Cerebrospinal Fluid A[[Beta].sub.42], Tau, and [F.sub.2]-Isoprostane Concentrations in Patients With Alzheimer Disease, Other Dementias, and in Age-Matched Controls.Recent efforts have concentrated on determining markers to screen for increased susceptibility to Alzheimer disease Alzheimer disease Degenerative brain disorder. It occurs in middle to late adult life, destroying neurons and connections in the cerebral cortex and resulting in significant loss of brain mass. (AD), to discriminate AD from other forms of dementia, and to quantify the efficacy of experimental therapeutics. Three major categories of markers have been investigated: genetic, neuroimaging, and biochemical. At a recent meeting convened by the National Institutes of Health, cerebrospinal fluid cerebrospinal fluid (CSF) Clear, colourless liquid that surrounds the brain and spinal cord and fills the spaces in them. It helps support the brain, acts as a lubricant, maintains pressure in the skull, and cushions shocks. (CSF Cerebrospinal Fluid (CSF) Analysis Definition Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. ) A[[Beta].sub.42] concentration, CSF tau level, and quantification of free radical--mediated damage to brain were discussed as potential biochemical markers for AD.[1] Others have quantified levels of CSF A[[Beta].sub.42] and tau, and have addressed their utility, alone or in combination, as biomarkers of AD.[2] [F.sub.2]-Isoprostanes ([F.sub.2]-IsoPs) have been employed widely as quantitative in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body. in vi·vo adj. Within a living organism. in vivo adv. biomarkers of oxidative damage.[3] [F.sub.2]-Isoprostanes are exclusive products of free radical-mediated damage to arachidonic acid arachidonic acid /arach·i·don·ic acid/ (ah-rak?i-don´ik) a polyunsaturated 20-carbon essential fatty acid occurring in animal fats and formed by biosynthesis from linoleic acid; it is a precursor to leukotrienes, prostaglandins, and that are formed esterified to lipid and then are hydrolyzed and released into extracellular fluid extracellular fluid n. Abbr. ECF 1. The interstitial fluid and the plasma, constituting about 20 percent of the weight of the body. 2. All fluid outside of cells, usually excluding transcellular fluid. . [F.sub.2]-Isoprostanes are elevated in diseased regions of brain from definite AD patients compared to controls/Cerebrospinal fluid levels of [F.sub.2]-IsoPs are elevated in probable AD patients compared to age-matched controls.[5,6] In contrast, we have found that plasma and urinary [F.sub.2]-IsoPs are not increased in probable AD patients.[7] In combination, these data indicate that CSF [F.sub.2]-IsoPs are biomarkers of oxidative damage to brain in AD. Since arachidonic acid is distributed among neuronal and nonneuronal elements in brain, [F.sub.2]-IsoPs are not specific for neuronal oxidative damage. However, the value of measuring CSF [F.sub.2]-IsoPs as biomarkers of AD relative to A[[Beta].sub.42] and tau is not known. Here we have determined CSF A[[Beta].sub.42], tau, and [F.sub.2]-IsoP levels in patients with probable AD, other forms of dementia, and in age-matched control individuals. METHODS All patients and control subjects were under care at Oregon Health Sciences University (Portland, Ore) or Vanderbilt University Medical Center The Vanderbilt University Medical Center (VUMC) is a collection of several hospitals and clinics associated with Vanderbilt University in Nashville, Tennessee. It comprises the following units:[2]
prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) guidelines for probable AD.[8] Diagnosis of dementia with Lewy bodies Dementia with Lewy bodies is the second most frequent cause of hospitalization for dementia, after Alzheimer's disease. Current estimates are that about 60-to-75% of diagnosed dementias are of the Alzheimer's and mixed (Alzheimer's and vascular dementia) type, 10-to-15% are Lewy followed published criteria.[9] Most patients were evaluated by neuroimaging studies, including all patients with normal pressure hydrocephalus normal pressure hydrocephalus n. A hydrocephalic condition in which the spinal fluid pressure remains normal, resulting from the inability of the arachnoid granulations to absorb cerebrospinal fluid, and characterized by progressive dementia. . Diagnoses in patients with non-AD forms of dementia were based on best clinical judgment. Nondemented controls were 50 years of age or older, without significant cognitive or neurologic symptoms, and had a normal neurologic examination neurologic examination A battery of clinical tests that evaluates a person's physiologic function and mental status, as well as the presence of any structural–organic lesions that may cause changes in neurologic function. Cf Psychiatric examination. and Mini-Mental State Examination The mini-mental state examination (MMSE) or Folstein test is a brief 30-point questionnaire test that is used to assess cognition. It is commonly used in medicine to screen for dementia. score of 28 or greater. Clinical Dementia Ratings,[10] Mini-Mental State Examination scores,[11] and Modified Ischemia Scores[12] were determined according to established protocols. Cerebrospinal fluid was obtained from the lumbar cistern cistern /cis·tern/ (sis´tern) a closed space serving as a reservoir for fluid, e.g., one of the enlarged spaces of the body containing lymph or other fluid. of 37 individuals diagnosed as nondemented controls (n = 10), probable AD (n = 19), or other forms of dementia (n = 8). Diagnoses in demented patients without probable AD were dementia with Lewy bodies (n = 1), normal pressure hydrocephalus (n = 3), primary progressive aphasia Primary progressive aphasia (PPA) is a gradually worsening disorder of speech with an insidious onset. It was first described by Marsel Mesulam in 1982. There is considerable controversy over the nosology of this disorder. (n = 3), and hippocampal sclerosis (n = 1). Results from clinical tests, age, sex, and disease duration are summarized in the Table.
Clinical Data and Demographic Information for Study Participants(*)
Control
Age, y (n)([dagger]) 66.4 [+ or -] 2.9 (10)
Gender (male:female) 3:2
Education, y (n)([dagger]) 16.3 [+ or -] 1.2 (6)
Disease duration, y (n)([dagger]) ...
CDR([double dagger]) 0, 0 to 0 ((4)
MMSE([double dagger]) 29, 28 to 30 (8)
MIS([double dagger]) 0, 0 to 0 (3)
AD
Age, y (n)([dagger]) 65.3 [+ or -] 2.7 (14)
Gender (male:female) 5:2
Education, y (n)([dagger]) 15.2 [+ or -] 0.8 (11)
Disease duration, y (n)([dagger]) 4.2 [+ or -] 0.7 (10)
CDR([double dagger]) 0.5, 0.5 to 1.0 (11)
MMSE([double dagger]) 24, 19 to 27 (11)
MIS([double dagger]) 0, 0 to 0 (8)
Other Dementia
Age, y (n)([dagger]) 66.6 [+ or -] 4.4 (8)
Gender (male:female) 3:1
Education, y (n)([dagger]) 14.3 [+ or -] 1.4 (7)
Disease duration, y (n)([dagger]) 4.0 [+ or -] 1.2 (6)
CDR([double dagger]) 0.5, 0.5 to 1.0 (7)
MMSE([double dagger]) 28, 25 to 29 (8)
MIS([double dagger]) 1, 0 to 3 (5)
(*) There was no significant difference in age or education level among
the 4 groups (both ANOVAs had P > .05). Duration of dementia was not
significantly different between patients with probable Alzheimer
disease (AD) or other dementias (unpaired t test, P > .05).
Nonparametric ANOVAs for Clinical Dementia Rating (CDR) and Mini-Mental
State Examination (MMSE) were significantly different among the 3
groups (P < .05); however, the Modified Ischemia Score (MIS) was not
statistically significant (P = .08).
([dagger]) Values are presented as mean [+ or -] SEM (n).
([double dagger]) Values are presented as median, 25th to 75th
percentile (n).
Following informed consent, CSF was obtained from the lumbar cistern at both institutions as previously described, separated into aliquots, and stored at -80 [degrees] C.[5] All CSF samples had protein, glucose, and cell counts within the normal ranges. A[[Beta].sub.42] and tau levels were determined by Athena Diagnostics, Worcester, Mass. [F.sub.2]-Isoprostane levels were determined according to published methods using gas chromatography/negative ion chemical ionization mass spectrometry mass spectrometry or mass spectroscopy Analytic technique by which chemical substances are identified by sorting gaseous ions by mass using electric and magnetic fields. and [[sup.2][H.sub.4]]-8-iso-[PGF PGF Probability Generating Function PGF Perpignan, France - Llabanere (Airport Code) PGF Polypeptide Growth Factor PGF Pen Gun Flare PGF Production Genomic Facility PGF Prince George Freenet PGF Pseudo Green Function .sub.2[Alpha]], as internal standard.[5] Statistical analysis was performed as described in the text using GraphPad Prism (San Diego, Calif). Nonparametric analysis of variance (ANOVA anova see analysis of variance. ANOVA Analysis of variance, see there ; Kruskal-Wallis test) was used to compare among the 3 groups of controls, AD, and non-AD dementia because the data sets did not have normal distributions. The Dunn multiple comparison test was used for post hoc comparisons to determine if significant differences existed between paired groups. In all tests [Alpha] was set at .05. RESULTS Cerebrospinal fluid concentrations of A[[Beta].sub.42], tau, and [F.sub.2]-IsoPs were analyzed for all individuals (Figure 1). Similar to results from previous studies, CSF A[[Beta].sub.42] levels decreased and CSF tau levels increased in probable AD patients compared to normal controls.[13-15] Nonparametric ANOVA (Kruskal-Wallis test) was statistically significant for CSF A[[Beta].sub.42] (P [is less than] .01) and tau (P [is less than] .05) levels when all 3 groups were compared. All 3 groups also were significantly different with respect to CSF [F.sub.2]-IsoP levels (Kruskal-Wallis test, P [is less than] .01). Repeated pairs analysis was performed to determine significant differences between controls and probable AD patients, controls and patients with other dementias, or probable AD patients and patients with other dementias. Controls and probable AD patients differed significantly in their CSF concentrations of A[[Beta].sub.42] (P [is less than] .01) and [F.sub.2]-IsoPs (P [is less than] .01), but not tau (P [is greater than] .05). Controls and patients with other dementias were not significantly different with respect to CSF A[[Beta].sub.42], [F.sub.2]-IsoP, or tau levels. Alzheimer disease patients and patients with other dementias had significantly different CSF levels of tau (P [is less than] .05), but not CSF A[[Beta].sub.42] or [F.sub.2]-IsoP levels. Cerebrospinal fluid levels of A[[Beta].sub.42], tau, and [F.sub.2]-IsoPs did not correlate with each other when comparing all individuals or just AD patients and controls. Moreover, the CSF concentrations of none of these 3 classes of molecules correlated with age, duration of illness, Clinical Dementia Rating, Mini-Mental State Examination score, Modified Ischemia Score, or number of [Epsilon]4 alleles of APOE APOE ε4 Molecular neurology The type 4 allele of the apolipoprotein E gene locus located on chromosome 19, which may↑ the risk of late-onset Alzheimer's disease, and has been associated with ↓ cerebral parietal metabolism; possession of an . [Figure 1 ILLUSTRATION OMITTED] Six individuals, 3 AD patients, 2 other dementia patients, and 1 control, were taking vitamin E vitamin E or tocopherol Fat-soluble organic compound found principally in certain plant oils and leaves of green vegetables. Vitamin E acts as an antioxidant in body tissues and may prolong life by slowing oxidative destruction of membranes. supplements in doses ranging from 400 to 2000 IU/day. A partially overlapping group of 12 individuals was taking vitamin C vitamin C or ascorbic acid Water-soluble organic compound important in animal metabolism. Most animals produce it in their bodies, but humans, other primates, and guinea pigs need it in the diet to prevent scurvy. or multivitamin mul·ti·vi·ta·min adj. Containing many vitamins. n. A preparation containing many vitamins. multivitamin supplements, giving a total of 4 AD patients, 4 patients with other dementias, and 4 controls who were taking antioxidant vitamin antioxidant vitamin Nutrition Any vitamin–eg, beta