The Promise of DTI (Imaging) in Neurology

Brain diffusion tensor imaging (DTI) is emerging as new important brain imaging tool in research.

Clinicial applications of DTI are lagging the research applications in development.

However, clinical applications are coming.

The Radiological Society of North America recently published a summary of potential application for DTI in Neurology on their website. You can access the website post HERE.

Three key areas were highlighted in this post including use of DTI for:

• Aiding Identification of Prognosis in Mild TBI
• Gender Effects on Sports-Related Head Injury
• Brain Mapping Neurosurgery

Included at the website are two You Tube Videos. Here is the video related to using DTI as a prognostic aid in TBI.

Dr. ML Lipton featured in the You Tube video has a free full-text published a study of DTI in soccer heading in the manuscript cited below. Click on the PMID to get to the manuscript.

In this manuscript the authors were able to identify change in white matter brain microstructure related to prevalence of soccer heading independent of concussion.

Image of white matter corona radiata is my screen shot from the iPad app Brain Tutor.

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Lipton ML, Kim N, Zimmerman ME, Kim M, Stewart WF, Branch CA, & Lipton RB (2013). Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology, 268 (3), 850-7 PMID: 23757503

Meditation and Medical Ethics

Medical ethics and mindfulness have a lot in common. I reached that conclusion after a recent conversation with my long-time friend Charlie Halpern about his effort to introduce mindfulness into legal education.

Charlie has been doing this at the UC Berkeley School of Law for the past several years through classes and elective retreats. He's an enthusiast and a believer. He feels, and many legal educators and law schools agree with him, that mindfulness practice increases empathy, compassion, and the ability to really hear what clients and others involved in negotiation and litigation are saying. He described how a professor at Berkely has taken to starting his classes with three minutes of silence. The professor reports that "sacrificing" three minutes of class time leads to a richer, more thoughtful class experience.

I've taught meditation to patients in a medical setting and have recommended meditation to many of my patients over the years. And I've written in this blog about how mindfulness practice can be woven into busy practitioners' lives. (See here and here.) But until the conversation I had with Charlie, I hadn't recognized the obvious connection between mindfulness and the way I've taught medical ethics.

In the semester-long course medical ethics course that I taught at Harvard Medical School, in addition to the topics that formed the intellectual content of the course, I encouraged the students to hone their skill at (a) observing their cognitive and emotional reactions to clinical situations that raise ethical issues, (b) treating these reactions as "data," not "truths," and then (c) reflecting on the "data" presented by their experience as one piece of ethical analysis before (d) reaching a conclusion. Over time, as demonstrated by clinicians who we regard as models of ethical action, this set of actions can become reflexive, done automatically and recurrently.

What I realized is that steps (a) and (b) are close cousins to what meditation teachers encourage their students to do. The setting is different - deliberate quiet and inwardness in meditation versus to what I'm inclined to call "meditation in action" in learning to be an ethically sensitive clinician. But the outcomes the teacher hopes for in the student - empathic connection with others, compassion, and seeing the truths that underlie complexity - are the same.

Recognizing the kinship between mindfulness and medical ethics is a valuable insight for ethics educators. An increasing number of students know something about meditation and respect the practice. Recognizing that skill at meditation can enhance their grasp of medical ethics, and, that skill at medical ethics fosters some of the key skills for meditation, enhances both domains.

Why are heart disease and dental health related?

Some years ago people became excited about the news that poor dental health, particularly gum disease, and heart disease are correlated. Not only that, but gum disease develops first! Post hoc ergo propter hoc ("after this, therefore because of this") right?

Soon we started hearing advice to take good care of our teeth (by brushing and flossing), because it will help us avoid heart disease. Meanwhile, scientists started looking for mechanisms behind this putative ability of oral bacteria to effect your cardiovascular health.

Not only has a causal relationship not been established, but, in my opinion it's highly unlikely, because there is a simpler explanation.

Correlation and causation

Suppose we have two things that are correlated: they happen so often together that they look like they might have a causal relationship.

There are several kinds of relationships that could be happening:

• The correlation is spurious. It's pure coincidence. They are not causally related at all, even though they happen together so often it looks like it isn't random.

  That's the thing about randomness. There is variability in it. A huge dataset is going to have some patterns in it, even though those patterns are no good for predicting future data [1].

If there really is a correlation, so that one can be used to predict the other when new data comes in, then there are still multiple possible underlying relationships, including:

• One causes the other.

