The Brain in Super Agers

My Twitter post on a recently published study of brain structure in a group of high performing older adults received quite a bit of attention (see below).

Felicia Sun and colleagues at Massachusetts General Hospital and Harvard Medical School selected an interesting research design.

A group of elderly subjects between the ages of 60 and 80 years were identified as showing "superaging". This was defined as scoring like young adults on two neuropsychological tests: The Long Delay Free Recall measure of the California Verbal Learning Test and part B of the Trail Making Test.

They then imaged the brain structure and function of the super agers using MRI. The results were compared to two groups: elderly adults without superior cognitive performance and younger adults with age-typical neuropsychological performance.

A key finding from their study was that super agers had brain hippocampal volumes greater than typical older adults and this measure was comparable to young adults.

Super agers also had greater brain volumes than typical older adults in the following regions:

• Anterior temporal cortex
• Medial frontal cortex
• Anterior midcingulate cortex

The authors noted in the discussion section:

"We found support for our hypothesis regarding the structural integrity of the default mode and salience networks, with superagers showing much less atrophy than typical older adults in key nodes of these networks, which we refer to as the "superageing signature".

The authors also note their longitudinal study was not able to identify the factors that may play a key role in super agers. Candidate factors include genetic factors, exercise, diet and social activity levels. These factors are likely to be studied in future research.

Readers with more interest in this study can access the free full-text manuscript by clicking the citation link below.

Figure of hippocampus is an iPad screen shot from the app 3D Brain.

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"Study suggests how 'super aging' older adults retain youthful memory abilities" #neuroscience #feedly https://t.co/DdlXUGbRRp

— W.R.Yates, M.D.✍ (@WRY999) September 14, 2016

Sun FW, Stepanovic MR, Andreano J, Barrett LF, Touroutoglou A, & Dickerson BC (2016). Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging. The Journal of neuroscience : the official journal of the Society for Neuroscience, 36 (37), 9659-9668 PMID: 27629716

Exercise in the Elderly: BDNF and Executive Function

Exercise promotes cognitive function in children, adults and elderly individuals.

The mechanism for this effect is unclear. Some of the effect may be due to a general improvement in vascular function and health.

Another potential mechanism is via increased neuroplasticity mediated by neurotrophic factors.

Brain-derived neurotrophic factor (BNDF) is a known contributor to brain neuroplasticity. Levels of BNDF can be determined with serum assays.

RL Leckie and colleagues recently found support for BNDF mediation in an exercise in an interventional study with an elderly population.

The key elements of the design for their study included the following elements.

• Participants: Adults between the ages of 55 and 80
• Exercise intervention: Daily supervised walking sessions beginning with 10 minutes increasing to 40 minutes. Control intervention included stretching and toning sessions lead by an exercise professional
• Cognitive assessment: Task-switching paradigm commonly used to assess executive function
• Blood assay: Serum brain-derived neurotropic factor (BNDF) levels and BDNF genotype
• Statistical analysis: Multivariate linear regression analysis with key dependent variable being cognitive performance after one year of intervention

The main findings from the study included:

• Serum BDNF increased in the exercise group
• This effect was limited to primarily the participants over 70 years of age
• Enhanced executive function following exercise was demonstrated in those over 70
• BDNF level increases in the over 70 age group correlated with cognitive performance

The authors note their does not mean exercise is not important for cognitive function in the younger age group (55-70 years of age). Their study only highlights the age interaction with BDNF in moderating a single executive function task.

BDNF levels decrease with age and the level of decrease in BDNF correlates with reduction in volume of the brain hippocampus. The hippocampus plays a key role in memory function and in decline in memory associated with aging.

It is quite possible that regular exercise after age 70 reduces the age related effect on cognition moderated by BDNF.

Readers with more interest in this study can access the free full text manuscript by clicking on the PMID link in the citation below.

Photo of ring kingfisher is from the author's files.

Follow the author on Twitter WRY999

Leckie RL, Oberlin LE, Voss MW, Prakash RS, Szabo-Reed A, Chaddock-Heyman L, Phillips SM, Gothe NP, Mailey E, Vieira-Potter VJ, Martin SA, Pence BD, Lin M, Parasuraman R, Greenwood PM, Fryxell KJ, Woods JA, McAuley E, Kramer AF, & Erickson KI (2014). BDNF mediates improvements in executive function following a 1-year exercise intervention. Frontiers in human neuroscience, 8 PMID: 25566019

Naps Boost Cognitive Performance in Seniors

Insomnia is a common complaint among elderly individuals. With aging, there is a pattern of decreased number of total sleep time and reduced time in deep sleep. Deep sleep is considered restorative sleep, an important component of feeling rested and alert the following day.


Sleep hygiene recommendations commonly warn against napping during the day time as it is felt to reduce the quantity and quality of sleep at night. However, many individuals report that napping during the day is helpful for them in getting sufficient sleep on a regular basis. Now there is some limited data that supports a role for regular napping for increasing total sleep time as well as some parameters of cognitive function.


