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1.  Neuropsychological characteristics of mild cognitive impairment subgroups 
Objective
To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.
Methods
MCI was classified as MCI‐amnestic type (MCI‐AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI‐multiple cognitive deficits type (MCI‐MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.
Results
MCI‐AT (n = 10) had worse verbal and non‐verbal memory performance than MCI‐MCDT (n = 28) or normal controls (n = 374). By contrast, MCI‐MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI‐AT or normal controls. MCI‐MCDT subjects had memory deficits, though they were less pronounced than in MCI‐AT. Of the MCI‐MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI‐MCDT with memory disorders had more language deficits than MCI‐MCDT without memory disorders. By contrast, MCI‐MCDT without memory deficits had more fine motor control deficits than MCI‐MCDT with memory deficits.
Conclusions
The most frequent form of MCI was the MCI‐MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI‐MCDT cases did not have memory impairment. Study of idiopathic amnestic and non‐amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
doi:10.1136/jnnp.2004.045567
PMCID: PMC2077558  PMID: 16103044
Alzheimer's disease; aging; dementia; mild cognitive impairment; neuropsychology
2.  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.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001170.
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)
doi:10.1371/journal.pmed.1001170
PMCID: PMC3274506  PMID: 22346736
3.  Neuropsychiatric Symptoms in Mild Cognitive Impairment: Differences by Subtype and Progression to Dementia 
Background
Neuropsychiatric symptoms (NPS) are common in patients with mild cognitive impairment (MCI). Little is known, however, about how NPS vary by MCI subtype (i.e., amnestic, single domain non-memory, and multiple domain). In addition, it is unclear whether NPS increase risk of progression to dementia. We investigated the distribution of NPS across MCI subtypes and determined whether NPS increase risk of progression to dementia.
Method
Participants were 521 patients diagnosed with MCI at the Alzheimer's Research Centers of California between 1988 and 1999. At baseline, patients were classified into MCI subtypes and were assessed for NPS.
Results
The mean number of NPS was 2.3 (range 0-9.6; 74% had ≥ 1 NPS). Patients with ≥ 4 NPS had more medical comorbidities and greater functional impairment (p ≤ 0.0001 for both). Patients with ≥ 4 NPS were more likely than patients with 0-3 NPS to have amnestic MCI (81% vs. 71%, respectively, p = 0.03), and patients with amnestic MCI were more likely than those with other subtypes to exhibit depressive symptoms. Patients with ≥ 4 NPS had nearly 2.5 times the odds of developing dementia at follow-up than patients with 0-3 NPS (adjusted OR = 2.44, 95% CI 1.07, 5.55).
Conclusion
NPS are common in MCI patients. Those with an elevated number of NPS may be more likely to have the amnestic subtype of MCI, and depression may be more common in amnestic MCI than in other subtypes. An elevated number of NPS may increase risk of progression to dementia for patients with MCI.
doi:10.1002/gps.2187
PMCID: PMC2735341  PMID: 19140134
Mild cognitive impairment; neuropsychiatric symptoms; dementia
4.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
Background:
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
Objective:
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
Methods:
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
Results:
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
Conclusions:
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
GLOSSARY
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
doi:10.1212/WNL.0b013e3181f39d0e
PMCID: PMC2942065  PMID: 20855849
5.  IDENTIFYING MILD COGNITIVE IMPAIRMENT AT BASELINE IN THE GINKGO EVALUATION OF MEMORY (GEM) STUDY 
Aging & mental health  2009;13(2):171-182.
Objectives
To identify, characterize and compare the frequency of Mild Cognitive Impairment (MCI) subtypes at baseline in a large, late-life cohort (N=3,063) recruited into a dementia prevention trial.
Method
A retrospective, data-algorithmic approach was used to classify participants as cognitively normal or MCI with corresponding subtype (e.g., amnestic vs. non-amnestic, single domain vs. multiple domain) based on a comprehensive battery of neuropsychological test scores, with and without Clinical Dementia Rating (CDR) global score included in the algorithm.
