Current Alzheimer Research - Volume 12, Issue 6, 2015

The incidence of dementia is rapidly increasing not only in developed countries but also in developing countries with rising aging populations. This trend is expected to worsen, with the number of cases possibly tripling in the coming decades. Over the last few decades, epidemiological studies have revealed that vascular-or lifestyle-related factors are associated with an increased risk of Alzheimer’s disease (AD) and dementia. Researches into the pathophysiological processes of AD have revealed that the pathological brain lesions of AD begin decades before the onset of symptoms. Many prevention studies have indicated that physical activity and/or mental training can improve cognition and daily life in subjects with AD or mild cognitive impairment (MCI). However, issues with early detection and preclinical staging and effective preventive approaches that are based on these stages remain unresolved. Therefore, we propose different strategies for AD prevention based on its preclinical stages: one involves physical and mental training that targets the risk factors in subjects without pathophysiological changes, and the second approach combines nonpharmacological and pharmacological methods and aims to treat MCI in individuals with amyloid deposits and/or neurodegeneration with drugs that target the amyloid cascade. The results of several ongoing and promising trials are expected in the next few years.

The concept of mild cognitive impairment (MCI) was first introduced for the purpose of identifying individuals in an intermediate state between no cognitive impairment and Alzheimer’s disease (AD). Recently, the heterogeneity of MCI has attracted attention as it has become clear that other diseases, such as cerebrovascular disease and Parkinson disease can also cause mild cognitive deficits, prompting a redefinition of MCI. Heterogeneity of MCI has been confirmed by neuropathological examinations. Most MCI patients not only possess amyloid plaques and neurofibrillary tau tangles, but also cerebral vascular pathology such as arteriosclerosis and cerebral amyloid angiopathy (CAA). CAA induces cerebral infarcts or hemorrhage of varying size and type, attributing to further cognitive impairment. Sporadic AD and CAA has been suggested to be the consequence of Aβ elimination failure, mainly caused by disturbance of the perivascular drainage system. Since severe CAA is an independent risk factor for dementia, facilitation of Aβ clearance has been suggested as a potential treatment of AD and MCI. Many epidemiological studies have shown that vascular risk factors increase incidence of MCI and its progression to AD. Accordingly, control of such factors has been shown to reduce risk of conversion to AD and ameliorate cognitive impairment in AD patients. Neurovascular approaches may therefore hold promise for the treatment of dementia in an era of preventive neurology.

Background: Detecting early signs of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) during the pre-symptomatic phase is becoming increasingly important for costeffective clinical trials and also for deriving maximum benefit from currently available treatment strategies. However, distinguishing early signs of MCI from normal cognitive aging is difficult. Biomarkers have been extensively examined as early indicators of the pathological process for AD, but assessing these biomarkers is expensive and challenging to apply widely among pre-symptomatic community dwelling older adults. Here we propose assessment of social markers, which could provide an alternative or complementary and ecologically valid strategy for identifying the pre-symptomatic phase leading to MCI and AD. Methods: The data came from a larger randomized controlled clinical trial (RCT), where we examined whether daily conversational interactions using remote video telecommunications software could improve cognitive functions of older adult participants. We assessed the proportion of words generated by participants out of total words produced by both participants and staff interviewers using transcribed conversations during the intervention trial as an indicator of how two people (participants and interviewers) interact with each other in one-on-one conversations. We examined whether the proportion differed between those with intact cognition and MCI, using first, generalized estimating equations with the proportion as outcome, and second, logistic regression models with cognitive status as outcome in order to estimate the area under ROC curve (ROC AUC). Results: Compared to those with normal cognitive function, MCI participants generated a greater proportion of words out of the total number of words during the timed conversation sessions (p=0.01). This difference remained after controlling for participant age, gender, interviewer and time of assessment (p=0.03). The logistic regression models showed the ROC AUC of identifying MCI (vs. normals) was 0.71 (95% Confidence Interval: 0.54 – 0.89) when average proportion of word counts spoken by subjects was included univariately into the model. Conclusion: An ecologically valid social marker such as the proportion of spoken words produced during spontaneous conversations may be sensitive to transitions from normal cognition to MCI.

