Current Alzheimer Research - Volume 7, Issue 4, 2010

Background: Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. Objective: Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. Results: The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. Conclusions: Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD. In our study, both tangle and plaque accumulation correlated to clinical decline but when AD is considered alone, the correlations are not as robust.

Patients with Mild Cognitive Impairment (MCI) not converted to dementia at one to three years follow-up represent an heterogeneous group across studies, by including ‘late converters’ but also patients without any neurodegenerative disease. We tested the hypothesis that the combination of memory and brain metabolic assessment could identify subgroups of memory decliners (MCI/Decl) and non-decliners (MCI/noDecl) before a long follow-up time is available. From twenty-nine patients with amnestic MCI (aMCI) at baseline, three groups were identified at follow-up: 10 patients who converted to AD (MCI/AD); 10 patients either showing episodic memory worsening or reaching the floor effect on memory and declining in other key tests (MCI/Decl) and 9 patients showing no memory worsening or even improvement (MCI/noDecl). They were compared with a group of fourteen elderly controls (CTR) by means of basal FDG-PET voxelbased analysis (SPM2). Two hypometabolic clusters were found in MCI/AD versus CTR, including the bilateral posterior cingulate cortex, the left parietal precuneus and the left fusiform gyrus. MCI/AD showed also a large hypometabolic region, mainly including the left medium and superior temporal gyri and inferior parietal lobule, when compared to MCI/noDecl. The MCI/Decl showed a hypometabolic region in the left medial temporal lobe versus both CTR (hippocampus) and MCI/noDecl (parahippocampal gyrus and hippocampus). No significant difference was found in the comparison between CTR and MCI/noDecl, neither in the comparison between MCI/Decl and MCI/AD. Thus, non converter MCI patients comprised a sub-group of ‘decliners’ with AD-like metabolic and cognitive patterns, likely including ‘late converters’, and a sub-group lacking this pattern, with stable or improving memory function and a brain metabolic picture similar to that in healthy controls. Combining neuropsychological and FDG-PET information could be used for prognostic purposes in aMCI patients at medium-term follow-up.

Background/Aims. The aim of this study was to investigate the diagnostic role of CSF β-amyloid(1-42) levels and auditory event-related potentials (AERPs) in the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Methods. In fifty three MCI patients (group 1) a lumbar puncture was performed and β-amyloid(1-42) levels were determined. Twenty patients (group 2) were re-examined after 11 months. During this period five of them progressed to AD. Neuropsychological and ERP examinations were performed in all patients at both exams. Results. Compared to MCI-stable patients, AD-converters showed significantly lower β-amyloid(1-42) values both for group 1 (Mann Whitney test, Z=-2.952, p=0.003; effect size r=-0.41) and group 2 (Z=-2.458, p=0.011; effect size r=- 0.55). On the other hand, the patients of group 1 who converted to AD had prolonged latencies and lower amplitudes of the P300 wave compared to those of the MCI-stable patients, although the differences were not significant. Conclusions. Compared to the separate use of CSF β-amyloid(1-42) and AERPs, higher values of sensitivity and specificity were achieved by the combined use of β-amyloid(1-42) levels and P300 latencies (80% and 98%) or amplitudes (100% and 89%) in the discrimination between AD-converters and MCI-stable patients. Therefore the combination of an electrophysiological and a biological marker is potentially of high diagnostic value for the early diagnosis of AD-converters.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimer's amyloid precursor protein and its toxic amyloidogenic derivative, Aβ. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1α signaling pathway, thus promoting HIF-1α mRNA and protein expression levels, as well as increasing transcription of HIF-1α-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growthassociated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimer's disease (AD), western blotting analysis of glycogen synthase kinase- 3β (GSK-3β) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3β (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Aβ25-35 toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinson's disease and AD in which oxidative stress and iron-mediated toxicity are involved.