Results
Overall, 15.7% of cases (n=480) were classified as MCI. Amnestic MCI was characterized as unilateral memory impairment (i.e., only verbal or only visual memory impaired) or bilateral memory impairment (i.e., both verbal and visual memory impaired). All forms of amnestic MCI were almost twice as frequent as non-amnestic MCI (10.0% vs. 5.7%). Removing the CDR = 0.5 (“questionable dementia”) criterion resulted in a near doubling of the overall MCI frequency to 28.1%.
Conclusion
Combining CDR and cognitive test data to classify participants as MCI resulted in overall MCI and amnestic MCI frequencies consistent with other large community-based studies, most of which relied on the “gold standard” of individual case review and diagnostic consensus. The present data-driven approach may prove to be an effective alternative for use in future large-scale dementia prevention trials.
doi:10.1080/13607860802380656
PMCID: PMC2767255  PMID: 19347684
MCI; Neuropsychology; Dementia Prevention Trials
6.  Modeling the heterogeneity in risk of progression to Alzheimer's disease across cognitive profiles in mild cognitive impairment 
Introduction
Heterogeneity in risk of conversion to Alzheimer's disease (AD) among individuals with mild cognitive impairment (MCI) is well known. Novel statistical methods that are based on partially ordered set (poset) models can be used to create models that provide detailed and accurate information about performance with specific cognitive functions. This approach allows for the study of direct links between specific cognitive functions and risk of conversion to AD from MCI. It also allows for further delineation of multi-domain amnestic MCI, in relation to specific non-amnestic cognitive deficits, and the modeling of a range of episodic memory functioning levels.
Methods
From the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, conversion at 24 months of 268 MCI subjects was analyzed. It was found that 101 of those subjects (37.7%) converted to AD within that time frame. Poset models were then used to classify cognitive performance for MCI subjects. Respective observed conversion rates to AD were calculated for various cognitive subgroups, and by APOE e4 allele status. These rates were then compared across subgroups.
Results
The observed conversion rate for MCI subjects with a relatively lower functioning with a high level of episodic memory at baseline was 61.2%. In MCI subjects who additionally also had relatively lower perceptual motor speed functioning and at least one APOE e4 allele, the conversion rate was 84.2%. In contrast, the observed conversion rate was 9.8% for MCI subjects with a relatively higher episodic memory functioning level and no APOE e4 allele. Relatively lower functioning with cognitive flexibility and perceptual motor speed by itself also appears to be associated with higher conversion rates.
Conclusions
Among MCI subjects, specific baseline cognitive profiles that were derived through poset modeling methods, are clearly associated with differential rates of conversion to AD. More precise delineation of MCI by such cognitive functioning profiles, including notions such as multidomain amnestic MCI, can help in gaining further insight into how heterogeneity arises in outcomes. Poset-based modeling methods may be useful for providing more precise classification of cognitive subgroups among MCI for imaging and genetics studies, and for developing more efficient and focused cognitive test batteries.
doi:10.1186/alzrt168
PMCID: PMC3707057  PMID: 23497709
7.  Novel ThickNet features for the discrimination of amnestic MCI subtypes 
NeuroImage : Clinical  2014;6:284-295.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Highlights
•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
doi:10.1016/j.nicl.2014.09.005
PMCID: PMC4215394  PMID: 25379441
Mild cognitive impairment; Cortical thickness; Network; ThickNet; Early detection; Alzheimer
8.  Everyday functioning in mild cognitive impairment and its relationship with executive cognition 
Objective
Elderly persons with mild cognitive impairment (MCI) are at increased risk of dementia and functional impairments. The present study investigated the contribution of three domains of executive cognition to everyday functioning among persons with MCI.
Methods
124 MCI patients and 68 cognitively normal elderly participants were administered a cognitive screening battery. These tests were used to divide patients into four subgroups (amnestic single domain, amnestic multiple domain, non-amnestic single domain, and non-amnestic multiple domain). Subjects were then administered 18 executive function tests that assess planning/problem-solving, working memory, and judgment. Performance of everyday activities and everyday cognition was rated with two informant-reported measures.
Results
All MCI subtypes had more difficulties in everyday activities than cognitively normal elderly participants. Multiple domain MCI patients had more functional impairments than single domain MCI patients. Contrary to our expectations, only one executive function component, working memory, contributed significantly to functional status after controlling for demographic, health-related and other cognitive factors.
