0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Age and Apolipoprotein E*4 Allele Effects on Cerebrospinal Fluid β-Amyloid 42 in Adults With Normal Cognition FREE

Elaine R. Peskind, MD; Ge Li, PhD, MD; Jane Shofer, MS; Joseph F. Quinn, MD; Jeffrey A. Kaye, MD; Chris M. Clark, MD; Martin R. Farlow, MD; Charles DeCarli, MD; Murray A. Raskind, MD; Gerard D. Schellenberg, PhD; Virginia M.-Y. Lee, PhD; Douglas R. Galasko, MD
[+] Author Affiliations

Author Affiliations: VA Puget Sound Health Care System, Mental Illness Research, Education, and Clinical Center (Drs Peskind, Li, and Raskind and Ms Shofer), Geriatric Research, Education, and Clinical Center (Dr Schellenberg), and Departments of Psychiatry and Behavioral Sciences (Drs Peskind, Li, and Raskind) and Medicine (Dr Schellenberg), University of Washington School of Medicine, Seattle; Department of Neurology, Oregon Health and Science University (Drs Quinn and Kaye) and Portland VA Medical Center (Dr Quinn), Portland; Department of Neurology, Institute on Aging, University of Pennsylvania, Philadelphia (Drs Clark and Lee); Department of Neurology, Indiana University School of Medicine, Indianapolis (Dr Farlow); Department of Neurology, University of California at Davis, Sacramento (Dr DeCarli); Department of Neurosciences, University of California at San Diego and VA Medical Center, San Diego (Dr Galasko).


Arch Neurol. 2006;63(7):936-939. doi:10.1001/archneur.63.7.936.
Text Size: A A A
Published online

Background  Decreased cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) concentration, but not Aβ40 concentration, is a biomarker for Alzheimer disease. This Aβ42 concentration decrease in CSF likely reflects precipitation of Aβ42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease.

Objective  To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF Aβ42 concentration in adults with normal cognition across the life span.

Design  The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF Aβ42 and Aβ40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method.

Subjects  One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years.

Results  The CSF Aβ42, but not the Aβ40, concentration decreased significantly with age. There was a sharp decrease in CSF Aβ42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF Aβ42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele.

Conclusion  These CSF Aβ42 findings are consistent with acceleration by the APOE*4 allele of pathogenic Aβ42 brain deposition starting in later middle age in persons with normal cognition.

Figures in this Article

Lower concentration of a long form of the β-amyloid protein ending at amino acid 42 (Aβ42) in cerebrospinal fluid (CSF) is a consistent biomarker of Alzheimer disease (AD).1,2 In contrast, CSF Aβ40 concentration is unaffected by AD. Aging and presence of theapolipoprotein E*4 (APOE*4) allele are the 2 strongest risk factors for AD. The presence of the APOE*4 allele interacts with aging to lower by 10 to 15 years the age of clinical dementia onset.3 Neuropathological studies have demonstrated that years before the onset of clinical dementia, plaques of insoluble aggregated Aβ protein, the neuropathological hallmark of AD, begin to accumulate in brain tissue.4 The Aβ peptide is generated by proteolytic processing of the amyloid precursor protein into a series of fragments 38 to 42 amino acids long; Aβ42 represents about 10% of synthesized Aβ but is by far the earliest and predominant Aβ species deposited in plaques in AD.5 Decreased concentration of Aβ42 in CSF is a consistent biomarker of AD1,2 and likely reflects deposition of Aβ42 in plaques.6 This Aβ deposition is considered central to the pathogenesis of AD. In transgenic mice that overexpress mutant amyloid precursor protein, Aβ42 deposition in the brain increases with age and parallels a decrease in CSF Aβ42 concentration.7 Animal and human neuropathology studies suggest that the presence of the APOE*4 allele hastens AD onset by modulating the deposition and clearance of Aβ to favor the formation of plaques.8

Herein, we estimated in adults with normal cognition the effects of age and APOE genotype on biomarkers related to the deposition in brain of Aβ. Specifically, we determined CSF Aβ42 concentration and APOE genotype in 184 healthy adults without dementia across a broad age range. We also measured CSF Aβ40 concentration to determine whether effects on CSF Aβ42 levels are selective. We hypothesized that CSF Aβ42 concentration would begin to decline years before the age at which clinical AD commonly presents; that this decline would be substantially accentuated by the presence of the APOE*4 allele; and that neither age nor presence of the APOE*4 allele would affect CSF Aβ40 concentrations.

