Neurophilosophy

THE dangers of obesity are very well known. Being overweight is associated with an increased risk of coronary heart disease and stroke, the two leading causes of death in the Western world. Gout is more common in overweight people, with the risk of developing the condition increasing in parallel with body weight. Obese people are twice as likely to develop type 2 diabetes as those who are not overweight, and being overweight is also associated with several types of cancer. The list goes on…

Less well known is the effect of obesity on the brain. In the past few years, however, it has emerged that being overweight in middle age is linked to an increased risk of Alzheimer’s Disease and other forms of dementia. Two new studies strengthen this association: the first, just published in the Annals of Neurology, shows that abdominal fat is linked to reduced brain volume in otherwise healthy middle-aged adults. The second, published last month in Proceedings of the National Academy of Sciences, shows that this reduction is associated with a common variant of an obesity-related gene.

Stephanie Debette of Boston University and her colleagues examined the association of various obesity indicators – including body mass index, waist circumference, waist-to-hip ratio and abdominal fat – with brain volume, as measured by structural magnetic resonance imaging. They recruited 733 participants for their study, all of whom were previously enrolled in the Framingham Heart Study, an ambitious longitudinal project started in 1948, whose aim is to identify the common factors contributing to cardiovascular disease by following the disease as it develops over long periods of time in large numbers of people. All of the earlier studies investigating the link between obesity and dementia have involved less than 300 participants, so this is the largest such study of its kind to date.

The researchers found that all of these obesity indicators were inversely associated with total brain volume – that is, the higher any indicator was, the smaller the brain volume – and that the association between abdominal fat and brain volume was the strongest of all. Waist-to-hip ratio was also found to be associated with increased temporal horn volume, independently of other obesity indicators. The temporal horn is a part of the ventricular system; its volume is known to increase with age, and in conditions such as Alzheimer’s Disease, depression and schizophrenia. Enlargement of the temporal horn invariably involves a reduction in the volume of temporal lobe structures such as the hippocampus, and thus is closely associated with memory impairments. (Indeed, temporal horn volume could serve as a useful marker for Alzheimer’s, in which the temporal lobe is one of the very first brain regions to be affected.)

brain volume obesity dementia.JPG

In the second study, April Ho of the Laboratory of Neuro Imaging at the University of California, Los Angeles and her colleagues analysed data obtained from 206 healthy elderly participants as part of a large five-year research project called the Alzheimer’s Disease Neuroimaging Initiative. The data were used to generate 3D maps of the participants’ brains, and then to see if brain structure is related to one variant (or allele) of the fat mass and obesity associated (FTO) gene. This risk allele is strongly associated higher body-mass index – carriers have, on average, ~1.2kg higher weight and 1cm greater waist circumference. It is relatively common, being carried by some 46% of Western Europeans.

Ho’s group found that the FTO risk allele also has a substantial effect on brain structure. Participants who carried at least one copy of the allele had marked reductions in the volume of various brain structures compared to average volumes in non-carriers and in the general population. Carriers of the allele had, on average, an 8% deficit in the volume of the frontal lobes and a 12% deficit in occipital lobe volume. A reduction in temporal lobe volume was observed in participants with a higher body-mass index, but not in carriers of the risk allele who have a body-mass index within the normal range. Those with higher body-mass index also showed volume deficits in all the other lobes of the brain, as well as in the brain stem and cerebellum (above).

Clearly, body-mass index and the FTO risk allele can affect brain structure independently of another, because significant differences in brain structure were observed in participants carrying the allele. FTO is known to highly expressed in the brain, and particularly in the cerebral cortex, but its function is still unclear, as is the mechanism by which a change in a single base pair in the gene can exert such a significant effect on brain structure. The reduced frontal lobe volume observed in carriers of the risk allele is interesting, as it has previously been associated with impairments of so-called executive functions, as well as in several types of memory, all of which are also impaired in Alzheimer’s and other forms of dementia.

How might being overweight or obese lead to a reduction in brain volume? Inflammation could mediate the effects of obesity on the brain. Adipose (fat) tissue is known to produce chemicals called cytokines, which may contribute to neurodegeneration. It contains immune system cells called macrophages and monocytes, too, which are also implicated in Alzheimer’s.

Whatever the mechanism, the recent findings have important health implications. Obesity is a major public health concern – there are some 300 million obese, and more than 1 billion overweight, people worldwide. These studies, and others that came before them, suggest that maintaining normal body weight throughout adulthood – and especially middle age – could minimize the risk, or even prevent, the onset of dementia in later life. They also reiterate the emerging view that changing one’s lifestyle – and particularly taking regular physical excercise – is probably the most effective way of reducing the risk of dementia in later life.