Conclusions
Functional abilities are compromised in all MCI subtypes. Working memory may be associated with functional impairments, but general cognitive measures account for more unique variance.
doi:10.1002/gps.2325
PMCID: PMC2987652  PMID: 19650160
everyday functioning; executive cognition; working memory; mild cognitive impairment
9.  Differences of Brain volume, Hippocampal volume, Cerebrovascular risk factors and APOE4 among MCI subtypes 
Archives of neurology  2009;66(11):1393-1399.
Objectives
To evaluate demographics, magnetic resonance imaging (MRI) measures, and Vascular risk among mild cognitive impairment (MCI) subtypes.
Design
Cross-sectional study.
Setting
Both clinics and the community.
Participants
A total of 153 subjects with MCI, 218 cognitively normal older individuals (controls), and 68 patients with Alzheimer disease.
Main Outcome Measures
Classification of subjects with MCI according to current subtype diagnostic convention based on neuropsychological performance, estimates of vascular risk based on medical history, research MRI unless there was a specific contraindication, and apolipoprotein E genotype.
Results
Of the 153 subjects with MCI, 65 were diagnosed with amnestic single-domain, 46 with amnestic multiple-domain, 27 with nonamnestic single-domain, and 15 with nonamnestic multiple-domain MCI. Analyses of control, MCI, and Alzheimer disease cases revealed significant differences in brain and hippocampal volumes between each group. Post hoc analyses of MRI measures among the MCI subtypes found that patients with amnestic single-domain MCI had significantly less brain atrophy and that hippocampal volume differed significantly from controls for the 2 amnestic forms of MCI. Apolipoprotein E genotype prevalence was significantly greater in the amnestic and nonamnestic subtypes of MCI. Conversely, the nonamnestic subtypes were more likely to have increased vascular risk and to be African American.
Conclusions
Amnestic forms of MCI appear to have demographic, genetic, and MRI findings suggestive of Alzheimer disease pathology, whereas the nonamnestic forms of MCI have findings suggestive of vascular disease. Importantly, however, all subjects with MCI showed evidence of brain injury, and the biological differences among subtypes are relatively subtle beyond the memory vs nonmemory groupings.
doi:10.1001/archneurol.2009.252
PMCID: PMC2909769  PMID: 19901172
Mild Cognitive Impairment; Subtypes; Magnetic Resonanace Imaging; white matter hyperintensities; cerebrovascular disease; Apolipoprotein E genotype; pathophysiology
10.  Complex activities of daily living vary by mild cognitive impairment subtype 
There is increasing consensus regarding the importance of operationally defining and measuring functional decline in mild cognitive impairment (MCI). However, few studies have directly examined functional abilities in MCI or its presumed subtypes and, to date, reported findings have been discrepant. Nondemented older adults (n = 120) were administered a comprehensive cognitive battery measuring multiple domains as well as a performance-based functional ability measure. Participants were characterized as either cognitively normal, amnestic MCI, or non-amnestic MCI. MCI individuals demonstrated decrements in instrumental activities of daily living (IADL) relative to their cognitively normal counterparts. Specifically, participants with amnestic MCI demonstrated significant decrements in financial management, whereas those with non-amnestic MCI showed poorer performance in abilities related to health and safety. Moreover, decreased functional abilities were associated with decrements in global cognitive functioning but not memory or executive functions in the MCI participants. Finally, logistic regression demonstrated that functional abilities accurately predicted MCI subtype. Results support the need for better delineation of functional decline in MCI. Given the implications of functional status for MCI diagnosis and treatment, the direct assessment of functional abilities is recommended. Results further suggest performance-based IADL assessment may have utility in distinguishing MCI subtypes.
doi:10.1017/S1355617710000330
PMCID: PMC2891154  PMID: 20374675
Mild cognitive impairment; Older adults; Neuropsychology; Activities of daily living; Amnestic; Nonamnestic
11.  Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction 
Objective
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.
Methods
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).
Results
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. .
