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1.  Novel ThickNet features for the discrimination of amnestic MCI subtypes 
NeuroImage : Clinical  2014;6:284-295.
Amnestic mild cognitive impairment (aMCI) is considered to be a transitional stage between healthy aging and Alzheimer's disease (AD), and consists of two subtypes: single-domain aMCI (sd-aMCI) and multi-domain aMCI (md-aMCI). Individuals with md-aMCI are found to exhibit higher risk of conversion to AD. Accurate discrimination among aMCI subtypes (sd- or md-aMCI) and controls could assist in predicting future decline.
We apply our novel thickness network (ThickNet) features to discriminate md-aMCI from healthy controls (NC). ThickNet features are extracted from the properties of a graph constructed from inter-regional co-variation of cortical thickness. We fuse these ThickNet features using multiple kernel learning to form a composite classifier. We apply the proposed ThickNet classifier to discriminate between md-aMCI and NC, sd-aMCI and NC and; and also between sd-aMCI and md-aMCI, using baseline T1 MR scans from the Sydney Memory and Ageing Study.
ThickNet classifier achieved an area under curve (AUC) of 0.74, with 70% sensitivity and 69% specificity in discriminating md-aMCI from healthy controls. The same classifier resulted in AUC = 0.67 and 0.67 for sd-aMCI/NC and sd-aMCI/md-aMCI classification experiments respectively.
The proposed ThickNet classifier demonstrated potential for discriminating md-aMCI from controls, and in discriminating sd-aMCI from md-aMCI, using cortical features from baseline MRI scan alone. Use of the proposed novel ThickNet features demonstrates significant improvements over previous experiments using cortical thickness alone. This result may offer the possibility of early detection of Alzheimer's disease via improved discrimination of aMCI subtypes.
•First structural covariance study on amnestic MCI subtypes and controls•Utilizes fusion of novel ThickNet features from baseline MRI scans alone•Proposed method improves discrimination power between md-aMCI & controls.•Suggests ThickNet features can capture subtle changes in early stages of MCI•Quantitative comparison of classification performance among subtypes of aMCI and controls
PMCID: PMC4215394  PMID: 25379441
Mild cognitive impairment; Cortical thickness; Network; ThickNet; Early detection; Alzheimer
2.  The Sub-Classification of Amnestic Mild Cognitive Impairment Using MRI-Based Cortical Thickness Measures 
Background: Amnestic mild cognitive impairment (aMCI) is considered to be the transitional stage between healthy aging and Alzheimer’s disease (AD). Moreover, aMCI individuals with additional impairment in one or more non-memory cognitive domains are at higher risk of conversion to AD. Hence accurate identification of the sub-types of aMCI would enable earlier detection of individuals progressing to AD.
Methods: We examine the group differences in cortical thickness between single-domain and multiple-domain sub-types of aMCI, and as well as with respect to age-matched controls in a well-balanced cohort from the Sydney Memory and Aging Study. In addition, the diagnostic value of cortical thickness in the sub-classification of aMCI as well as from normal controls using support vector machine (SVM) classifier is evaluated, using a novel cross-validation technique that can handle class-imbalance.
Results: This study revealed an increased, as well as a wider spread, of cortical thinning in multiple-domain aMCI compared to single-domain aMCI. The best performances of the classifier for the pairs (1) single-domain aMCI and normal controls, (2) multiple-domain aMCI and normal controls, and (3) single and multiple-domain aMCI were AUC = 0.52, 0.66, and 0.54, respectively. The accuracy of the classifier for the three pairs was just over 50% exhibiting low specificity (44–60%) and similar sensitivity (53–68%).
Conclusion: Analysis of group differences added evidence to the hypothesis that multiple-domain aMCI is a later stage of AD compared to single-domain aMCI. The classification results show that discrimination among single, multiple-domain sub-types of aMCI and normal controls is limited using baseline cortical thickness measures.
PMCID: PMC4033252  PMID: 24904520
amnestic; mild cognitive impairment; subtype; cortical thickness; classification; early detection; Alzheimer
3.  Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study 
PLoS Medicine  2012;9(2):e1001170.
A set of cross-sectional surveys carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India reveal the prevalence and between-country variation in mild cognitive impairment at a population level.
Rapid demographic ageing is a growing public health issue in many low- and middle-income countries (LAMICs). Mild cognitive impairment (MCI) is a construct frequently used to define groups of people who may be at risk of developing dementia, crucial for targeting preventative interventions. However, little is known about the prevalence or impact of MCI in LAMIC settings.
Methods and Findings
Data were analysed from cross-sectional surveys established by the 10/66 Dementia Research Group and carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India on 15,376 individuals aged 65+ without dementia. Standardised assessments of mental and physical health, and cognitive function were carried out including informant interviews. An algorithm was developed to define Mayo Clinic amnestic MCI (aMCI). Disability (12-item World Health Organization disability assessment schedule [WHODAS]) and informant-reported neuropsychiatric symptoms (neuropsychiatric inventory [NPI-Q]) were measured. After adjustment, aMCI was associated with disability, anxiety, apathy, and irritability (but not depression); between-country heterogeneity in these associations was only significant for disability. The crude prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Country differences changed little (range 0.6%–4.6%) after standardization for age, gender, and education level. In pooled estimates, aMCI was modestly associated with male gender and fewer assets but was not associated with age or education. There was no significant between-country variation in these demographic associations.