carotene–provitamin A, ascorbic acid–vitamin C, and alpha-tocopherol–vitamin E with antioxidant activity. See Antioxidant, Antixoxidant therapy. supplements. Cerebrospinal fluid A[[Beta].sub.42], tau, and [F.sub.2]-IsoP levels for these 12 individuals were not significantly different from those of the other members of their respective groups. The optimum value of CSF [F.sub.2]-IsoP for discriminating AD from non-AD was greater than 25 pg/mL, as estimated by maximizing the sum of sensitivity (90%) and specificity (61%) for AD (n = 37). Combining CSF [F.sub.2]-IsoP levels greater than 25 and the published discriminant dis·crim·i·nant n. An expression used to distinguish or separate other expressions in a quantity or equation. value of A[[Beta].sub.42] less than 1125 pg/mL,[14] sensitivity and specificity for AD were 90% and 83% (n = 37), respectively (Figure 2). Finally, CSF A[[Beta].sub.42], tau, and [F.sub.2]-IsoP levels were combined into a 2-step algorithm for diagnosing AD. If CSF [F.sub.2]-IsoP levels were less than 25 pg/mL, then the individual was classified as non-AD. If CSF [F.sub.2]-IsoP levels were greater than 25 pg/mL, then CSF A[[Beta].sub.42] and tau levels were considered according to the method of Galasko et al.[14] Sensitivity and specificity values for AD versus non-AD with this algorithm were 84% and 89% (n = 37), respectively. For comparison, application of the CSF A[[Beta].sub.42] and tau classification system of Galasko et al[14] yielded 95% sensitivity and 50% specificity for AD in these 37 individuals. [Figure 2 ILLUSTRATION OMITTED] COMMENT This study tested the hypothesis that quantification of CSF [F.sub.2]-IsoPs, when added to the classification system based on CSF A[[Beta].sub.42] and tau levels, improved the laboratory diagnostic accuracy for AD. In our group of 37 probable AD patients, patients with other dementias, and controls, the classification system of Galasko et al,[14] based on CSF A[[Beta].sub.42] and tau levels alone, had high sensitivity but unacceptably low specificity for AD. Combined analysis of CSF A[[Beta].sub.42] and [F.sub.2]-IsoP levels, or [F.sub.2]-IsoP levels followed by the classification system of Galasko et al,[14] largely preserved sensitivity and improved specificity relative to classification with A[[Beta].sub.42] and tau alone. An advantage of our analysis is that we included patients with other forms of dementia, and not just AD patients and controls, in the sensitivity and specificity calculations. However, our study is limited by a relatively small number of individuals in each group. Thus, the sensitivity and specificity values determined should be used to compare the different classification systems, and not as optimized values for classification. Future larger studies are needed to precisely define the sensitivity and specificity of simultaneous measurements of CSF A[[Beta].sub.42], tau, and [F.sub.2]-IsoPs in dementing illnesses. Biomarkers that screen for increased susceptibility to AD, that assist in the differential diagnosis differential diagnosis n. Determination of which one of two or more diseases with similar symptoms is the one from which the patient is suffering. Also called differentiation. of dementia, or that may be used to assess response to therapy are important goals. Our study suggests that quantification of [F.sub.2]-IsoPs in CSF may be a useful addition to existing biomarkers for probable AD patients. It is likely that the approach of using multiple biomarkers that reflect different aspects of AD pathogenesis, altered A[Beta] metabolism, disruption of the neuronal cytoskeleton cytoskeleton System of microscopic filaments or fibres, present in the cytoplasm of eukaryotic cells (see eukaryote), that organizes other cell components, maintains cell shape, and is responsible for cell locomotion and for movement of the organelles within it. , and increased free radical damage, among others, will provide the most accurate laboratory discrimination among controls and patients with different forms of dementia. This work was supported by National Institutes of Health (Bethesda, Md) grants AG00774, AG16835, DK48831, GM15431, DK26657, and CA77839, as well as grants from the Alzheimer's Association, Chicago, Ill (Dr T. J. Montine), a Burroughs-Wellcome Clinical Scientist Award in Translational Research, Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , NC (Dr Morrow), and a Department of Veterans Affairs Career Development Award, Portland, Ore (Dr Quinn). References [1.] Imaging and Biological Markers for the Diagnosis and Progression of Alzheimer's Disease Alzheimer's disease (ăls`hī'mərz, ôls–), degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia. . Bethesda, Md: National Institutes of Health, National Institute on Aging The National Institute on Aging is a division of the U.S. National Institutes of Health, located in Bethesda, Maryland. Formed in 1974, NIA's mission is to improve the health and well-being of older Americans through research. It is the primary U.S. ; 1999. [2.] Galasko D. Cerebrospinal fluid opens a window on Alzheimer's disease. Arch Neurol. 