  Something about the process of heart disease increases the risk of gum disease, or something about the process of gum disease increases the risk heart disease.

• A third thing causes both.

  There is something that elevates the risk of both gum disease and heart disease.

In this post, I suggest a hypothesis in this category. It goes like this:

• Fermentable carbohydrates (those that break down in the mouth, i.e. sugars and starches) cause tooth decay, unhealthy dental plaque, and gum disease.
• Eating carbohydrates increases the risk of heart disease.
• Therefore the correlation between gum disease and and heart disease may be due to a common causal factor.

It could well be that dental disease simply manifests faster, which would mean you can use it as a warning sign. Covering up the evidence with extensive oral hygiene routines wouldn't address the real problem.

Fermentable carbohydrates cause tooth decay and gum disease

What are fermentable carbohydrates? They are certain sugars, including the simple sugars glucose and fructose, and the sugars that result from starches that begin digestion in the mouth through amylase, particularly maltose [2].

Cavities form when bacteria in plaque ferment carbohydrates into acid, lowering the pH of dental plaque below a critical level that results in demineralisation of tooth enamel. The bacterial species that do this thrive best in the resulting acidic environment, which is hostile to other species. So fermentable carbohydrates both provide fuel for the bacteria, and when metabolised create a selective environment for them. [3], [4].

Plaque itself accumulates to excess because of those same fermentable carbohydrates. Periodontal disease (gum disease) is an inflammatory response to bacterial products in dental plaque [5].

Carbohydrate and heart disease

We already know that a low carb diet has a better effect on heart disease risk factors than any other intervention. If you have metabolic syndrome, then a low carb diet is the best treatment. Therefore, conversely, eating a lot of carbohydrates increases your risk comparatively.

Moreover, poor dental health is so correlated with diabetes (the canonical metabolic syndrome disease) that some authors have called periodontitis a complication of diabetes [6]. The ability of scientists to uphold such a backwards concept is hard to comprehend.

Here's a particularly ridiculous promotion of that idea from the American Dental Association. If I didn't find it such an irresponsible abuse of authority, I'd be laughing hysterically [7].

What does dental disease signify and what should you do about it?

It's my contention that dental disease is a risk factor for heart disease and diabetes and all other diseases secondary to metabolic syndrome, but not because dental disease is a cause of those; rather because it is a fast manifesting symptom of a detrimental diet.

While writing this post, I came upon an article proposing the same idea [8]. I don't have full access to the paper, but here is the abstract:

"Two contradictory hypotheses on the role of dietary carbohydrates in health and disease shape how dental-systemic associations are regarded. On one side, Cleave and Yudkin postulated that excessive dietary fermentable carbohydrate intake led—in the absence of dental interventions such as fluorides—first to dental diseases and then to systemic diseases. Under this hypothesis, dental and systemic diseases shared—as a common cause—a diet of excess fermentable carbohydrates. Dental diseases were regarded as an alarm bell for future systemic diseases, and restricting carbohydrate intake prevented both dental and systemic diseases. On the opposite side, Keys postulated the lipid hypothesis: that excessive dietary lipid intake caused systemic diseases. Keys advocated a diet high in fermentable carbohydrate for the benefit of general health, and dental diseases became regarded as local dietary side effects. Because general health takes precedence over dental health when it comes to dietary recommendations, dental diseases became viewed as local infections; interventions such as fluorides, sealants, oral hygiene, antimicrobials, and dental fillings became synonymous with maintaining dental health, and carbohydrates were no longer considered as a common cause for dental-systemic diseases. These opposing dietary hypotheses have increasingly been put to the test in clinical trials. The emerging trial results favor Cleave-Yudkin’s hypothesis and may affect preventive approaches for dental and systemic diseases."

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If you have dental plaque accumulation, tooth decay, or gum disease, don't brush it off. It's a warning to you that your diet is unhealthy.

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Footnotes and References

[1]

That's why you should never trust a study that takes all of its data and reports a correlation, without holding out some of the data (and not peeking!) and showing that the relationship found in the first set also holds in the second set. Think NHANES. Even then you have to trust the scientists that they didn't look at the second set before coming up with the hypothesis. Even then, you have to take into account that again by random chance the pattern held in the first set also holds in the second.

