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.     

Plasma biomarkers for mild cognitive impairment and Alzheimer's disease

Purpose of review: With the move toward development of disease modifying treatments, there is a need for more specific diagnosis of early Alzheimer's disease (AD) and mild cognitive impairment (MCI), plasma biomarkers are likely to play an important role in this. We review the current state of knowledge on plasma biomarkers for MCI and AD, including unbiased proteomics and very recent longitudinal studies.Recent findings: With the use of proteomics methodologies, some proteins have been identified as potential biomarkers in plasma and serum of AD patients, including alpha-1-antitrypsin, complement factor H, alpha-2-macroglobulin, apolipoprotein J, apolipoprotein A-I. The findings of cross-sectional studies of plasma amyloid beta (Aβ) levels are conflicting, but some recent longitudinal studies have shown that low plasma Aβ1–42 or Aβ1–40 levels, or Aβ1–42/Aβ1–40 ratio may be markers of cognitive decline. Other potential biomarkers for MCI and AD reflecting a variety of pathophysiological processes have been assessed, including isoprostanes and homocysteine (oxidative stress), total cholesterol and ApoE4 allele (lipoprotein metabolism), and cytokines and acute phase proteins (inflammation). A panel of 18 signal proteins was reported as markers of MCI and AD.Summary: A variety of potential plasma biomarkers for AD and MCI have been identified, however the findings need replication in longitudinal studies. This area of research promises to yield interesting results in the near future.     

CSF biomarkers for mild cognitive impairment and early Alzheimer's disease

A correct clinical diagnosis, early in the course of Alzheimer's disease (AD), is of importance given the currently available symptomatic treatment with acetylcholine esterase inhibitors. The development of disease-modifying drugs like beta-sheet breakers or gamma- and beta-secretase inhibitors, emphasizes the need of improved diagnostic accuracy, especially in patients with mild cognitive impairment (MCI) that have incipient AD. Therefore, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Three cerebrospinal fluid biomarkers (the 42 amino acid form of beta-amyloid (A beta), total tau, and phospho tau) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal aging, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. If these biomarkers are used in combination with a careful medical history, clinical examination, standard laboratory tests and imaging techniques of the brain, the diagnostic accuracy may be appropriate for the clinical evaluation of MCI cases.     

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.     

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.     

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.     

EEG synchronization in mild cognitive impairment and Alzheimer's disease

OBJECTIVES: To compute the synchronization likelihood of multichannel electroencephalogram (EEG) data in Alzheimer (AD) patients, subjects with mild cognitive impairment (MCI) and subjects with subjective memory complaints (SC). MATERIAL AND METHODS: EEGs (200 Hz sample frequency; 21 channels; average reference) were recorded in 10 AD patients (two males; age 76.2; SD 9.36; range 59-86), 17 subjects with MCI (eight males; age 77.41; SD 6.25; range 62-88) and 20 subjects with SCI (11 males; age 68.9; SD 12.96; range: 51-89). The synchronization likelihood, a novel type of coherence measure, was computed, comparing each channel with all other channels, for the 2-6, 6-10, 10-14, 14-18, 18-22 and 22-50 Hz band. RESULTS: The synchronization likelihood was significantly decreased in the 14-18 and 18-22 Hz band in AD patients compared with both MCI subjects and healthy controls. Lower beta band synchronization correlated with lower Mini-Mental state examination (MMSE) scores. CONCLUSION: Loss of beta band synchronization occurs early in mildly affected AD patients and correlates with cognitive impairment.     

Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment

The neural basis of the amnesia characterizing early Alzheimer's disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.     

New developments in mild cognitive impairment and Alzheimer's disease

PURPOSE OF REVIEW: In this paper, we review current concepts of Alzheimer's disease, recent progress in diagnosis and treatment and important developments in our understanding of its pathogenesis with a focus on beta-amyloid both as culprit and therapeutic target. RECENT FINDINGS: The amyloid cascade hypothesis of Alzheimer's disease pathogenesis continues to predominate with evidence suggesting that small oligomeric forms of Abeta-42 rather than fibrils or senile plaques are the key pathological substrates. The concept of mild cognitive impairment continues to be refined to define better those patients who will progress to Alzheimer's disease. Structural and functional imaging techniques and cerebrospinal fluid biomarkers are gaining acceptance as diagnostic markers of Alzheimer's disease, with a potentially exciting advance being the ability to image amyloid in vivo using novel positron emission tomography ligands. Whilst available treatments afford only symptomatic benefits, disease-modifying treatments may be within reach. Despite the halting of the first amyloid beta-vaccination trial due to adverse effects, amyloid immunotherapy continues to show promise, with new approaches already entering clinical trials. Other therapeutic strategies under investigation include inhibition of beta -and gamma-secretase, key enzymes implicated in Alzheimer's disease pathogenesis. SUMMARY: Current research demonstrates the potential for diagnostic strategies and disease modifying treatments to follow from an ever more detailed understanding of the molecular mechanisms underlying the pathogenesis of Alzheimer's disease.     

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.     

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.     

Hormonal treatment, mild cognitive impairment and Alzheimer's disease

A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.     

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.     

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.     

Abnormal visual search in mild cognitive impairment and Alzheimer's disease

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined the status of visual attention-related processing in such patients in relation to healthy older adults and patients with Alzheimer's disease (AD) by measuring performance on a computer-based visual search task. We tested 20 older adult control participants, 13 patients with amnestic mild cognitive impairment and 12 patients with AD. Patients with AD and with MCI exhibited a significant detriment in visual search performance compared to the older adult controls. The deficit in visual search was greater for the patients with AD than the patients with MCI. The pattern of results displayed by the MCI group indicates that patients who appear clinically to suffer only from a deficit in memory also display a deficit in visual attention-related processing, which although not as severe as those with AD, represents a significant detriment in such performance compared to that seen in healthy ageing.     

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Background:

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Methods:

Ninety‐one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high‐resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1‐CA2 transition zone (CA1‐2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.

Results:

Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1‐2, and total hippocampal volumes. MCI had smaller CA1‐2 volumes. Discriminant analysis and power analysis showed that CA1‐2 was superior to total hippocampal volume for distinction between controls and MCI.

Conclusion:

The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.