On the basis of not only the endosymbiotic theory of eukaryotic cell organization and evolution but also of observations of transcellular communication via Tunneling NanoTubes (TNTs), the hypothesis is put forward that when mitochondria, which were once independently living prokaryote-like organisms, are subjected to detrimental genetic, toxic, or environmental conditions, including age-related endogenous factors, they can regress towards their original independent state. At that point, they can become potentially pathogenic intruders within their eukaryotic host cell. Because of the protoplasmic disequilibrium caused by an altered, or mutated, mitochondrial population, certain host cells with a minimal capacity for self-renewal, such as dopaminergic neurons, risk a loss of function and degenerate. It is also proposed that altered mitochondria, as well as their mutated mtDNA, can migrate, via TNTs, into adjacent cells. In this way, neurodegenerative states are propagated between cells (glia and/or neurons) of the Central Nervous System (CNS) and lead to conditions such as Alzheimer's and Parkinson's disease. This proposal finds indirect support from observations on rotenone-poisoned glioblastoma cells which have been co-cultured with non-poisoned cells. Immunocytochemical techniques revealed that mitochondria, moving along the TNTs, migrated from the poisoned cells towards the healthy cells. It has also been demonstrated by means of immunocytochemistry that, in glioblastoma cell cultures, Amyloid Precursor Protein (APP) is present in TNTs, hence it may migrate from one cell to neighbouring cells. This datum may be of high relevance for a better understanding of Alzheimer's Disease (AD) since molecular, cellular, and animal model studies have revealed that the formation of amyloid beta (Aβ) and other derivatives of the APP are key pathogenic factors in AD, causing mitochondrial dysfunction, free radical generation, oxidative damage, and inflammation. Furthermore, the present data demonstrate the presence of α-synuclein (α-syn) within TNTs, hence a similar pathogenic mechanism to the one surmised for AD, but centred on α-syn rather than on Aβ, may play a role in Parkinson's Disease (PD). As a matter of fact, α-syn can enter mitochondria and interact with complex I causing respiratory deficiency and increased oxygen free radical production. In agreement with this view, it has been demonstrated that, in comparison with normal subjects, PD patients show a significant accumulation of α-syn at Substantia Nigra and Striatal level, predominantly associated with the inner mitochondrial membrane. These observations suggest that potentially neuropathogenic proteins, such as Aβ and α- syn, can not only diffuse via the extra-cellular space but also move from cell to cell via TNTs and hence propagate mitochondrial damage and cell degeneration. A mathematical model (see Appendix) is proposed for the simulation the pathogenic consequences of the migration via TNTs of altered mitochondria and/or of their mtDNA. The results of the present simulation are compatible with the proposal that mutated mitochondrial agents behave as though they were infectious particles migrating through a continuum of interconnected cells.

A proline-rich polypeptide complex (PRP), subsequently called Colostrinin™ (CLN), was first isolated from ovine colostrum , was shown to possess immunoregulatory properties, including effects on the maturation and differentiation of murine thymocytes and humoral and cellular immune responses, both in vivo and in vitro. PRP seems to restore balance in cellular immune functions and is not species specific. PRP is a complex of peptides of molecular masses ranging from 500 to 3000 Da. The polypeptide contains 25% proline and 40% hydrophobic amino acids. PRP shows a regulatory activity in cytokine (IFN, TNF-α, IL-6, IL-10) induction and possesses the ability to inhibit the overproduction of oxygen reactive species and nitric oxide. Besides its immunoregulatory activity, PRP also showed psychotropic properties, improving cognitive activity and behavior of old rats, humans, and chickens. The properties of PRP prompted the authors to propose the complex for the treatment neurodegenerative disorders. Beneficial effects of PRP/Colostrinin were shown for the first time in double-blind placebo-controlled trials and long-term open-label studies. The results were confirmed in multicenter clinical trials. A very important property of PRP/Colostrinin is the prevention of Aβ aggregation and the disruption of already existing aggregates. The same properties were expressed by one of PRP's components, a nonapeptide (NP). Moreover, PRP modulates neurite outgrowth, suppresses uncontrolled activation of cells, reduces 4-HNE-mediated cellular damage, and modulates expression in cellular redox regulation, cell proliferation, and differentiation. Its biological response modifying activity can play an important role in its use in the treatment of Alzheimer's disease.

The objective was to characterize the non-oscillatory independent components (ICs) of the auditory event-related potential (ERP) waveform of an oddball task for normal and newly diagnosed Alzheimer's disease (AD) subjects, and to seek biomarkers for AD. Single trial ERP waveforms were analysed using independent components analysis (ICA) and k-means clustering. Two stages of clustering depended upon the magnitudes and latencies, and the scalp topographies of the non-oscillatory back-projected ICs (BICs) at electrode Cz. The electrical current dipole sources of the BICs were located using Low Resolution Electromagnetic Tomography (LORETA). Generally 3-10 BICs, of different latencies and polarities, occurred in each trial. Each peak was associated with positive and negative BICs. The trial-to-trial variations in their relative numbers and magnitudes may explain the variations in the averaged ERP reported, and the delay in the averaged P300 for AD patients. The BIC latencies, topographies and electrical current density maximum locations varied from trial-to-trial. Voltage foci in the BIC topographies identify the BIC source locations. Since statistical differences were found between the BICs in healthy and AD subjects, the method might provide reliable biomarkers for AD, if these findings are reproduced in a larger study, independently of other factors influencing the comparison of the two populations. The method can extract artefact- and EEG-free single trial ERP waveforms, offers improved ERP averages by selecting the trials on the basis of their BICs, and is applicable to other evoked potentials, conditions and diseases.