[2]

Evidence type: review Food starches and dental caries Lingström P, van Houte J, Kashket S. Crit Rev Oral Biol Med. 2000;11(3):366-80. "In general, it is only the gelatinized starches that are susceptible to enzymatic breakdown, i.e., are bioavailable. In the human mouth, starches can be hydrolyzed by salivary and bacterial amylases into maltose, maltotriose, and low-molecular-weight dextrins (Mbrmann and Muhlemann, 1981). Starch hydrolysis on the teeth is very rapidly initiated, and entrapped particles of food can accumulate high levels of maltose and maltotriose, which are good substrates for bacterial acid production (Neff, 1967; Imfeld, 1983; Kashket et al., 1994, 1996). Maltose fermentation requires bacterial adaptation under certain conditions (Kashket et al., 1994). In humans, however, plaque bacteria appear to be adapted and can ferment this sugar without delay (Neff, 1967; Imfeld, 1983; Lingstrbm et al., 1993a)."

[3]

Evidence type: review Dental plaque as a biofilm and a microbial community – implications for health and disease Philip D, Marsh BMC Oral Health20066(Suppl 1):S14 DOI: 10.1186/1472-6831-6-S1-S14 "Clinical studies have shown that caries is associated with increases in the proportions of acidogenic and aciduric (acid-tolerating) bacteria, especially mutans streptococci (such as S. mutans and S. sobrinus) and lactobacilli, which are capable of demineralizing enamel [16, 17, 18, 19]. These bacteria can rapidly metabolize dietary sugars to acid, creating locally a low pH. These organisms grow and metabolize optimally at low pH. Under such conditions they become more competitive, whereas most species associated with enamel health are sensitive to acidic environmental conditions. However, although mutans streptococci are strongly implicated with caries, the association is not unique; caries can occur in the apparent absence of these species, while mutans streptococci can persist without evidence of detectable demineralization [20, 13]. Indeed, in such circumstances, some acidogenic, non-mutans streptococci are implicated with disease [18, 21, 22]. Detailed studies of the glycolytic activity of a large number of oral streptococci have shown that some strains of non-mutans streptococci(e.g. S. mitis biovar 1 and S. oralis) can still metabolize sugars to acid at a moderately low environmental pH at rates comparable to those achieved by mutans streptococci[15]. ... "Caries is a result of changes in the environment due to acid production from the fermentation of dietary carbohydrates, which selects for acidogenic and acid-tolerating species such as mutans streptococci and lactobacilli."

[4]

Evidence type: review Sugars and dental caries Riva Touger-Decker and Cor van Loveren Am J Clin Nutr October 2003 vol. 78 no. 4 881S-892S "Caries is caused by the dissolution of the teeth by acid produced by the metabolism of dietary carbohydrates by oral bacteria. The 2 primary bacteria involved in caries formation are mutans streptococci and lactobacilli. ... "The caries process can be described as loss of mineral (demineralization) when the pH of plaque drops below the critical pH value of 5.5; the critical value for enamel dissolution is 5–6, and an average pH of 5.5 (8, 9) is the generally accepted value. Redisposition of mineral (remineralization) occurs when the pH of plaque rises."

[5]

Evidence type: authority Periodontal (Gum) Disease: Causes, Symptoms, and Treatments NIH "The longer plaque and tartar are on teeth, the more harmful they become. The bacteria cause inflammation of the gums that is called “gingivitis.” In gingivitis, the gums become red, swollen and can bleed easily. Gingivitis is a mild form of gum disease that can usually be reversed with daily brushing and flossing, and regular cleaning by a dentist or dental hygienist. This form of gum disease does not include any loss of bone and tissue that hold teeth in place. Periodontitis When gingivitis is not treated, it can advance to “periodontitis” (which means “inflammation around the tooth”). In periodontitis, gums pull away from the teeth and form spaces (called “pockets”) that become infected. The body’s immune system fights the bacteria as the plaque spreads and grows below the gum line. Bacterial toxins and the body’s natural response to infection start to break down the bone and connective tissue that hold teeth in place. If not treated, the bones, gums, and tissue that support the teeth are destroyed. The teeth may eventually become loose and have to be removed."

[6]	Evidence type: epidemiology Periodontal disease: The sixth complication of diabetes Löe H1. Diabetes Care. 1993 Jan;16(1):329-34.

[7]

I should acknowledge that a Cochrane review did find a very modest and possibly transient lowering of HbA1C after treatment for periodontitis. So the pamphlet is not completely baseless. However, it strikes me as a bit like the advice to lower salt for blood pressure, in that it has at best a very small effect and that effect is on one symptom, and that effect is negligible in comparison with the effect of lowering dietary carbohydrates. So not only is it unclear whether the effect is systemic — whether that would translate into an effect in further outcomes, but more importantly, it distracts from the fact that there is a way to effect HbA1c in a strong reliable way. This is why I see it as laughable and irresponsible. Evidence type: meta-analysis Treatment of periodontal disease for glycaemic control in people with diabetes mellitus Simpson TC, Weldon JC, Worthington HV, Needleman I, Wild SH, Moles DR, Stevenson B, Furness S, Iheozor-Ejiofor Z. Cochrane Database Syst Rev. 2015 Nov 6;11:CD004714. doi: 10.1002/14651858.CD004714.pub3. "Abstract BACKGROUND: Glycaemic control is a key issue in the care of people with diabetes mellitus (DM). Periodontal disease is the inflammation and destruction of the underlying supporting tissues of the teeth. Some studies have suggested a bidirectional relationship between glycaemic control and periodontal disease. This review updates the previous version published in 2010. OBJECTIVES: The objective is to investigate the effect of periodontal therapy on glycaemic control in people with diabetes mellitus. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 31 December 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2014, Issue 11), MEDLINE via OVID (1946 to 31 December 2014), EMBASE via OVID (1980 to 31 December 2014), LILACS via BIREME (1982 to 31 December 2014), and CINAHL via EBSCO (1937 to 31 December 2014). ZETOC (1993 to 31 December 2014) and Web of Knowledge (1990 to 31 December 2014) were searched for conference proceedings. Additionally, two periodontology journals were handsearched for completeness, Annals of Periodontology (1996 to 2003) and Periodontology 2000 (1993 to 2003). We searched the US National Institutes of Health Trials Registry (http://clinicaltrials.gov) and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of people with type 1 or type 2 DM (T1DM/T2DM) with a diagnosis of periodontitis. Interventions included periodontal treatments such as mechanical debridement, surgical treatment and antimicrobial therapy. Two broad comparisons were proposed:1. periodontal therapy versus no active intervention/usual care;2. periodontal therapy versus alternative periodontal therapy. DATA COLLECTION AND ANALYSIS: For this review update, at least two review authors independently examined the titles and abstracts retrieved by the search, selected the included trials, extracted data from included trials and assessed included trials for risk of bias.Our primary outcome was blood glucose levels measured as glycated (glycosylated) haemoglobin assay (HbA1c).Our secondary outcomes included adverse effects, periodontal indices (bleeding on probing (BOP), clinical attachment level (CAL), gingival index (GI), plaque index (PI) and probing pocket depth (PPD)), cost implications and diabetic complications. MAIN RESULTS: We included 35 studies (including seven from the previous version of the review), which included 2565 participants in total. All studies used a parallel RCT design, and 33 studies (94%) only targeted T2DM patients. There was variation between studies with regards to included age groups (ages 18 to 80), duration of follow-up (3 to 12 months), use of antidiabetic therapy, and included participants' baseline HbA1c levels (from 5.5% to 13.1%).We assessed 29 studies (83%) as being at high risk of bias, two studies (6%) as being at low risk of bias, and four studies (11%) as unclear. Thirty-four of the studies provided data suitable for analysis under one or both of the two comparisons.Comparison 1: low quality evidence from 14 studies (1499 participants) comparing periodontal therapy with no active intervention/usual care demonstrated that mean HbA1c was 0.29% lower (95% confidence interval (CI) 0.48% to 0.10% lower) 3 to 4 months post-treatment, and 0.02% lower after 6 months (five studies, 826 participants; 95% CI 0.20% lower to 0.16% higher).Comparison 2: 21 studies (920 participants) compared different periodontal therapies with each other. There was only very low quality evidence for the multiple head-to-head comparisons, the majority of which were unsuitable to be pooled, and provided no clear evidence of a benefit for one periodontal intervention over another. We were able to pool the specific comparison between scaling and root planing (SRP) plus antimicrobial versus SRP and there was no consistent evidence that the addition of antimicrobials to SRP was of any benefit to delivering SRP alone (mean HbA1c 0.00% lower: 12 studies, 450 participants; 95% CI 0.22% lower to 0.22% higher) at 3-4 months post-treatment, or after 6 months (mean HbA1c 0.04% lower: five studies, 206 patients; 95% CI 0.41% lower to 0.32% higher).Less than half of the studies measured adverse effects. The evidence was insufficient to conclude whether any of the treatments were associated with harm. No other patient-reported outcomes (e.g. quality of life) were measured by the included studies, and neither were cost implications or diabetic complications.Studies showed varying degrees of success with regards to achieving periodontal health, with some showing high levels of residual inflammation following treatment. Statistically significant improvements were shown for all periodontal indices (BOP, CAL, GI, PI and PPD) at 3-4 and 6 months in comparison 1; however, this was less clear for individual comparisons within the broad category of comparison 2. AUTHORS' CONCLUSIONS: There is low quality evidence that the treatment of periodontal disease by SRP does improve glycaemic control in people with diabetes, with a mean percentage reduction in HbA1c of 0.29% at 3-4 months; however, there is insufficient evidence to demonstrate that this is maintained after 4 months.There was no evidence to support that one periodontal therapy was more effective than another in improving glycaemic control in people with diabetes mellitus.In clinical practice, ongoing professional periodontal treatment will be required to maintain clinical improvements beyond 6 months. Further research is required to determine whether adjunctive drug therapies should be used with periodontal treatment. Future RCTs should evaluate this, provide longer follow-up periods, and consider the inclusion of a third 'no treatment' control arm.Larger, well conducted and clearly reported studies are needed in order to understand the potential of periodontal treatment to improve glycaemic control among people with diabetes mellitus. In addition, it will be important in future studies that the intervention is effective in reducing periodontal inflammation and maintaining it at lowered levels throughout the period of observation."