An algorithm-derived diagnosis of aMCI showed few sociodemographic associations but was consistently associated with higher disability and neuropsychiatric symptoms in addition to showing substantial variation in prevalence across LAMIC populations. Longitudinal data are needed to confirm findings—in particular, to investigate the predictive validity of aMCI in these settings and risk/protective factors for progression to dementia; however, the large number affected has important implications in these rapidly ageing settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Currently, more than 35 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. Dementia, the commonest form of which is Alzheimer's disease, mainly affects older people and, because more people than ever are living to a ripe old age, experts estimate that, by 2050, more than 115 million people will have dementia. At present, there is no cure for dementia although drugs can be used to manage some of the symptoms. Risk factors for dementia include physical inactivity, infrequent participation in mentally or socially stimulating activities, and common vascular risk factors such as high blood pressure, diabetes, and smoking. In addition, some studies have reported that mild cognitive impairment (MCI) is associated with an increased risk of dementia. MCI can be seen as an intermediate state between normal cognitive aging (becoming increasingly forgetful) and dementia although many people with MCI never develop dementia, and some types of MCI can be static or self-limiting. Individuals with MCI have cognitive problems that are more severe than those normally seen in people of a similar age but they have no other symptoms of dementia and are able to look after themselves. The best studied form of MCI—amnestic MCI (aMCI)—is characterized by memory problems such as misplacing things and forgetting appointments.
Why Was This Study Done?
Much of the expected increase in dementia will occur in low and middle income countries (LAMICs) because these countries have rapidly aging populations. Given that aMCI is frequently used to define groups of people who may be at risk of developing dementia, it would be useful to know what proportion of community-dwelling older adults in LAMICs have aMCI (the prevalence of aMCI). Such information might help governments plan their future health care and social support needs. In this cross-sectional, population-based study, the researchers estimate the prevalence of aMCI in eight LAMICs using data collected by the 10/66 Dementia Research Group. They also investigate the association of aMCI with sociodemographic factors (for example, age, gender, and education), disability, and neuropsychiatric symptoms such as anxiety, apathy, irritability, and depression. A cross-sectional study collects data on a population at a single time point; the 10/66 Dementia Research Group is building an evidence base to inform the development and implementation of policies for improving the health and social welfare of older people in LAMICs, particularly people with dementia.
What Did the Researchers Do and Find?
In cross-sectional surveys carried out in six Latin American LAMICS, China, and India, more than 15,000 elderly individuals without dementia completed standardized assessments of their mental and physical health and their cognitive function. Interviews with relatives and carers provided further details about the participant's cognitive decline and about neuropsychiatric symptoms. The researchers developed an algorithm (set of formulae) that used the data collected in these surveys to diagnose aMCI in the study participants. Finally, they used statistical methods to analyze the prevalence, distribution, and impact of aMCI in the eight LAMICs. The researchers report that aMCI was associated with disability, anxiety, apathy, and irritability but not with depression and that the prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Other analyses show that, considered across all eight countries, aMCI was modestly associated with being male (men had a slightly higher prevalence of aMCI than women) and with having fewer assets but was not associated with age or education.
What Do These Findings Mean?
These findings suggest that aMCI, as diagnosed using the algorithm developed by the researchers, is consistently associated with higher disability and with neuropsychiatric symptoms in the LAMICs studied but not with most sociodemographic factors. Because prevalidated and standardized measurements were applied consistently in all the countries and a common algorithm was used to define aMCI, these findings also suggest that the prevalence of aMCI varies markedly among LAMIC populations and is similar to or slightly lower than the prevalence most often reported for European and North American populations. Although longitudinal studies are now needed to investigate the extent to which aMCI can be used as risk marker for further cognitive decline and dementia in these settings, the large absolute numbers of older people with aMCI in LAMICs revealed here potentially has important implications for health care and social service planning in these rapidly aging and populous regions of the world.
Additional Information
Please access these Web sites via the online version of this summary at
Alzheimer's Disease International is the international federation of Alzheimer associations around the world; it provides links to individual associations, information about dementia, and links to three World Alzheimer Reports; information about the 10/66 Dementia Research Group is also available on this web site
The Alzheimer's Society provides information for patients and carers about dementia, including information on MCI and personal stories about living with dementia
The Alzheimer's Association also provides information for patients and carers about dementia and about MCI, and personal stories about dementia
A BBC radio program that includes an interview with a man with MCI is available
MedlinePlus provides links to further resources about MCI and dementia (in English and Spanish)
PMCID: PMC3274506  PMID: 22346736
4.  Using Voxel-Based Morphometry to Examine the Relationship between Regional Brain Volumes and Memory Performance in Amnestic Mild Cognitive Impairment 
Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disorder, in which morphological alterations of brain tissue develop many years before the first neuropsychological and clinical changes occur. Among the first and most prominent symptoms are deficiencies of declarative memory functions. This stage of precursory symptoms to AD has been described as amnestic mild cognitive impairment (aMCI) and is discussed as a potential AD prodrome. As therapy in the later stages of AD has been shown to be of limited impact, aMCI would be the key target for early intervention. For that purpose a comprehensive neuropsychological and anatomical characterization of this group is necessary. Previous neuropsychological investigations identified tests which are highly sensitive in diagnosing aMCI and very early AD. However, the sensitivity of those neuropsychological tests to the particular structural neuropathology in aMCI remains to be specified. To this end, we investigated 25 patients with single-domain aMCI. All participants underwent extensive neuropsychological testing and anatomical scanning with structural magnetic resonance imaging. Voxel-based morphometry (VBM) was performed to identify brain regions that show a significant correlation between regional brain volume and behavioral measures of memory and executive functioning. We found that performance in a variety of mnemonic tests was directly related to the integrity of the medial temporal lobe cortex (MTLC). Moreover, impairment of memory sub-functions in aMCI might be detected earlier than overt structural damage. By this, these findings contribute to the identification of cerebral structures associated with memory deficits in aMCI.