Conclusions
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.
doi:10.1002/gps.2535
PMCID: PMC3204866  PMID: 20845402
Mild Cognitive Impairment; Depression; Executive Dysfunction; Neuropsychiatric symptoms
12.  SELECTIVITY OF EXECUTIVE FUNCTION DEFICITS IN MILD COGNITIVE IMPAIRMENT 
Neuropsychology  2009;23(5):607-618.
Impairment in executive cognition (EC) is now recognized as relatively common among older persons with mild cognitive impairment (MCI), and may be predictive of the development of dementia. However, both MCI and executive functioning are broad and heterogeneous constructs. The present study sought to determine whether impairments in specific domains of EC are associated with specific subtypes of MCI. 124 MCI patients were divided into four subgroups (amnestic versus nonamnestic, and single- versus multiple-domain) based on their performance of widely-used neuropsychological screening tests. These patients and 68 normal elderly were administered 18 clinical and experimental tests of executive function. Principal components analysis suggested two highly reliable EC components, planning/problem-solving and working memory, and a less reliable third component, judgment. Planning/problem-solving and working memory, but not judgment, were impaired among the MCI patients. This was true even among those with Apure amnestic@ MCI, the least impaired group overall. Multiple-domain MCI patients had more severe impairments in planning/problem-solving and working memory than single-domain patients, leading to the supposition that they, not pure amnestic MCIs, are at highest risk of imminent dementia.
doi:10.1037/a0015851
PMCID: PMC2769993  PMID: 19702414
executive function; mild cognitive impairment; dementia; principal components analysis; flexibility; working memory; planning
13.  Stability of Different Subtypes of Mild Cognitive Impairment among the Elderly over a 2- to 3-Year Follow-Up Period 
Background/Aims
To investigate the longitudinal stability and progression of different subtypes of mild cognitive impairment (MCI) in older adults.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1159/000211803
PMCID: PMC2814021  PMID: 19365121
Cognitive subtypes; Mild cognitive impairment; Longitudinal prediction; Alzheimer's disease
14.  Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort 
Neurology  2009;73(22):1866-1872.
Background:
The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population.
Methods:
A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia.
Results:
A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7.
Conclusion:
Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.
GLOSSARY
= Alzheimer disease;
= area under the curve;
= confidence interval;
= cognitive impairment no dementia;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= European Australasian Stroke Prevention in Reversible Ischemia Trial;
= European Australasian Stroke Prevention in Reversible Ischemia Trial, cognitive substudy;
= hazard ratio;
= lacunar infarct;
= mild cognitive impairment;
= modified Rankin scale;
= no cognitive impairment;
= Oxfordshire Community Stroke Project;
= partial anterior circulation infarct;
= posterior circulation infarct;
= receiver operating curve;
= total anterior circulation infarct;
= vascular dementia;
= Wechsler Adult Intelligence Scale–Revised;
= Wechsler Memory Scale–Revised.
doi:10.1212/WNL.0b013e3181c3fcb7
PMCID: PMC2788800  PMID: 19949033
15.  Patterns of Atrophy differ among Specific Subtypes of Mild Cognitive Impairment 
Archives of neurology  2007;64(8):1130-1138.
Objective
To investigate patterns of cerebral atrophy associated with specific subtypes of mild cognitive impairment (MCI).
Design
Case-control study
Setting
Community-based sample at a tertiary referral center
Patients
One hundred and forty-five subjects with MCI subjects and 145 age and gender-matched cognitively normal controls. MCI subjects were classified as amnestic single cognitive domain, amnestic multi-domain, non-amnestic single-domain and non-amnestic multi-domain MCI. The non-amnestic single-domain subjects were also divided into language, attention/executive, and visuospatial groups based on the specific cognitive impairment.
Main Outcome Measure
Patterns of grey matter loss in the MCI groups compared to controls assessed using voxel-based morphometry
Results
The amnestic single and multi-domain groups both showed loss in the medial and inferior temporal lobes compared to controls, while the multi-domain group also showed involvement of the posterior temporal lobe, parietal association cortex and posterior cingulate. The non-amnestic single-domain subjects with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups.
