Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.
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.
Raskind
M A
MA
Department of Veterans Affairs Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC), Seattle, Washington, USA.
Peskind
E R
ER
Holmes
C
C
Goldstein
D S
DS
D000316:Adrenergic alpha-Agonists / Q000097:blood / Q000138:chemical synthesis; D000317:Adrenergic alpha-Antagonists / Q000097:blood / Q000134:cerebrospinal fluid; D000368:Aged; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid*; D000963:Antimetabolites / Q000097:blood / Q000134:cerebrospinal fluid; D002396:Catechols / Q000097:blood / Q000134:cerebrospinal fluid*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003000:Clonidine / Q000097:blood / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000175:diagnosis; D004295:Dihydroxyphenylalanine / Q000097:blood / Q000134:cerebrospinal fluid; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000134:cerebrospinal fluid; D009474:Neurons / Q000378:metabolism; D009483:Neuropsychological Tests; D009638:Norepinephrine / Q000096:biosynthesis / Q000097:blood / Q000134:cerebrospinal fluid*; D015016:Yohimbine / Q000097:blood / Q000134:cerebrospinal fluid
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000963:Antimetabolites; D002396:Catechols; D015016:Yohimbine; D008734:Methoxyhydroxyphenylglycol; D004295:Dihydroxyphenylalanine; D003000:Clonidine; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine