A virtual environment for the assessment and the rehabilitation of the visuo-constructional ability in dementia patients

This study proposes a VE that offers a reliable diagnosis of the stage of cognitive decline in dementia patients and assists the delay of this decline in terms of the visuo-constructional ability. The proposed VE, in the case of the assessment, presents a visuo-constructional completion task, which requires spatial perception, motor memory and the perception of the target object. In the case of the rehabilitation the VE uses sound as audio-feedback that, with the aid of the music perception, tends to develop an enhancement in the visuo-construction ability of the dementia patients that can be generalized even outside of the VE. The study examined 30 subjects that were normal controls (N), 30 patients suffering from memory disorders (Age-Associated Memory Impairment--AAMI) and 30 suffering from Alzheimer's Disease (AD). The results showed that there is a significant correlation between the performance in the visuo-constructional task and the dementia diagnosis. It also seems that the visuo-constructional ability of the (AD) patients can be statistically improved by the audio experience in the VE. The empirical results of this study offer an alternative diagnosis and treatment of dementia patients and could share some light in the brain sub-systems that are responsible for the visuo-constructional ability. Further studies are required in order to investigate the nature of this phenomenon more.

Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer's disease?

BACKGROUND: Virtual reality testing of everyday activities is a novel type of computerized assessment that measures cognitive, executive, and motor performance as a screening tool for early dementia. This study used a virtual reality day-out task (VR-DOT) environment to evaluate its predictive value in patients with mild cognitive impairment (MCI). METHODS: One hundred thirty-four patients with MCI were selected and compared with 75 healthy control subjects. Participants received an initial assessment that included VR-DOT, a neuropsychological evaluation, magnetic resonance imaging (MRI) scan, and event-related potentials (ERPs). After 12 months, participants were assessed again with MRI, ERP, VR-DOT, and neuropsychological tests. RESULTS: At the end of the study, we differentiated two subgroups of patients with MCI according to their clinical evolution from baseline to follow-up: 56 MCI progressors and 78 MCI nonprogressors. VR-DOT performance profiles correlated strongly with existing predictive biomarkers, especially the ERP and MRI biomarkers of cortical thickness. CONCLUSIONS: Compared with ERP, MRI, or neuropsychological tests alone, the VR-DOT could provide additional predictive information in a low-cost, computerized, and noninvasive way.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

Dementia in patients with atrial fibrillation and the value of the Hachinski ischemic score.

AIM To assess the prevalence of vascular dementia, mixed dementia and Alzheimer's disease in patients with atrial fibrillation, and to evaluate the accuracy of the Hachinski ischemic score for these subtypes of dementia. METHODS A nested case-control study was carried out. A total of 103 of 784 consecutive patients evaluated for cognitive status at the Ambulatory Geriatric Clinic had a diagnosis of atrial fibrillation. Controls without atrial fibrillation were randomly selected from the remaining 681 patients using a 1:2 matching for sex, age and education. RESULTS The prevalence of vascular dementia was twofold in patients with atrial fibrillation compared with controls (21.4% vs 10.7%, P = 0.024). Alzheimer's disease was also more frequent in the group with atrial fibrillation (12.6% vs 7.3%, P = 0.046), whereas mixed dementia had a similar distribution. The Hachinski ischemic score poorly discriminated between dementia subtypes, with misclassification rates between 46% (95% CI 28-66) and 70% (95% CI 55-83). In patients with atrial fibrillation, these rates ranged from 55% (95% CI 32-77) to 69% (95% CI 39-91%). In patients in whom the diagnosis of dementia was excluded, the Hachinski ischemic score suggested the presence of vascular dementia in 11% and mixed dementia in 30%. CONCLUSIONS Vascular dementia and Alzheimer's disease, but not mixed dementia, are more prevalent in patients with atrial fibrillation. The discriminative accuracy of the Hachinski ischemic score for dementia subtypes in atrial fibrillation is poor, with a significant proportion of misclassifications.