[8]	Evidence type: review Dietary Carbohydrates and Dental-Systemic Diseases P. Hujoel JDR June 2009 vol. 88 no. 6 490-502

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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Photo of pair of pin-tail ducks is from my files.

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

An Ethical Perspective on Shared Medical Appointments

Stories about shared medical appointments keep popping up in the news, most recently in this New York Times article. The format involves bringing together a group of patients - as many as 15, but typically 8 - 12 - with a doctor or nurse practitioner, for a 90 minute discussion of shared medical problems, such as diabetes. Although group visits are not for everyone, the response of patients who participate and clinicians who lead the sessions are generally quite positive.

Group visits arose to promote efficiency. Although current discussions describe the format as an innovation developed in response to the parlous state of contemporary medicine, in 1905 Dr. Joseph Hersey Pratt, a Boston physician, began to lead "classes" for patients with tuberculosis. Pratt documented results that were as good as the best sanataria, but his method fell into oblivion.

In 1975 I had the privilege of starting a group visit program for patients with chronic psychiatric ailments at the Harvard Community Health Plan HMO . I conducted the group in collaboration with an excellent psychiatric nurse. I spoke with patients individually and to the group as a whole. If I wanted to recommend a medication to patient A, I often asked patient B, who was taking the medication, to talk with A about it. It was set up as a "drop in" group. Patients could come every week or just intermittently.

Physicians who lead shared medical appointments experience a different relationship with patients than in the 1:1 format. The group is more informal, and the physician often acts as a facilitator of patient-to-patient exchange, rather than as an authority. The framework tends to bring out the humanity of clinicians and patients. It's difficult for the leaders to be cold, detached or pompous.

I don't know how well the aspiration for efficiency holds up, but I do know - from my own experience and from the literature - that group visits encourage a holistic, humane way of relating between doctors and patients. The rationale for the format tends to be presented in an apologetic manner: the health system is in a mess/physicians are too harried to pay enough attention/you'll get to spend more time with your doctor in a group. These statements are true. But apology undersells the value of shared medical appointments. For patients with chronic conditions that must be managed over time, the group format can bring out a patient's own strengths and initiative and allow physicians to tap into their capacity to care in a down-to-earth human manner in new ways.

That's an ethical achievement, not just a matter of efficiency!

[To learn more about shared medical appointments, a Massachusetts General Hospital guide to conducting group visits is here,  a description of the group visit program at the Cleveland Clinic is here, and a VA guide to setting  up a group visit program for patients with diabetes is here. If you would like pdf versions of my articles about Pratt and about the HMO group program, send me your email address via the comment function.]

Free Alcohol Use Reduction App

An investigational app and online program to reduce alcohol intake is now available free to the public.

This tool is an application of cognitive bias modification. A link to a study supporting cognitive bias modification is noted in the citation below. Click on the PMID link to get to the abstract.

The program uses a 15 minutes per day tool for four days.

The program was developed at the London School of Economics by Professor Paul Dolan.

Users who sign up to use the tool will be providing data to further determine the effectiveness of the app.

Read more about this tool at Science Daily HERE.

A link to the program and app can be found HERE.

Follow me on Twitter @WRY999 HERE.