PMCID: PMC3719379  PMID: 23888131
voxel-based morphometry; amnestic mild cognitive impairment; neuropsychological tests; medial temporal lobe; episodic memory; semantic memory
5.  Graph analysis of verbal fluency test discriminate between patients with Alzheimer's disease, mild cognitive impairment and normal elderly controls 
Verbal fluency is the ability to produce a satisfying sequence of spoken words during a given time interval. The core of verbal fluency lies in the capacity to manage the executive aspects of language. The standard scores of the semantic verbal fluency test are broadly used in the neuropsychological assessment of the elderly, and different analytical methods are likely to extract even more information from the data generated in this test. Graph theory, a mathematical approach to analyze relations between items, represents a promising tool to understand a variety of neuropsychological states. This study reports a graph analysis of data generated by the semantic verbal fluency test by cognitively healthy elderly (NC), patients with Mild Cognitive Impairment—subtypes amnestic (aMCI) and amnestic multiple domain (a+mdMCI)—and patients with Alzheimer's disease (AD). Sequences of words were represented as a speech graph in which every word corresponded to a node and temporal links between words were represented by directed edges. To characterize the structure of the data we calculated 13 speech graph attributes (SGA). The individuals were compared when divided in three (NC—MCI—AD) and four (NC—aMCI—a+mdMCI—AD) groups. When the three groups were compared, significant differences were found in the standard measure of correct words produced, and three SGA: diameter, average shortest path, and network density. SGA sorted the elderly groups with good specificity and sensitivity. When the four groups were compared, the groups differed significantly in network density, except between the two MCI subtypes and NC and aMCI. The diameter of the network and the average shortest path were significantly different between the NC and AD, and between aMCI and AD. SGA sorted the elderly in their groups with good specificity and sensitivity, performing better than the standard score of the task. These findings provide support for a new methodological frame to assess the strength of semantic memory through the verbal fluency task, with potential to amplify the predictive power of this test. Graph analysis is likely to become clinically relevant in neurology and psychiatry, and may be particularly useful for the differential diagnosis of the elderly.
PMCID: PMC4114204  PMID: 25120480
semantic verbal fluency; graph analysis; elderly; Alzheimer's disease; mild cognitive impairment
6.  Different Patterns of White Matter Disruption among Amnestic Mild Cognitive Impairment Subtypes: Relationship with Neuropsychological Performance 
Amnestic mild cognitive impairment (aMCI) is recognized as the prodromal phase of Alzheimer’s disease (AD). Evidence showed that patients with multiple-domain (MD) aMCI were at higher risk of converting to dementia and exhibited more severe gray matter atrophy than single-domain (SD) aMCI. The investigation of the microstructural abnormalities of white matter (WM) among different subtypes of aMCI and their relations with cognitive performances can help to understand the variations among aMCI subtypes and to construct potential imaging based biomarkers to monitor the progression of aMCI. Diffusion-weighted MRI data were acquired from 40 patients with aMCI (aMCI-SD: n = 19; aMCI-MD: n= 21) and 37 healthy controls (HC). Voxel-wise and atlas-based analyses of whole-brain WM were performed among three groups. The correlations between the altered diffusion metrics of the WM tracts and the neuropsychological scores in each subtype of aMCI were assessed. The aMCI-MD patients showed disrupted integrity in multiple WM tracts across the whole-brain when compared with HCs or with aMCI-SD. In contrast, only few WM regions with diffusion changes were found in aMCI-SD as compared to HCs and with less significance. For neuropsychological correlations, only aMCI-MD patients exhibited significant associations between disrupted WM connectivity (in the body of the corpus callosum and the right anterior internal capsules) and cognitive impairments (MMSE and Digit Symb-Coding scores), whereas no such correlations were found in aMCI-SD. These findings indicate that the degeneration extensively exists in WM tracts in aMCI-MD that precedes the development of AD, whereas underlying WM pathology in aMCI-SD is imperceptible. The results are consistent with the view that aMCI is not a uniform disease entity and presents heterogeneity in the clinical progression.
