Alzheimer Neuropathologic Alterations in Aged Cognitively Normal Subjects

Davis, Daron G.; Schmitt, Frederick A.; Wekstein, David R.; Markesbery, William R.

doi:10.1097/00005072-199904000-00008

Cited by 484 publications

(285 citation statements)

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“…[21][22][23] However, this lack of association may be due to the multiple forms of Ab assembly, such that memory impairment and neurotoxicity may be due to soluble oligomers of Ab. Indeed, the level of soluble Ab, in particular Ab1-40, correlates with synaptic changes and disease severity in AD [24][25][26][27][28][29][30] (Table 1).…”

Section: Biology Of Ab In the Brain And Peripherymentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Biology Of Ab In the Brain And Peripherymentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…Recent reports indicate that the neuropathologic changes of AD, including neurofibrillary tangles and amyloid plaques, not only occur in MCI (Markesbery et al, 2006;Petersen et al, 2006) but are also found in some individuals who are clinically normal (Bennett et al, 2006;Davis et al, 1999;Morris et al, 1996Morris et al, , 2001Price & Morris, 1999;Storandt et al, 2006). While diagnostic and imaging markers are being developed to detect early pathologic changes during life (Andreasen & Blennow, 2005;Klunk et al, 2003Klunk et al, , 2004Schoonenboom et al, 2005), clinical performance on tests of memory remains the most widely accepted marker of prodromal AD in at-risk individuals Albert, 2002).…”

Section: Introductionmentioning

confidence: 99%

Intelligence quotient–adjusted memory impairment is associated with abnormal single photon emission computed tomography perfusion

Rentz

Huh

Sardinha

et al. 2007

J. Inter. Neuropsych. Soc.

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Cognitive reserve among highly intelligent older individuals makes detection of early Alzheimer's disease (AD) difficult. We tested the hypothesis that mild memory impairment determined by IQ-adjusted norms is associated with single photon emission computed tomography (SPECT) perfusion abnormality at baseline and predictive of future decline. Twenty-three subjects with a Clinical Dementia Rating (CDR) score of 0, were reclassified after scores were adjusted for IQ into two groups, 10 as having mild memory impairments for ability (IQ-MI) and 13 as memory-normal (IQ-MN). Subjects underwent cognitive and functional assessments at baseline and annual follow-up for 3 years. Perfusion SPECT was acquired at baseline. At follow-up, the IQ-MI subjects demonstrated decline in memory, visuospatial processing, and phonemic fluency, and 6 of 10 had progressed to a CDR of 0.5, while the IQ-MN subjects did not show decline. The IQ-MI group had significantly lower perfusion than the IQ-MN group in parietal0precuneus, temporal, and opercular frontal regions. In contrast, higher perfusion was observed in IQ-MI compared with IQ-MN in the left medial frontal and rostral anterior cingulate regions. IQ-adjusted memory impairment in individuals with high cognitive reserve is associated with baseline SPECT abnormality in a pattern consistent with prodromal AD and predicts subsequent cognitive and functional decline. (JINS, 2007, 13, 821-831.)

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“…It is not surprising therefore that the cascade of immunological events that can be observed in the brain of an AD patient are found to occur very early in the progression of the disease in those same brain regions that later show the greatest concentration of senile plaques and atrophy (Cagnin et al, 2001). Moreover, the development of inflammation within neuronal populations and regions known to be vulnerable in the brains of AD coincide with the memory impairments observed in the early stages of AD pathology (Davis et al, 1999). The brain's inflammatory response leads to a cascade of self-perpetuating cellular events including increased release of prostaglandins (Katsuura et al, 1989), enhanced release of glutamate (Emerit et al, 2004), and blockade of glutamate uptake by glia (Rothwell et al, 1997).…”

Section: Neuroinflammation and Alzheimer's Diseasementioning

confidence: 99%

Inflammation and aging: Can endocannabinoids help?

Marchalant

Wenk

2008

Biomedicine & Pharmacotherapy

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SummaryAging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, a growing concern exist linked to long-term, slowly debilitating diseases that have not yet found a cure, such as Alzheimer's disease. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer's disease will be discussed in this review.

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Alzheimer Neuropathologic Alterations in Aged Cognitively Normal Subjects

Cited by 484 publications

References 0 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Intelligence quotient–adjusted memory impairment is associated with abnormal single photon emission computed tomography perfusion

Inflammation and aging: Can endocannabinoids help?

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