17 May 2009. Star Trek fans remember that species 8472 hails from the realm of “fluidic space.” Alzforum fans know that cerebrospinal fluid (CSF) is home to Aβ42, tau, and a host of other species that could turn out to be biomarkers for Alzheimer disease (AD) or other memory disorders. One of those species is brain-derived neurotrophic factor (BDNF), which is reduced in the CSF of AD patients. In the May 1 PLoS ONE, researchers led by Thomas Montine at the University of Washington, Seattle, add another dimension to BDNF biology. They report that CSF BDNF levels drop as people age and are lowest in those with poorest recall. The authors suggest that reduced secretion of the neurotrophin may be one reason for age-related cognitive decline, though not specifically AD.
BDNF is widely produced in the brain, and it provides trophic support for a variety of neurons and neural networks. A single amino acid change in the protein—valine to methionine—has been associated with poorer cognitive performance in healthy volunteers. In the AD brain, the trophin is down in the hippocampus (see Murray et al., 1994 and ARF related news story) and the parietal cortex (see Michalski et al., 2003), regions susceptible to disease pathology. Brain BDNF levels are also decreased in preclinical stages of AD (see Peng et al., 2005) and the factor is being explored as a potential therapeutic for Alzheimer’s (see ARF related news story).
Montine and colleagues compared CSF levels of BDNF among 128 cognitively normal people, 21 with AD, and nine with mild cognitive impairment. First author Ge Li and colleagues found that CSF BDNF was lower in AD patients compared to older normal adults, confirming previous reports from this and other groups (see Blasko et al., 2006): Plasma levels of BDNF are also reportedly lower in AD (see Laske et al., 2006). But Li and colleagues also found that CSF BDNF correlated with age in apparently normal volunteers. Though the variation in levels was considerable, statistically they were lower in older subjects. Women fared better, having slightly higher levels than men. Neither the presence of an ApoE4 allele, a risk factor for AD, or the valine/methionine BDNF status correlated with CSF levels.
Li found that higher CSF BDNF levels (after adjusting for age, years of education, gender, ApoE, CSF Aβ42 and tau, and methionine-BDNF status) correlated with better scores in tests of memory and cognition (immediate and delayed recall and the Trails Making Test Part B). In 50 of the normal volunteers who had at least one follow-up visit within an average of 3.3 years, lower baseline BDNF in the CSF also associated with greater annual decline in immediate and delayed recall scores, even after adjusting for Aβ42 and tau, suggesting that the change is independent of preclinical AD. “Our data suggest that reduced secretion of BDNF in the central nervous system is one mechanism that may contribute to age-related cognitive decline,” write the authors. The authors did not appear to adjust for level of exercise in the volunteers, though exercise is known to boost BDNF in animal models (see ARF related news story).
Margaret Fahnestock, McMaster University, Hamilton, Ontario, Canada, agrees that is a possibility. “Our data shows that BDNF decreases early in preclinical stages. So we think it is causative in AD and not a stretch to think age-related cognitive decline is also BDNF related,” she told ARF. Fahnestock’s lab has reported age-related declines in proBDNF in the brain, though she found that males tended to have more BDNF than females.
“We acknowledge that this study has a relatively small sample size and short duration of follow-up, and further studies are needed to validate our results,” write Li and colleagues.—Tom Fagan.
Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu C-E, Bekris LM, Raskind MA, Galasko DR, Montine TJ. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS ONE 2009 May 1; 4: e5424. Abstract