Conclusions
The pattern of atrophy in the amnestic groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the different patterns in the language and attention/executive groups suggest that these subjects may have a different underlying disorder.
doi:10.1001/archneur.64.8.1130
PMCID: PMC2735186  PMID: 17698703
16.  MILD COGNITIVE IMPAIRMENT, DEMENTIA AND SUBTYPES AMONG OLDEST OLD WOMEN 
Archives of neurology  2011;68(5):631-636.
Objective
To determine the prevalence of mild cognitive impairment (MCI), dementia and subtypes among oldest old women.
Design
Prospective cohort study
Setting
Women, Cognitive Impairment Study of Exceptional Aging
Participants
1299 oldest old (≥ 85 years) women
Main Outcome Measures
All women completed a neuropsychological test battery. Those who screened positive for possible cognitive impairment (n=634) were further assessed for a diagnosis of dementia, MCI, or normal by an expert panel. Remaining women were considered cognitively normal. Dementia and MCI subtypes were determined using standard criteria.
Results
The women had a mean age of 88.2 years and 27.0% were ≥90 years; 231 women (17.8%) were diagnosed with dementia and 301 (23.2%) with MCI for a combined cognitive impairment prevalence of 41.0%. Clinical features consistent with Alzheimer’s disease and mixed dementia were most common, each accounting for 40% of dementia cases. Amnestic multiple domain and non-amnestic single domain were the most common MCI types, accounting for 33.9% and 28.9% of cases respectively. Cognitive impairment was more frequent among women ≥90 years compared to those 85–89 years (dementia 28.2% vs. 13.9%, p<0.0001, and MCI 24.5% v. 22.7%, p=0.02) and more common among women with less education, history of stroke, and prevalent depression.
Conclusions
In this large sample of oldest old women, approximately 40% had clinically adjudicated cognitive impairment. Subtypes of dementia and MCI were similar to younger populations. Our results suggest that women in the fastest growing demographic, the oldest old, should be carefully screened for cognitive disorders, especially high risk groups.
doi:10.1001/archneurol.2011.82
PMCID: PMC3108074  PMID: 21555638
17.  Multiple Cognitive Deficits in Amnestic Mild Cognitive Impairment 
Objective
To determine if more widespread cognitive deficits are present in a narrowly defined group of patients with the amnestic form of mild cognitive impairment (MCI).
Methods
From a larger sample of patients clinically diagnosed as meeting the criteria of Petersen et al. for amnestic MCI, we selected 22 subjects who had Clinical Dementia Rating scores of zero on all domains besides memory and orientation. These MCI subjects with presumably isolated memory impairments were compared to 35 age-matched normal controls and 33 very mild Alzheimer's disease (AD) patients on a battery of neuropsychological tests.
Result
In addition to the expected deficits in episodic memory, the amnestic MCI group performed less well than the controls but better than the AD group on design fluency, category fluency, a set shifting task and the Stroop interference condition. Over half the amnestic MCI group (vs. none of the normal controls) scored at least 1 standard deviation below control means on 4 or more of the nonmemory cognitive tasks.
Conclusions
Isolated memory impairment may be fairly uncommon in clinically diagnosed amnestic MCI patients, even when the criteria for amnestic MCI are fairly narrow. Additional cognitive impairments are likely to include fluency and executive functioning. These more diffuse deficits argue for comprehensive cognitive assessments, even when the patient and family are reporting only memory decline, and are consistent with the increase in attention paid to the heterogeneity of MCI.
doi:10.1159/000095303
PMCID: PMC2631274  PMID: 16931884
Amnestic mild cognitive impairment; Alzheimer's disease; Executive function; Fluency
18.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Background
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.
Methods
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.
Results
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]).
Conclusions
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.
doi:10.1016/j.jalz.2013.01.001
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.  An Investigation of PreMCI: Subtypes and Longitudinal Outcomes 
Background/Aims
To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI).
Methods
We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: 1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or 2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination.
Results
The rates of progression to MCI or dementia over an average 2 to 3 year period was 3.7% for NCI subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms and hippocampal atrophy were not associated with progression.
