Alzheimer's disease neuroimaging initiative and mild cognitive impairment]

Alzheimer's disease (AD) generally begins with mild memory problems in an insidious manner and progresses to develop multiple cognitive as well as functional impairment within a few years. Currently, the diagnosis of AD requires multiple cognitive deficits including memory disturbance and exclusion of other dementing disorders. However, normal elderly people quite commonly complain of increasing forgetfulness with age. Mild cognitive impairment (MCI) is generally regarded as an intermediate state between normal aging and dementia. In other words, MCI refers to persons that are not normal nor clinically diagnosed dementia. (Winblad et al. J. Intern. Med. 2004). When daily functioning is impaired as a result of cognitive decline, dementia is the appropriate diagnostic label. Alzheimer's Disease Neuroimaging Initiative (ADNI) aims at; 1) Major goal is collection of data and to establish a brain imaging and biomarker database; 2) Determine the optimum methods for acquiring and processing images for clinical trials: 3) Develop "standards" for imaging, biomarkers; 4) "Validate" imaging and biomarker data by correlating with behavioral data to facilitate new AD therapies by disease modifiers. Japan-ADNI will be started as a part of world wide ADNI. Currently, gamma-secretase modifiers and Abeta aggregation inhibitors as well as amyloid vaccination are under clinical trials.     

Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease

Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). MCI patients experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. An issue currently under investigation is whether MCI represents the preclinical stages of AD or a distinct and static cognitive aetiology. In an attempt to address this issue, the present investigations are adopting a convergent approach to the detection of preclinical AD, where multiple risk factors are considered when making a diagnosis. Currently, one of the most important tools when assessing early cognitive changes is neuropsychological evaluation. MCI subjects typically record neuropsychological performance between that of healthy older individuals and demented patients. Tests assessing new learning, delayed recall and attention/executive function seem to provide valuable information for screening and diagnosis of MCI and early AD if interpreted properly. Recommendations concerning methodological issues and the early management of neuropsychological MCI studies were made.     

Mild cognitive impairment: To treat or not to treat

Mild cognitive impairment (MCI) refers to memory deficits in excess of normal aging, but not sufficient for the diagnosis of Alzheimer’s disease (AD). In general, patients with MCI are not disabled and have no other obvious cognitive deficits other than memory. Many studies have shown that patients with MCI are more likely to progress to AD than age-matched controls. Drug therapy to prevent or delay deterioration in patients with MCI has been tested only very recently. The results of three clinical trials are discussed. One of two trials with donepizil suggests that donepizil may delay onset of AD, but the effect is modest and the side effects are problematic. Galantamine appeared to be associated with excess deaths, and vitamin E was not effective. No medications are currently indicated for the prevention of dementia in patients with MCI.     

Mild Cognitive Impairment: Diagnosis,Longitudinal Course,and Emerging Treatments

Mild cognitive impairment (MCI) is widely regarded as the intermediate stage of cognitive impairment between the changes seen in normal cognitive aging and those associated with dementia. Elderly patients with MCI constitute a high-risk population for developing dementia, in particular Alzheimer’s disease (AD). Although the core clinical criteria for MCI have remained largely unchanged, the operational definition of MCI has undergone several revisions over the course of the last decade and remains an evolving diagnosis. Prognostic implications of this diagnosis are becoming clearer with regard to the risk of progressive cognitive deterioration. Although patients with MCI may represent an optimal target population for pharmacological and non-pharmacological interventions, results from clinical trials have been mixed and an effective treatment remains elusive. This article provides a brief overview of the evolution of the concept of MCI and reviews current diagnostic criteria, the longitudinal course of the disorder, and current and emerging treatments for MCI.     

Update on mild cognitive impairment

Mild cognitive impairment (MCI) refers to persons whose memory or other cognitive abilities are not normal, but who do not have clinically diagnosed dementia. MCI has received considerable attention in the medical literature over the past few years. There were 63 original reports in the English language literature with the term "mild cognitive impairment" in the title in 2001 and 2002, in contrast to only 26 articles in the prior decade. Although criteria for MCI are not a matter of secure agreement, a consensus is emerging that MCI is common, is associated with significant mortality and morbidity, particularly the development of AD, and is due, in large part, to the same pathologic processes responsible for Alzheimer’s disease (AD). Current research efforts are geared towards understanding factors that contribute to the development of dementia among persons with MCI and towards intervention studies aimed at preventing the development of dementia among persons with MCI.     

Nonepisodic memory deficits in amnestic MCI.

