Original Articles| Volume 46, ISSUE 6, P756-765, September 15, 1999

Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer’s disease

  • Murray A Raskind
    Address reprint requests to Murray A. Raskind, MD, VA Puget Sound Health Care System, Mental Health Service (116), 1660 S. Columbian Way, Seattle, WA 98108
    Department of Veterans Affairs Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) and University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, Washington (MAR, ERP), USA
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  • Elaine R Peskind
    Department of Veterans Affairs Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) and University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, Washington (MAR, ERP), USA
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  • Courtney Holmes
    Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (CH, DSG); USA
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  • David S Goldstein
    Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (CH, DSG); USA
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      Background: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer’s disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms.
      Methods: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied.
      Results: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects.
      Conclusions: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.


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