Cerebrospinal Fluid Beta-Amyloid 42 Is Reduced before the Onset of Sporadic Dementia: A Population-Based Study in 85-Year-Olds

Skoog, Ingmar; Davidsson, Pia; Aevarsson, Olafur; Vanderstichele, Hugo; Vanmechelen, Eugeen; Blennow, K.

doi:10.1159/000068478

Cited by 173 publications

(113 citation statements)

References 39 publications

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“…Aβ accumulation and deposition in the AD brain can begin 10 y before the appearance of the first symptoms (2, 32). The concept of "preclinical AD" indicates that AD pathologies are present but AD symptoms are not (49,50). Several anti-Aβ therapeutic strategies are being pursued to treat AD; however, it is likely that treatment will need to begin during the preclinical phase to prevent or limit plaque accumulation to be beneficial in reducing the risk of developing AD (51,52).…”

Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

303

307

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

303

307

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“…112 A recent population-based study also found that reduced CSF A␤42 is present in asymptomatic elderly who developed dementia during a 3-year follow-up period. 113 The fact that only ϳ15% of MCI cases progress to AD each year 6 makes a very extensive follow-up period (more than 5 years) needed to ascertain which MCI patients will not develop dementia, i.e., have stable MCI. This may introduce a risk that the specificity figures in these studies thus far are too low.…”

Section: MCImentioning

confidence: 99%

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

2004

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Summary:The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of ␤-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson's disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as ␥-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.

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“…Two population-based studies have found a significant reduction in CSF Aβ42 in cognitively normal elderly people that later developed dementia [11,12]. In the same material, there was no significant change in CSF T-τ or P-τ in individuals that later developed AD 'CSF biomarkers, especially CSF Aβ42, may predict preclinical AD in cognitively normal elderly individuals.…”

Section: Csf Biomarkers To Identify Ad Preclinicallymentioning

confidence: 93%

What is the Future for CSF Biomarkers in the Prediction of Cognitive Decline and Alzheimer’s Disease?

Blennow

Zetterberg

2008

Aging Health

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Cerebrospinal Fluid Beta-Amyloid 42 Is Reduced before the Onset of Sporadic Dementia: A Population-Based Study in 85-Year-Olds

Cited by 173 publications

References 39 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

What is the Future for CSF Biomarkers in the Prediction of Cognitive Decline and Alzheimer’s Disease?

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