Photo of painting titled "Peasants Enjoying a Beer at Pub in Fribourg" is from Wikipedia Creative Common file. Citation: By François Louis Jaques (1877–1937) (Beurret & Bailly) [Public domain], via Wikimedia Commons

Gladwin TE, Rinck M, Eberl C, Becker ES, Lindenmeyer J, & Wiers RW (2015). Mediation of cognitive bias modification for alcohol addiction via stimulus-specific alcohol avoidance association. Alcoholism, clinical and experimental research, 39 (1), 101-7 PMID: 25623410

A New Chromosome Y Risk for Alzheimers

There are many risk factors for Alzheimer's Disease (AD) including history of head trauma and family history of AD.

The strongest risk factor is advanced age. Yearly risk for AD is about 1% per year in 70 year old populations jumping to around 7% in 90 year old groups.

Now a recent study is shedding some light on a new risk for AD in men. This risk appears to be related to a chromosome Y phenomenon known to be associated with aging.

Elderly men show a tendency to lose the Y chromosome from a small percentage of cells over time. This phenomenon is known as loss of Y or LOY.

The percentage of blood cells with LOY can be determined. A study recently published in Journal of Human Genetics (see citation below) found significant support for higher percentage of LOY being linked to AD risk.

Here are the key findings:

• In a sample of 3218 elderly men 17% showed evidence of LOY chromosome mosaicism
• LOY percentage rates were strongly positively correlated with older age
• Men with AD had higher rates of LOY than age-matched men without AD (adjusted odds ratio=2.80)
• Two prospective studies found higher rates of incident AD in men with LOY (adjusted odds ratio=6.80)

These findings are not simply minor as the effect of LOY on risk appears similar in magnitude to the strongest genetic risk factor for AD, APOE gene status.

LOY has also been linked to a higher risk of cancer, so it appears to be a non-specific risk factor.

The authors of this study note;

"Regardless of the underlying mechanism(s) for the increased risk of AD and cancer in men with LOY in blood, our and other's published results reinforce a role of factors on chromosome Y in various, still poorly explored biological processes, other than sex determination and sperm production."

LOY is not yet a common test in clinical practice. However, I think we will be hearing much more on this association with potential for screening and intervention studies.

Access the free full-text manuscript by clicking on the DOI link in the citation below.

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d sperm production.

Dumanski JP et al (2016). Mosiac loss of chromosome Y in blood is associated with Alzheimer's disease American Journal of Human Genetics : 10.1016/j.ajhg.2016.05.014

Atheism, Humanism and Secular Ethics at the University of Miami

Between September 10, 2007 and today, I've written 82 posts about religion and spirituality. I've been especially interested in the moral underpinnings of the health professions. I've thought of health care as a calling throughout my career. But where does the call come from?

Historically, the call has been seen as coming from god and god's servants - saints, bodhisattvas and other benevolent beings who urge us to care for others. But what about health care workers who do not derive their calling from a theology?

I hope this question will be high on the list of research topics when the newly endowed chair of "atheism, humanism and secular ethics" at the University of Miami is filled. I learned from the New York Times article about the chair that it was endowed by Louis J. Appignani, an 83 year-old retired businessman who supports non-theist causes. The University was uncomfortable defining the chair as one of "atheism" studies, but Mr. Appignani insisted that the "atheism" be part of the title, and accepted the addition of "humanism and secular ethics."

In an increasingly secular population it's crucial to deepen public understanding of morality that is not based on religious theologies. Over the centuries, religious communities have been powerful advocates for good causes (e.g., abolition of slavery) but also for evil causes (e.g., "holy" war). For atheists and secular humanists to make a full contribution to the moral arc of the future, we need a deeper understanding of how the non-theological domain functions. Let's hope that the University of Miami chair contributes to this process.

When the chair is filled, there will be a great deal to learn from studying those who are called to the vocation of health care!

Does Flu Vaccination Reduce Dementia Risk?

In my daily review of neuroscience news I ran across an article flu vaccination and dementia risk in heart failure.

This study was reported at the 3rd World Congress on Acute Heart Failure by Dr. Ju-Chi Liu from Taipei Medical University.

So how might influenza vaccination be related to dementia risk?  We do know acute influenza infection reaches the brain causing headache and increasing brain inflammation, at least temporarily. We also know brain inflammation may be involved in the mechanism of amyloid and tau protein deposition in the brain. So this link has some potential biological plausibility.