Conclusion
Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct charateristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.
doi:10.1016/j.jalz.2011.03.002
PMCID: PMC3341845  PMID: 22546351
PreMCI; Mild Cognitive Impairment; amnestic MCI; Alzheimer’s disease; MRI; Neuropsychological Tests; Memory Impairment; Hippocampal Volumes
20.  CONTRIBUTIONS OF NEUROPSYCHOLOGY AND NEUROIMAGING TO UNDERSTANDING CLINICAL SUBTYPES OF MILD COGNITIVE IMPAIRMENT 
The original conceptualization of mild cognitive impairment (MCI) was primarily as an amnestic disorder representing an intermediate stage between normal aging and Alzheimer’s dementia (AD). More recently, broader conceptualizations of MCI have emerged that also encompass cognitive domains other than memory. These characterizations delineate clinical subtypes that commonly include amnestic and non-amnestic forms, and that involve single and multiple cognitive domains. With the advent of these broader classifications, more specific information is emerging regarding the neuropsychological presentation of individuals with MCI, risk for dementia associated with different subtypes of MCI, and neuropathologic substrates connected to the clinical subtypes. This review provides an overview of this burgeoning literature specific to clinical subtypes of MCI. Focus is primarily on neuropsychological and structural neuroimaging findings specific to clinical subtypes of MCI as well as the issue of daily functioning. Although investigations of non-amnestic subtypes using advanced neuroimaging techniques and clinical trials are quite limited, we briefly review these topics in MCI because these data provide a framework for future investigations specifically examining additional clinical subtypes of MCI. Finally, the review comments on select methodological issues involved in studying this heterogeneous population, and future directions to continue to improve our understanding of MCI and its clinical subtypes are offered.
doi:10.1016/S0074-7742(09)00405-X
PMCID: PMC2864107  PMID: 19501714
21.  Changes in everyday function among individuals with psychometrically defined Mild Cognitive Impairment in the ACTIVE Study 
Objectives.
Because many individuals with Mild Cognitive Impairment (MCI) will progress to a dementia diagnosis, this population is at high risk for losing functional independence. We examine trajectories of change in everyday function for individuals with cognitive deficits suggestive of MCI.
Design.
We utilized data from the longitudinal, multi-site Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, which allowed for post-hoc classification of MCI status at baseline using psycho metric definitions for amnestic MCI, non-amnestic MCI, multi-domain MCI, and no MCI.
Setting.
Six U.S. cities.
Participants.
2832 volunteers (mean age 74 years; 26% African American) living independently, recruited from senior housing, community centers, and hospitals and clinics.
Measurements.
Mixed effect models examined changes in self-reported instrumental and basic activities of daily living (IADLs and ADLs) from the MDS Home Care Interview in 2,358 participants over a three-year period.
Results.
In models for IADL performance, IADL difficulty, and a Daily Functioning Composite, there was a significant time by MCI classification interaction for each MCI subtype, indicating that all MCI groups showed faster rates of decline in everyday function relative to cognitively normal participants with no MCI.
Conclusion.
Results demonstrate the importance of MCI as a clinical entity that not only predicts progression to dementia but also predicts functional declines in activities that are key to autonomy and quality of life. MCI classification guidelines should allow for functional changes in MCI, and clinicians should monitor for such changes. Preservation of function may serve as a meaningful outcome for intervention efforts.
doi:10.1111/j.1532-5415.2007.01245.x
PMCID: PMC2153444  PMID: 17661957
Mild Cognitive Impairment; functional change; ADL; IADL
22.  Clinical differences among mild cognitive impairment subtypes in Parkinson’s disease 
Background
Mild cognitive impairment is increasingly recognized as a construct in Parkinson’s disease (PD) and occurs in about 25% of non-demented PD patients. Although executive dysfunction is the most frequent type of cognitive deficit in PD, the cognitive phenotype of PD mild cognitive impairment (PD-MCI) is broad. PD-MCI subtypes are represented by amnestic and nonamnestic domain impairment as well as single- and multiple-domain impairment. However, it is unclear whether patients with different PD-MCI subtypes also differ in other clinical characteristics besides cognitive profile.
Methods
We studied 128 PD-MCI subjects at our Movement Disorders center, comparing clinical, motor, and behavioral characteristics across the PD-MCI subtypes.
