Prenatal Smoking and Offspring Schizophrenia

The topic prevention of brain disorders  is commonly neglected. This is despite increasing evidence for evidence-based support for prevention opportunities.

This issue is highlighted in a recent study out of Finland that examined prenatal nicotine metabolite levels and offspring diagnosis of schizophrenia.

In this study, Solja Niemela and the Finnish research team examined all live births in Finland between 1983 and 1998.

What makes this study powerful is the measurement of maternal serum cotinine levels in maternal serum during the early and mid stages of prenancy. Cotinine is a metabolite and the levels of cotinine reflect the level of nicotine consumption.

The key findings from this study include the following points:

• Measuring cotinine levels as a continuous variable yielded an increased odds ratio for schizophrenia of 3.41 (95% CI 1.86-6.24)
• Mothers in the highest cotinine level group had a 38% increase in offspring schizophrenia rates
• These findings included controlling for potential confounding variables including maternal age and parental history of psychiatric disorders

Interestingly a PubMed search found a second study linking maternal smoking with increased risk of offspring diagnosis of bipolar disorder (odds ratio 2.01, 95% CI 1.48-2.53).

These two studies in combination support a potential non-specific effect of prenatal nicotine exposure on risk for two of the most impairing psychiatric disorders. 

These two studies also support aggressive smoking cessation efforts in young women before pregnancy or at the latest very early after conception.

You can find more information about these two studies by clicking on the citation links below.

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Niemelä, S., Sourander, A., Surcel, H., Hinkka-Yli-Salomäki, S., McKeague, I., Cheslack-Postava, K., & Brown, A. (2016). Prenatal Nicotine Exposure and Risk of Schizophrenia Among Offspring in a National Birth Cohort American Journal of Psychiatry DOI: 10.1176/appi.ajp.2016.15060800

Talati A, Bao Y, Kaufman J, Shen L, Schaefer CA, & Brown AS (2013). Maternal smoking during pregnancy and bipolar disorder in offspring. The American journal of psychiatry, 170 (10), 1178-85 PMID: 24084820

Quick Aspirin Use Reduces Stroke Risk in TIA

A free full-text commentary in the Lancet summarizes recent evidence of the benefit of aspirin in stroke prevention.

This commentary focused on what is called secondary prevention. Secondary prevention is defined as prevention following events related to the disease in question.

So secondary prevention in stroke would be reduction in stroke risk in those who have had a stroke or pre-stroke syndromes such as transient ischemic attacks (TIA).

The key take-home message from the commentary by Graeme Hankey includes:

• Aspirin following mild stroke reduced risk of recurrent ischemic stroke by 49%
• In a summary of 12 trials in those with TIA or ischemic stroke, aspirin reduced risk of any further stroke by 51%, reduced risk of fatal or disabiling stroke by 66% and reduced risk of myocardial infarction by 70%
• Adding another agent (dipyridamole) to aspirin did not reduce stroke risk any further in 12 weeks of follow-up but did appear to add some benefit long-term

Active trials of new drugs for stroke prevention are ongoing and will become available in the next several years. These interventions may provide additional secondary prevention options for clinicians and patients. 

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

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Hankey, G. (2016). The benefits of aspirin in early secondary stroke prevention The Lancet DOI: 10.1016/S0140-6736(16)30511-6

Top Ten Brain Posts 2015: Mediterranean Diet and Alzheimer's

The Brain Post with the second highest pageview count for 2015 was my review of a study of the Mediterranean Diet and Alzheimer's Prevention.

You can access the original post by clicking:

HERE

This study found a link between adherence to a Mediterranean diet with thicker brain cortical regions in the left brain hemisphere.

The regions with increased thickness are regions known to be affected in Alzheimer's disease.

We are a long way from finding a definitive way to modify diet to reduce the incidence of Alzheimer's dementia. Look for this topic to be a continued focus of significant research attention.

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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.

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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

Neurobiology of Child Neglect/Abuse: Nemeroff Lecture Notes

I had the opportunity to attend the Warren Neuroscience Lecture presented by Dr. Charles Nemeroff in Tulsa, OK on June 2, 2015.

Dr. Nemeroff has been an international leader in research in mood and anxiety disorders. His recent focus has been on the effects of adverse childhood environments on risk for adult mood and anxiety disorders. 

Here are my notes that summarize some of the key points from his lecture.

Introduction:

• Stress is an important factor in understanding depression
• Early life stress is a risk factor for later adult depression
• Genes account for a significant portion of the variation in risk following stress exposure
• Brain systems that regulate emotions are disrupted during episodes of major depression

Psychiatry research slowed by complexity of brain, multiple cell types, complex heterogeneous disorders. But we are beginning to understand the key role genes play in a variety of key disorders. Genetic factors account for 65% of bipolar disorder variance, 50% of schizophrenia variance and around 35% of variance in major depression.

