Cortical biochemistry in MCI and Alzheimer disease - Lack of correlation with clinical diagnosis
ABSTRACT Mild cognitive impairment, hypothesized to be prodromal Alzheimer disease (AD), shows abundant senile plaques and neurofibrillary tangles, but its biochemical correlates remain undefined.
Biochemical profiles of Abeta, tau, alpha-synuclein, and oxidative pathologies were characterized in middle frontal gyrus, inferior parietal cortex, and entorhinal cortex in postmortem frozen brains from subjects diagnosed antemortem with no cognitive impairment, mild cognitive impairment, or AD.
Insoluble Abeta and tau, as well as tissue isoprostanes, from each brain region analyzed did not correlate with the clinical diagnosis proximate to death, but insoluble Abeta and 8,12-iso-iPF(2alpha)-VI levels from gray matter of all brain regions correlated strongly with the burden of AD pathology, whereas insoluble tau did not.
The biochemical alterations in cortical tau, Abeta, and isoprostane do not reflect the onset of clinical dementia.
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ABSTRACT: Evidence suggests that amyloid-beta (Aβ) deposition parallels sleep deficits in Alzheimer's disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aβ levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aβ concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aβ42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aβ40 and Aβ42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aβ burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aβ levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration.NeuroImage 05/2014; 98. DOI:10.1016/j.neuroimage.2014.05.027 · 6.13 Impact Factor
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ABSTRACT: Misfolding, oligomerization, and aggregation of the amyloid-beta (Abeta) peptide is widely recognized as a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have identified soluble Abeta oligomers as the main pathogenic agents and provided evidence that such oligomeric Abeta aggregates are neurotoxic, disrupt synaptic plasticity, and inhibit long-term potentiation. A promising therapeutic strategy in the battle against AD is the application of short synthetic peptides which are designed to bind to specific Abeta-regions thereby neutralizing or interfering with the devastating properties of oligomeric Abeta species. In the present study, we investigated the neuroprotective properties of the amyloid sequence derived pentapeptide LPYFDa in vitro as well as its memory preserving capacity against Abeta(42)-induced learning deficits in vivo. In vitro we showed that neurons in culture treated with LPYFDa are protected against Abeta (42) -induced cell death. Moreover, in vivo LPYFDa prevented memory impairment tested in a contextual fear conditioning paradigm in mice after bilateral intrahippocampal Abeta (42) injections. We thus showed for the first time that an anti-amyloid peptide like LPYFDa can preserve memory by reverting Abeta (42) oligomer-induced learning deficits.Journal of Alzheimer's disease: JAD 01/2010; 19(3):991-1005. DOI:10.3233/JAD-2010-1297 · 3.61 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Abeta) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD.Ageing research reviews 05/2009; 8(4):285-305. DOI:10.1016/j.arr.2009.04.002 · 7.63 Impact Factor