Dataset Information

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer's Disease in Amnestic Mild Cognitive Impairment.

ABSTRACT:

Background/aims

Disease-modifying therapy for Alzheimer's disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD.

Methods

We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of A?_1-42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau¹⁸¹) in CSF with INNOTEST enzyme-linked immunosorbent assay.

Results

For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF A?_1-42, t-Tau, and p-Tau¹⁸¹ were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/A?_1-42 and -p-Tau¹⁸¹/A?_1-42 ratios defined cutoff values at 0.298 and 0.059, respectively.

Conclusions

CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum.

SUBMITTER: Park JE

PROVIDER: S-EPMC6465729 | biostudies-literature | 2019 Jan-Apr

REPOSITORIES: biostudies-literature

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Publications

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer's Disease in Amnestic Mild Cognitive Impairment.

Park Jung Eun JE Choi Kyu Yeong KY Kim Byeong C BC Choi Seong-Min SM Song Min-Kyung MK Lee Jang Jae JJ Kim Jahae J Song Ho-Chun HC Kim Hoo-Won HW Ha Jung-Min JM Seo Eun Hyun EH Song Woo Keun WK Park Sung-Gyoo SG Lee Jung Sup JS Lee Kun Ho KH

Dementia and geriatric cognitive disorders extra 20190101 1

<h4>Background/aims</h4>Disease-modifying therapy for Alzheimer's disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD.<h4>Methods</h4>We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Posi ...[more]

PMID: 31011328

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Project description:To compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI).Randomized controlled trial.Veterans Affairs Medical Center clinical research unit.Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years).Participants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet.The CSF concentrations of ?-amyloid (A?42 and A?40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition.For the aMCI group, the LOW diet increased CSF A?42 concentrations, contrary to the pathologic pattern of lowered CSF A?42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF A?42, whereas the HIGH diet increased CSF A?42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet.Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of A?42, lipoproteins, oxidative stress, and insulin.

Project description:BACKGROUND:Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. OBJECTIVE:To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-? 42 (A?42) peptide. METHODS:Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/A?42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n?=?105) or diagnosed with MCI (n?=?244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/A?42. RESULTS:When included in models alone or in combination with CSF p-tau181/A?42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. CONCLUSIONS:These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.

Project description:BackgroundPhase-contrast magnetic resonance imaging (PC-MRI) enables quantification of cerebrospinal fluid (CSF) flow and total cerebral blood (tCBF) flow and may be of value for the etiological diagnosis of neurodegenerative diseases. This investigation aimed to study CSF flow and intracerebral vascular flow in patients with Alzheimer's disease (AD) and patients with amnesic mild cognitive impairment (a-MCI) and to compare the results with patients with idiopathic normal pressure hydrocephalus (NPH) and with healthy elderly volunteers (HEV).MethodsTen a-MCI and 9 mild AD patients were identified in a comprehensive neurological and neuropsychological assessment. They underwent brain MRI; PC-MRI pulse sequence was performed with the following parameters: two views per segment; flip angle: 25° for vascular flow and 20° for CSF flow; field-of-view (FOV): 14 × 14 mm²; matrix: 256 × 128; slice thickness: 5 mm; with one excitation for exams on the 3 T machine, and 2 excitations for the 1.5 T machine exams. Velocity (encoding) sensitization was set to 80 cm/s for the vessels at the cervical level, 10 or 20 cm/s for the aqueduct and 5 cm/s for the cervical subarachnoid space (SAS). Dynamic flow images were analyzed with in-house processing software. The patients' results were compared with those obtained for HEVs (n = 12), and for NPH patients (n = 13), using multivariate analysis.ResultsArterial tCBF and the calculated pulsatility index were significantly greater in a-MCI patients than in HEVs. In contrast, vascular parameters were lower in NPH patients. Cervical CSF flow analysis yielded similar values for all four populations. Aqueductal CSF stroke volumes (in μl per cardiac cycle) were similar in HEVs (34 ± 17) and AD patients (39 ± 18). In contrast, the aqueductal CSF was hyperdynamic in a-MCI patients (73 ± 33) and even more so in NPH patients (167 ± 89).ConclusionOur preliminary data show that a-MCI patients present with high systolic arterial peak flows, which are associated with higher mean total cerebral arterial flows. Aqueductal CSF oscillations are within normal range in AD and higher than normal in NPH. This study provides an original dynamic vision of cerebral neurodegenerative diseases, consistent with the vascular theory for AD, and supporting primary flow disturbances different from those observed in NPH.

Project description:IntroductionBiomarkers that will reliably predict the onset of Alzheimer's disease (AD) are urgently needed. Although cerebrospinal fluid (CSF) amyloid beta 1-42 (A?42), total tau, and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI), the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1-43 (A?43) aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF A?43 in a 2-year longitudinal study of aMCI and early AD.Materials and methodsCerebrospinal fluid was collected at baseline, and after one and 2 years from patients with AD (n = 19), and patients with aMCI (n = 42). Of these, 21 progressed to AD during the 2 years of study, whereas 21 did not. Controls (n = 32) were lumbar punctured at baseline only. CSF analyses of A?43, A?42, and total tau were carried out with ELISA.ResultsAt baseline, CSF A?43, CSF A?42 and ratios with total tau could be used to separate controls from all three patient groups. CSF A?43, but not A?42, could separate patients with aMCI who progressed to AD during the 2 years of follow-up, from those that did not. The CSF total tau/A?43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/A?42 ratio. CSF A?43 levels, but not A?42 levels, decreased from baseline to 2 years in the AD group.Discussion and conclusionCSF A?43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF A?43 distinguishes between subgroups of patients with aMCI better than CSF A?42, it may prove to be a useful additional biomarker for identifying aMCI patients at greatest risk of AD.

Dataset Information

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer's Disease in Amnestic Mild Cognitive Impairment.

Background/aims

Methods

Results

Conclusions

Publications

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer's Disease in Amnestic Mild Cognitive Impairment.

Similar Datasets

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