The neuropathological profile of mild cognitive impairment (MCI): a systematic review

Whether mild cognitive impairment (MCI) has a distinct neuropathological profile that reflects an intermediate state between no cognitive impairment and dementia is not clear. Identifying which biological events occur at the earliest stage of progressive disease and which are secondary to the neuropathological process is important for understating pathological pathways and for targeted disease prevention. Many studies have now reported on the neurobiology of this intermediate stage. In this systematic review, we synthesize current evidence on the neuropathological profile of MCI. A total of 162 studies were identified with varied definition of MCI, settings ranging from population to specialist clinics and a wide range of objectives. From these studies, it is clear that MCI is neuropathologically complex and cannot be understood within a single framework. Pathological changes identified include plaque and tangle formation, vascular pathologies, neurochemical deficits, cellular injury, inflammation, oxidative stress, mitochondrial changes, changes in genomic activity, synaptic dysfunction, disturbed protein metabolism and disrupted metabolic homeostasis. Determining which factors primarily drive neurodegeneration and dementia and which are secondary features of disease progression still requires further research. Standardization of the definition of MCI and reporting of pathology would greatly assist in building an integrated picture of the clinical and neuropathological profile of MCI.     

Outcome in subgroups of mild cognitive impairment (MCI) is highly predictable using a simple algorithm

Although it is well recognized that MCI represents a risk state for subsequent dementia, estimates of conversion vary widely according to the diagnostic criteria employed. There are currently no simple cognitive predictors of high and low risk of progression. We followed 107 non-demented non-depressed subjects from an original cohort of 124—sub-classified as follows: pure amnestic MCI (22), multi-domain MCI (54), non-amnestic MCI (10) and worried well (21). At 2 years, outcome varied considerably. Of the multi-domain MCI group 59% progressed to dementia and only 5% improved. By contrast, in pure amnestic MCI only 18% progressed and 41% improved. Of non-amnestic MCI patients 70% improved. The best predictor of progression was a combination of the Addenbrooke’s cognitive examination (ACE) and the paired associate learning task (PAL), which produced high negative predictive (90%) and sensitivity (94%) values. The results indicate very different outcomes according to whether patients have pure amnestic versus multi-domain MCI. While the latter is an aggressive disorder, the former is more benign and unstable even in a clinic setting. Patients with scores >88 on the ACE and/or <14 errors on the PAL can be confidently reassured of a good prognosis.     

事件相关电位在轻度认知功能障碍诊断中的意义

目的探讨轻度认知功能障碍和阿尓茨篋〉氖录喙氐缥?ERP:N100、P300)变化。方法根据Peterson制订的MCI诊断标准,筛选出21例MCI患者(MCI组),22例正常对照者(NC组)以及20例阿尓茨篋?AD)组患者,分别用英国OXFORD脑电生理仪记录事件相关电位(ERP:N100,P300)和视觉诱发电位(VEP)情况。结果(1)AD组MMSE评分(16.52±2.17分)及MCI组(24.33±1.34分)低于正常对照组[(26.57±1.43)分,P<0.01]。(2)AD组与MCI组靶波幅P3和非靶波幅P2均见降低,与NC组比较也有显著性差异(P<0.05、P<0.01)。(3)N100潜伏期、波幅变化不是很大(P>0.05)。(4)AD组P300靶刺激中的P2、P3波潜伏期与MMSE分值呈负相关(P<0.05、P<0.01)。结论AD和MCI患者的P300有多项指标异常对于临床诊断AD和MCI患者有一定价值。事件相关电位与认知功能存在明显相关性,提示事件相关电位可以客观反映AD和MCI患者的认知功能障碍。     

Exploring the validity of mild cognitive impairment (MCI) subtypes: Multiple-domain amnestic MCI is the only identifiable subtype at longitudinal follow-up

Background: Epidemiological research exploring risk factors for Alzheimer’s dementia resulted in the identification of the mild cognitive impairment (MCI) profile. Subsequently, distinct subtypes of MCI have been proposed; however, the validity of these as diagnostic entities remains uncertain. Design and participants: The aim of the present study was to examine the longitudinal neuropsychological profiles of MCI subtypes. A total of 118 adults aged 60–90 years were classified at screening as amnestic (a-MCI), nonamnestic (na-MCI), and multiple-domain amnestic (a-MCI+) and were assessed at two time points across 20 months on a comprehensive neuropsychological assessment battery. Results: The a-MCI+ group displayed the poorest performance of all groups in terms of episodic memory, working memory, attention, and executive functioning. Conclusions: These findings suggest that the a-MCI+ subtype is the only variant that is recognizable via neuropsychological testing. In contrast, the differentiation between single-domain subtypes and healthy controls is difficult and may not be achievable through current neuropsychological assessment practices.     

