Review: Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia

Background

Mild cognitive impairment and cognitive impairment, no dementia, are emerging terms that encompass the clinical state between normal cognition and dementia in elderly people. Controversy surrounds their characterization, definition and application in clinical practice. In this article, we provide physicians with practical guidance on the definition, diagnosis and treatment of mild cognitive impairment and cognitive impairment, no dementia, based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.

Methods

We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that had mild cognitive impairment or cognitive impairment, no dementia, as the outcome. Subsequent to the conference, we searched for additional articles published between January 2006 and January 2008. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.

Results

We identified 2483 articles, of which 314 were considered to be relevant and of good or fair quality. From a synthesis of the evidence in these studies, we made 16 recommendations. In brief, family physicians should be aware that most types of dementia are preceded by a recognizable phase of mild cognitive decline. They should be familiar with the concepts of mild cognitive impairment and of cognitive impairment, no dementia. Patients with these conditions should be closely monitored because of their increased risk for dementia. Leisure activities, cognitive stimulation and physical activity could be promoted as part of a healthy lifestyle in elderly people and those with mild cognitive impairment. Vascular risk factors should be treated optimally. No other specific therapies can yet be recommended.

Interpretation

Physicians will increasingly see elderly patients with mild memory loss, and learning an approach to diagnosing states such as mild cognitive impairment is now warranted. Close monitoring for progression to dementia, promotion of a healthy lifestyle and treatment of vascular risk factors are recommended for the management of patients with mild cognitive impairment.

Articles to date in this series

• Chertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.
• Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 2008;178:548-56.
• Feldman HH, Jacova C, Robillard A, et al. Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ 2008;178:825-36.

     

Diagnostic accuracy, effectiveness and cost for cognitive impairment and dementia screening of three short cognitive tests applicable to illiterates

Background

Illiteracy, a universal problem, limits the utilization of the most widely used short cognitive tests. Our objective was to assess and compare the effectiveness and cost for cognitive impairment (CI) and dementia (DEM) screening of three short cognitive tests applicable to illiterates.

Methods

Phase III diagnostic test evaluation study was performed during one year in four Primary Care centers, prospectively including individuals with suspicion of CI or DEM. All underwent the Eurotest, Memory Alteration Test (M@T), and Phototest, applied in a balanced manner. Clinical, functional, and cognitive studies were independently performed in a blinded fashion in a Cognitive Behavioral Neurology Unit, and the gold standard diagnosis was established by consensus of expert neurologists on the basis of these results. Effectiveness of tests was assessed as the proportion of correct diagnoses (diagnostic accuracy [DA]) and the kappa index of concordance (k) with respect to gold standard diagnoses. Costs were based on public prices at the time and hospital accounts.

Results

The study included 139 individuals: 47 with DEM, 36 with CI, and 56 without CI. No significant differences in effectiveness were found among the tests. For DEM screening: Eurotest (k = 0.71 [0.59–0.83], DA = 0.87 [0.80–0.92]), M@T (k = 0.72 [0.60–0.84], DA = 0.87 [0.80–0.92]), Phototest (k = 0.70 [0.57–0.82], DA = 0.86 [0.79–0.91]). For CI screening: Eurotest (k = 0.67 [0.55–0.79]; DA = 0.83 [0.76–0.89]), M@T (k = 0.52 [0.37–0.67]; DA = 0.80 [0.72–0.86]), Phototest (k = 0.59 [0.46–0.72]; DA = 0.79 [0.71–0.86]). There were no differences in the cost of DEM screening, but the cost of CI screening was significantly higher with M@T (330.7±177.1€, mean±sd) than with Eurotest (294.1±195.0€) or Phototest (296.0±196.5€). Application time was shorter with Phototest (2.8±0.8 min) than with Eurotest (7.1±1.8 min) or M@T (6.8±2.2 min).

Conclusions

Eurotest, M@T, and Phototest are equally effective. Eurotest and Phototest are both less expensive options but Phototest is the most efficient, requiring the shortest application time.     