Altered Electrophysiology of Semantic Word Processing in Alzheimer's Disease and Semantic Dementia

With the progressing course of Alzheimer's disease (AD), deficits in declarative memory increasingly restrict the patients' daily activities. Besides the more apparent episodic (biographical) memory impairments, the semantic (factual) memory is also affected by this neurodegenerative disorder. The episodic pathology is well explored; instead the underlying neurophysiological mechanisms of the semantic deficits remain unclear. For a profound understanding of semantic memory processes in general and in AD patients, the present study compares AD patients with healthy controls and Semantic Dementia (SD) patients, a dementia subgroup that shows isolated semantic memory impairments. We investigate the semantic memory retrieval during the recording of an electroencephalogram, while subjects perform a semantic priming task. Precisely, the task demands lexical (word/nonword) decisions on sequentially presented word pairs, consisting of semantically related or unrelated prime-target combinations. Our analysis focuses on group-dependent differences in the amplitude and topography of the event related potentials (ERP) evoked by related vs. unrelated target words. AD patients are expected to differ from healthy controls in semantic retrieval functions. The semantic storage system itself, however, is thought to remain preserved in AD, while SD patients presumably suffer from the actual loss of semantic representations.

Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease

OBJECTIVE The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.

Correlation between disease severity and brain electric LORETA tomography in Alzheimer's disease

OBJECTIVE To compare EEG power spectra and LORETA-computed intracortical activity between Alzheimer's disease (AD) patients and healthy controls, and to correlate the results with cognitive performance in the AD group. METHODS Nineteen channel resting EEG was recorded in 21 mild to moderate AD patients and in 23 controls. Power spectra and intracortical LORETA tomography were computed in seven frequency bands and compared between groups. In the AD patients, the EEG results were correlated with cognitive performance (Mini Mental State Examination, MMSE). RESULTS AD patients showed increased power in EEG delta and theta frequency bands, and decreased power in alpha2, beta1, beta2 and beta3. LORETA specified that increases and decreases of power affected different cortical areas while largely sparing prefrontal cortex. Delta power correlated negatively and alpha1 power positively with the AD patients' MMSE scores; LORETA tomography localized these correlations in left temporo-parietal cortex. CONCLUSIONS The non-invasive EEG method of LORETA localized pathological cortical activity in our mild to moderate AD patients in agreement with the literature, and yielded striking correlations between EEG delta and alpha1 activity and MMSE scores in left temporo-parietal cortex. SIGNIFICANCE The present data support the hypothesis of an asymmetrical progression of the Alzheimer's disease.

Diagnosing the Prodromal State of Alzheimer's Disease

Mild Cognitive Impairment- Amnestic Subtype (MCIa) is a putative prodromal stage of Alzheimer’s Disease (AD) characterized by focal deficits in episodic verbal memory. Less is known about relative deficits in visuospatial learning, although there is ample evidence indicating involvement of the hippocampus in visuospatial learning, as well as hippocampal degeneration in early AD. The aim of this study was to better characterize the components of working memory dysfunction in people with MCIa to increase the ability to reliably diagnose this disease. Fifty-six elderly adults diagnosed with MCIa and 94 healthy elderly completed a hidden maze learning task. Results indicated similar functioning between groups on measures of reasoning, problem solving, and accuracy. However, MCIa subjects were less efficient at learning the hidden path, making more errors per second on average (Cohen’s d= -.78) and requiring a longer time to complete the maze (Cohen’s d=.77). The learning curve between the first two trials was four times as steep for healthy elderly compared to MCIa (slopes = 4.9 vs. 1.24, respectively), indicating that MCIa subjects exhibited relative difficulty in holding and making effective use of an internal spatial map in order to improve performance. Our results suggest that MCIa patients have focal deficits in visuospatial working memory, with relative preservation of functioning on other more global measures of cognitive functioning. This particular pattern of results may be specific to the amnestic variant of MCI.