PMCID: PMC4085483  PMID: 23603396
Amnestic mild cognitive impairment; diffusion tensor imaging; multiple-domain; single-domain; TBSS; white matter
7.  Recognition of Facial Emotional Expression in Amnestic Mild Cognitive Impairment 
We examined whether recognition of facial emotional expression would be affected in amnestic mild cognitive impairment (aMCI). A total of 50 elderly persons met the initial inclusion criteria, 10 were subsequently excluded (Geriatric Depression Score >5). 22 subjects were classified with aMCI based on published criteria (single domain aMCI [SD-aMCI], n = 10; multiple domain aMCI [MD-aMCI], n = 12); 18 subjects were cognitively normal. All underwent standard neurological and neuropsychological evaluations as well as tests of facial emotion recognition (FER) and famous faces identification (FFI). Among normal controls, FFI was negatively correlated with MMSE and positively correlated with executive function. Among patients with aMCI, FER was correlated with attention/speed of processing. No other correlations were significant. In a multinomial logistic regression model adjusted for age, sex, and education, a poorer score on FER, but not on FFI, was associated with greater odds of being classified as MD-aMCI (odds ratio [OR], 3.82; 95% confidence interval [CI], 1.05–13.91; p = 0.042). This association was not explained by memory or global cognitive score. There was no association between FER or FFI and SD-aMCI (OR, 1.13; 95% CI, 0.36–3.57; p = 0.836). Therefore, FER, but not FFI, may be impaired in MD-aMCI. This implies that in MD-aMCI, the tasks of FER and FFI may involve segregated neurocognitive networks.
PMCID: PMC3918473  PMID: 22954669
assessment of cognitive disorders/dementia; cognitive aging; emotion; mild cognitive impairment; neuropsychiatric symptoms
8.  Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction 
Mild cognitive impairment (MCI) is a syndrome thought to be a prodrome of dementia for some patients. One subtype, amnestic MCI, may be specifically predispose patients to develop Alzheimer’s Dementia (AD). Since dementia has been associated with a range of neuropsychiatric symptoms (NPS), we sought to examine the prevalence of NPS in MCI and its subtypes.
1779 participants in the National Alzheimer Coordinating Center (NACC) with MCI were included in this study. All participants were evaluated systematically with a thorough cognitive battery, clinical interview, and consensus diagnoses, and subtyped as: 1) amnestic (aMCI) (single- or multiple-domain) vs. non-amnestic (non-aMCI); 2) executive dysfunction-MCI (exMCI) (single- or multiple-domain) vs. no executive dysfunction-MCI (non-exMCI); 3) both aMCI and exMCI; 4) and neither aMCI nor exMCI. Additionally , aMCI vs. nonaMCI and exMCI vs. non-exMCI dichotomies were explored. NPS were assessed with the Neuropsychiatric Inventory (NPI-Q) and Geriatric Depression Scale (GDS).
1379 participants (77.5%) met criteria for aMCI and 616 (34.6%) for exMCI. No differences were observed in the prevalence of NPS between aMCI vs. non-aMCI. However, exMCI was associated with greater severity of depression, anxiety, agitation, disinhibition, irritability, and sleep problems, although these differences do not persist after adjustment for several variables. .
While there were few associations between aMCI and NPS, the presence of executive dysfunction in MCI was associated with greater severity of symptoms and specifically with depression (evidenced by GDS score) and anxiety. These findings may have implications for MCI prognosis and need to be explored in longitudinal studies.
PMCID: PMC3204866  PMID: 20845402
Mild Cognitive Impairment; Depression; Executive Dysfunction; Neuropsychiatric symptoms
9.  Stability of Different Subtypes of Mild Cognitive Impairment among the Elderly over a 2- to 3-Year Follow-Up Period 
To investigate the longitudinal stability and progression of different subtypes of mild cognitive impairment (MCI) in older adults.
We classified 217 individuals with no cognitive impairment (NCI), amnestic MCI (aMCI) based on a single test (aMCI-1) or multiple tests (aMCI-2+), nonamnestic MCI (naMCI) based on a single test (naMCI-1) or multiple tests (naMCI-2+), or amnestic + nonamnestic MCI (a+naMCI), using their baseline neuropsychological test scores, and performed annual follow-up evaluations for up to 3 years.
None of the subjects with aMCI-2+ reverted to normal during follow-up, with 50% of these subjects remaining stable and 50% worsening over time. Similarly, less than 20% of subjects with aMCI-2+ and a+naMCI reverted to NCI during the follow-up period, whereas 50% of aMCI-1 and 37% with naMCI-1 reverted to NCI during this same period.
Reversion to NCI occurs much more frequently when the diagnosis of MCI is based on the results of a single neuropsychological test than when it is based on the results of more memory tests. In epidemiological studies and clinical trials the diagnosis of MCI will likely be more stable if impairment on more than one test is required for amnestic and/or nonamnestic domains.
PMCID: PMC2814021  PMID: 19365121
Cognitive subtypes; Mild cognitive impairment; Longitudinal prediction; Alzheimer's disease
10.  Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease in an Asian Memory Clinic – Evidence for a Clinical Spectrum 
To determine if mild cognitive impairment (MCI) represents a continuum of cognitive and functional deficits.
