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

Brain Imaging and Alzheimer's Disease Prediction

Enhanced early detection of risk for Alzheimer's dementia and other forms of dementia is key to prevention and early intervention.

Brain imaging holds promise as a pre-clinical disease risk assessment tool in Alzeimer's dementia.

Dementia risk has been linked to several brain imaging abnormalities found with magnetic resonance imaging. These abnormalities have included atrophy of the brain hippocampus, medial temporal lobe as well as white matter hyperintensities.

A recent study from France examined whether brain MRI findings can improve Alzheimer's and other dementia prediction over conventional known risk factors.

Here are the key elements of the design of this study:
Subjects: French citizens 65 years and old living at home participating in a longitudinal study of dementia with interviews two, four, six and ten years after baseline interview
Brain imaging: 1.5 Tesla MRI with estimation of white matter lesion volume, hippocampal volume (right and left summed) and total brain volume
Dementia diagnosis: all subjects screened at each interview, with targeted neuropsychological testing and neurologist consensus assessment
Standard dementia risk model variables: age, gender, education, smoking status, alcohol use, functional daily living skills, cognition screening tests, cardiovascular disease, diabetes status, systolic blood pressure and apolipoprotein epsilon 4 status.

The research team found a statistically significant smaller hippocampal and total brain volume at baseline in those later developing dementia. White matter lesion scores showed a trend (p.076) with later dementia.

However, adding the imaging data to the standard dementia risk model did not add statistically to the predictive power for all-cause dementia to the model.

The baseline imaging in this study took place around the year 1999 to 2000. Since then, more specific brain imaging tools targeted towards Alzheimer's have emerged including amyloid plaque markers. 

These enhanced imaging tools may have better power at adding power to our prediction models.

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

Photo of meerkats from the Cincinnati Zoo are from the author's files.

Follow the author on Twitter @WRY999

Stephan BC, Tzourio C, Auriacombe S, Amieva H, Dufouil C, Alpérovitch A, & Kurth T (2015). Usefulness of data from magnetic resonance imaging to improve prediction of dementia: population based cohort study. BMJ (Clinical research ed.), 350 PMID: 26099688

Brain Volume Differences in ADHD Normalize By Adulthood

Brain volume differences in ADHD have been documented in some childhood studies.

ADHD symptoms diminish with maturation in many but not all individuals. It is unclear whether this improvement in symptoms is also related to maturation of brain regions.

A recent study from the Netherlands provides some answers on this issue. A. Marten H. Onnink and colleagues performed a structural MRI study of 119 adults with ADHD compared to a group of controls.

This study is important because it examined effects of gender, comorbid depression and treatment history on key brain regions including the basal ganglia, amygdala and hippocampus.

The key findings from this study include the following:

• Women with adult ADHD showed no differences from controls on brain volume measures
• Men with adult ADHD showed reduced right caudate volumes and these volumes were negatively correlated with current hyperactivity symptom scores
• Comorbid major depression in adult ADHD was linked to smaller hippocampus volumes. ADHD without a history of depression was not linked to any differences in hippocampal volumes

A history of major depression in ADHD subjects was common (37% of men and 52% of women). Additionally, this sample high rates of current stimulant use (69% of the sample).

The authors note their study found essentially no link between adult ADHD and brain volumes. The only exception was the finding of reduced right caudate volumes in men with ADHD. 

The authors also note:

"Although male and female adults with ADHD have similar phenotypic features in terms of symptom rating and comorbidity patterns, the gender-specific finding for caudate nucleus volume suggests that partially distinct neurobiological deficits underlie ADHD in males and females."

Structural brain measures are only one element of brain imaging in ADHD and other disorders. In my previous posts, I reviewed studies linking ADHD with functional connectivity (white matter) deficits in both children and adults.

Studies of neural networks in ADHD continue to be an important area for future research. Understanding network abnormalities will be key in understanding the pathophysiology of the disorder.

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

Figure is from a screen shot of the basal ganglia from the iPad app 3D Brain. It illustrates the brain caudate region found to be reduced in adult men but not women with ADHD.

Follow the author on Twitter @WRY999.

Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Kan CC, Buitelaar J, & Franke B (2014). Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 24 (3), 397-409 PMID: 24345721

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

Exercise in the Prevention of Alzheimer's Disease

Growing evidence links physical activity to improved cognitive outcome in elderly individuals.

Few studies have examined effects of exercise on those at highest risk for Alzheimer's disease.

J Carson Smith and colleagues recently published a prospective study of a cohort of older adults using structural magnetic resonance imaging.