In the Taiwanese study, 20,509 subjects with a diagnosis of heart failure were followed via centralized records. About half received flu vaccination during follow up. Subjects receiving at least one flu vaccination had a 35% lower rate of dementia diagnosis compared to those not receiving any vaccination. Subjects receiving three or more vaccinations had a 55% lower risk of recorded dementia diagnosis on follow up.

I went to PubMed looking for more research for this association and a similar finding has been published by the same research group in a free full-text manuscript in patients with chronic kidney disease (CKD). The key elements of this study were:

• Subjects: All 32,844 individuals with a chronic kidney disease diagnosis in the Taiwan National Health Insurance Research Database. From this set 11,843 subjects had sufficient data for the study.
• Case definition: Influenza vaccination during the study period
• Outcome definition: Research database definition of dementia during follow up period
• Results: After controlling for confounding variables, influenza vaccination case subjects had a 36% lower rate of dementia diagnosis compared to those not vaccinated (odds ratio=.64)

Interestingly, there appeared to be a dose dependent effect with those receiving multiple influenza vaccinations showing even lower rates of dementia.

Also, somewhat unexpectedly, vaccinations given outside of the typical influenza season showed a greater effect.

The authors note in their discussion:

"In clinical practice, we suggest that CKD patients with high dementia risk be vaccinated."

The authors note dementia risk is increased in CKD with hypertension, high blood cholesterol and diabetes.

The most important potential implication in these two studies, is whether influenza might reduce dementia risk in the general non-medically ill population. I think we will have more research on this issue soon.

There are many reasons for regular influenza vaccination. Preserving brain health may be another important reason for expanded vaccination efforts.

You can access the free full-text manuscript of the CKD and dementia paper by clicking on the PMID link in the citation below.

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Figure of influenza virus in post is from Wikipedia Creative Commons file authored by: National Institutes of Health; originally uploaded to en.wikipedia by TimVickers (25 October 2006), transferred to Commons by Quadell using CommonsHelper

Liu JC, Hsu YP, Kao PF, Hao WR, Liu SH, Lin CF, Sung LC, & Wu SY (2016). Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study. Medicine, 95 (9) PMID: 26945371

Emotional Processing: A Key to Depression Treatment?

In my last post I reported on the use of machine learning to aid in predicting response to depression treatment.

Another interesting depression prediction tool is being investigated in a trial in England funded by the Oxford Health NHS Foundation Trust.

This trial uses a visual facial recognition tool. The hypothesis is that early antidepressant action can be identified by changes in facial emotional recognition.

This trial stems from work by Catherine Harmer Ph.D. from the University of Oxford. Her work in this area is highlighted in the free full-text manuscript citation at the end of this post.

In this full-text manuscript the authors review research suggesting antidepressants drug action may be due to the direct effect on emotional processing. 

Clinicians know that clinical recognition of an antidepressant response may take six weeks for a single antidepressant drug. It may be even longer if dosage escalation is needed to test a specific drug.

Facial emotional recognition is a potential earlier marker of antidepressant response. In the review cited below, facial recognition changes as early as two weeks have predicted a positive drug response.

Antidepressant drugs appear to alter emotional processing in healthy non-depressed adults. This may allow for wider screening of new investigational antidepressant drugs.

You can read more about the NHS trial at MedicalXpress HERE.

Click on the PMID link in the citation below for a link to the free full-text review.

Image of limbic system known to be involved in emotional processing is my screen shot from the iPad app 3D Brain.

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Image of brain is my screen shot from the iPad app 3D Brain.

Pringle A, & Harmer CJ (2015). The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment. Dialogues in clinical neuroscience, 17 (4), 477-87 PMID: 26869848

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.

Follow me on Twitter @WRY999:  HERE.

Image is an iPad screenshot from the app 3D Brain.

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

Predicting Depression Treatment Response: Machine Learning

Treatment of depression remains primarily an uninformed clinical process. Several effective drug and psychotherapy interventions are available. 

However, there is no reliable way to determine which treatment is likely to be the most effective for an individual patient.

A recent study that used machine learning techniques to address this problem has been published.

A research team from Yale University used clinical data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial in the U.S. 

I served as an investigator in the STAR*D and am happy to see this database still in use.

In the current study, the research team used machine learning with a group of 164 pre-treatment variables. From this group of variables, 25 were identified as providing predictive value of response/non-response to treatment with a standard antidepressant drug citalopram.