Clinical data of 164 subjects with no dementia (ND, n = 52), uncertain dementia (n = 69), and mild probable Alzheimer's disease (AD, n = 43) were reviewed. Uncertain dementia patients were classified as pre-MCI (n = 11), early amnestic MCI (e-aMCI, n = 15) and late amnestic MCI (l-aMCI, n = 15). Cognitive assessments [Chinese Mini-Mental State Examination (CMMSE) and a validated neuropsychological battery], functional assessments (Lawton's scale for instrumental activities of daily living) and neuroimaging (ischemic lesions and medial temporal lobe atrophy) were reviewed.
ND, aMCI and mild AD subjects demonstrated a significant trend for worsening performance for all cognitive and functional measures (ANOVA, p < 0.05). Pre-MCI subjects performed significantly better than aMCI subjects in all verbal memory domains (p < 0.001), while l-aMCI had worse functional performance (p = 0.007), a trend towards greater depressive symptoms (p = 0.05) and higher medial temporal lobe atrophy scores (p = 0.06). l-aMCI subjects were more likely than either pre-MCI or e-aMCI to progress to dementia over a mean follow-up period of 2.5 years (46.7 vs. 9.1 and 20.0%, respectively).
Clinical delineation of aMCI allows the differentiation of those likely to progress for better correlation to biomarker development.
PMCID: PMC3199896  PMID: 22163238
Alzheimer's disease; Clinical dementia rating; Disease spectrum; Mild cognitive impairment
11.  The overall impairment of core executive function components in patients with amnestic mild cognitive impairment: a cross-sectional study 
BMC Neurology  2012;12:138.
It remains unclear how executive function (EF) is affected in the stage of amnestic mild cognitive impairment (aMCI). Previous studies using different methods to assess EF in patients with aMCI have reached inconsistent conclusions. The aim of the study was to explore the characteristics of EF impairments in patients with aMCI.
We investigated three core components of EF (i.e., working memory, response inhibition and task switching) based on the theoretical model of EF proposed by Miyake et al. (2000) in 34 aMCI patients and 36 healthy elderly controls using computerized tasks programmed with E-prime (the 2-back task and the keep track task for working memory, the stop-signal task and the Stroop task for response inhibition and the more-odd shifting task for task switching). The overall EF and the three individual EF components were compared between groups. For EF components that were impaired, the extent of impairment was compared using a paired analysis. The aMCI group was further divided into EF-intact and EF-deficit groups according to their performances on the EF tests in clinical neuropsychological assessments. We tested for group differences among the normal controls and the EF-intact and EF-deficit aMCI groups and paid special attention to the comparisons between the EF-intact aMCI group and the control group.
Compared to the control group, overall EF was significantly impaired in patients with aMCI (Wilks’ λ=0.572,P<0.001). Four tasks (the 2-back task, the keep track task, the stop-signal task and the more-odd shifting task) that tapped the three core components of EF displayed group differences that favored the normal controls. The results of the Stroop task revealed no differences in performance between the two groups. The EF-intact aMCI patients also exhibited significantly impaired capabilities in the four tasks compared to the normal controls. There were no significant differences in the extent of impairment between the four affected tasks in the aMCI group, suggesting that the three core EF components were impaired to the same extent.
Both the overall EF and all of the core EF components in the Miyake model of EF (working memory, response inhibition and task switching) were significantly impaired in aMCI patients, regardless of whether they had shown obvious clinical executive dysfunction.
PMCID: PMC3552868  PMID: 23164134
Amnestic mild cognitive impairment; Executive dysfunction; Neuropsychological tests; Inhibition; Working memory
12.  Mnemonic strategy training improves memory for object location associations in both healthy elderly and patients with amnestic mild cognitive impairment: a randomized, single-blind study 
Neuropsychology  2012;26(3):385-399.
To evaluate the efficacy of mnemonic strategy training versus a matched-exposure control condition and also to examine the relationship between training-related gains, neuropsychological abilities, and medial temporal lobe volumetrics in patients with amnestic mild cognitive impairment (aMCI) and age-matched healthy controls.
Twenty-three of 45 screened healthy controls and 29 of 42 screened aMCI were randomized to mnemonic strategy or matched-exposure groups. Groups were run in parallel, with participants blind to the other intervention. All participants completed five sessions within two weeks. Memory testing for object-location associations was performed during sessions one and five and at a one-month follow-up. During sessions 2–4, participants received either mnemonic strategy training or a matched number of exposures with corrective feedback for a total of 45 object-location associations. Structural MRI was performed in most participants and medial temporal lobe volumetrics were acquired.
Twenty-one healthy controls and 28 aMCI patients were included in data analysis. Mnemonic strategy training was significantly more beneficial than matched-exposure immediately after training, p =.006, pη2 = .16, and at one month, p<.001, pη2 = .35, regardless of diagnostic group (healthy controls or aMCI). Although aMCI patients demonstrated gains comparable to the healthy control groups, their overall performance generally remained reduced. Mnemonic strategy-related improvement was positively correlated with baseline memory and executive functioning and negatively with inferior lateral ventricle volume in aMCI patients; no significant relationships were evident in matched-exposure patients.
Mnemonic strategies effectively improve memory for specific content for at least one month in aMCI.