The key elements of the design of their study included the following elements:
Participants: 97 adults between the ages of 65 and 89
Physical activity level: Frequency and intensity of leisure activity was assessed using the Stanford Brief Activity Survey
Alzheimer's risk status: Assessed using APOE genotype
Brain scanning protocol: Magnetic resonance imaging of brain using a 3T scanner at baseline and 18 months later. The brain hippocampal volume was identified as a key structure involved in APOE-related atrophy and memory decline
Statistical analysis: Participants were grouped in low and high physical activity groups and those with and without high-risk APOE Alzheimer's risk

The research team identified a statistically significant interaction between high-risk Alzheimer's participant and physical activity:

"Hippocampal volume decreased 3% in the High Risk/Low PA (physical activity) group whereas the volumetric changes in the remaining three groups were negligible."

The high-risk Alzheimer's group that participated in higher levels of physical activity appeared to have significant protection against hippocampal atrophy. To reach the higher levels of physical activity in the study they had to endorse one of the following levels:

• Brisk walking 15 minutes daily three or more days per week
• Jogging 15 minutes daily three or more days per week
• Swimming 15 minutes daily three or more days per week
• Moderately difficult chores 45 minutes daily three or more days per week
• Regular jogging, running, bicycling or swimming 30 minutes or more
• Playing sports such as handball or tennis an hour or more 

The authors examine the potential mechanisms for physical activity to reduce hippocampal atrophy in those with the high risk APOE genotype.

They note the beneficial effect of exercise may be through effects on cholinergic function, brain lipid metabolism or reduced neuroinflammation.

If this study is replicated it is an important finding with several implications.

One implication is that it may be one of the first research findings to support routine genetic testing for APOE and Alzheimer's risk. Those identified as high risk by APOE status could be targeted for aggressive behavioral interventions to increase physical activity along with increased surveillance of cognitive function.

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

Follow the author on Twitter WRY999

Photo of roseate spoonbill at sunset is from the author's files.

Smith JC, Nielson KA, Woodard JL, Seidenberg M, Durgerian S, Hazlett KE, Figueroa CM, Kandah CC, Kay CD, Matthews MA, & Rao SM (2014). Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. Frontiers in aging neuroscience, 6 PMID: 24795624

Fitness, Hippocampus and Forgetting

Hippocampus in Green from 3D Brain iPad App

Cardiorespiratory fitness appears to be associated with a variety of benefits in cognitive functioning.  The mechanisms for this benefit are unclear.  Association studies do not provide evidence for the pathways between related variables.  For understanding pathways, clinical trials, longitudinal studies and multivariate approaches are more powerful approaches.

Amanda Szabo and colleagues at the University of Illinois at Urbana-Champaign recently published a multivariate study looking at fitness, hippocampus and forgetting in a group of elderly adults in the journal Neuropsychology.  The hippocampus is a brain region known to crucial to working memory.  Changes in hippocampal volume have been linked to age-related cognitive decline and the development of Alzheimer's disease.

The key elements of design in this study included:
Subjects: 158 older adults with a mean age of 66.5 years
Variables: Fitness level as measured by VO2 estimate from a graded exercise test, brain hippocampal volume from a brain 3T MRI scan, spatial working memory task, subjective rating of forgetfulness (Frequency of Forgetting Questionnaire)
Statistics: Path analysis examining direct and indirect effects of fitness on hippocampal volume, working memory test performance and subject rating of forgetfulness using the comparative fit index (CFI)

The authors started with a presumed pathway model for the mechanism of the relationship between fitness and forgetfulness in the following pathway:

• fitness levels predict hippocampal volume
• hippocampal volumes predicts working memory function performance
• working memory performance predicts subjective forgetfulness

Fitness levels were associated with a variety of sociodemographic and medical variables at baseline including: self-reported physical activity, presence of hypertension, cardiovascular disease, body mass index, education level, gender and age.  These baseline variables were evaluated and controlled in the final pathway analysis.

The authors found their predicted model held up in the analysis: "cardiorespiratory fitness is associated with the frequency of forgetting indirectly through its influence on hippocampal volume and, in turn, spatial working memory".

The study noted fitness level is not the sole determinant of hippocampal atrophy.  Age alone is an independent contributor of hippocampal atrophy.  Fitness may reduce the effects of age-related hippocampal atrophy and forgetfulness but it is unable to reverse the effect.

So fitness is not a panacea but it appears to be an important factor in maintaining cognitive function in later life.  Now, I just wonder if my wife can help me find my running shoes?

3D Brain image of the hippocampus in green screen shot from the author's collection.

Szabo, A., McAuley, E., Erickson, K., Voss, M., Prakash, R., Mailey, E., Wójcicki, T., White, S., Gothe, N., Olson, E., & Kramer, A. (2011). Cardiorespiratory fitness, hippocampal volume, and frequency of forgetting in older adults. Neuropsychology, 25 (5), 545-553 DOI: 10.1037/a0022733