Association between cardiorespiratory fitness and Alzheimer's mortality: A prospective cohort study

Context. Alzheimer’s disease is a major source of morbidity and mortality in aging societies. Preventive measures, such as increasing cardiorespiratory fitness, to reduce the risk of Alzheimer’s disease mortality have not been sufficiently examined.^ Objective. To examine the association between levels of cardiorespiratory fitness and Alzheimer’s disease mortality.^ Design, Setting, and Patients. A prospective cohort study of 53,911 men and 18,876 women (mean age, 51.4 [SD, 10.0] years; range 20-88) enrolled in the Cooper Center Longitudinal Study who completed a baseline health examination during 1970-2006. The primary exposure, cardiorespiratory fitness, was assessed via a maximal exercise test. Fitness was categorized according to age- and sex-specific tertiles based on the participants’ distribution of maximal treadmill exercise test duration, in metabolic equivalent tasks (METs). The main outcome measure was Alzheimer’s disease mortality, defined as the underlying or contributing cause of death using the National Death Index and death certificates through December 31, 2006.^ Results. There were 175 Alzheimer’s disease deaths during a mean follow up of 37 years and 1,309,170 person-years of exposure. Women in the high fitness category had a 70% reduction in risk of Alzheimer’s mortality compared to women in the low fitness category (HR=0.3; 95% CI, 0.1-0.8; P=.02), while adjusting for potential confounders. Similarly, women in the moderate fitness category had a 70% reduction in risk for AD mortality compared to women in the low fit category (HR=0.3; 95% CI, 0.1-0.7; P=.005). Among men, the relationship between fitness level and AD mortality risk was examined but none were of statistical significance. The adjusted comparison of men in the high fitness category to low fit men yielded an HR of 0.9 (95% CI, 0.6-1.5; P=.79), while moderately fit men compared to low fit men yielded an HR of 1.3 (95% CI, 0.9-1.9; P=.21).^ Conclusions. Higher levels of cardiorespiratory fitness were associated with decreased risk of AD mortality, in women. No statistically significant association was found among men. Physical fitness may be an important protective factor against Alzheimer’s disease death in women, further supporting its clinical and public health values.^

Diffusion Tensor Imaging in Alzheimer's disease

Attentional control and Information processing speed are central concepts in cognitive psychology and neuropsychology. Functional neuroimaging and neuropsychological assessment have depicted theoretical models considering attention as a complex and non-unitary process. One of its component processes, Attentional set-shifting ability, is commonly assessed using the Trail Making Test (TMT). Performance in the TMT decreases with increasing age in adults, Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). Besides, speed of information processing (SIP) seems to modulate attentional performance. While neural correlates of attentional control have been widely studied, there are few evidences about the neural substrates of SIP in these groups of patients. Different authors have suggested that it could be a property of cerebral white matter, thus, deterioration of the white matter tracts that connect brain regions related to set-shifting may underlie the age-related, MCI and AD decrease in performance. The aim of this study was to study the anatomical dissociation of attentional and speed mechanisms. Diffusion tensor imaging (DTI) provides a unique insight into the cellular integrity of the brain, offering an in vivo view into the microarchitecture of cerebral white matter. At the same time, the study of ageing, characterized by white matter decline, provides the opportunity to study the anatomical substrates speeded or slowed information processing. We hypothesized that FA values would be inversely correlated with time to completion on Parts A and B of the TMT, but not the derived scores B/A and B-A.