OBJECTIVE: To (a) compare patients with amnestic Mild Cognitive Impairment (MCI), mild Alzheimer disease (AD), and a group of healthy elderly persons on nonepisodic memory measures; (b) examine which measures are independent of level of education in the groups studied. BACKGROUND: Episodic memory impairment is a cardinal feature of preclinical AD. However, a number of other cognitive measures are also sensitive to the preclinical stage of AD and deficits in multiple domains characterize AD several years before clinical diagnosis. MATERIALS AND METHODS: Patients with amnestic MCI (N=31), patients with mild probable AD (N=15), and healthy elderly controls (N=27) were compared on nonepisodic memory tasks measuring fluid intelligence, working memory, processing speed, verbal fluency, and visual-perceptual and motor functions. Amnestic MCI patients were selected based on clinical criteria and a subgroup was also selected based on psychometric criteria. RESULTS: Multivariate analyses of covariance, controlling for the effects of age, education, and sex, showed that fluid intelligence, working memory, processing speed, semantic fluency, visual-perceptual function, and complex motor function were significantly worse in the MCI than the elderly control group. Working memory, processing speed, semantic fluency, and complex motor tasks were significantly worse in the mild probable AD than the MCI group. The analyses were corroborated using the psychometrically derived MCI group. CONCLUSIONS: (a) Performance on multiple nonepisodic memory measures is affected in the preclinical stage of AD, indicating that broad cognitive impairment characterizes that stage. (b) Complex motor tasks were independent of level of education in our sample, and may have practical utility in the early detection of dementia.     

轻度认知功能障碍的认识

轻度认知功能障碍（MCI）是指介于痴呆和正常衰老之间的认知功能损害状态。由于概念的混淆、方法的差异及标准的不同,MCI在临床实践中存在着不少困惑。本文回顾了认知功能损害的研究历史,讨论了MCI的概念、诊断标准、临床分型、与正常老化和痴呆的鉴别以及临床预后,探讨了MCI与阿尔茨海默病的关系。     

Mild cognitive impairment: transition between aging and Alzheimer's disease

The concept of the boundary between normal aging and early Alzheimer's disease is a focus of a great deal of research in the field of aging and dementia. Presumably there is a continuum of function between normality and the earliest signs of Alzheimer's disease. This transitional condition has been labeled mild cognitive impairment. Mild cognitive impairment refers to individuals who have a memory impairment greater than what one would expect for age, yet general cognitive function is preserved. Similarly activities of daily living are normal. However, the memory function of these individuals is abnormal for age and education. These subjects do not meet criteria for Alzheimer's disease. When mild cognitive impairment subjects are followed longitudinally, they tend to convert to clinically probable Alzheimer's disease as a rate of 10-15% per year. This is in contrast to normal elderly subjects who will develop Alzheimer's disease at a rate of 1-2% per year. Certain predictor variables are available to determine which subjects are more likely to progress at a rapid rate. Mild cognitive impairment is an important topic for research in aging and dementia and has also become the subject of several multicenter treatment trials.     

Rates of hippocampal atrophy correlate with change in clinical status in aging and AD

BACKGROUND: The cognitive continuum in the elderly population can be conceptually divided into those who are functioning normally (control subjects), those with a mild cognitive impairment (MCI), and those with probable AD. OBJECTIVES: To test the hypothesis that the annualized rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD). METHODS: The authors identified 129 subjects from the Mayo Clinic AD Research Center/AD Patient Registry who met established criteria for normal control subjects, MCI, or probable AD, both at entry and at the time of a subsequent clinical follow-up evaluation 3 +/- 1 years later. Each subject underwent an MRI examination of the head at the time of the initial assessment and at follow-up clinical assessment; the annualized percentage change in hippocampal volume was computed. Subjects who were classified as controls or patients with MCI at baseline could either remain cognitively stable or could decline to a lower functioning group over the period of observation. RESULTS: The annualized rates of hippocampal volume loss for each of the three initial clinical groups decreased progressively in the following order: AD > MC > control. Within the control and MCI groups, those who declined had a significantly greater rate of volume loss than those who remained clinically stable. The mean annualized rates of hippocampal atrophy by follow-up clinical group were: control-stable 1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%, AD 3. 5%. CONCLUSION: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the cognitive continuum from normal to MCI to AD.     