PMCID: PMC3348454  PMID: 22409311
cognitive rehabilitation; associative memory; MRI; hippocampal volume; aging
13.  Course and etiology of dysexecutive MCI in a community sample 
Amnestic MCI (aMCI) is associated with an elevated risk of progressing to Alzheimer’s disease. Much less is known about the course of dysexecutive MCI (dMCI). The goals of this study were to determine: How the profile of cognitive deficits differs over time between patients with dMCI, aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with strokes and white matter hyperintensities on MRI than aMCI.
A prospective evaluation of an inception cohort of 1167 ethnically-diverse elders recruited from an urban community-based sample and followed with clinical and neuropsychological testing over an average of 4.5 years (SD=0.8). A subset of the subjects had MRI scans. We compared four groups of MCI patients: single domain amnestic and dysexecutive MCI and multiple domain MCI with and without executive dysfunction.
Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple domain MCI did not increase risk of progression to dementia. Patients with multiple domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer’s type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to have strokes, but not white matter hyperintensities, detected on MRI than patients with aMCI.
DMCI appears to follow a different course, and be less associated with AD and more associated with stroke, than aMCI.
PMCID: PMC3933297  PMID: 23452959
14.  Pre-MCI and MCI 
To compare clinical, imaging, and neuropsychological characteristics and longitudinal course of subjects with premild cognitive impairment (Pre-MCI), who exhibit features of MCI on clinical examination but lack impairment on neuropsychological examination, to subjects with no cognitive impairment (NCI), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and mild dementia.
For 369 subjects, clinical dementia rating sum of boxes (CDR-SB), ApoE genotyping, cardiovascular risk factors, parkinsonism (UPDRS) scores, structural brain MRIs, and neuropsychological testing were obtained at baseline, whereas 275 of these subjects received an annual follow-up for 2–3 years.
At baseline, Pre-MCI subjects showed impairment on tests of executive function and language, higher apathy scores, and lower left hippocampal volumes (HPCV) in comparison to NCI subjects. Pre-MCI subjects showed less impairment on at least one memory measure, CDR-SB and UPDRS scores, in comparison to naMCI, aMCI and mild dementia subjects. Follow-up over 2–3 years showed 28.6% of Pre-MCI subjects, but less than 5% of NCI subjects progressed to MCI or dementia. Progression rates to dementia were equivalent between naMCI (22.2%) and aMCI (34.5%) groups, but greater than for the Pre-MCI group (2.4%). Progression to dementia was best predicted by the CDR-SB, a list learning and executive function test.
This study demonstrates that clinically defined Pre-MCI has cognitive, functional, motor, behavioral and imaging features that are intermediate between NCI and MCI states at baseline. Pre-MCI subjects showed accelerated rates of progression to MCI as compared to NCI subjects, but slower rates of progression to dementia than MCI subjects.
PMCID: PMC3175279  PMID: 21422909
Algorithmic diagnosis; Alzheimer disease; amnestic MCI; clinical diagnosis; dementia; hippocampal volume; longitudinal analysis; MCI; mild cognitive impairment; MRI; neuropsychological tests; pre-MCI
15.  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.
PMCID: PMC3568924  PMID: 21406427
Mild Cognitive Impairment; Dementia; Alzheimer’s Disease; Screening; Memory
16.  Enhancing Diagnostic Accuracy of aMCI in the Elderly: Combination of Olfactory Test, Pupillary Response Test, BDNF Plasma Level, and APOE Genotype 
Background. Amnestic Mild Cognitive Impairment (aMCI) often progresses to Alzheimer's disease. There are clinical markers and biomarkers to identify the degenerative process in the brain. Objectives. To obtain the diagnostic values of olfactory test, pupillary response to tropicamide 0.01%, BDNF plasma level, and APOE ε4 in diagnosing aMCI. Methods. Cross-sectional, comparative analysis. Results. There were 109 subjects enrolled (aMCI: 51, normal cognition: 58) with age 64 ± 5.54 years. For diagnosing aMCI, cut-off point for the olfactory score was <7 out of 10 and >22% for pupil dilatation response. Low BDNF plasma level was related significantly with olfactory deficits and aMCI (P < 0.05). Four of five subjects with homozygote e4 presented with multiple-domain aMCI. This group displayed the lowest means of olfactory score and the highest means of pupillary hypersensitivity response (P < 0.0001). Combination of olfactory deficit and pupillary hypersensitivity response in detection of aMCI was beneficial with Sp 91% and PPV 87%. In conjunction with clinical markers, BDNF plasma level and presence of APOE e4+ improved Sp and PPV. Conclusions. Combination of olfactory test and pupillary response test was useful as diagnostic tool in aMCI. In conjunction with clinical markers, low level of BDNF plasma and presence of APOE e4 improved the diagnostic value.
PMCID: PMC3929508  PMID: 24639912
17.  Spatial memory impairments in amnestic mild cognitive impairment in a virtual radial arm maze 
This study aims to apply the virtual radial arm maze (VRAM) task to find spatial working memory and reference memory impairments in patients of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Spatial memory functions between aMCI converters and nonconverters are also compared using VRAM results.