Validation of multi-stage telephone-based identification of cognitive impairment and dementia

Background  

Many types of research on dementia and cognitive impairment require large sample sizes. Detailed in-person assessment using batteries of neuropyschologic testing is expensive. This study evaluates whether a brief telephone cognitive assessment strategy can reliably classify cognitive status when compared to an in-person "gold-standard" clinical assessment.     

Serum amino acid profiles in patients with mild cognitive impairment and in patients with mild dementia or moderate dementia

Neurodegenerative disorders are one of the greatest global challenges for social and health care in the twenty-first century. Nowadays, determination of cerebrospinal fluid biomarkers for early diagnosis is served by a complex sample preparation procedure with limited diagnostic accuracy. Furthermore, neuroimaging methods are expensive, time-consuming and are not readily available for use as a complimentary and common screening method. Recently, researchers have shown an increased interest in the identification and characterization of new blood biomarkers of dementia to minimize the limitations associated with the current methods of biomarker determination. Amino acids play many important roles in the central nervous system, acting as neuromodulators, neurotransmitters and regulators of energy metabolism. The aim of this study was to evaluate if serum amino acid levels change along the continuum from no cognitive impairment to moderate dementia, and to identify putative biomarkers for early diagnosis of neurodegenerative diseases. Serum levels of 16 amino acids were determined in 3 groups of patients—22 with mild cognitive impairment, 45 with mild dementia and 28 with moderate dementia—by high-performance liquid chromatography (HPLC) with fluorescence detection using AccQ Tag column (Waters). The most exciting result is the significantly elevated concentration of arginine in patients with both stages of dementia as compared to mild cognitive impairment individuals. Recent accumulating evidence suggests the implication of changed arginine metabolism in the pathogenesis of neurodegenerative diseases. We conclude that amino acids profiling might be helpful in searching for biomarkers of neurogenerative diseases. In the present study, we discovered that arginine in plasma may have a putative diagnostic value for dementia.

     

Drebrin与认知功能障碍

树突棘和突触的病理改变在认知功能障碍发病机制中具有十分重要的作用,研究表明大脑发育调节蛋白（developmentregulationbrainprotein,Drebrin）能够调节树突棘和突触的形态和重塑。Drebrin的减少可能通过树突棘内细胞骨架变化,使树突棘的形态结构受到影响,导致突触功能和结构的变化。但目前阿尔茨海默病（Alzheimer’Sdisease,AD）脑内突触病理变化的具体机制及Drebrin和突触之间的关系仍不明确。探讨Drebrin与认知功能的关系及其机制,对临床上早期干预认知功能障碍、寻找AD的有效诊断治疗措施具有重要意义。     

Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in cognitive decline and enhancement of oxidative loads in the brain. Flavonoids have been considered to exert human health benefits by anti-oxidant and anti-inflammatory properties. The present study is aimed to elucidate the neuroprotective effect of catechin hydrate (CH), a natural flavanoid with potential antioxidant and anti-inflammatory properties, on intracerebroventricular streptozotocin (ICV-STZ) induced neuronal loss and memory impairment. To test this hypothesis, male Wistar rats were pretreated with CH (10 and 20 mg/kg bwt) orally once daily for 21 days and then bilaterally injected with ICV-STZ (3 mg/kg bwt), while sham group rats receive the same volume of vehicle. After 2 weeks of ICV-STZ infusion, rats were tested for cognitive performance using Morris water maze (MWM) test and then sacrifice for biochemical and histopathological assays. CH was found to be successful in upregulating the antioxidant status and prevented the memory loss. The expression of choline acetyl transferase (ChAT) was decreased in ICV-STZ group and CH pretreatment increases the expression of ChAT. Moreover, inflammatory mediators like TNF-α, IL-1β levels and expression of iNOS were significantly attenuated by CH pretreatment. The study suggests that CH is effective in preventing memory loss, ameliorating the oxidative stress and might be beneficial for the treatment of sporadic dementia of Alzheimer’s type (SDAT).     