All procedures were approved by the institutional review boards of the participating institutions; all subjects provided written informed consent. Ninety-four men and 90 women (age range, 21-88 years [mean ± SD age, 50 ± 20 years]) underwent detailed clinical and laboratory evaluation and had no clinically significant abnormalities. Subjects had Mini-Mental State Examination9 scores between 26 and 30 (mean ± SD, 28.8 ± 1.5), Clinical Dementia Rating Scale10 scores of 0, and no evidence or history of cognitive or functional decline. For subjects older than 50 years, scores on delayed recall were higher than a cutoff of 1.5 SD lower than age-adjusted means (for both the Logical Memory11 and New York University paragraph tests12). We collected CSF in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. Samples with more than 500 red blood cells per milliliter were excluded. Samples were frozen immediately on dry ice and stored at −80°C until assay. The Aβ42 and Aβ40 concentrations were measured in the 10th milliliter of CSF collected using sensitive, well-validated sandwich enzyme-linked immunosorbent assays.13 The APOE genotypes were performed by a restriction digest method.14,15

We examined the relationship between Aβ42 (or Aβ40) concentration and age and APOE genotype using a linear regression model of Aβ42 (or Aβ40) concentration on age and APOE*4 status. Age was modeled as an orthogonal quadratic polynomial to separate out linear from quadratic trends in the Aβ peptide–age relationship. Interaction with APOE*4 status was also modeled to determine if trends differed by presence or absence of the APOE*4 allele. To assess selectivity of changes in Aβ42 concentration, we also examined if the ratio of Aβ42-Aβ40 concentration was influenced by age and the APOE*4 allele. The ratio was modeled directly as a dependent variable on age and APOE*4 status and, indirectly, using a regression of Aβ42 concentration on age and APOE*4 status with Aβ40 concentration as an additional covariate. Because Aβ40 and Aβ42 are both produced by cleavage from amyloid precursor protein by β and γ secretase, there should be a fixed ratio of secretion of these forms of Aβ into CSF. We hypothesized that different disposition of these molecules would be demonstrated as changes in the ratio of Aβ42-Aβ40 concentration.

Lower levels of Aβ42 were associated with older age and with presence of the APOE *4 allele. There was a significant difference in the relationship between age and Aβ42 concentration by APOE*4 allele status (interaction between age and APOE*4 status, P = .01). The relationship for APOE*4-positive subjects was strongly linear with Aβ42 concentration decreasing as age increased. This linear relationship was absent for APOE*4-negative subjects. The quadratic component of the age term indicated that there was a change in the trend in the relationship between age and Aβ42 concentration for both groups but the shape of the curves differed markedly (Figure, A). For APOE*4-negative subjects, mean Aβ42 concentration rose slightly until approximately age 50 years, then fell slightly with increasing age. In contrast, for APOE*4-positive subjects, Aβ42 concentration declined slightly in younger subjects, then declined rapidly beginning between ages 50 and 60 years. Graphical assessment confirms that changes in trend occurred between ages 50 to 60 years for both APOE*4-positive and APOE*4-negative subjects, but the slope of subsequent CSF Aβ42 concentration decline was markedly greater in the APOE*4-positive subjects.

Place holder to copy figure label and caption
Figure.

Cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) (A) and Aβ40 (B) concentrations by age and apolipoprotein E (APOE*4) allele status in 184 normal adults aged 21 to 88 years. Closed triangles represent APOE*4-positive subjects; A = Loess-fitted line for APOE*4-positive subjects. Open circles represent APOE*4-negative subjects; B = Loess-fitted line for APOE*4-negative subjects.

Graphic Jump Location

There was also a significant interaction between age and APOE*4 in the regression model of Aβ40 concentration (P = .02). In contrast to Aβ42 concentration, Aβ40 concentration did not change with age in APOE*4-positive subjects (P = .68) and increased linearly with age in APOE*4-negative subjects (P<.001), with neither relationship having a significant quadratic component (Figure, B). Regression of the ratio of Aβ42-Aβ40 concentration showed a significant trend with age (P<.001); the ratio values were stable until about age 50 years, then the ratio decreased sharply as age increased (data not shown). This decrease was stronger for APOE*4-positive subjects, but this difference was not quite statistically significant (interaction between age and APOE*4 status, P = .13). These results were confirmed by a regression of Aβ42 concentration on age and APOE*4 status, adjusting for Aβ40 concentration.

We also examined whether CSF Aβ42 levels were related to scores on delayed recall tests and on the Mini-Mental State Examination, using partial correlation controlling for age. None of these test scores showed a significant association at P<.05.