Clinical predictors of non-response included:

• High baseline depression severity scores
• Presence of psychomotor agitation at baseline
• Reduced energy ratings at baseline (fatigue)

Predictors of depression remission included:

• Current employment
• Higher level of education
• Lower scores on depression insight

The research team was able to build a machine learning model that showed a 63% sensitivity and 66% specificity in prediction response to citalopram. This was statistically greater than random (chance) prediction.

Addition support for their model was gained by replication in a second study of citalopram in depression.

This is an important and exciting finding that suggests low-cost symptom biomarkers may aid in the treatment selection for depression.

You can access the abstract of this important work by clicking HERE or by clicking on the PMID link in the citation below. 

Follow the author on Twitter WRY999 HERE.

Photo of sunset on Captiva Island, Florida is from my personal files. 

Chekroud AM, Zotti RJ, Shehzad Z, Gueorguieva R, Johnson MK, Trivedi MH, Cannon TD, Krystal JH, & Corlett PR (2016). Cross-trial prediction of treatment outcome in depression: a machine learning approach. The lancet. Psychiatry, 3 (3), 243-50 PMID: 26803397

Language Disorder in Preschoolers

Well-designed large population-based studies of the prevalence and correlates of learning disabilities in preschool children are rare.

A research group working out of University College London has address that issues with a large study of language disorder in a group of over 7000 4 and 5 year olds in England.

A stratified group of 529 children received a comprehensive assessment of language along with assessment of IQ, social, emotional and behavior function.

The study found the following important points.

• The prevalence of language disorders in the sample was 9.9%
• This group consisted of 7.6% with language disorder of unknown origin and 2.3% with language disorder associated with intellectual disability or known medical condition
• Language disorder diagnosis was linked to a wide array of other problems including failure to make academic progress
• A significant number of children with normal non-verbal IQ demonstrated language disorder

The authors of the study not their findings suggest that out of every classroom with 30 students, two will have significant language problems. This supports comprehensive screening early to identify these children at high-risk for academic failure.

You can read more about this study in MedicalXpress HERE.

The free full-text manuscript can be accessed HERE.

Follow me on Twitter WRY999.

Photo of children at play during sunset is from my personal collection. 

Norbury, C., Gooch, D., Wray, C., Baird, G., Charman, T., Simonoff, E., Vamvakas, G., & Pickles, A. (2016). The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study Journal of Child Psychology and Psychiatry DOI: 10.1111/jcpp.12573

Shift Work Linked to Slowed Cognition

Working variable shifts involves shifting typical sleep cycles repetitively over time.

This shifting is known to be associated with temporary insomnia. It also produces a biological stress likely to have significant adverse effects.

A recent study helps to potentially understand some of the ways shift work may affect cognition.

A group of researcher from Sweden examined a database of 7000 subjects. This cohort completes a series of comprehensive interviews as well as neuropsychological tests including one known as the Trail Making test. The Trail Making test is a type of timed connect the dots test that measures psychomotor speed and visuomotor processing.

Active and recent shift workers in the study performed significantly slower on the Trail Making test than those with regular work cycles.

This study is limited by the cross sectional design and correlation does not equal causation.  However it does suggest that shift work may contribute to impairment in a significant area of cognitive performance.

You can read more about this study at MedicalXpress HERE.

The free full-text manuscript can be accessed HERE (click on PDF link).

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Photo is from my personal files showing a landscape on the Italian Riviera.

Nurses Frequently Attending Church Live Longer

The Harvard-based Nurses' Health Study has been a remarkably productive longitudinal health study.

My wife has been a subject in this study and frequently completes interval questionnaires regarding her health status.

A recent publication looked at the relationship between religious service attendance and mortality in the Nurses's Health Study cohort.

This manuscript tried to provide a more valid look at the relationship between religiosity/spirituality and health. Previous studies have found a link between church attendance and longer life but these studies were vulnerable to reverse causation confounding.

Mortality rates over a 20 year period were reduced in a scaled manner compared to those control subjects who id not attend church by the following amounts:

• Attends church less than once per week: 13% lower mortality
• Attends church once per week: 26% lower mortality
• Attends church more than once per week: 33% lower mortality

Potentially confounding factors that were controlled included diet, physical activity, smoking status and body mass index.

The research team suggests church attendance rates may be a proxy for social support, a factor known to influence mortality risk.

Read more about this study at the ScienceDaily website HERE.

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Photo of willet birds on seashore is from the my files.

Li, S., Stampfer, M., Williams, D., & VanderWeele, T. (2016). Association of Religious Service Attendance With Mortality Among Women JAMA Internal Medicine DOI: 10.1001/jamainternmed.2016.1615