Campbell and colleagues studied the effects of a month-long napping regimen in a series of individuals between the ages of 50 and 88 years of age. Key elements of the research design included:

• Inclusion criteria: age over 50 with self-reported good physical health, subjective insomnia complaints allowed but subjects had to score less than 5 on the Pittsburgh Sleep Quality Index and 2 or less on the sleep latency item from this scale, no regular sleeping medications, not taking psychotropic meds or other medications known to affect sleep, minor but not major medical problems, no periodic limb movements on baseline polysomnography
• Study variables/procedures: Sleep diaries and actigraphy at home 1 to 2 weeks before baseline laboratory examination, 3 consecutive nights and 2 days spent in sleep lab with polysomnography and neuropsychological testing including a test of logical reasoning, mathematical processing, letter memory search and reaction time test.
• Intervention: Randomization to either directed 45 minute nap or 2 hour nap, at least 5 times per week but recommended daily, to be completed in single setting before 6 pm to include daily sleep logs
• Outcome measures: Subjects returned for sleep lab evaluation for 2 nights at 2 and 4 weeks after randomization

The key elements of the outcome of the study:

• Napping did not change any of the night time sleep parameter: sleep onset latency, sleep efficiency or total nocturnal sleep time
• In 24 hour assessment of sleep both groups increased their total sleep time although as expected the long nap group had a longer total sleep time than the short nap group
• Neuropsychological performance improved in both groups at 2 and 4 weeks on three of the four neuropsychological measures (all but reaction time). The improvement was not statistically significant but the longer nap group tended to show greater improvement
• Adherence to recommended nap assignment: (9/11) in the short nap group met defined adherence while 5/10 in the long nap group met adherence—this difference was not significant

Although a small sample study, this research finding seems allay some concerns about a regular nap regimen for those over age 55 years of age. There does not appear to be evidence that napping impairs nocturnal sleep in duration or quality. The added sleep during the day with a nap in this study was accompanied by improvement in some elements of cognitive function. This improvement appeared to continue through 4 weeks and may not have reached its peak by that time. The authors note that none of the subjects were regular nappers before entering the study. 


So the take home message from the study is that for those 50 or older if you are taking a daily nap and feel it helps you, keep doing it. If you are not taking a daily nap and would like to consider adding one, it does not appear to be a risk for disrupting nocturnal sleep and you may get some cognitive boost from a daily napping regimen.


Photo of napping kittens courtesy of Wikepedia Commons author Tilman Piesk.


Campbell, S., Stanchina, M., Schlang, J., & Murphy, P. (2011). Effects of a Month-Long Napping Regimen in Older Individuals Journal of the American Geriatrics Society, 59 (2), 224-232 DOI: 10.1111/j.1532-5415.2010.03264.x

Is Erythropoetin (EPO) a Candidate Drug for Depression?

Erythropoetin (EPO) is a naturally produced hormone that controls erythropoiesis (red blood cell production).  It’s been commercially available in the U.S. since 1989 and is used commonly used to combat anemia associated with chemotherapy treatment in cancer.  In addition to its effect on red blood cells, EPO appears to play a key role in the brain response to neuronal injury and some role in the healing of wounds.

EPO is infamous because of its use by cyclists and other athletes for performance enhancement.  By increasing the number of red blood cells, EPO can increase oxygen carrying capacity and produce improved aerobic performance.  Since it is a natural product, EPO was initially very difficult to assay for doping recognition.

EPO is felt to have effects on neuroplasticity, the ability of the brain to repair and maintain neurons.  Some classes of antidepressants (lithium, MAO-B inhibitors) show increased neuroplasticity in animal models.  Working back from this, it is possible to propose that drugs with neuroplasticity may be good candidates for novel antidepressant drug development.

This is the line of thinking being followed by a group of Danish researchers.  They note that EPO may also be able to directly affect some of the cognitive impairment associated with major mood disorders.  Here is a summary of some of this research and current research:

Effects of EPO in emotional processing biases associated with major depression:  Functional magnetic resonance imaging has been very helpful in showing in showing how people with depression process emotions.  Depressed patients tend to over-react to pictures of sad faces and under-react to pictures of happy faces.  In effect, they over-respond to negative stimuli and under-respond to positive stimuli.  Antidepressants appear to influence emotional processing moving those with depression in a direction of non-depressed individuals.  The effect appears to occur in brain regions known to be involved in emotional control.

Miskowiak and colleagues at the University Hospital of Copenhagen, used fMRI to study the change in emotional processing in major depression.  Seventeen subjects with acute major depression received either 40,000 IU of EPO or placebo via IV drip.  Three days later, fMRI studies showed EPO produced a reduced response to negative faces.  These effects were demonstrated in the amygdala, hippocampus, ventromedial prefrontal cortex and parietal cortex.  Subjects also demonstrated improved memory on a memory task provided after administration of EPO.  These effects with EPO mimic effects seen by antidepressants in those with depression. 

Current clinical trial of EPO for depression and neurocognitive symptoms in depression:  The Danish team is now conducting a clinical trial of EPO with the design outlined in the last manuscript below.  The key elements of the design for this study include: 

• Cases Definition: Treatment-resistant depression or patients with bipolar disorder in full or partial remission with residual cognitive problems
• Drug: EPO 40,000 IU IV or placebo once weekly for 8 weeks
• fMRI: Screening and week 14
• Neuropsych Testing: Baseline, week 9 and week 14
• Psychopathological Ratings:  Weekly for 5 weeks, week 9  and 14
• Safety monitoring:  Hematology, blood chemistries, BDNF, inflammatory and metabolic markers  regularly throughout the study.

EPO can have adverse effects.  Increased red cell blood mass can produce an increased clotting risk potentially increasing risk for thromboembolism, stroke or myocardial infarction.  Despite the potential risk, I think EPO deserves study and with these initial promising results may provide hope for a novel treatment for depression.

Image of molecular model for the hormone EPO courtesy of Creative Commons at Wikipedia—author unknown. 

Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, & Harmer CJ (2009). Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study. Psychopharmacology, 207 (1), 133-42 PMID: 19705104


Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, & Harmer CJ (2010). Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients. Psychopharmacology, 210 (3), 419-28 PMID: 20401747


Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, & Kessing LV (2010). Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials, 11 PMID: 20942940