Alzheimer's disease and mild cognitive impairment

As our society ages, age-related diseases assume increasing prominence as both personal and public health concerns. Disorders of cognition are particularly important in both regards, and Alzheimer's disease is by far the most common cause of dementia of aging. In 2000, the prevalence of Alzheimer's disease in the United States was estimated to be 4.5 million individuals, and this number has been projected to increase to 14 million by 2050. Although not an inevitable consequence of aging, these numbers speak to the dramatic scope of its impact. This article focuses on Alzheimer's disease and the milder degrees of cognitive impairment that may precede the clinical diagnosis of probable Alzheimer's disease, such as mild cognitive impairment.     

Neuropsychological markers of progression from mild cognitive impairment to Alzheimer's disease

To find early clinical markers that may predict a likely progression to Alzheimer's disease (AD), the authors performed neuropsychological tests on 82 mild cognitive impairment (MCI) subjects. After 3 years, 38 patients developed AD while 44 retained the diagnosis of MCI. The cognitive differences between the groups were studied. Patients who developed AD showed significantly lower values than did MCI subjects in some neuropsychological scores (P = .02-.001), with sensitivities and specificities higher than 84% and 64%, respectively, for detecting early-onset AD, with a 7.9-fold increased risk of converting to AD (P < .001). Regarding the logistic regression model, the CAMCOG Memory and Perception cognitive screening items were the optimum independent tools to classify the patients who will progress to AD, showing a relative risk of progression of 10.5 (P = .002), 5.5 (P = .008), and 3.9 times (P = .05), respectively, with a sensibility of of 92.1% and a specificity 72.7%.     

Insight and cognitive impairment: effects on quality-of-life reports from mild cognitive impairment and Alzheimer's disease patients

This study follows previous work to determine the effect of patient insight and cognitive impairment on the reliability and validity of self-reported quality of life (QOL) from patients diagnosed with Alzheimer's disease (AD) and mild cognitive impairment (MCI). AD and MCI patients (N = 68) and their caregivers participated. Patients with impaired insight provided QOL ratings that were less reliable than those provided by patients with better insight. Patient-caregiver agreement for. QOL reports was used as an index of validity. Neither better insight nor lesser cognitive impairment suggested better agreement. Thus, even when patient insight is intact, patient reports are unlikely to agree with caregiver reports. Patient and caregiver reports about patient QOL may represent 2 unique, yet potentially valid, perspectives.     

Nonlinear biomarker interactions in conversion from mild cognitive impairment to Alzheimer's disease

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid‐β42, total tau, phosphorylated tau), [18^F]florbetapir, hippocampal volume and brain‐age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R² = 0.51, p < .001); the strongest independently contributing biomarker was hippocampal volume (R² = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p < .001) for various two‐way interaction models. The best performing model included an interaction between amyloid‐β‐PET and P‐tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker ‘space', providing information for personalised or stratified healthcare or clinical trial design.     

Neuropathology of mild cognitive impairment Alzheimer's disease]

The pathological study of mild cognitive impairment (MCI) was very few. Consecutive 1,628 autopsy cases from the Brain Bank for Aging Research (BBAR) with the mean age of 80.7 years were employed for this study. All the cases were studied with the BBAR protocol (www.mci.gr.jp/BrainBank/) and clasasified into Braak's seven neuforibrillary tangle (NFT) stages (0-VII) and four senile plaque (SP) stages (0-C). CDR from the most recent 545 cases were independently evaluated by three neurologists in two different occasions. Among the 1,628 cases, 10.1% fulfilled morphological requirement of Alzheimer disease, consisting of NFT stage equal to or more than IV and SP stage equal to or more than C. Postmortem assessment of CDR was possible for 486 cases amoug 545 cases with frozem half brain and 57 cases were classified into CDR 0.5. CDR 0.5 group was clinicopathologically classified into 33 cases with degenerative changes, nine cases with vascular changes and four cases with combined degenerative and vascular changes. Only 6 among the 57 cases presented pure AD pathology. These data indicate that the pathological background of MCI is not always Alzheimer disease and combined pathology with AD as well as non-AD pathology should be carefully ruled out. For this purpose, ADNI (Alzheimer Disease Neuroimage Initiative) approach could be useful to identify MCI stage of AD.     

Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study

BackgroundKnowledge of risk factors is essential for developing strategies that prevent or minimise transitions from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and death. The aim of this study was to assess risk factors for progression to AD and death among Chinese individuals with cognitive impairment.MethodsWe conducted a multisite, population-based cohort study on 437 community-dwelling elderly MCI residents in Taiyuan, China from 2010 to 2014. MCI, AD, death from AD and death from a cause other than AD were specified as disease states during the natural history of dementia. Transition-specific Cox model was fitted and hazard ratio (HR) with 95% confidence intervals (CIs) was estimated.ResultsAnalyses showed that risk factors played different roles in affecting transitions to AD and death. Risk factors for transition from MCI to AD were being female (HR: 1.82; 95%CI: 1.20–2.77), older age (HR: 3.09; 95%CI: 1.81–5.25), reading occasionally (HR: 1.79; 95%CI: 1.11–2.89), current smoking (HR: 1.74; 95%CI: 1.15–2.65), light–moderate alcohol drinker (HR: 2.24; 95%CI: 1.42–3.53), cerebrovascular disease (HR: 2.70; 95%CI: 1.68–4.34), hyperlipidemia (HR: 1.87; 95%CI: 1.16–3.02) and diabetes (HR: 1.81; 95%CI: 1.18–2.77). Only cerebrovascular disease (HR: 3.04; 95%CI: 1.22–7.58) was a significant risk factor for transition from MCI to death from a cause other than AD. Older age (HR: 10.68; 95%CI: 1.16–97.93) and low level education (HR: 0.14; 95%CI: 0.05–0.44) were significant predictors for transition from AD to death from a cause other than AD.ConclusionsParticipants with advanced age, low-level education, history of harmful alcohol consumption or smoking, cerebrovascular disease, hyperlipidemia, diabetes or who were female were at increased risk of transitioning to AD or death. Strategies to control modifiable risk factors in specific disease stage should be implemented to decrease the conversion to AD or death among Chinese patients with MCI.     

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.     

Predictive models for mild cognitive impairment to Alzheimer's disease conversion

正Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disease as well as the most common form of dementia. It usually affects the older population, but early onset AD is still possible(Ritchie et al., 2015). Recent studies propose that AD is a middle-life disease(Ritchie et al.,2015).     

Gender-specificities in Alzheimer's disease and mild cognitive impairment

Background Amnestic Mild Cognitive Impairment (MCI) is a condition with an increased risk for developing Alzheimer's disease (AD). Presently, gender differences are neglected in the assessment of MCI and AD. Methods We examined verbal and visuospatial episodic memory in 143 subjects diagnosed as healthy controls (HC; N = 48, Mini-Mental State Examination (MMSE) 29.2 ± 1.0 (mean ± standard deviation)), MCI (N = 43,MMSE 28.5 ± 1.4), and AD (N = 49, MMSE 25.1 ± 2.2). Findings Female HC and MCI subjects performed better on verbal episodic memory tasks than males. In contrast, visuospatial episodic memory was better in male than female AD patients. Conclusions We interpret the results in light of a genderspecific cognitive reserve and conclude that the gender-specificity of neuropsychological performance needs to be accounted for in clinical diagnosis of Alzheimer’s disease.     

Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer's disease

BACKGROUND: Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer's disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD. METHODS: Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were followed for an average of 2 years. Twelve subjects (23.5%) progressed from MCI to possible/probable AD and 39 subjects (76.5%) remained stable or improved. Baseline Neuropsychiatric Inventory indices were compared between groups. RESULTS: Subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100 vs. 59%). Depression (67 vs. 31%) and apathy (50 vs. 18%) were more common in subjects who were later diagnosed with AD. After statistical adjustments for other baseline demographic variables, these specific symptoms were less robust predictors of progression to AD than the presence of any psychopathology. CONCLUSIONS: These findings suggest that neuropsychiatric symptoms in MCI are a predictor of progression to AD. Depression and apathy appear to be most useful for identifying MCI subjects at highest risk of developing dementia.     

Diagnosing the mild cognitive impairment stage of Alzheimer's disease]

Recently, it has become important to diagnose Alzheimer's Disease (AD) at an early stage due to the development of AD therapy. Also, there is increasing recognition of a class of elderly people with complaints of memory loss but who nevertheless do not meet the criteria for dementia. "Mild cognitive impairment" (MCI) is the term used for this disorder, and amnestic MCI is highly converted to AD. In this study we evaluated the accuracy of diagnosis of amnestic MCI by cerebrospinal fluid total-tau protein (CSF/total-tau), cerebrospinal fluid amyloid beta 1-42 protein (CSF/A beta 1-42), and cerebral blood flow in the posterior cingulate cortex using SPECT. CSF/total-tau was the most appropriate to discriminate between normal cognitive individuals and those with amnestic MCI. We also evaluated the CSF/total-tau and MRI images between patients with stable MCI and those with progressive MCI, including those who converted to AD in the following two years. The stable type was characterized by normal CSF/total-tau levels and relatively high grade periventricular white matter lesions (PWML). Conversely, the progressive type was characterized by high CSF-tau levels and relatively low grade PWML. We speculate that stable MCI is due to ischemic change with in the white matter lesion, while progressive MCI may represent a previous stage of AD.     

