Biological Markers of Alzheimers Disease and Mild Cognitive Impairment

Abstract

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.

Unraveling the Role of Metal Ions and Low Catalytic Activity of Cytochrome C Oxidase in Alzheimer’s Disease

“…Not only would this exacerbate the already low ATP synthesis, but it would provide a pool of free or poorly bound heme, thereby establishing conditions thought to be conducive for formation of beta amyloid proteins (Good et al 1992;Honda et al 2004;Huang et al 2006;Atamna, and Boyle 2006); beta amyloid proteins are established anatomical markers of AD (Hampel et al 2004;Maccioni et al 2004). It appears therefore, that inhibition of COX whether by high metal ion concentration or otherwise may be at the CRUX of the matter in early stages of AD and other neurodegenerative disorders.…”

“…Specifically, PD is characterized by the presence of Lewy bodies and Lewy neuritis in the brain (Forno 1996;Hughes et al 2001;Oakley et al 2007) while the AD brain is characterized by the presence of neurofibrillary tangles and amyloid plaques (Hampel et al 2004;Maccioni et al 2004). Biochemically, both AD and PD are characterized by low activity of the mitochondrial enzyme cytochrome c oxidase (COX; Parker et al 1994a;Parker and Parks 1995;Mohan et al 2009) but the etiology of both diseases remain uncertain.…”

Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

“…AD plaques may increase Ab 25-35-induced neurotoxicity in vitro and invivo. Also, Ab is toxic to neurons in vitro and the level of Ab load correlates well with the degree of cognitive impairment in vivo [3]. In fact, accumulation of Ab appears to be sufficient to cause dementia [2].…”

Noninvasive Brain Imaging for Experimental Medicine in Drug Discovery and Development

“…In this way, imaging can contribute both to defining the relationship between the putative causal organism, molecule or gene and to an appreciation for the way in which biological functions are changed by disease; for example, in Alzheimer's disease there is the exciting prospect of using amyloidspecific PET ligands to assess the relationship between amyloid deposition, brain structural changes, clinical symptoms and circulating amyloid biomarkers in the blood. [38][39][40][41] Imaging can contribute, by its definition of system responses, to a better understanding of mechanisms of recovery in a similar way to its contribution to markers of disease, for example, in studies of brain plasticity. [30,[42][43][44][45][46] Differentiating between different forms of clinical syndromes as specific diseases has the special potential to establish predictive factors for drug response.…”