Results
We found varying proportions of impairment subtypes: nonamnestic single-domain (47.7%), amnestic multiple-domain (24.2%), amnestic single-domain (18.8%), and nonamnestic multiple-domain (9.5%). Attentional/executive functioning and visuospatial abilities were the most frequently impaired domains. PD-MCI subtypes differed in their motor features with nonamnestic multiple-domain PD-MCI subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in age, PD duration, medication use, mood or behavioral disturbances, or vascular disease were not significant.
Conclusions
In addition to differing cognitive profiles, PD-MCI subtypes differ in motor phenotype and severity but not in mood, behavioral, or vascular co-morbidities. Greater postural instability and gait disturbances in the nonamnestic multiple-domain subtype emphasize shared non-dopaminergic neural substrates of gait and cognition in PD. Furthermore, increased burden of cognitive dysfunction, rather than type of cognitive deficit, may be associated with greater motor impairment in PD-MCI.
doi:10.1002/mds.25062
PMCID: PMC3412930  PMID: 22778009
amnestic; dementia; gait; mild cognitive impairment; nonamnestic
23.  Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease in an Asian Memory Clinic – Evidence for a Clinical Spectrum 
Objectives
To determine if mild cognitive impairment (MCI) represents a continuum of cognitive and functional deficits.
Methods
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.
Results
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).
Conclusions
Clinical delineation of aMCI allows the differentiation of those likely to progress for better correlation to biomarker development.
doi:10.1159/000327519
PMCID: PMC3199896  PMID: 22163238
Alzheimer's disease; Clinical dementia rating; Disease spectrum; Mild cognitive impairment
24.  Prevalence of Mild Cognitive Impairment by Multiple Classifications: The MYHAT Project 
Objectives
To estimate and compare the frequency and prevalence of mild cognitive impairment (MCI) and related entities using different classification approaches at the population level.
Design
Cross-sectional epidemiologic study of population-based cohort recruited by age-stratified random sampling from electoral rolls.
Setting
Small-town communities in western Pennsylvania, USA
Participants
Of 2036 individuals aged 65 years and older, 1982 participants with normal or mildly impaired cognition (age-education-corrected Mini-Mental State scores ≥ 21).
Measurements
Demographics, neuropsychological assessment expressed as cognitive domains, functional ability, subjective reports of cognitive difficulties; based on these measurements, operational criteria for the Clinical Dementia Rating (CDR) scale, the 1999 criteria for Amnestic MCI, the 2004 Expanded criteria for MCI, and new, purely cognitive criteria for MCI.
Results
A CDR rating of 0.5 (questionable dementia) was obtained by 27.6% of participants, while 1.2% had CDR ≥ 1 (mild or moderate dementia). Among those with CDR <1, 2.27% had Amnestic MCI and 17.61% had Expanded MCI, while 34.6 % had MCI by purely cognitive classification. Isolated executive function impairment was the least common, while impairment in multiple domains including executive function was the most common. Prevalence estimates weighted against the US Census are also provided.
Conclusions
The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified, and the degree of overlap with other criteria. Prospective followup is needed to determine progression from MCI to dementia, and thus empirically develop improved MCI criteria with good predictive value.
doi:10.1097/JGP.0b013e3181cdee4f
PMCID: PMC2906673  PMID: 20220597
MCI criteria; subjective memory; epidemiology
25.  Subclinical cerebrovascular disease in mild cognitive impairment 
Neurology  2009;73(6):450-456.
Background:
Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample.
Methods:
A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI.
Results:
WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-ɛ4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains.
Conclusion:
White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.
GLOSSARY
= Alzheimer disease;
= Boston Diagnostic Aphasia Examination;
= Benton Visual Retention Test;
= cerebral amyloid angiopathy;
= confidence interval;
= cerebrovascular disease;
= fluid-attenuated inverse recovery;
= mild cognitive impairment;
= odds ratio;
= Selective Reminding Test;
= Wechsler Adult Intelligence Scale–Revised;
= Washington/Hamilton Heights–Inwood Columbia Aging Project;
= white matter hyperintensity.
doi:10.1212/WNL.0b013e3181b1636a
PMCID: PMC2727144  PMID: 19667320

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