Article

Cerebrospinal Fluid Abnormalities and Rate of Decline in Everyday Function Across the Dementia Spectrum Normal Aging, Mild Cognitive Impairment, and Alzheimer Disease

Department of Neurology, Johns Hopkins School of Medicine, 1620 McElderry St, Reed Hall East 2, Baltimore, MD 21205, USA.
Archives of neurology (Impact Factor: 7.42). 06/2010; 67(6):688-96. DOI: 10.1001/archneurol.2010.118
Source: PubMed

ABSTRACT

To investigate the effect of cerebrospinal fluid (CSF) abnormalities on the rate of decline in everyday function in normal aging, mild cognitive impairment (MCI), and mild Alzheimer disease (AD).
Immunoassays of total tau (t-tau), tau phosphorylated at threonine 181 (p-tau(181)), and beta-amyloid 1-42 (Abeta(42)) concentrations were performed in CSF obtained from participants in the Alzheimer's Disease Neuroimaging Initiative. Random effects regressions were used to examine the relationship among CSF abnormalities, cognitive impairment (assessed with the Alzheimer Disease Assessment Scale-cognitive subscale [ADAS-Cog]), and functional decline (assessed with the Pfeffer Functional Activities Questionnaire) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment.
Fifty-eight sites in the United States and Canada.
One hundred fourteen cognitively intact adults, 195 patients with MCI, and 100 patients with mild AD. Main Outcome Measure Decline in the Pfeffer Functional Activities Questionnaire score.
Abnormalities in all CSF analytes were associated with functional decline in MCI, and all but the t-tau:Abeta(42) ratio were associated with functional decline in controls. No abnormal CSF analyte was associated with functional decline in AD. Among controls, p-tau(181) concentration was the most sensitive to functional decline, whereas in MCI it was Abeta(42) concentration. Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI, whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD. The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status. Across all diagnostic groups, persons with both tau and Abeta(42) abnormalities exhibited the steepest rate of functional decline.
Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI. However, they do not predict further functional degradation in patients with AD. Persons with comorbid tau and Abeta(42) abnormalities are at greatest risk of functional loss.

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    • "Cerebrospinal fluid (CSF) biomarkers (A␤ 42 , total tau, and phosphorylated tau) exhibit an acceptable diagnostic accuracy for incipient AD even during pre-dementia stages [2]. However, none of these biomarkers can be used to assess the rate and/or stage of clinical deterioration, because they do not clearly correlate with the severity of dementia and functional decline in patients suffering from AD [3] [4]. A␤-oligomers could be a new powerful diagnostic as well as surrogate marker of AD, because the levels of A␤-oligomers in the brain correlate with the severity of the cognitive impairment [5] [6]. "

    Full-text · Dataset · Feb 2013
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    • "These authors identified a significant relation between functional impairment and pathological burden, especially neuritic plaques within the medial temporal, occipital and orbital frontal regions. One study analyzing CSF and plasma biomarkers found no significant biomarkers of functional decline in AD [9]. In contrast, others have shown a significant relationship between low levels of plasma Aβ42 and C-reactive protein and functional decline in ADLS [10]. "
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    ABSTRACT: Functional impairment is common in Alzheimer's disease (AD) and related to increased caregiver burden and institutionalization. There is a dearth of research investigating the relationship between specific biomarkers and basic activities of daily living (BADLs) such as toileting, feeding, dressing, grooming, bathing, and ambulating. The present study examined the relationship between serum based biomarkers and specific ADLs in a sample of AD patients. Data were collected from 196 participants enrolled in the Texas Alzheimer's Research and Care Consortium Project and diagnosed with AD. BADLs were measured using the Lawton-Brody Physical Self-Maintenance Scale. A panel of 22 biomarkers previously found to be related to AD pathology was used for the analysis. Stepwise regression modeling was used to assess the link between the biomarkers and BADLs. Results were also examined by gender. Nine of the 22 biomarkers were significantly related to BADLs. When stratified by gender, the biomarkers accounted for 32% of the variance in the males and 27% in females. The pattern of significant biomarkers differed by gender with IL 7 and Tenascin C significantly related to BADLs for females and IL 15 significantly related to BADLs for males. The results of this study indicated that a small number of serum based biomarkers are related to BADLs, and these biomarkers differed by gender.
    Full-text · Article · May 2012 · Journal of Alzheimer's disease: JAD
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    • "Cerebrospinal fluid (CSF) biomarkers (A␤ 42 , total tau, and phosphorylated tau) exhibit an acceptable diagnostic accuracy for incipient AD even during pre-dementia stages [2]. However, none of these biomarkers can be used to assess the rate and/or stage of clinical deterioration, because they do not clearly correlate with the severity of dementia and functional decline in patients suffering from AD [3] [4]. A␤-oligomers could be a new powerful diagnostic as well as surrogate marker of AD, because the levels of A␤-oligomers in the brain correlate with the severity of the cognitive impairment [5] [6]. "
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    ABSTRACT: Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity.
    Full-text · Article · Jan 2012 · Journal of Alzheimer's disease: JAD
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