Early childhood abuse and neglect is common. Recent surveys estimate prevalence rates for each of the following:

• Physical abuse 15-28% of general population in U.S.
• Sexual abuse in 11-21% 
• Emotional abuse in 11-36%
• Parental divorce or separation in 25%

Early childhood abuse and neglect has multiple effects in neurobiology and later adult mood and anxiety disorder risk:

• Increased adult cerebral spinal marker of stress known as corticotrophin releasing factor (CRF)
• Increase serum ACTH and cortisol
• Increase inflammatory markers  such as interleukin-6
• Decreased cerebral spinal fluid oxytocin that may impair social function and bonding with children
• Reduced brain cortex thickness and hyperactivy amygdala response
• Increased adult PTSD and depression
• Increased adult rates of substance abuse
• Increased risk of suicidal behavior and completed suicide

There is a growing body of evidence that ten or more genes influence vulnerability to childhood abuse and neglect including genes regulating the HPA axis, serotonin function and a gene known as FKBP5. These genetic effects may interact with environmental stresses to reduce or amplify stress vulnerability. Stress may be viewed as a teratogen that influences genetic features through epigenetic and gene regulation effects.

For clinicians there are important treatment implications:

• Major depression in the context of moderate to severe childhood abuse is less responsive to medication or to psychotherapy intervention
• Childhood abuse and neglect in bipolar disorder is linked to early onset, greater severity and poor treatment response.

During the discussion following the lecture Dr. Nemeroff noted the importance of population-based efforts to reduce societal levels of exposure to child abuse and neglect including:

• Early education with teacher training to look for evidence of abuse/neglect
• Increased training for primary care physicians treating infants/children
• Increased training and funding for social services that evaluate and treat children referred for child abuse/neglect
• Increased detection and surveillance for sexual predators
• More research in the treatment of sexual disorders including pedophilia. There is almost no NIH funding in this area and little research interest and activity.

Below I have added citations featured in the presentation to allow readers with more interest to delve into some of the primary research studies.

Image is this post is "PBB Protein CRH image" from Wikipedia chapter on CRH. Image by ProteinBoxBot.  Licensed under Public Domain via Wikimedia Commons  

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Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, & Nemeroff CB (2000). Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA, 284 (5), 592-7 PMID: 10918705

Heim C, Mletzko T, Purselle D, Musselman DL, & Nemeroff CB (2008). The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biological psychiatry, 63 (4), 398-405 PMID: 17825799

Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, & Ressler KJ (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA, 299 (11), 1291-305 PMID: 18349090

Saveanu, R., & Nemeroff, C. (2012). Etiology of Depression: Genetic and Environmental Factors Psychiatric Clinics of North America, 35 (1), 51-71 DOI: 10.1016/j.psc.2011.12.001

Exercise Guidelines in Prevention of Alzheimer's Disease

A series of seven guidelines for the prevention of Alzheimer's disease (AD) has recently been published.

These guidelines resulted from a conference of experts in nutrition and the brain.

The guidelines included a recommendation for 40 minutes of aerobic exercise three times a week.

Support for this exercise recommendation by experts was linked to 2 areas of research:

• Observational studies show lower rates of AD in regular exercise groups compared to sedentary groups
• A single clinical trial found reduced brain atrophy and improved memory following an intervention where elderly adults were randomized to a 40 minute three times a week protocol

I recently summarized another manuscript looking at the association of exercise and brain imaging in those with the APOE genotype linked to Alzheimer's disease. This study was published following the expert conference manuscript.

There certainly need to be more randomized clinical trials of exercise therapy in groups at high risk for cognitive decline and Alzheimer's disease.

Here is the list of all 7 prevention recommendations from the manuscript. Readers can access the free full-text manuscript by clicking on the PMID link below.

Prevention Recommendations for Alzheimer's Disease

1. Minimize dietary saturated and trans fats
2. Increase intake of vegetables, fruits, legumes and grains
3. Daily vitamin E intake from foods of 15 mg
4. Daily vitamin B12 in diet or supplement with blood B12 level monitoring
5. Daily multivitamins not recommended but if used avoid those with iron and copper
6. Aluminum link to AD is controversial but avoid antacids and baking soda that contains aluminum
7. Aerobic exercise of 40 minutes at least 3 times per week

I have previously summarized 10 prevention strategies in AD that include non-nutrition based features that can be found here.

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Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, Fraser G, Kesler S, Levin SM, Lucey B, Morris MC, & Squitti R (2014). Dietary and lifestyle guidelines for the prevention of Alzheimer's disease. Neurobiology of aging, 35 Suppl 2 PMID: 24913896