Prevention of CIND by physical activity: different impact on VCI-ND compared with MCI

BACKGROUND: Cognitive impairment that does not meet the criteria for dementia ("Cognitive Impairment, No Dementia" -- CIND) is a heterogeneous category with an increased risk of dementia. While greater physical activity is generally associated with a lower odds of both dementia and CIND, whether this effect applies across subgroups is not known. OBJECTIVES: To investigate the association between physical activity and the risk of vascular CIND (VCI-ND) or mild cognitive impairment (MCI). METHODS: In the Canadian Study of Health and Aging community-dwelling cohort, of 4683 people who were not impaired at baseline, 3945 remained without cognitive impairment at 5 years, 454 were diagnosed with CIND, and 284 with dementia. Incident CIND and VCI-ND (n=163) and MCI (n=100) subtypes were investigated in relation to baseline physical activity, stratified by sex. RESULTS: In women, moderate-high exercise was associated with a lower odds of CIND (OR=0.62, 95% CI=0.46-0.84) and VCI-ND (0.34, 0.18-0.63) relative to low exercise. There was no association for men or for MCI. CONCLUSION: Exercise appears to reduce the risk of VCI-ND in women. Whether the lack of an effect of exercise on the odds of MCI reflects that 'prevented AD' is indistinguishable from MCI is an intriguing possibility that merits further study.     

CERAD test performances in amnestic mild cognitive impairment and Alzheimer's disease

OBJECTIVES: The aim of the study was to examine the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test performances cross-sectionally in patients suffering from amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Moreover, we wanted to determine the sensitivity to amnestic MCI and mild AD, as well as the specificity of different CERAD subtests in our study groups. MATERIAL AND METHODS: Fifteen healthy elderly individuals, 15 amnestic MCI patients and 15 probable AD patients suffering from mild dementia were tested with the CERAD neurocognitive dementia screening test. RESULTS: Significant differences were found in all CERAD tests except Constructional praxis (copy) and Clock drawing between the controls and the AD group. The MCI group was differentiated from the controls only in the Wordlist learning test. In the language tests the sensitivity to MCI and AD was quite low and the specificity very high. In the savings scores the sensitivity to AD was high, but the specificity rather low. The Wordlist recognition test screened no false positives using the current cut-off score and the sensitivity to AD was 0.6, but only one MCI patient was detected using the current cut-off score. Raising the cut-off score also raised the sensitivity to MCI without dramatic loss of specificity. Cut-off scores for the Wordlist learning test and Wordlist delayed recall, which have been found to differentiate normal aging from dementia, are lacking in the Finnish CERAD. The current data indicates that the Wordlist learning test might be relatively sensitive to MCI. CONCLUSIONS: The results indicate that the Finnish CERAD test battery with its current cut-off scores has low sensitivity to MCI, and using it as a sole cognitive screening instrument for MCI and preclinical dementia might result in false negatives.     

White matter lesions - age-adjusted values for cognitively healthy and demented subjects

OBJECTIVES: To develop age-adjusted norms for white matter lesions (WML) and to differentiate dementia from mild cognitive impairment and normal aging. MATERIALS AND METHODS: 240 patients underwent a comprehensive clinical, neuropsychological and MRI examination. A scale was developed quantify WML in anatomically defined regions by rating size and frequency. FLAIR sequences were used to determine a global and a frontal score. The scores were correlated with the psychometric test results and the final clinical diagnosis: cognitively normal (CN), mild cognitive impairment (MCI), Alzheimer's Disease (AD), vascular dementia (VD). Age-adjusted curves for WML scores were calculated by means of a non-parametic smoothing method. RESULTS: WML scores of the whole cerebrum and the frontal lobe were significantly increased in vascular dementia as compared to CN, MCI and AD. Individual WML scores correlated significantly with age and neuropsychological test results. For the age range 55-72, the WML scores of VD were significantly different from those of CN, MCI and AD. CONCLUSIONS: Age-corrected WML load was significantly higher in vascular dementia as compared to MCI, AD and cognitively normals over a wide age range.     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

From mild cognitive impairment to dementia: a prevalence study in a district of Tuscany, Italy

OBJECTIVE: A door-to-door two-phase study was designed in order to estimate the prevalence of cognitive deficit amongst the residents of a district in Tuscany (central Italy). Identification of cases with mild cognitive impairment (MCI) was given high priority, because this condition has been suggested as a term for the boundary area between normal aging and dementia. METHODS: Of the 1600 subjects who completed the screening phase, 354 scored under the cut-off point of the Mini Mental State Examination and Clinical Dementia Rating and were investigated by means of a standardized diagnostic protocol. RESULTS: The prevalence of MCI and age-related cognitive decline was 4.9 and 9.3%, respectively; low levels of education significantly increased the risk of these conditions. The prevalence of dementia over age 65 was 6.2%, with a significant risk association with age. In our population, Alzheimer's disease was the most frequent type of dementia (prevalence rate 4.2%) and increased risk depending on age, sex and education has been found. CONCLUSIONS: Our findings are somewhat similar to previous studies. Further epidemiological and longitudinal studies are warranted to identify which diagnostic category is more predictive for dementia.     