Prevalence of mild cognitive impairment: a population-based study in elderly subjects

OBJECTIVES: Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia, especially Alzheimer's disease (AD). In follow-up studies, more than 50% of MCI subjects have been converted to dementia in 3-4 years. However, the epidemiology of MCI is not well known. This study was designed to determine the prevalence of MCI in an elderly population. METHODS: A total of 806 subjects (60-76 years of age) from a population-based random sample of 1150 subjects living in the city of Kuopio in eastern Finland were evaluated. Neuropsychological tests and a structured interview including the modified Clinical Dementia Rating (CDR) were used to apply the diagnostic criteria of MCI as proposed by Mayo Clinic Alzheimer's Disease Research Centre. Thus, subjects having a test score more than 1.5 SDs below the age appropriate mean in memory tests and a CDR score of 0.5 but no dementia, were diagnosed as having MCI. RESULTS: A total of 43 subjects, 5.3%, met the MCI criteria. MCI was more prevalent in older and less-educated subjects, but no difference was found between men and women. The CDR appeared to be the most important part of the criteria. The memory tests had less impact on prevalence variables. CONCLUSIONS: The low prevalence of MCI indicate that in a population-based study design its criteria may identify a more homogeneous group of subjects at the lower end of the cognitive continuum as contrasted with various other criteria of cognitive impairment in the elderly population. This is compatible with follow-up studies showing a high probability of dementia in the MCI group. Thus, probable candidates for trials of preventive intervention for dementia can be screened from the elderly population using these diagnostic criteria.     

Early symptoms and signs of cognitive deficits might not always be detectable in persons who develop Alzheimer's disease

OBJECTIVE:Clinical syndromes such as amnestic mild cognitive impairment (MCI) are highly predictive of future development of Alzheimer's disease (AD), but it is not known how many of the individuals that develop the disease can be identified with these syndromes. This study aims to determine how many individuals with AD show detectable symptoms or clinical signs of cognitive deficits three years before diagnosis.METHODS: 152 incident AD cases were identified in a dementia-free cohort of 1417 persons aged 75-95, after three-year follow-up from a prospective population-based study, the Kungsholmen Project. Symptoms of cognitive impairment including the subjective report of memory problems, and cognitive deficits were objectively measured with an extensive neuropsychological test battery at baseline. Incident AD was clinically diagnosed according to DSM-IIIR criteria at three-year follow-up.RESULTS: Only half of future AD cases reported subjective memory problems three years before diagnosis. More than one-third of incident AD cases did not exhibit detectable deficits in any of the investigated specific cognitive domains. Only 38.3% had both subjective complaints and domain-specific cognitive deficits.CONCLUSIONS: Symptoms and signs currently used to define MCI are not always present in persons who develop AD. Increasing the number of potentially identifiable and treatable preclinical AD cases is unfeasible unless more sensitive subjective and objective markers are identified. Furthermore, as only half of future AD cases report subjective memory problems three years before diagnosis, the number of persons coming to the attention of medical care is limited.     

Inhibition impairments in Alzheimer's disease, mild cognitive impairment and healthy aging: Effect of congruency proportion in a Stroop task

The goal of this study was to assess inhibition and goal maintenance in persons with Alzheimer's disease, mild cognitive impairment, healthy older adults and younger adults. This was done by using a task that compared the Stroop effect in pure blocks, that comprised only incongruent trials, with the Stroop effect in mixed blocks, in which 25% of trials were incongruent and 75% were congruent (Kane & Engle, 2003). Those conditions were administered to 20 healthy younger and 20 older control participants, and to 20 participants meeting criteria for MCI and 11 for AD. Results show reduced resistance to interference as a consequence of healthy aging and only partially impaired goal-maintenance capacities. Interference and goal maintenance are also impaired when comparing MCI and AD to healthy older adults, with AD suffering from a more severe impairment than MCI. In addition, there is a partial preservation of goal-maintenance capacities in MCI because reducing response speed allows them to maintain a level of error rate similar to that of healthy older adults. In contrast, AD persons suffer from a complete breakdown of goal-maintenance capacities, as is suggested by deficits on both response time and error rates.     

Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches.     

The significance of thyroid-stimulating hormone and homocysteine in the development of Alzheimer's disease in mild cognitive impairment: a 6-year follow-up study

Mild cognitive impairment (MCI) represents a transition between normal aging and Alzheimer's disease (AD). The aim of this study was to investigate the predictive value of vitamin B12/folate, homocysteine, standard laboratory parameters, and concomitant diseases for development of AD in persons with an MCI diagnosis. Development of dementia was followed for 6 years in 93 consecutively recruited MCI persons. Information concerning the above factors was obtained from medical journals. Thirty-four percent of participants converted to AD within 6 years. A forward stepwise logistic regression was performed. The odds ratio (OR) for the Mini-Mental State Examination (MMSE) was 0.777; for age, 1.084; and for thyroid stimulating hormone (TSH), 0.287. The OR for homocysteine was 1.287 at 60 years of age and 1.087 at 65 years of age. Lower TSH levels together with the more established factors lower MMSE, higher homocysteine levels, and age were found to be predictive factors of AD. This may have clinical implications with regard to monitoring TSH levels and thyroxin substitution in MCI patients.     