DNA-repair in mild cognitive impairment and Alzheimer's disease

While the pathogenesis of the sporadic form of Alzheimer disease (late onset Alzheimer disease, LOAD) is not fully understood, it seems to be clear that a combination of genetic and environmental factors are involved and influence the course of the disease. Among these factors, elevated levels of oxidative stress have been recognized and individual differences in the capacity to deal with DNA damage caused by its effects have been the subject of numerous studies. This review summarizes the research on DNA repair proteins and genes in the context of LOAD pathogenesis and its possible prodromal stage, mild cognitive impairment (MCI). The current status of the research in this field is discussed with respect to methodological issues which might have compromised the outcome of some studies and future directions of investigation on this subject are depicted.     

Serum proteomics in amnestic mild cognitive impairment

We have explored proteins related to mild cognitive impairment (MCI). The serum proteome of 35 amnestic MCI patients and 35 cognitively healthy persons was investigated by LC MS. We identified 108 differentially expressed peptides between MCI patients and controls, belonging to 39 proteins. Eight proteins were selected for further investigation by quantitative protein measurements using a MRM assay; apolipoprotein E, carboxypeptidase N subunit 2, complement factor B (CFAB), galectin‐3 binding protein (LG3BP), lumican, serum amyloid A‐4 protein (SAA4), serum amyloid P‐component, and sex hormone binding globulin. Results of the quantitative protein measurements showed significantly decreased levels of carboxypeptidase N subunit 2, CFAB, LG3BP, SAA4, and serum amyloid P‐component in serum from amnestic MCI patients compared with cognitive healthy controls (two‐sided t‐test; p < 0.05). Apolipoprotein E and lumican showed no significant difference in protein levels, sex hormone binding globulin could not be quantified since the MRM assay did not reach the required sensitivity. A model based on the three most significantly decreased proteins (CFAB, LG3BP, and SAA4) showed a sensitivity and specificity of 73 and 66%, respectively, for the initial sample set. A small external validation set yielded 77% sensitivity and 75% specificity.     

Reorganization of functional networks in mild cognitive impairment

Whether the balance between integration and segregation of information in the brain is damaged in Mild Cognitive Impairment (MCI) subjects is still a matter of debate. Here we characterize the functional network architecture of MCI subjects by means of complex networks analysis. Magnetoencephalograms (MEG) time series obtained during a memory task were evaluated by synchronization likelihood (SL), to quantify the statistical dependence between MEG signals and to obtain the functional networks. Graphs from MCI subjects show an enhancement of the strength of connections, together with an increase in the outreach parameter, suggesting that memory processing in MCI subjects is associated with higher energy expenditure and a tendency toward random structure, which breaks the balance between integration and segregation. All features are reproduced by an evolutionary network model that simulates the degenerative process of a healthy functional network to that associated with MCI. Due to the high rate of conversion from MCI to Alzheimer Disease (AD), these results show that the analysis of functional networks could be an appropriate tool for the early detection of both MCI and AD.     

Visual personal familiarity in amnestic mild cognitive impairment

Background

Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer''s disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general concept or helps to identify an object or a person.

Methodology/Principal Findings

Using functional magnetic resonance imaging, we investigated the neural networks associated with the perception of personal familiar faces and places in patients with amnestic mild cognitive impairment and healthy control subjects. Irrespective of stimulus type, patients compared to control subjects showed lower activity in right prefrontal brain regions when perceiving personally familiar versus unfamiliar faces and places. Both groups did not show different neural activity when perceiving faces or places irrespective of familiarity.

Conclusions/Significance

Our data highlight changes in a frontal cortical network associated with knowledge-based personal familiarity among patients with amnestic mild cognitive impairment. These changes could contribute to deficits in social cognition and may reduce the patients'' ability to transition from basic to complex situations and tasks.