Effectiveness of the Takeda Three Colors Combination Test as a screening test for dementia

Background:  The aged population is increasing worldwide and it is expected that dementia, for which aging is a risk factor, will increase as well. A critical issue then becomes a community's capacity for the early detection of dementia among its senior citizens. In the present paper, we report on the development and potential use of a screening test for dementia that can be administered and assessed easily in a short period of time by non-specialist clinicians and represents no burden for those undergoing the screening.
Methods:  Three hundred and sixty senior citizens, over 60 years of age, participated in the study. Of these, 126 had Alzheimer's disease (AD), 60 had vascular dementia (VaD), 41 had mild cognitive impairment (MCI), and 133 were healthy volunteers (control group). A screening test for dementia, which consisted of a colored cards configuration memory task (the Takeda Three Colors Combination Test; TTCC) was examined for sensitivity, specificity, reliability and criterion-related validity.
Results:  Sufficient sensitivity and specificity were demonstrated for each clinical group (AD, VaD) and the control group. The sensitivity of the TTCC was 0.94, 0.82, and 0.71 for the AD, VaD, and MCI groups, respectively; specificity was 0.83. In addition, sufficient reliability and validity were established. Administration of the TTCCand assessment procedures required only 1 or 2 min.
Conclusion:  Satisfactory sensitivity and specificity were indicated for both the AD and VaD groups, with sufficient reliability and validity also indicated. Thus, the TTCC is an effective dementia screening test.     

Addition of EEG improves accuracy of a logistic model that uses neuropsychological and cardiovascular factors to identify dementia and MCI

To investigate whether addition of EEG would improve accuracy of a logistic model that uses neuropsychological assessment and cardiovascular history to identify dementia and mild cognitive impairment (MCI) as a single group, we collected data and constructed logistic models from a sample of 78 normal adults and 33 patients (aged 50-85 years). To determine accuracy, we compared logistic regression results to a geriatrician's diagnosis of MCI or dementia that included Alzheimer's disease, vascular dementia or mixed dementia. We found that the addition of EEG (non-linear complexity) to a logistic model that included both neuropsychological assessment (ADAS-Cog) and cardiovascular history increased overall accuracy from 80% to 92%. The logistic model identified dementia and MCI as a single group comprised of the following subgroups (with accuracies): Alzheimer's disease (92%; 12/13), vascular dementia (73%; 8/11), mixed dementia (100%; 4/4), and mild cognitive impairment (80%; 4/5). Whereas the analysis is limited by small sample sizes and mixing of diverse pathologies, the findings do provide support that the subgroups may share changes in neuropsychological, cardiovascular, and electroencephalographic factors (specifically ADAS-Cog total score, cardiovascular history, and EEG complexity). Taken together, the study results provide support that EEG might complement the clinician's evaluation of dementia and MCI.     

Intracranial volume in mild cognitive impairment,Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.     

Neuropsychological characteristics of mild vascular cognitive impairment and dementia after stroke

BACKGROUND: Post-stroke cognitive impairment is frequent, with characteristic impairments of attentional and executive performance. OBJECTIVE: The study aims to determine whether the profile and severity of impairment in vascular Cognitive Impairment No Dementia (vascular CIND) is intermediate between that seen in stroke patients without significant cognitive impairment and patients with post-stroke dementia and thus to establish if the potential value of vascular CIND is a useful concept for predicting further cognitive decline and dementia in stroke patients. METHODS: Stroke patients (n=381) > 75 were recruited from representative hospital-based stroke registers in Tyneside and Wearside, UK. Sixty six age matched controls were also recruited. A detailed battery of neuropsychological assessments was completed 3 months post stroke. RESULTS: Deficits of attention (z=5.7; p <0.0001) and executive function (z=5.9; p <0.0001) were seen even in stroke patients without vascular CIND, compared to controls. However, stroke patients with CIND were significantly more impaired again on tests of executive function (z=10.3; p <0.0001) compared to those not meeting CIND criteria; and also had greater impairments of memory (z=10.4; p <0.0001) and language expression (z=10.1; p <0.0001). A similar overall profile of deficits was evident in the CIND and the dementia group, but specific deficits were significantly more pronounced in those with dementia, particularly in orientation (z=7.2; p <0.0001) and memory (z=5.8; p <0.0001). CONCLUSIONS: The current study indicates that attentional and executive impairments are frequent in stroke patients, but deficits of memory, orientation and language are more indicative of CIND and dementia. Further longitudinal studies are required to clarify the relationship between specific lesions and the progression of specific cognitive deficits in post-stroke patients.     