Ensemble transcript interaction networks: A case study on Alzheimer's disease

Systems biology techniques are a topic of recent interest within the neurological field. Computational intelligence (CI) addresses this holistic perspective by means of consensus or ensemble techniques ultimately capable of uncovering new and relevant findings. In this paper, we propose the application of a CI approach based on ensemble Bayesian network classifiers and multivariate feature subset selection to induce probabilistic dependences that could match or unveil biological relationships. The research focuses on the analysis of high-throughput Alzheimer's disease (AD) transcript profiling. The analysis is conducted from two perspectives. First, we compare the expression profiles of hippocampus subregion entorhinal cortex (EC) samples of AD patients and controls. Second, we use the ensemble approach to study four types of samples: EC and dentate gyrus (DG) samples from both patients and controls. Results disclose transcript interaction networks with remarkable structures and genes not directly related to AD by previous studies. The ensemble is able to identify a variety of transcripts that play key roles in other neurological pathologies. Classical statistical assessment by means of non-parametric tests confirms the relevance of the majority of the transcripts. The ensemble approach pinpoints key metabolic mechanisms that could lead to new findings in the pathogenesis and development of AD

Alterations of cross-frequency coupling in MEG resting state recordings in Mild Cognitive Impairment patients

The default mode network (DMN) has received growing attention in recent years because it seems to be involved in the neuropathology of psychiatric and neurodegenerative disorders such as autism, schizophrenia and Alzheimer Disease. It has been defined as a task negative network, beca use the activity of all its brain regions is increased during the resting state and suspended during external or goal directed tasks.

Analysis of spontaneous MEG activity in mild cognitive impairment and Alzheimer's disease using spectral entropies and statistical complexity measures

Alzheimer's disease (AD) is the most common cause of dementia. Over the last few years, a considerable effort has been devoted to exploring new biomarkers. Nevertheless, a better understanding of brain dynamics is still required to optimize therapeutic strategies. In this regard, the characterization of mild cognitive impairment (MCI) is crucial, due to the high conversion rate from MCI to AD. However, only a few studies have focused on the analysis of magnetoencephalographic (MEG) rhythms to characterize AD and MCI. In this study, we assess the ability of several parameters derived from information theory to describe spontaneous MEG activity from 36 AD patients, 18 MCI subjects and 26 controls. Three entropies (Shannon, Tsallis and Rényi entropies), one disequilibrium measure (based on Euclidean distance ED) and three statistical complexities (based on Lopez Ruiz–Mancini–Calbet complexity LMC) were used to estimate the irregularity and statistical complexity of MEG activity. Statistically significant differences between AD patients and controls were obtained with all parameters (p < 0.01). In addition, statistically significant differences between MCI subjects and controls were achieved by ED and LMC (p < 0.05). In order to assess the diagnostic ability of the parameters, a linear discriminant analysis with a leave-one-out cross-validation procedure was applied. The accuracies reached 83.9% and 65.9% to discriminate AD and MCI subjects from controls, respectively. Our findings suggest that MCI subjects exhibit an intermediate pattern of abnormalities between normal aging and AD. Furthermore, the proposed parameters provide a new description of brain dynamics in AD and MCI.

Network-based biomarkers in Alzheimer's disease: review and future directions

By 2050 it is estimated that the number of worldwide Alzheimer?s disease (AD) patients will quadruple from the current number of 36 million people. To date, no single test, prior to postmortem examination, can confirm that a person suffers from AD. Therefore, there is a strong need for accurate and sensitive tools for the early diagnoses of AD. The complex etiology and multiple pathogenesis of AD call for a system-level understanding of the currently available biomarkers and the study of new biomarkers via network-based modeling of heterogeneous data types. In this review, we summarize recent research on the study of AD as a connectivity syndrome. We argue that a network-based approach in biomarker discovery will provide key insights to fully understand the network degeneration hypothesis (disease starts in specific network areas and progressively spreads to connected areas of the initial loci-networks) with a potential impact for early diagnosis and disease-modifying treatments. We introduce a new framework for the quantitative study of biomarkers that can help shorten the transition between academic research and clinical diagnosis in AD.

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloid-beta peptide (Aβ) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for Aβ, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor κB-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to Aβ deposits, and in cerebrospinal fluid from AD patients there was ≈5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by Aβ-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to Aβ, consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of Aβ on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.