We assessed the spatial memory in 20 normal controls, 20 aMCI, and 20 mild AD subjects using VRAM. The Mini-Mental State Examination, Clinical Dementia Rating scale, and other neuropsychological tests were given to the subjects in conjunction with the VRAM test. Scores in working memory errors and reference memory errors were compared among the three groups using repeated measures analysis of variance. In addition, aMCI patients were followed-up after 5 years and surveyed for AD conversion rate.
In AD patients, both spatial working and reference memory were impaired. However, in aMCI subjects, only spatial reference memory was impaired. Significant spatial reference memory impairment was found in the aMCI converter group when compared to the nonconverter group.
Spatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD. In aMCI patients, more severe spatial reference memory deficit is a neuropsychological marker for AD conversion. VRAM may be well utilized in humans to assess spatial memory in normal aging, in aMCI, and in AD.
PMCID: PMC4000250  PMID: 24790448
spatial behavior; Alzheimer’s disease; user computer interface; cognition
18.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex.
Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline.
Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]).
Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.
PMCID: PMC3830601  PMID: 23562428
Mild cognitive impairment; Risk factors; Type 2 diabetes; Incidence; Cohort studies; Population-based studies; Sex differences; Diabetic retinopathy; Diabetic neuropathy
19.  Functional impairment in elderly patients with mild cognitive impairment and mild Alzheimer's disease 
Archives of general psychiatry  2011;68(6):617-626.
The original mild cognitive impairment (MCI) criteria exclude substantial functional deficits, but recent reports suggest otherwise. Identifying the extent, severity, type, and correlates of functional deficits that occur in MCI and mild Alzheimer’s disease (AD) can aid in early detection of incipient dementia and identify potential mechanistic pathways to disrupted instrumental activities of daily living (IADLs).
To examine the number, type, and severity of functional impairments and identify the clinical characteristics associated with functional impairment across individuals with amnestic MCI (aMCI) and those with mild AD.
The study uses baseline data from the Alzheimer’s Disease Neuroimaging Initiative.
Data from the Alzheimer’s Disease Neuroimaging Initiative was collected at multiple research sites in the US and Canada.
The samples included 229 controls, 394 aMCI, and 193 AD patients.
The 10-item Pfeffer Functional Activities Questionnaire (FAQ) assessed function.
Informant-reported FAQ deficits were common in patients with aMCI (72.3%) and AD (97.4%) but were rarely self-reported by controls (7.9%). The average severity per FAQ deficit did not differ between patients with aMCI and controls; both were less impaired than patients with AD (P < .001). Two FAQ items (remembering appointments, family occasions, holidays, and medications; assembling tax records, business affairs, or other papers) were specific (0.95) in differentiating controls from the combined aMCI and AD groups (only 34.0% of patients with aMCI and 3.6% of patients with AD had no difficulty with these 2 items). The severity of FAQ deficits in the combined aMCI and AD group was associated with worse Trailmaking Test A scores and smaller hippocampal volumes (P < .001). Within the aMCI group, functionally intact individuals had greater hippocampal volumes and better Auditory Verbal Learning Test 30-minute delay and Trailmaking Test A (P < .001) scores compared with those with moderate or severe FAQ deficits. Patients with a high number of deficits were more likely to express the APOE ε4 allele (63.8%) compared with patients with no (46.8%) or few (48.4%) functional deficits.
Mild IADL deficits are common in individuals with aMCI and should be considered in MCI criteria. Two IADLs, remembering appointments, family occasions, holidays, and medications and assembling tax records, business affairs, or other papers, appear to be characteristic of clinically significant cognitive impairment. In patients with aMCI, impairment in memory and processing speed and greater medial temporal atrophy were associated with greater IADL deficits
PMCID: PMC3682408  PMID: 21646578
20.  Analysis of Verbal Fluency Ability in Amnestic and Non-Amnestic Mild Cognitive Impairment 
The purpose of this study was to investigate the pattern of performance on letter and category fluency tests of individuals with mild cognitive impairment (MCI). Previous research has suggested that organization strategies, including “clustering” (i.e., groups of related words) and “switching” (i.e., shift from one cluster to another), are important for efficient verbal fluency performance. Participants were 25 individuals with single-domain amnestic MCI (aMCI), 49 with multidomain aMCI, 16 with non-amnestic MCI (naMCI), and 90 cognitively healthy older adults. Fluency performances were analyzed across two 30-s intervals for total words produced, cluster size, and switching. Analyses of variance (ANOVAs) with follow-up tests revealed that the single-domain aMCI group performed comparably with healthy controls on each dependent measure across both fluency tasks. In contrast, the multidomain aMCI group showed performance decrements in total words and switching production compared with healthy controls on both fluency tasks, whereas the naMCI group produced fewer words and switches on letter fluency. Each group generated more words and switches during the first 30-s on both fluency tasks, with the exception of the naMCI group, whose switching on letter fluency did not decrease as the task progressed. As indicated by the single-domain aMCI group's unimpaired performance, our findings demonstrate that verbal fluency performance decreases as domains beyond memory become impaired in MCI. Reduced switching ability, which has been linked to prefrontal executive functioning, contributed the most to the poorer performance of individuals with multidomain MCI and naMCI.