Biological markers of Alzheimer's disease and mild cognitive impairment

The diagnosis of Alzheimer's disease (AD) is mainly performed by excluding other disorders with similar clinical features. In addition, an analysis of symptoms and signs, blood studies and brain imaging are major ingredients of the clinical diagnostic work-up. However, the diagnosis based on these instruments is unsatisfactory, indicating the need of a highly sensitive and reliable approaches, selective for AD and based on biological markers. Ideally, such markers should reflect the pathophysiological mechanisms of AD, which according to the current hypotheses, derive from the actions of two major protein aggregates, the extracellular beta-amyloid (Abeta) plaques and the neurofibrillary tangles. Since AD is a multifactorial disease, other factors that cause neuronal insult and that contribute to neuronal degeneration in AD include free radical and oxidative stress promoting molecules, proinflammatory cytokines and neurotoxic agents. In this context, the search for anomalous levels or changes in the molecular patterns of Abeta(1-42) or Abeta(1-40), hyperphosphorylated tau isoforms, oxidation products in the cell or cytokines such as interleukin-1 or 6 facilitates the selection of biomarkers in AD. There is clear evidence that the cerebrospinal fluid (CSF) levels of beta(1-42) are significantly reduced in AD patients as compared with senile controls, while increased levels of tau have been revealed. The CSF levels of these proteins reflect their metabolism in the central nervous system. Approaches using ELISA and immunochemical methods for the quantification of these markers in CSF have been preferentially used. Diagnosis criteria and number of patients exhibits variations in the different reports, while clinico-pathological studies are scarce. An increasing number of studies suggest that supplementary use of these CSF markers preferably in combination, adds to the accuracy of an AD diagnosis.     

A point-based tool to predict conversion from mild cognitive impairment to probable Alzheimer's disease

BackgroundOur objective in this study was to develop a point-based tool to predict conversion from amnestic mild cognitive impairment (MCI) to probable Alzheimer's disease (AD).MethodsSubjects were participants in the first part of the Alzheimer's Disease Neuroimaging Initiative. Cox proportional hazards models were used to identify factors associated with development of AD, and a point score was created from predictors in the final model.ResultsThe final point score could range from 0 to 9 (mean 4.8) and included: the Functional Assessment Questionnaire (2‒3 points); magnetic resonance imaging (MRI) middle temporal cortical thinning (1 point); MRI hippocampal subcortical volume (1 point); Alzheimer's Disease Cognitive Scale—cognitive subscale (2‒3 points); and the Clock Test (1 point). Prognostic accuracy was good (Harrell's c = 0.78; 95% CI 0.75, 0.81); 3-year conversion rates were 6% (0‒3 points), 53% (4‒6 points), and 91% (7‒9 points).ConclusionsA point-based risk score combining functional dependence, cerebral MRI measures, and neuropsychological test scores provided good accuracy for prediction of conversion from amnestic MCI to AD.     

Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease

Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer's disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E epsilon4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.     

Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study

Activity and reactivity of the default mode network in the brain was studied using functional magnetic resonance imaging (fMRI) in 28 nondemented individuals with mild cognitive impairment (MCI), 18 patients with mild Alzheimer's disease (AD), and 41 healthy elderly controls (HC). The default mode network was interrogated by means of decreases in brain activity, termed deactivations, during a visual encoding task and during a nonspatial working memory task. Deactivation was found in the default mode network involving the anterior frontal, precuneus, and posterior cingulate cortex. MCI patients showed less deactivation than HC, but more than AD. The most pronounced differences between MCI, HC, and AD occurred in the very early phase of deactivation, reflecting the reactivity and adaptation of the network. The default mode network response in the anterior frontal cortex significantly distinguished MCI from both HC (in the medial frontal) and AD (in the anterior cingulate cortex). The response in the precuneus could only distinguish between patients and HC, not between MCI and AD. These findings may be consistent with the notion that MCI is a transitional state between healthy aging and dementia and with the proposed early changes in MCI in the posterior cingulate cortex and precuneus. These findings suggest that altered activity in the default mode network may act as an early marker for AD pathology.     

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.     

Aging, mild cognitive impairment, and Alzheimer's disease

Research in the field of aging and dementia is moving forward at a rapid pace, in both basic biology of dementing disorders and clinical investigations. These two approaches to research on aging and dementia need to advance in parallel, such that when work on the pathophysiology of these disorders is translated into therapeutic practice, the appropriately characterized clinical cohorts will be available for therapeutic trials of these treatment strategies.