Visual search in mild cognitive impairment: a longitudinal study

In the study of Alzheimer's disease, a multidisciplinary research approach has identified significant abnormality in several areas of visual and visual attention-related brain function in addition to those typically measured as part of clinical diagnosis. This raises the possibility that a similar approach applied to amnestic mild cognitive impairment (aMCI) will increase our understanding of its theoretical and clinical constructs, particularly if functions whose integrity is heterogeneous with respect to etiological outcome can be found. In this study we examined visual search performance (the brain's ability to search effectively throughout the environment for a particular object) in aMCI compared to healthy aging. Cross-sectionally, visual search performance in aMCI was significantly poorer than in healthy aging, with greater intra-group performance heterogeneity in the aMCI compared to the healthy older adult group. This outcome illustrates that although individuals within an aMCI group ostensibly have the same condition they can differ substantially with respect to the integrity of aspects of brain function. Such findings may have implications for the clinical management of the individual patient. The results from the longitudinal aspect of this study also illustrate how heterogeneity in the performance of brain operations other than memory in aMCI may help to inform the likelihood of their developing dementia, as those patients who were diagnosed with dementia within 2.5 years of baseline measurement showed significantly poorer visual search performance compared to those who did not.     

轻度认知功能障碍的神经心理学研究

轻度认知功能障碍（Mlid cognitive imairment,MCI）是近年来提出的新概念,是一种介于正常老化的认知改变和阿尔茨海默病（Alzheimer＇s Disease,AD）之间的中间状态,是目前人们关注的焦点问题.     

De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI)

BACKGROUND: There is inadequate information regarding the neuropsychiatric aspect of Mild Cognitive Impairment (MCI). OBJECTIVE: To determine the neuropsychiatric profile of MCI, and compare this with normal controls and patients with mild Alzheimer's Disease (AD). DESIGN: Cross-sectional assessment of psychiatric symptoms in subjects that are enrolled in Mayo Clinic's longitudinal study of normal aging, MCI and dementia. METHODS AND PARTICIPANTS: The Neuropsychiatric Inventory (NPI) was administered to normal control subjects, MCI subjects and patients with early AD. Individual NPI domain scores and total NPI scores were compared among the three groups after controlling for age, educational status, Dementia Rating Scale (DRS) and Mini-Mental State Examination (MMSE) scores. Statistical analysis was performed by utilizing ANOVA, chi2 and Fisher's exact test. RESULTS: Data were analyzed on 514 normal controls, 54 MCI subjects, and 87 subjects with mild AD (CDR of 0.5 or 1); females consisted of 60.3%, 53.7% and 57.5%; and, the average ages (SD) were 77.8 (1.95), 79 (4.6), 80.5 (14.6) respectively. ANOVA pair-wise comparison revealed that both MMSE and DRS differences among the three groups were significantly different at (p = 0.05). The total NPI scores were significantly different (p =0.0001, F = 107.93) among the three groups using ANOVA. Pair-wise comparison of individual behavioral domain of NPI showed statistically significant differences between MCI and normals; and MCI and AD (p = 0.001). Group differences on NPI remained after controlling for age and education at p = 0.0375 and p = 0.0050 respectively. CONCLUSION: The neuropsychiatric pattern is reminiscent of the clinical, neuroimaging and neuropsychological profile of MCI. It gives further credence to the view that MCI is indeed the gray zone, with overlap on both ends of the pole.     

Self-awareness of cognitive efficiency: Differences between healthy elderly and patients with mild cognitive impairment (MCI)

Introduction: Self-estimation of performance implies the ability to understand one’s own performance with relatively objective terms. Up to date, few studies have addressed this topic in mild cognitive impairment (MCI) patients. The aim of the present study was to compare objective measures of performance with subjective perception of specific performance on cognitive tests and investigate differences in assessment between MCI patients and healthy elderly. Method: Thirty-five participants diagnosed with MCI (women = 16, men = 19, mean age = 65.09 years ±SD = 7.81, mean education = 12.83 years ±SD = 4.32) and 35 control subjects similar in terms of age and education (women = 20, men = 15, mean age = 62.46 years ± SD = 9.35, mean education = 14.26 ± SD = 2.84) were examined with an extended battery of neuropsychological tests. After every test they were asked to self-evaluate their performance by comparing it to what they considered as average for people of their age and educational level. This self-evaluation was reported on a scale ranging from –100 to +100. Results: Significant differences were found in the self-assessment patterns of the two groups in memory measures of verbal and visual delayed recall, visuospatial perception, and tests of attention. MCI patients overestimated their performance on every cognitive domain while control participants underestimated their performance on measures of verbal memory. Conclusions: The present results indicate that accuracy of self-report is not uniform across groups and functional areas. The discrepancies in the MCI patients indicate unawareness of their memory deficits, which is contradictory to subjective memory complaints as being an important component for clinical diagnosis.     

Mild cognitive impairment is associated with mild parkinsonian signs in a door-to-door study

Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥65 years (n=687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n=111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p<0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR =1.19, 95% CI, 1.05 to 1.35, p=0.006) and higher limb bradykinesia scores (OR=1.75, 95% CI, 1.2 to 2.56, p=0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.     