Clinical trials in mild cognitive impairment: lessons for the future

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.     

Mild cognitive impairment: believe it or not?

Mild cognitive impairment (MCI) was previously defined as a transitional state that can precede dementia, but the condition and the rates of conversion remain controversial. MCI is now the focus of natural history studies, along with Alzheimer's disease (AD) prevention. The objective of our review will be to consider the question of whether MCI is a well enough established entity that it can be a diagnosis in medical practice and a valid target of Alzheimer's prevention therapy. MCI was originally defined by Petersen et al. (1999) as progressive memory loss, prodrome of Alzheimer's disease. More recently MCI has been expanded to other cognitive domains with other potential causes like normal aging, fronto-temporal dementia, and vascular dementia. Despite many consensus conferences, experts cannot agree on critical aspects of the MCI, particularly with respect to its clinical utility. Based on neuropsychological studies, a hippocampal memory profile has been proposed for MCI as prodromal AD. Further research is needed to advance these criteria. We have no doubt, however, that in the future, the diagnosis of AD as disease (not only a dementia syndrome) will be made in the early pre-dementia stage and will be drawn from a combination of neuropsychological, neuro-imaging and CSF biomarkers.     

Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease

Neuropsychological deficits, such as poor episodic memory, are consistent features of mild cognitive impairment and also that of early stage of dementia. The aim of the present study was to detect cognitive dysfunction among patients with Alzheimer's disease or with mild cognitive impairment (MCI), which refers to a transitional state between the cognition of normal aeging and mild dementia regarded as a high-risk condition for the development of clinically probable Alzheimer's disease (AD). Computerized tests of memory, attention and executive functions were studied in groups of AD subjects (n=15) and MCI subjects (n=25). On all measures, the performance of the AD group was significantly weaker compared to healthy individuals or to the MCI group. The performance of both the AD and MCI patients in the Paired Associate Learning test was significantly impaired, which may suggest that MCI patients are already in the early stages of the disease.     

Task switching capacities in persons with Alzheimer's disease and mild cognitive impairment

Task switching is an executive capacity that relies on a set of separate components implicating a fronto-parietal network of brain areas. In the present study, different components implicated in task switching were assessed in persons with Alzheimer's disease (AD), persons with mild cognitive impairment (MCI), and their matched healthy controls. The procedure implicated presentation of a two-digit stimulus, and task switching involved either conceptual or spatial switching. Global switching was measured by comparing blocks that involved non-switch trials to blocks that included switch trials, whereas local switching was measured by comparing performance across single trials in the switch blocks. Furthermore, the paradigm measured practice effects. Persons with AD showed larger local and global switch cost than healthy controls suggesting that their deficits encompass both reconfiguration of new action sets and maintenance of potentially relevant tasks within working memory. Importantly, the deficit was large in spatial switching but negligible in the conceptual condition. Persons with MCI only showed global switching impairment, suggesting a deficit restricted to the concurrent maintenance of two relevant task sets, and as in AD, this impairment was limited to spatial switching. Interestingly, persons with MCI, but not AD patients, improved their switching capacities upon practice. These findings indicate that switching deficit is selective in both MCI and AD persons, and is thus supportive of the notion that different mechanisms are involved in task switching. The pattern across condition is coherent with a continuum between those two clinical groups.     

Emotional processing in bipolar disorder: Behavioural and neuroimaging findings

Mild cognitive impairment (MCI) was previously defined as a transitional state that can precede dementia, but the condition and the rates of conversion remain controversial. MCI is now the focus of natural history studies, along with Alzheimer's disease (AD) prevention. The objective of our review will be to consider the question of whether MCI is a well enough established entity that it can be a diagnosis in medical practice and a valid target of Alzheimer's prevention therapy. MCI was originally defined by Petersen et al. () as progressive memory loss, prodrome of Alzheimer's disease. More recently MCI has been expanded to other cognitive domains with other potential causes like normal aging, fronto-temporal dementia, and vascular dementia. Despite many consensus conferences, experts cannot agree on critical aspects of the MCI, particularly with respect to its clinical utility. Based on neuropsychological studies, a hippocampal memory profile has been proposed for MCI as prodromal AD. Further research is needed to advance these criteria. We have no doubt, however, that in the future, the diagnosis of AD as disease (not only a dementia syndrome) will be made in the early pre-dementia stage and will be drawn from a combination of neuropsychological, neuro-imaging and CSF biomarkers.