1999;56:655-656. [3.] Morrow JD, Roberts LJ. The isoprostanes: unique bioactive bi·o·ac·tive adj. Of or relating to a substance that has an effect on living tissue. bioactive having an effect on or eliciting a response from living tissue. products of lipid peroxidation. Prog Lipid Res. 1997;36:1-21. [4.] Pratico D, Lee VM, Trojanowski JQ, et al. Increased [F.sub.2]-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo. FASEB FASEB Federation of American Societies for Experimental Biology J. 1998;12:1777-1784. [5.] Montine TJ, Beal ME Cudkowicz ME, et al. Increased cerebrospinal fluid [F.sub.2]-isoprostane concentration in probable Alzheimer's disease. Neurology. 1999; 52:562-565. [6.] Montine TJ, Markesbery WR, Zackert W, Sanchez SC, Roberts LJ 2nd, Morrow ID. The magnitude of brain lipid peroxidation correlates with the extent of degeneration but not with density of neuritic plaques or neurofibrillary tangles Neurofibrillary tangles Abnormal structures, composed of twisted masses of protein fibers within nerve cells, found in the brains of people with Alzheimer's disease. Mentioned in: Dementia , or with APOE genotype in Alzheimer's disease patients. Am J Pathol. 1999;155:863-868. [7.] Montine TJ, Shinobu L, Montine KS, et al. No difference in plasma or urine [F.sub.2]-isoprostanes among patients with Huntington's disease Huntington's disease, hereditary, acute disturbance of the central nervous system usually beginning in middle age and characterized by involuntary muscular movements and progressive intellectual deterioration; formerly called Huntington's chorea. or Alzheimer's disease and controls. Ann Neurol. 2000;48:950-. [8.] McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979 Health and Human Services, HHS Task Force on Alzheimer's disease. Neurology. 1984;34:939-944. [9.] McKeith IG, Perry EK, Perry RH. Report of the second Dementia With Lewy Body International Workshop: diagnosis and treatment: Consortium on Dementia With Lewy Bodies. Neurology. 1999;53:902-905. [10.] Hughes CP, Berg L, Danziger WE, et al. A new scale for the staging of dementia. Br J Psychiatry. 1982;140:566-572. [11.] Rosen WG, Mobs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-1364. [12.] Hachinski VC, Iliff ED, Zilhka E, et al. Cerebral blood flow Cerebral blood flow, or CBF, is the blood supply to the brain in a given time.[1] In an adult, CBF is 750 mls/min or 15% of the cardiac output. On a weight basis, this is 50 to 54 milllitres/100grams/minute. in dementia. Arch Neurol. 1975;32:632-637. [13.] Arai H, Terjima M, Miura M, et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's disease. Ann Neurol. 1995;38:649-652. [14.] Galasko D, Chang L, Mutter R, et al. High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer's disease and relation to apolipoprotein E apolipoprotein E A 34-kD cholesterol-binding glycoprotein, which comprises 15% of VLDL; apoE maps to chromosome 19, is secreted by macrophages that mediate the uptake of lipoproteins–VLDL, HDL, LDL and cholesterol esters into cells via distinct binding genotype. Arch Neurol. 1998;55:937-945. [15.] Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction in beta-amyloid [peptide.sub.42] in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 1995;38:643-648. Accepted for publication November 30, 2000. From the Departments of Pathology (Drs T. J. Montine and K. S. Montine), Pharmacology (Drs T. J. Montine and Morrow), Medicine (Dr Morrow), and Psychiatry (Ms McFarland) and the Center for Molecular Neurosciences (Dr T. J. Montine), Vanderbilt University Medical Center, Nashville, Tenn; and the Departments of Neurology and Radiology (Drs Kaye and Quinn), Oregon Health Sciences University, Portland, Ore. Reprints: Thomas J. Montine, MD, PhD, Department of Pathology, Vanderbilt University Medical Center, C3321-A Medical Center North, Nashville, TN 37232 (e-mail: tom.montine@mcmail.vanderbilt.edu). |
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