Classification criteria for mild cognitive impairment: a population-based validation study

OBJECTIVE: To evaluate the predictive validity and temporal stability of diagnostic criteria for mild cognitive impairment (MCI). BACKGROUND: MCI has been proposed as a nosologic entity referring to elderly persons with subclinical cognitive deficits due to incipient dementia. Classification criteria, which have been derived from small, selected clinical groups, are currently disputed, and have not yet been assessed within the general population. METHODS: Subjects meeting current criteria for MCI and also age-associated cognitive decline (AACD-a similar concept that is assumed to be related to normal cognitive aging processes rather than incipient dementia) were identified within each of three waves of a longitudinal population study, which included a standardized neurologic examination. RESULTS: In the general population, the prevalence of MCI was estimated to be 3.2% and AACD 19.3%. MCI was a poor predictor of dementia within a 3-year period, with an 11.1% conversion rate. Subjects with MCI also constituted an unstable group, with almost all subjects changing category each year. Discriminant function analysis failed to isolate a homogeneous clinical group. Subjects classified as AACD, contrary to the theoretical assumptions underlying the disorder, represented a more stable group, with a 28.6% conversion rate to dementia over 3 years (relative risk = 21.2). CONCLUSION: MCI criteria perform poorly when applied to a representative population sample. The authors propose modifications to current diagnostic criteria to increase their capacity to detect incipient dementia.     

Disability and mild cognitive impairment: a longitudinal population-based study.

OBJECTIVE: To determine whether mild cognitive deficit is associated with parallel changes in ability to perform activities of daily living. BACKGROUND: While considerable research has been conducted on the effect of senile dementia and other neurodegenerative disorders on ability to perform everyday activities, little is known about the much larger group of elderly persons suffering from mild cognitive deficits. METHODS: Disability prevalence was estimated in 368 persons over the age of 65 years recruited from the general population via a general practitioner network. Subjects were followed over a 3-year period using computerized cognitive assessment and observations of everyday functioning. Standardized neurological assessment in the third year permitted the identification of subjects who have evolved towards dementia. RESULTS: An overall disability prevalence was found in the general population of 26.3%, with 30.8% in subjects with sub-clinical cognitive impairment. Longitudinal follow-up showed cognitive decline over time without dementia to be paralleled by changes in activity performance, with visuospatial deficits having the most marked effect on overall functioning. High intelligence quotient (IQ) and education are seen to reduce the degree of activity loss, but only when senile dementia is not present. CONCLUSIONS: Difficulties in the performance of everyday activities were found more frequently in non-demented subjects with mild cognitive deficits than in the general population. High pre-morbid levels of ability are seen to have a protective effect. A diagnosis of dementia should not therefore be required by persons with cognitive impairment applying for home help.     

轻度认知损害的神经心理学研究进展

"轻度认知损害(MCI)"的概念由Reisberg等[1]在编制认知障碍分级量表即全面衰退量表(GDS)时首次提出,将认知功能和社会职业功能轻度损害但日常生活活动能力(ADL)无明显影响的老年人归为轻度认知损害.     

Stability of clinical condition in mild cognitive impairment is related to cortical sources of alpha rhythms: an electroencephalographic study

Previous evidence has shown that resting eyes-closed cortical alpha rhythms are higher in amplitude in mild cognitive impairment (MCI) than Alzheimer's disease (AD) subjects (Babiloni et al. [2006a]: Human Brain Mapp 27:162-172; [2006b]: Clin Neurophysiol 117:252-268; [2006c]: Neuroimage 29:948-964; [2006d]: Ann Neurol 59:323-334; [2006e]: Clin Neurophysiol 117:1113-1129; [2006f]: Neuroimage 31:1650-1665). This study tested the hypothesis that, in amnesic MCI subjects, high amplitude of baseline cortical alpha rhythms is related to long-term stability of global cognition on clinical follow-up. Resting electroencephalographic (EEG) data were recorded in 100 amnesic MCI subjects during eyes-closed condition. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), and beta2 (20-30 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Global cognition was indexed by mini mental state evaluation (MMSE) score at the time of EEG recordings (baseline) and about after 1 year. Based on the MMSE percentage difference between baseline and 1-year follow-up (MMSEvar), the MCI subjects were retrospectively divided into three arbitrary groups: DECREASED (MMSEvar ≤ -4%; N = 43), STABLE (MMSEvar ≈ 0; N = 27), and INCREASED (MMSEvar ≥ +4%; N = 30). Subjects' age, education, individual alpha frequency, gender, and MMSE scores were used as covariates for statistical analysis. Baseline posterior cortical sources of alpha 1 rhythms were higher in amplitude in the STABLE than in the DECREASED and INCREASED groups. These results suggest that preserved resting cortical neural synchronization at alpha frequency is related to a long-term (1 year) stable cognitive function in MCI subjects. Future studies should use serial MMSE measurements to confirm and refine the present results.