Objective: To carry out meaningful comparisons on results of different research studies on mild cognitive impairment (MCI), it is critical to select an appropriate objective memory test to examine memory deficit. We aim to refine the operational criteria of amnestic MCI (aMCI) on neuropsychological tests that optimally balance the sensitivity and specificity. Methods: We focused on 206 non-demented subjects from memory clinic. We then classified each individual as having MCI or subjective cognitive decline (SCD) according to different neuropsychological criteria. By following them longitudinally, clinical outcomes were compared to evaluate the stability of MCI diagnoses and prediction of progression. Results: The delayed recall of auditory verbal learning test (AVLT_DR) identified 116 subjects as MCI, resulted in the conversion rate as 44% over the roughly 30-month time interval, missed 7.8% incipient Alzheimer’s disease (AD) patients in SCD group who eventually converted to dementia. The delayed recall of complex figure test (CFT_DR) identified fewer MCI patients (n=95) and misdiagnosed more preclinical AD patients (15.3%), in comparison with AVLT criterion. Criterion requiring deficits in both tests produced higher conversion rate (54.3%), but resulted in higher misdiagnosis rate (14.7%) simultaneously. The AVLT criterion had the largest area under the curve (0.7248, p<0.05). Conclusion: AVLT is superior to CFT in the stability of diagnoses and prediction of progression. In the clinical setting, the “one test” criterion AVLT has similar sensitivity to both-deficits methods, and is optimal in balancing sensitivity and specificity.

Mild cognitive impairment (MCI) describes a transitional state in progression from normal aging to dementia, especially Alzheimer's disease (AD). Currently, there is no effective pharmacological treatment that offers a long-term beneficial effect to delay the progression to dementia. There is growing evidence that supports an important role of non-pharmacological cognitive interventions. Therefore, it is warranted to clarify the distinct forms of cognitive interventions and their effects based on previous clinical trials. We aimed to provide a review of clinical trials of non-pharmacological cognitive interventions for MCI and to address the characteristics of the study patients, cognitive intervention programs and short-term / long-term benefits of the interventions. A total of 32 articles were identified according to the inclusion criteria. The results showed positive effects for both objective and subjective outcome variables, and these effects persisted from 1 month up to 5 years. Although many of the positive effects were related to improvement in trained tasks, alterations in neuroimaging and the transfer effects shown by some studies are encouraging. Future research in this area requires a larger sample size with a wider spectrum of MCI, more instructive outcome measures and a longer follow up duration.

Cognitive impairment is a major concern in elderly people, and a variety of nonpharmacological therapies (NPTs) have been developed to help with cognitive decline. One of the most popular therapies is cognitive training, which includes pencil-and-paper puzzles, computerized games, or the combination of the two. Training is designed to have participants perform diverse exercises in one or more cognitive domains. Most clinical training trials indicate that well-organized tasks are clinically effective for cognitive improvement. Neural plasticity is a probable explanation for positive training effects. EEG and fMRI research show that the electrical activity and metabolism of specific brain areas are changed, and these changes are retained for a long period after training. Studies on mice to uncover the cellular and molecular changes underlying neural connectivity have found effective changes in brain networks after learning or training. Rac1 and NMDA receptors are thought to be involved in hippocampal neurogenesis, which is induced by learning. Here we review clinical trials of cognitive training, published during the last five years, and summarized some important characteristics of training tasks design. The probable role of neuronal plasticity and molecular mechanisms in training effects also are discussed. Most importantly, we discuss key ways to modifying the design of tasks based on studies we review. This review mainly identifies and discusses the reasons for positive training effects on cognition from clinical and neurophysiological perspectives. Based on the findings and their related mechanisms, further studies should design more effective and specific training tasks.

Since the increasing population of aging, cognitive training is focused as one of the non-pharmacological preventive approach of cognitive decline. Although the accumulation of the knowledge, they hardly reflect to the programs for clinical use. We developed a task set named “Atama-no-dojo,” designed to activate multiple cognitive functions and enhance motivational incentives. The objective of our study is to confirm the effect of our program through a 6 months group intervention program. The intervention program conducted in a day service center for 6 months in the duration of 45 minutes per day, 4 days per month for a total of 25 sessions. Participants worked to the tasks on the screen all together with filling in the answering sheet. Neuropsychological tests, SF36 and GDS were assessed at pre-/post-intervention periods. Participants filled in a questionnaire about impression to the program at the last training session. Fourteen women (82.2±2.9 years old) were analyzed and significant changes were found in the improvement of memory, attention, inhibition, GDS and some items of SF36. All participants recognized the program as fun and wanted to continue. Some of the participants’ positive impressions to the program correlated to cognitive improvement. The improved cognitive functions by 6 months intervention of “Atama-no-dojo” were mainly related to prefrontal cortex and the motivational incentives seemed supported the effect of task contents. We recognized the importance of task difficulty setting and motivational incentives to reduce frustration from working on difficult tasks and enhance the effects of improvement from activating brain function.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder pathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The aggregation of Aβ precedes tau pathologies in AD; however, the causal relation between the two pathologies and the mechanisms by which aggregated forms of Aβ contribute to cortical thinning are not fully understood. We proposed quantitative Aβ-weighted cortical thickness analysis to investigate the regional relationship between cortical thinning and amyloid plaque deposition using magnetic resonance (MR) and Pittsburg Compound B (PiB) positron emission tomography (PET) images in patients with AD, mild cognitive impairment (MCI), and subjects with normal cognition. We hypothesized that there are cortical areas that have prominent changes associated with Aβ deposition and there are areas that are relatively independent from Aβ deposition where pathologies other than Aβ (such as tau) are predominant. The study was performed using MRI and PiB PET data from the Alzheimer’s Disease Neuroimaging Initiative. We measured accuracy of classification models in three different pairs of groups comparing AD, MCI, and normal cognition. Classification models that used Aβ-weighted cortical thickness were not inferior to classification models that used only cortical thickness or amyloid deposition. In addition, based on timing of changes in cortical thinning and Aβ deposition such as Aβ deposition after cortical thinning; cortical thinning after Aβ deposition, or concurrent Aβ deposition and cortical thinning, we identified three types of relationships between cortical thinning and Aβ deposition: (1) Aβ-associated cortical thinning; (2) Aβ-independent cortical thinning; and (3) Aβ deposition only without cortical thinning. Taken together, these findings suggest that Aβ-weighted cortical thickness values can be used as an objective biomarker of structural changes caused by amyloid pathology in the brain.