The rate of conversion of mild cognitive impairment to dementia: predictive role of depression

BACKGROUND: Mild cognitive impairment (MCI) is a condition referring to the persons with cognitive deficits measurable in some form or another, but not meeting criteria for dementia, and who have an increased risk of becoming demented. OBJECTIVE: To establish the rate of progression to dementia in MCI, to investigate the risk of conversion for amnestic vs multiple-domains subtypes, and to identify the predictors of progression. METHODS: MCI (n = 105) individuals enrolled in a longitudinal study received annual clinical and psychometric examinations for up to a mean of 3 years. The diagnosis of MCI according to Mayo Clinic Petersen's Criteria was conducted by a panel of specialists. RESULTS: After 3 years of follow-up, 23 of 105 subjects with MCI were diagnosed with dementia. 40 showed cognitive decline not dementia, 34 were stable and showed no cognitive decline or improvement, while eight showed cognitive improvement. CONCLUSIONS: We conclude that conversion rate from MCI to DSM-IIIR dementia was 21.9% over a period of 3 years. The occurrence of depressive symptoms may constitute a predictor for those who are more likely to progress to dementia. The risk of conversion to dementia was higher among the subjects with an evidence of impairment extending beyond memory than with those who suffered only from memory deficits, and the subjects who converted to dementia in this subtype had significantly higher baseline plasma total homocysteine levels than non-converters.     

Validation of the modified telephone interview for cognitive status (TICS-m) in Hebrew

INTRODUCTION: The validity of the Hebrew version of the Telephone Interview for Cognitive Status-Modified (TICS-m) for Mild Cognitive Impairment (MCI), for dementia, and for cognitive impairment (either MCI or dementia) was investigated. METHODS: Of the 10 059 who took part of the Israel Ischemic Heart Disease Cohort, 1902 of the 2901 survivors in 1999 had TICS-m interviews. Those with a score of 27 or below and a random sample with a score of 28 or 29 were invited to have a physician's examination for the diagnosis of dementia. The analysis was performed on the 576 who agreed. RESULTS: Based on physician's diagnosis, 269 were diagnosed as suffering from dementia, 128 as suffering from MCI, and 179 were diagnosed with no cognitive impairment. The TICS-m Hebrew version's internal consistency was very high (Cronbach's alpha = 0.98) and showed a strong convergent validity with the MMSE (r = 0.82; p < 0.0005). The sensitivity was 100% for each of the conditions. Finally, after controlling for age, education and hearing impairment, TICS-m was a strong predictor of dementia, MCI and cognitive impairment. CONCLUSION: At a cut-off of 27/50 the Hebrew version of the TICS-m is a useful screening instrument to identify subjects suffering from mild cognitive impairment, dementia and cognitive impairment (MCI or dementia).     

轻度认知功能障碍的神经影像学最新研究进展

轻度认知功能障碍（mild cognitive impairment，MCI）是介于正常老化、痴呆之间的一种临 床状态，表现为轻度的记忆和智能损害，达不到痴呆诊断标准，但有进展为痴呆的高风险。因此，早 发现、早诊断、早治疗非常关键。在MCI的具体诊断上，神经影像诊断表现出显著的临床应用价值， 该诊断方式在早期诊断MCI及预防AD疾病的发生上具有显著作用。本文综述了当前国内外应用神经 影像学诊断MCI的方法与结果，为进一步诊断及治疗MCI提供依据。     

Rate of progression of mild cognitive impairment to dementia – meta‐analysis of 41 robust inception cohort studies

Objective: To quantify the risk of developing dementia in those with mild cognitive impairment (MCI). Method: Meta‐analysis of inception cohort studies. Results: Forty‐one robust cohort studies were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to Alzheimer’s disease (AD) and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia, AD and VaD was 9.6%, 8.1% and 1.9%, respectively in specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non‐Mayo defined MCI and clinical trials are also reported. Conclusion: The ACR is approximately 5–10% and most people with MCI will not progress to dementia even after 10 years of follow‐up.     