A previous study that measured CSF Aβ42 concentration found a nonlinear relationship with age,16 while another showed no relationship with age.17 However, in these previous studies, APOE genotypes were not determined and characterization to assure that subjects were cognitively normal was minimal. Studies in which APOE genotyping was performed have demonstrated decreased CSF Aβ42 concentration in APOE*4-positive vs APOE*4-negative subjects. No age × APOE*4 interactions were seen, but the age ranges of subjects in these studies were limited (mean ± SD age, 59 ± 8 years18 and 58 ± 7 years19) and young subjects were not included. To our knowledge, the present study is the only study that examined effects of the APOE*4 allele across a broad age range. It is also the only study, to our knowledge, that measured both Aβ40 as well as Aβ42 concentrations to assess the specificity of these effects on the more pathogenic 42 amino acid–length Aβ species. Our results suggest that the APOE*4 allele is associated with selective alteration of the fate of Aβ42, but not Aβ40, that results in decreasing concentration of Aβ42 in CSF during the normal adult life span. In persons with the APOE*4 allele, decline in CSF Aβ42 concentration possibly begins in young adulthood, followed by marked acceleration of this decline beginning in midlife—decades before clinical manifestations of AD. β-amyloid 40, although also found in amyloid plaques, did not show the same association of decreased CSF concentration with age and presence of the APOE*4 allele. Because Aβ42 and Aβ40 are produced by the same secretases, the concentrations of these forms of Aβ are initially in equilibrium. Our results are therefore consistent with differential aggregation and deposition in the brain, clearance, or binding to carrier molecules that selectively affects Aβ42. These results do suggest that sequestration of Aβ42 in the brain occurs early in APOE*4 allele carriers, bolstering evidence for this as a key initiating factor in AD pathogenesis. Measuring Aβ concentration in CSF provides an indirect estimation of the net effect of production, clearance, aggregation, and deposition; therefore, we cannot determine which of these factors is most important. Our results are consistent with the findings of a recent study of asymptomatic adult carriers of presenilin mutations who had low levels of CSF Aβ42, lending further support to a decrease in CSF Aβ42 concentration as a preclinical biomarker for AD.20

These findings have implications for the preclinical diagnosis of AD, as well as for treatment. Follow-up of cohorts such as ours will be important to affirm our cross-sectional findings and to assess whether subjects who fall in the lowest part of the age- and APOE-adjusted range for CSF Aβ42 concentration have the highest risk of developing AD. It will also be important to correlate CSF Aβ42 concentration with methods of assessing brain amyloid deposition in vivo, such as positron emission tomographic scanning with the Pittsburgh Compound-B.21 Therapeutic strategies aimed at prevention of AD may need to be applied in early midlife or even younger ages to have maximal effect on amyloid deposition. Primary prevention trials for AD targeting elderly persons may be too late to affect the early stages of disease pathology.

Correspondence: Elaine R. Peskind, MD, VA Puget Sound Health Care System, S-116MIRECC, 1660 S Columbian Way, Seattle, WA 98108 (peskind@u.washington.edu).

Accepted for Publication: December 23, 2005.

Author Contributions:Study concept and design: Peskind, Farlow, Raskind, and Galasko. Acquisition of data: Peskind, Quinn, Kaye, Clark, Farlow, DeCarli, Raskind, Schellenberg, Lee, and Galasko. Analysis and interpretation of data: Peskind, Li, Shofer, Kaye, Farlow, Raskind, Lee, and Galasko. Drafting of the manuscript: Peskind, Li, Shofer, Farlow, Raskind, Lee, and Galasko. Critical revision of the manuscript for important intellectual content: Peskind, Li, Shofer, Quinn, Kaye, Clark, Farlow, DeCarli, Raskind, Schellenberg, and Galasko. Statistical analysis: Li and Shofer. Obtained funding: Peskind, Raskind, and Galasko. Administrative, technical, and material support: Peskind, Kaye, Farlow, Raskind, Schellenberg, Lee, and Galasko. Study supervision: Peskind, Kaye, Farlow, and Lee.

Funding/Support: This study was supported by grants AG05136, AG08419, AG08017, AG10124, AG10133, AG23185, and M01 RR00034 from the US National Institute on Aging; the National Alzheimer's Coordinating Center; Friends of Alzheimer's Research; Alzheimer's Association of Western and Central Washington; and the Department of Veterans Affairs.

Role of the Sponsor: None of the funding sources had a role in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication.

