogated by means of decreases in brain activity, termed deactivations, during a visual encoding task and during a nonspatial working memory task. Deactivation was found in the default mode network involving the anterior frontal, precuneus, and posterior cingulate cortex. MCI patients showed less deactivation than HC, but more than AD. The most pronounced differences between MCI, HC, and AD occurred in the very early phase of deactivation, reflecting the reactivity and adaptation of the network. The default mode network response in the anterior frontal cortex significantly distinguished MCI from both HC (in the medial frontal) and AD (in the anterior cingulate cortex). The response in the precuneus could only distinguish between patients and HC, not between MCI and AD. These findings may be consistent with the notion that MCI is a transitional state between healthy aging and dementia and with the proposed early changes in MCI in the posterior cingulate cortex and precuneus. These findings suggest that altered activity in the default mode network may act as an early marker for AD pathology.     

Sensorimotor network rewiring in mild cognitive impairment and Alzheimer's disease

This study aimed at elucidating whether (a) brain areas associated with motor function show a change in functional magnetic resonance imaging (fMRI) signal in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), (b) such change is linear over the course of the disease, and (c) fMRI changes in aMCI and AD are driven by hippocampal atrophy, or, conversely, reflect a nonspecific neuronal network rewiring generically associated to brain tissue damage. FMRI during the performance of a simple motor task with the dominant right‐hand, and structural MRI (i.e., dual‐echo, 3D T1‐weighted, and diffusion tensor [DT] MRI sequences) were acquired from 10 AD patients, 15 aMCI patients, and 11 healthy controls. During the simple‐motor task, aMCI patients had decreased recruitment of the left (L) inferior frontal gyrus compared to controls, while they showed increased recruitment of L postcentral gyrus and head of L caudate nucleus, and decreased activation of the cingulum compared with AD patients. Effective connectivity was altered between primary sensorimotor cortices (SMC) in aMCI patients vs. controls, and between L SMC, head of L caudate nucleus, and cingulum in AD vs. aMCI patients. Altered fMRI activations and connections were correlated with the hippocampal atrophy in aMCI and with the overall GM microstructural damage in AD. Motor‐associated functional cortical changes in aMCI and AD mirror fMRI changes of the cognitive network, suggesting the occurrence of a widespread brain rewiring with increasing structural damage rather than a specific response of cognitive network. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Subjective memory complaints in Chinese subjects with mild cognitive impairment and early Alzheimer's disease

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia. However, there is inconsistent opinion as to the validity of subjective memory complaints as a criterion for diagnosis. OBJECTIVE: This study aimed to examine the potential significance of applying a short memory questionnaire in the assessment of Chinese subjects with MCI and early dementia. METHODS: Three hundred and six ambulatory Chinese subjects were recruited. Each participant completed a short memory questionnaire. They were also assessed with the Chinese versions of the mini-mental state examination (CMMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), category verbal fluency test (CVFT) and span tests. Severity of cognitive impairment was evaluated using the Clinical Dementia Rating (CDR); subjects with CDR 0.5 were further classified into MCI not demented (MCIND) and MCI possible incipient dementia (MCIID) depending on the subscale scores of CDR. RESULTS: An increasing frequency of memory complaints with increasing CDR was observed (Kruskal Wallis test, chi square = 21.29, df 3, p < 0.001). With a cutoff of 3 or more memory complaints, the memory questionnaire demonstrated a sensitivity of 65.3% and 70.4% in identifying subjects with incipient and early dementia respectively. Significant associations between memory complaints and most cognitive test performance were found (Spearman's correlations, p < 0.01). Logistic regression analysis revealed that educational level, the memory questionnaire, ADAS-Cog total and delayed recall scores were significant predictors of MCIID status. CONCLUSIONS: The findings suggested that a short memory questionnaire is useful in the screening of MCI, particularly in subjects who already present with subtle functioning disturbances. Subjective memory complaints were significant correlated with objective performance of memory functions, reflecting the usefulness of memory complaints in the assessment of MCI.     

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.     

The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study

A 24-week, randomized, double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 polyunsaturated fatty acids (PUFAs) monotherapy in people with cognitive impairment and to explore its effects on cognitive function and general clinical condition in these participants. Twenty three participants with mild or moderate Alzheimer's disease and twenty three with mild cognitive impairment were randomized to receive omega-3 PUFAs 1.8 g/day or placebo (olive oil). The data of 35 (76%) participants with at least one post-treatment visit was analyzed. There were no severe adverse effects in either group and it suggests that omega-3 PUFAs were well tolerable in this population. The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale (CIBIC-plus) than those in the placebo group over the 24 week follow-up (p=0.008). There was no significant difference in the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) change during follow-up in these two groups. However, the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment (p=0.03), which was not observed in those with Alzheimer's disease. Higher proportions of eicosapentaenoic acid on RBC membranes were also associated with better cognitive outcome (p=0.003). Further studies should be considered with a larger-sample size, diet registration, higher dosages, comparisons between different combinations of PUFAs, and greater homogeneity of participants, especially those with mild Alzheimer's disease and mild cognitive impairment.