Cerebrospinal beta-amyloid (1–42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline

Riemenschneider, Matthias; Schmolke, Michael; Lautenschlager, Nicola T.; Guder, W.G.; Vanderstichele, Hugo; Vanmechelen, Eugeen; Kurz, Alexander

doi:10.1016/s0304-3940(00)00976-9

Cited by 72 publications

(44 citation statements)

References 13 publications

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“…In addition, the concentrations of severe AD patients in this study were similar to those in HC, which is not consistent with most studies on CSF Ab 1-42 published so far. [5][6][7]9,[26][27][28][29] In this individual study, increased CSF Ab 42 was also found in depression, while two other studies have found normal levels of Ab in depressed patients 7,30 Moreover, in the measurement of Ab proteins, the assay used in the study of Jensen et al was different from the assay used to quantitate Ab in the other studies. This may have influenced the concentrations measured in their study group.…”

Section: Discussionmentioning

confidence: 78%

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Hampel¹,

Teipel²,

Fuchsberger³

et al. 2003

Mol Psychiatry

286

196

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Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) bamyloid 1-42 (Ab 1-42 ) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Ab 1-42 and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Ab 1-42 and CSF tau. The levels of CSF tau were increased, whereas levels of Ab 1-42 were decreased in MCI subjects. Ab 1-42 predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Ab 1-42 , but not other predictor variables (tau protein, gender, age, apolipoprotein E e4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (Po0.05). Our findings support the notion that CSF tau and Ab 1-42 may be useful biomarkers in the early identification of AD in MCI subjects.

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Section: Discussionmentioning

confidence: 78%

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Hampel¹,

Teipel²,

Fuchsberger³

et al. 2003

Mol Psychiatry

286

196

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“…The concentration of A␤ in the cerebrospinal fluid has been estimated as in the nanomolar range or even lower (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). This is below the "critical micelle concentration" for A␤ (13) and at the margin of the critical concentration (C r ), at which A␤ solutions can extend fibrillar seeds (14,15).…”

mentioning

confidence: 99%

Site-specific Effects of Peptide Lipidation on β-Amyloid Aggregation and Cytotoxicity

Qahwash

Boire

Lanning

et al. 2007

Journal of Biological Chemistry

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␤-Amyloid (A␤) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of A␤ by 4-hydroxynonenal (4-HNE) initially increases the hydrophobicity of these peptides and subsequently leads to additional reactions, such as peptide cross-linking. To model these initial events, without confounding effects of subsequent reactions, we modified A␤ at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-A␤, K28-OA-A␤, and N␣-OA-A␤. Octanoylation of these sites on A␤-(1-40) had strikingly different effects on fibril formation. K16-OA-A␤ and K28-OA-A␤, but not N␣-OA-A␤, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-A␤ peptides to cross-seed solutions of A␤ was the inverse of their ability to form fibrils on their own (i.e. A␤ ≈ N␣-OA-A␤ Ͼ Ͼ K16-OA-A␤ Ͼ Ͼ K28-OA-A␤). By CD spectroscopy, K16-OA-A␤ and K28-OA-A␤ had increased ␤-sheet propensity compared with A␤-(1-40) or N␣-OA-A␤. K16-OA-A␤ and K28-OA-A␤ were more amphiphilic than A␤-(1-40) or N␣-OA-A␤, as shown by lower "critical micelle concentrations" and higher monolayer collapse pressures. Finally, K16-OA-A␤ and K28-OA-A␤ are much more cytotoxic to N2A cells than A␤-(1-40) or N␣-OA-A␤. The greater cytotoxicity of K16-OA-A␤ and K28-OA-A␤ may reflect their greater amphiphilicity. We conclude that lipidation can make A␤ more prone to aggregation and more cytotoxic, but these effects are highly site-specific.Alzheimer disease, the most prevalent neurodegenerative disorder, leads to progressive memory loss, disability and eventually death (1). It is characterized by the accumulation of extracellular plaques of amyloid ␤ (A␤) 2 (2). Although aggregation of A␤ appears to be important in the pathogenesis of Alzheimer disease, one of the unanswered questions is how A␤ peptides aggregate at the low concentrations at which they exist in the central nervous system. The concentration of A␤ in the cerebrospinal fluid has been estimated as in the nanomolar range or even lower (3-12). This is below the "critical micelle concentration" for A␤ (13) and at the margin of the critical concentration (C r ), at which A␤ solutions can extend fibrillar seeds (14, 15). One recently proposed answer to this question is that an aggregation-prone, covalently modified A␤ could catalyze aggregation of the unmodified peptide. In addition to catalyzing peptide aggregation, aldehyde-modified A␤ could also be cytotoxic to neurons by itself. Oxidative stress, a possible pathogenic factor in Alzheimer disease, can lead to the formation of reactive lipid aldehydes, such as 4-HNE (16 -21) and cholesterol oxides (22), among others. Indeed, 4-HNE immunoreactivity is detected in plaques and cerebrospinal fluid of patients with Alzheimer disease (19,20) and is believed to play a role in many other neurodegenerative diseases, including Parkinson disease (23-26), Lewy body dis...

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“…Various studies have suggested that singly or in combination, CSF tau and Aß amyloid measurements may increase the accuracy of the diagnosis of AD. The levels of tau in the CSF of AD patients averages about twice that of normals, while Aß 1-42 levels are about half that of age-matched controls (35)(36)(37)(38)(39). Although there is overlap in the range of values of these markers in patients with other forms of dementia and AD, the finding of high tau and low CSF Aß 1-42 may be supportive of an AD diagnosis in a patient meeting diagnostic criteria for possible or probable AD.…”

Section: Recent Developments In Alzheimer's Diseasementioning

confidence: 99%

Recent Developments in Alzheimer’s Disease

Cras¹

2001

Acta Clinica Belgica

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Cerebrospinal beta-amyloid (1–42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline

Cited by 72 publications

References 13 publications

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Site-specific Effects of Peptide Lipidation on β-Amyloid Aggregation and Cytotoxicity

Recent Developments in Alzheimer’s Disease

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