The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment

The Diagnostic Statistical Manual-5 (DSM-5) has included a category named the neurocognitive disorder which was formally known in DSM-IV as ‘dementia, delirium, amnestic, and other cognitive disorders’. The DSM-5 distinguishes between ‘mild’ and ‘major’ neurocognitive disorders. Major neurocognitive disorder replaces the DSM-IV's term ‘dementia or other debilitating conditions’. A pivotal addition is ‘mild neurocognitive disorder (mNCD)’ defined by a noticeable decrement in cognitive functioning that goes beyond normal changes seen in aging. It is a disorder that may progress to dementia – importantly, it may not.

Presently, our understanding of mNCD is derived from research on mild cognitive impairment (MCI). Whereas there is currently no clear treatment for mNCD, many experimental therapies now and into the future will focus upon secondary prevention, namely decreasing the risk of progression to major NCD. In this article, we will focus on mNCD by reviewing the relevant literature on MCI. We will review the research on the incidence and prevalence of MCI, conversion rates from MCI to dementia, risk factors for conversion of MCI to dementia, comorbidity of MCI with other neuropsychiatric disorders (NPS), and the development of treatment strategies for neuropsychiatric disorders in MCI.

The presence of NPS is common among individuals with MCI and is an important risk for progression to dementia. However, there has been little research on effective treatments for NPS in MCI. Clinicians and investigators must determine if the treatment of the NPS in mNCD will improve quality of life and help reduce the progression of the cognitive impairment.     

The Gothenburg MCI study: Design and distribution of Alzheimer’s disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up

There is a need for increased nosological knowledge to enable rational trials in Alzheimer’s disease (AD) and related disorders. The ongoing Gothenburg mild cognitive impairment (MCI) study is an attempt to conduct longitudinal in-depth phenotyping of patients with different forms and degrees of cognitive impairment using neuropsychological, neuroimaging, and neurochemical tools. Particular attention is paid to the interplay between AD and subcortical vascular disease, the latter representing a disease entity that may cause or contribute to cognitive impairment with an effect size that may be comparable to AD. Of 664 patients enrolled between 1999 and 2013, 195 were diagnosed with subjective cognitive impairment (SCI), 274 with mild cognitive impairment (MCI), and 195 with dementia, at baseline. Of the 195 (29%) patients with dementia at baseline, 81 (42%) had AD, 27 (14%) SVD, 41 (21%) mixed type dementia (=AD + SVD = MixD), and 46 (23%) other etiologies. After 6 years, 292 SCI/MCI patients were eligible for follow-up. Of these 292, 69 (24%) had converted to dementia (29 (42%) AD, 16 (23%) SVD, 15 (22%) MixD, 9 (13%) other etiologies). The study has shown that it is possible to identify not only AD but also incipient and manifest MixD/SVD in a memory clinic setting. These conditions should be taken into account in clinical trials.     

Defining dementia: clinical criteria for the diagnosis of vascular dementia

The recognition of cerebrovascular disease (CVD) as a contributing factor and a cause of dementia has led to the development of clinical criteria for vascular dementia (VaD). Due to high specificity, the consensus criteria developed by the National Institute for Neurological and Communicative Disorders and Stroke (NINDS)–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) have been used in controlled clinical trials to select patients with pure VaD. VaD is predominantly a subcortical frontal form of dementia with prominent executive dysfunction. In contrast, the criteria of the NINCDS–Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD and from other forms of dementia. Moreover, CVD may precipitate the clinical expression of AD. Although no criteria have been created specifically for patients having AD with CVD, the ischemic score, the Informant Questionnaire on Cognitive Decline in the Elderly and a history of prestroke mild cognitive impairment (MCI) may be useful for identifying patients with this mixed form of dementia.     

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.     

Cerebral blood flow measured by arterial spin labeling MRI at resting state in normal aging and Alzheimer’s disease

Arterial spin labeling (ASL) magnetic resonance imaging uses arterial blood water as an endogenous tracer to measure cerebral blood flow (CBF). In this review, based on ASL studies in the resting state, we discuss state-of-the-art technical and data processing improvements in ASL, and ASL CBF changes in normal aging, mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other types of dementia. We propose that vascular and AD risk factors should be considered when evaluating CBF changes in aging, and that other validated biomarkers should be used as inclusion criteria or covariates when evaluating CBF changes in MCI and AD. With improvements in hardware and experimental design, ASL is proving to be an increasingly promising tool for exploring pathogenetic mechanisms, early detection, monitoring disease progression and pharmacological response, and differential diagnosis of AD.     

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.