Forman MS, Mufson EJ, Leurgans S, et al. Cortical biochemistry in MCI and Alzheimer disease: Lack of correlation with clinical diagnosis

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Blvd., 605B Stellar-Chance Building, Philadelphia, PA 19104, USA.
Neurology (Impact Factor: 8.29). 04/2007; 68(10):757-63. DOI: 10.1212/01.wnl.0000256373.39415.b1
Source: PubMed


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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    • "c o m / l o c a t e / y n b d i have shown that Aβ42 polymerizes into fibrils more rapidly than Aβ40 and accumulates more readily in amyloid plaques (Roher et al., 1993; Bitan et al., 2003). Many biochemical characterizations have revealed that the concentration of Aβ40 and Aβ42 are both increased in brain samples from AD compared to non-demented Controls (Lue et al., 1999; McLean et al., 1999; Wang et al., 1999; Näslund et al., 2000; Fonte et al., 2001; Ingelsson et al., 2004; Forman et al., 2007; Tremblay et al., 2007; Julien et al., 2008). By applying a procedure that extracts insoluble proteins from brain samples using sequentially buffered water, detergent and formic acid (FA), Aβ peptides are segregated into biochemical compartments defined by their solubility (Tremblay et al., 2007; Steinerman et al., 2008). "
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    ABSTRACT: The accumulation of insoluble amyloid-beta (Aβ) peptides is associated with neurodegenerative disorders, such as Alzheimer's disease (AD). As essential tremor (ET) could involve neurodegenerative processes in the cerebellum, we quantified soluble and insoluble Aβ in cerebellar cortices from patients diagnosed with ET (n=9), compared to Controls (n=16) or individuals with Parkinson's disease (n=10). Although ante-mortem cognitive performance was not documented, all individuals included had the diagnosis of AD ruled out by a neuropathologist. ELISA-determined concentrations of insoluble Aβ42 in ET patients displayed a bimodal distribution, with a median 246-fold higher than in Controls (P<0.01, Kruskal-Wallis). Higher Aβ42 concentrations were measured in the parietal cortex of the same ET patients, compared to Controls (107-fold median increase, P<0.01, Kruskal-Wallis), but similar phosphorylated tau levels were detected. The rise in cerebellar insoluble Aβ42 concentrations is not associated to APP expression and processing or the ApoE4 status. However, Aβ42 levels in ET individuals were correlated with cerebellar insoluble phosphorylated tau (r(2)=0.71, P=0.005), unphosphorylated neurofilament heavy chain (NF-H. r(2)=0.50, P=0.030) and Lingo-1 (r(2)=0.73, P=0.007), indicative of a generalized neurodegenerative process involving the cerebellum. Our results suggest prevalent accumulations of insoluble Aβ42 in the cerebellum of ET, but not in age-matched PD. Whether this anomaly plays a role in ET symptoms warrants further investigations. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Neurobiology of Disease
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    • "In line with these findings, previous evidence has shown that insoluble Aβ 42 extracted from entorhinal cortex is correlated with density of neuritic plaques as well as with the Braak stage (Forman et al., 2007). Furthermore, MCI subjects have shown fewer neurons in the entorhinal cortex than HO subjects, decreasing the number of neurons in layer II by 60% and in layer IV by 40% (Gomez-Isla et al., 1996). "
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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.
    Full-text · Article · May 2014 · NeuroImage
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    • "Once released, Aβ due to its physico-chemical properties has the strong tendency to misfold, oligomerize and to aggregate into fibrils and plaques [2]. Although amyloid plaques represent a major hallmark of AD, they correlate poorly with the progression of the disease [3]. Interestingly, more recent studies have identified soluble Aβ-oligomer assemblies as the main pathogenic agents which, in contrast to plaques, do correlate well with the mental decline observed in AD patients [1,4–7]. "
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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.
    Full-text · Article · Jan 2010 · Journal of Alzheimer's disease: JAD
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