Although recent evidence has emerged that Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients show both regional brain abnormalities and topological degeneration in brain networks, our understanding of the effects of white matter fiber aberrations on brain network topology in AD and aMCI is still rudimentary. In this study, we investigated the regional volumetric aberrations and the global topological abnormalities in AD and aMCI patients. The results showed a widely distributed atrophy in both gray and white matters in the AD and aMCI groups. In particular, AD patients had weaker connectivity with long fiber length than aMCI and normal control (NC) groups, as assessed by fractional anisotropy (FA). Furthermore, the brain networks of all three groups exhibited prominent economical small-world properties. Interestingly, the topological characteristics estimated from binary brain networks showed no significant group effect, indicating a tendency of preserving an optimal topological architecture in AD and aMCI during degeneration. However, significantly longer characteristic path length was observed in the FA weighted brain networks of AD and aMCI patients, suggesting dysfunctional global integration. Moreover, the abnormality of the characteristic path length was negatively correlated with the clinical ratings of cognitive impairment. Thus, the results therefore suggested that the topological alterations in weighted brain networks of AD are induced by the loss of connectivity with long fiber lengths. Our findings provide new insights into the alterations of the brain network in AD and may indicate the predictive value of the network metrics as biomarkers of disease development.

Background: Cognitive and motor performance can be supported, especially in older subjects, by different types of brain activations, which can be accurately studied by functional magnetic resonance imaging (fMRI). Vascular risk factors (VRFs) are extremely important in the development of cognitive impairment, but few studies have focused on the fMRI cortical activation characteristics of healthy subjects with and without silent cerebrovascular disease including white matter hyperintensities (WMH) and carotid stenosis (CS) performing cognitive tasks. Methods: Thirty-five volunteers with and without asymptomatic unilateral carotid stenosis above 70% and variable degrees of WMH underwent performance of a simple motor and cognitive task during an fMRI session. Results: While the performance of the motor task resulted in a cortical activation dependent of age but not of WMH and carotid stenosis, performance of the cognitive task was accompanied by a significantly increased activation independently correlated with age, presence of WMH as well as of carotid stenosis. Conclusions: in this study, cognitive domains regulating attention and working memory appear to be activated with a pattern influenced by the presence of carotid stenosis as well as by white matter hyperintensities. The impairment of these cognitive abilities is of high relevance in Alzheimer’s disease pathology. The fMRI pattern shown in patients with asymptomatic but significant carotid stenosis might be related to chronic cerebrovascular hypoperfusion, a critical pathophysiological mechanisms in AD. In these patients, carotid endoarterectomy should be considered also for AD prevention and might be recommended.

Background: Resting-state functional magnetic resonance imaging (RS-fMRI) appears as a promising imaging technique to identify early biomarkers of Alzheimer type neurodegeneration, which can be more sensitive to detect the earliest stages of this disease than structural alterations. Recent findings have highlighted interesting patterns of alteration in resting-state activity at the mild cognitive impairment (MCI) prodromal stage of Alzheimer’s disease. However, it has not been established whether RS-fMRI alterations may be of any diagnostic use at the individual patient level and whether parameters derived from RS-fMRI images add any quantitative predictive/classificatory value to standard cognitive tests (CTs). Methods: We computed a set of 444 features based on RS-fMRI and used 21 variables obtained from a neuropsychological assessment battery of tests in 29 MCI patients and 21 healthy controls. We used these indices to evaluate their impact on MCI/healthy control classification using machine learning algorithms and a 10-fold cross validation analysis. Results: A classification accuracy (sensitivity/ specificity/area under curve/positive predictive value/negative predictive value) of 0.9559 (0.9620/0.9470/ 0.9517/0.9720/0.9628) was achieved when using both sets of indices. There was a statistically significant improvement over the use of CTs only, highlighting the superior classificatory role of RS-fMRI. Conclusions: RS-fMRI provides complementary information to CTs for MCI-patient/healthy control individual classification.