Galasko  DChang  LMotter  R  et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55937- 945
PubMed Link to Article
Andreasen  NMinthon  LDavidsson  P  et al.  Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58373- 379
PubMed Link to Article
Khachaturian  ASCorcoran  CDMayer  LSZandi  PPBreitner  JCCache County Study Investigators, Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: the Cache County Study. Arch Gen Psychiatry 2004;61518- 524
PubMed Link to Article
Braak  HBraak  E Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18351- 357
PubMed Link to Article
Gravina  SAHo  LEckman  CB  et al.  Amyloid beta protein (A beta) in Alzheimer's disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995;2707013- 7016
PubMed Link to Article
Strozyk  DBlennow  KWhite  LRLauner  LJ CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 2003;60652- 656
PubMed Link to Article
Kawarabayashi  TYounkin  LHSaido  TCShoji  MAshe  KHYounkin  SG Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci 2001;21372- 381
PubMed
Huang  YWeisgraber  KHMucke  LMahley  RW Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. J Mol Neurosci 2004;23189- 204
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Morris  JC Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1)173- 176, discussion 177-178
PubMed Link to Article
Wechsler  DStone  CP Manual: Wechsler Memory Scale.  New York, NY: Psychological Corp; 1983
Flicker  CFerris  SHReisberg  B Mild cognitive impairment in the elderly: predictors of dementia. Neurology 1991;411006- 1009
PubMed Link to Article
Suzuki  NCheung  TTCai  XD  et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994;2641336- 1340
PubMed Link to Article
Emi  MWu  LLRobertson  MA  et al.  Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics 1988;3373- 379
PubMed Link to Article
Hixson  JEVernier  DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31545- 548
PubMed
Shoji  MKanai  MMatsubara  E  et al.  The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently. Neurobiol Aging 2001;22209- 215
PubMed Link to Article
Sjogren  MVanderstichele  HAgren  H  et al.  Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values. Clin Chem 2001;471776- 1781
PubMed
Sunderland  TMirza  NPutnam  KT  et al.  Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biol Psychiatry 2004;56670- 676
PubMed Link to Article
Prince  JAZetterberg  HAndreasen  NMarcusson  JBlennow  K APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology 2004;622116- 2118
PubMed Link to Article
Moonis  MSwearer  JMDayaw  MP  et al.  Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology 2005;65323- 325
PubMed Link to Article
Klunk  WEEngler  HNordberg  A  et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55306- 319
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) (A) and Aβ40 (B) concentrations by age and apolipoprotein E (APOE*4) allele status in 184 normal adults aged 21 to 88 years. Closed triangles represent APOE*4-positive subjects; A = Loess-fitted line for APOE*4-positive subjects. Open circles represent APOE*4-negative subjects; B = Loess-fitted line for APOE*4-negative subjects.

Graphic Jump Location

Tables

References

Galasko  DChang  LMotter  R  et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998;55937- 945
PubMed Link to Article
Andreasen  NMinthon  LDavidsson  P  et al.  Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58373- 379
PubMed Link to Article
Khachaturian  ASCorcoran  CDMayer  LSZandi  PPBreitner  JCCache County Study Investigators, Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: the Cache County Study. Arch Gen Psychiatry 2004;61518- 524
PubMed Link to Article
Braak  HBraak  E Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18351- 357
PubMed Link to Article
Gravina  SAHo  LEckman  CB  et al.  Amyloid beta protein (A beta) in Alzheimer's disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995;2707013- 7016
PubMed Link to Article
Strozyk  DBlennow  KWhite  LRLauner  LJ CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 2003;60652- 656
PubMed Link to Article
Kawarabayashi  TYounkin  LHSaido  TCShoji  MAshe  KHYounkin  SG Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci 2001;21372- 381
PubMed
Huang  YWeisgraber  KHMucke  LMahley  RW Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. J Mol Neurosci 2004;23189- 204
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Morris  JC Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(suppl 1)173- 176, discussion 177-178
PubMed Link to Article
Wechsler  DStone  CP Manual: Wechsler Memory Scale.  New York, NY: Psychological Corp; 1983
Flicker  CFerris  SHReisberg  B Mild cognitive impairment in the elderly: predictors of dementia. Neurology 1991;411006- 1009
PubMed Link to Article
Suzuki  NCheung  TTCai  XD  et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994;2641336- 1340
PubMed Link to Article
Emi  MWu  LLRobertson  MA  et al.  Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics 1988;3373- 379
PubMed Link to Article
Hixson  JEVernier  DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31545- 548
PubMed
Shoji  MKanai  MMatsubara  E  et al.  The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently. Neurobiol Aging 2001;22209- 215
PubMed Link to Article
Sjogren  MVanderstichele  HAgren  H  et al.  Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values. Clin Chem 2001;471776- 1781
PubMed
Sunderland  TMirza  NPutnam  KT  et al.  Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biol Psychiatry 2004;56670- 676
PubMed Link to Article
Prince  JAZetterberg  HAndreasen  NMarcusson  JBlennow  K APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology 2004;622116- 2118
PubMed Link to Article
Moonis  MSwearer  JMDayaw  MP  et al.  Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology 2005;65323- 325
PubMed Link to Article
Klunk  WEEngler  HNordberg  A  et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55306- 319
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 75

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com


Allele