Objectives: To examine the relationship between multiple measures of health care costs and health utilities, quality of life, and other factors in Alzheimer's Disease (AD). Research Design: Data were obtained via caregiver proxy at baseline and 3- 6- and 9-months following study entry on 421 patients with AD who participated in the CATIE-AD trial of antipsychotic medication. Spearman rank correlations and mixed models (using logged costs) were used to examine the correlates of health care costs. Measures: Health care costs include inpatient hospital, nursing home, residential care, combined institutional, outpatient, ancillary drug, and total costs. Correlates include the AD-Related Quality of Life Scale (ADRQoL) and Health Utilities Index (HUI)-III. Results: Total monthly health care costs averaged $1,205 during the study period. Each .10 increment on the HUI-III (stronger health utilities) was associated with a decrease in institutional, outpatient, and total costs of 9.7%, 6.9%, and 8.2%, respectively. Each one-point increase on the ADRQoL (better quality of life) was associated with an increase in ancillary drug and total costs of 1.7% and 2.1%. Total costs tended to be lower for female patients (β=-.325) with better physical functioning (β=-.017) but higher for less cognitively impaired individuals (β=.038). Older (β=.025), non- Hispanic Whites (β=.575) tended have higher outpatient costs, those with better physical functioning lower institutional costs (β=-.019). Drug costs tended to be lower for females (β=-.427) and higher for those with greater psychiatric symptoms (β=.016). Conclusion: The HUI-III findings suggest that health utilities could be combined with other known correlates of costs to inform resource allocation cost-effectiveness analyses associated with AD. The ADRQoL findings suggest that better quality of life may make it easier for caregivers to identify problems and/or to access and maintain certain types of health system contacts.

Introduction: Alzheimer's disease (AD) is one of the most important causes of morbidity and functional decline among the elderly and gives rise to substantial costs for society. There is today limited data on resource utilization and quality of life in AD, in particular in the severe stage of the disease. Aims & Methods: The objectives of this study were to estimate the relationship between costs, patient and caregiver quality of life, and disease severity. For 233 patients in Sweden and their caregivers cross-sectional data on cognitive function (MMSE), ADL ability, behavioral disturbances, formal and informal resource use and health related quality of life (HRQoL) were collected by questionnaires to caregivers and to the treating physician. Patients were stratified into the disease stages mild, moderate and severe AD based on MMSE-scores. Results: The mean annual total cost in 2007 USD was 23,400 in mild, 56,800 in moderate and 71,400 in severe AD. Special forms of accommodation accounted for the majority of costs. Costs were higher for patients with lower cognitive function, lower ADL ability and more behavioral disturbances, with ADL ability being the most consistent predictor of costs. There were significant differences in HRQoL between the disease stages: health utility scores were 0.64 in mild, 0.39 in moderate and 0.24 in severe AD. Conclusions: The societal costs of AD are very high, especially for patients with moderate and severe AD. This implies that treatments with the ability to delay progression of the disease into more severe stages have the potential to save large costs for society.

The main data on oral health and dental pathologies affecting Alzheimer's disease (AD) patients were reviewed. Oral health declines and dental pathologies increase with progression of AD. Poor oral hygiene, difficulty in wearing dentures, and the inability to self-care, including carrying out oral hygiene procedures are the most probable cause of impaired oral health in AD. Collection of information on oral/dental conditions from AD patients or their caregivers/ relatives is often difficult and scientific literature on the topic is sparse . The majority of data on the subject consist in retrospective studies affected to some extent by subjective views of dental professionals involved. Appropriate dental interventions in adult-onset dementia disorders will decrease pain and oral pathology and consequently could contribute to maintain enough oral and nutritional health in these patients. Dental treatment in early stages of the disease are important and should be finalized at producing a stable oral condition. This could improve the quality of life and contribute to decrease worsening of oral situations in the later stages of the disease when dental treatment may be difficult. The problem of awareness of good oral health for keeping quality of life more acceptable in adult-onset dementia disorders is discussed.