PMCID: PMC3888195  PMID: 23917346
Mild cognitive impairment; Fluency; Language and language disorders; Executive functioning
21.  Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease 
Neurology  2008;71(24):1986-1992.
Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD.
Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated.
With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up.
Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.
AD = Alzheimer disease; ADRDA = Alzheimer's Disease and Related Disorders Association; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; CDRSB = Clinical Dementia Rating Sum of Boxes; ERC = entorhinal cortex; FADRC-CC = Florida Alzheimer's Disease Research Center–Clinical Core; HPC = hippocampus; HR = hazard ratio; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MTA = medial temporal lobe atrophy; MTL = medial temporal lobe; NACC = National Alzheimer's Coordinating Center; naMCI = nonamnestic mild cognitive impairment; NCI = no cognitive impairment; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke; NS = not significant; PRC = perirhinal cortex; VRS = visual rating system.
PMCID: PMC2676975  PMID: 19064880
22.  The brain structural and cognitive basis of odor identification deficits in mild cognitive impairment and Alzheimer’s disease 
BMC Neurology  2014;14:168.
The objectives of this study were to explore the relationship between olfactory impairment, cognitive measures, and brain structure volumes in healthy elderly individuals, compared to patients with amnestic mild cognitive impairment (aMCI) or early Alzheimer’s disease (AD). The primary aim was to elucidate possible differences in cognitive scores and brain structure volumes between aMCI/AD patients with relatively intact odor identification (OI) ability and those with reduced ability.
Twelve patients with aMCI, six with early AD, and 30 control subjects were included. OI abilities were assessed with the Brief Smell Identification Test (B-SIT) and Sniffin Sticks Identification Test (SSIT). Neuropsychological tests of executive functions and memory were performed. Brain structural volumes were obtained from T1 weighted 3D MRI at 3 Tesla. Statistical comparisons between the patients with aMCI and AD indicated no significant differences in performance on most tests. Since the groups were small and AD patients were in an early phase of disease, all patients were subsequently considered together as a single group for studying OI. Patients were subdivided into relatively intact (scores >50%) and reduced OI (≤ 50% score) on the olfactory tests.
The aMCI/AD group with reduced OI ability, as measured by both B-SIT and SSIT, had significantly smaller hippocampal volume as compared to the patient group with OI scores > 50%. There was a significant association between OI scores and hippocampal volume in the patient (not the control) group. Similar changes with tests of executive function and memory were not found. Low OI scores on B-SIT were associated with conversion from aMCI to AD in patients. The reduced OI patient group was significantly faster on Rey complex figure copying than the fairly intact OI group.
The results from this pilot study suggest that the reduction in the size of hippocampus in connection with early AD is associated more with loss of OI ability rather than loss of memory, thus demonstrating that impaired OI is an early marker of medial temporal lobe degeneration.
PMCID: PMC4236673  PMID: 25154749
Dementia; B-SIT; Hippocampus; Neurodegeneration; Olfaction; SSIT
23.  Short-Term Delayed Recall of Auditory Verbal Learning Test Is Equivalent to Long-Term Delayed Recall for Identifying Amnestic Mild Cognitive Impairment 
PLoS ONE  2012;7(12):e51157.
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.
PMCID: PMC3517417  PMID: 23236445
24.  Famous Landmark Identification in Amnestic Mild Cognitive Impairment and Alzheimer's Disease 
PLoS ONE  2014;9(8):e105623.
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.
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.
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.
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.
PMCID: PMC4140812  PMID: 25144755
25.  Differences in learning rates for item and associative memories between amnestic mild cognitive impairment and healthy controls 
It has been established that the overall performance of associative memory was disproportionately impaired in contrast to item memory in aMCI (Amnestic mild cognitive impairment) patients, but little is known about the specific aspects of the memory process that show differences between aMCI and healthy controls. By comparing an item-item associative learning test with an individual item learning test, the present study investigated whether the rate of learning was slower in associative memory than in item memory in aMCI. Furthermore, we examined whether deficits in intertrial acquisition and consolidation contributed to the potential disproportionate impairments in the learning rate of associative memory for aMCI patients. In addition, we further explored whether the aMCI-discriminative power of the associative memory test increases more than that of the item memory test when the number of learning-test trials increases.
A group of 40 aMCI patients and 40 matched control participants were administered a standardized item memory test (Auditory Verbal Learning Test, AVLT) and a standardized associative memory test (Paired Associative Learning Test, PALT), as well as other neuropsychological tests and clinical assessments.
The results indicated that the learning rate deficits in aMCI patients were more obvious for associative memory than for item memory and that the deficits resulted from impairments in both intertrial acquisition and consolidation. In addition, the receiver operating characteristic curve and logistical regression analysis revealed that the discriminative power of the associative memory test for aMCI was larger than that of the item memory test, especially with more than one learning-test trials.
Due to more deficits in learning rate of associative memory than that of item memory, the discriminative power for aMCI tended to be larger in associative memory than in item memory when the number of learning-test trials increased. It is suggested that associative memory tests with multiple trials may be particularly useful for early detection of aMCI.
PMCID: PMC3751153  PMID: 23886305
Mild cognitive impairment; Associative memory; Item memory; Learning rate

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