Debette, S., et. al. (2010). Visceral fat is associated with lower brain volume in healthy middle-aged adults Ann. Neurol. DOI: 10.1002/ana.22062

Ho, A., et. al. (2010). A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc. Nat. Acad. Sci. 107: 8404-8409. [PDF]

Rosengren, A., et. al. (2005). Body Mass Index, Other Cardiovascular Risk Factors, and Hospitalization for Dementia. Arch. Intern. Med. 165: 321-326 [PDF]

Gorospe E.C. & Dave, J. K. (2007). The risk of dementia with increased body mass index. Age Ageing 36: 23-29. [PDF]

Comments

#1 Mills
June 16, 2010

Is the link vitamin D?

Vitamin D deficiency is linked to dementia, schizophrenia and depression and increased obesity is known to reduce serum vitamin D levels.
#2 Travis
June 16, 2010

Those are some very interesting studies!

I’m still trying to think of a mechanism which could explain why waist-to-hip ratio (WHR) is associated with increased temporal horn volume. The thing about WHR is that it’s a proxy for visceral fat, which *wasn’t* associated with temporal horn volume. I’m wondering if that could be a Type 1 error… because otherwise it’s hard to make sense of it.

The associations of BMI and body fat distribution with total brain volume are intriguing. Can inflammation cause the brain to shrink? I ask because in general, obesity (and especially abdominal obesity) is associated with enlarged organs (think fatty liver disease), rather than reduced organs. But it’s hard to find an organ that I know less about than the brain, so I’d be interested to hear more on the plausibility of obesity directly leading to smaller brain size.
#3 Noel
June 16, 2010

[there are some 300 million obese, and more than 1 billion overweight, people worldwide..]

These findings sounds scary. Although we all know well how important it is to maintain BMI and body fat at healthy level, there are always people who just simply reluctant to move their feet or change their diet habits.
#4 Mo
June 17, 2010

@Mills: Vitamin D could be involved, but the link between obesity and brain volume is likely to be far more complex than a single small molecule.

@Noel: I don’t like comments that are posted purely for promotional purposes – and yours clearly was – so I removed the hyperlink to your bike shop.

@Travis: I know very little about obesity, but what if WHR is not as good a proxy for visceral fat as we think it is? This 2007 paper suggests that skinfold measurements and waist circumference may be better determinants of body fat distribution.
#5 Travis
June 17, 2010

You’ll get no argument from me that WHR is a less-than-ideal measure of body fat distribution (although the paper you mention above didn’t actually measure visceral fat).

So if we agree that WHR isn’t the ideal measure of body fat distribution, how to make sense of the finding that this one weak measure is associated with temporal horn volume, when other far superior measures like visceral fat itself are not? (the study above used a ratio of total central-to-peripheral fat mass, which in general is a much weaker correlate of metabolic health than visceral fat itself)

Travis
#6 Monado
June 17, 2010

On the other hand, maybe early dementia starts with a tendency to eat whatever you damn well want.
#7 speedwell
June 18, 2010

Is weight loss surgery (with successful weight loss) linked to a reversal (or stopping) of brain shrinkage and dementia?
#8 Crazy Mermaid
June 24, 2010

It’s too bad that I didn’t have a baseline brainscan MRI done before the onset of my mental illness so that I could have compared it to my current one. It would have been enlightening to see whether/how much my temporal horn increased in size upon the onset of my mental illness.
#9 peter vd berg
July 11, 2010

Typical case of nonsense correlation. It’s getting a bit pathetic the lengths vendors of diets/surgery/pills/sport go to scare people in buying their products.

It’s almost like global warming, obesity causes every affliction known to man:

The hypothesis that obesity is detrimental to the health.

It doesn’t take much reading to discover this to be completely false but nevertheless time and time again we are brainwashed that we must be slim, be sportive, eat healthy.

So how is it nevertheless possible that we’re brainwashed to believe so, to go so far as to take cholesterol lowering medication, whose dangerous side effects far outweigh the benefits (if any) whereas there only is a correlation between CVD, but no causal relation has ever been proven.
http://petrossa.wordpress.com/2010/04/16/the-disease-fat-does-not-exist/
#10 Dr George
July 14, 2010

Working at the coal face I am often asked by my patients, what does this mean to me?
There is a lot of scary information out there, between the cardiac risks, diabetes, osteoarthritis I am already able to demonstrate my patients are suffering I just don’t think I will be promoting this information too hard to my patients.

I think the work of doctors is already cut out when it comes to promoting healthy activities so I am working hard to highlight the risks of doing nothing but then working hard to find ways to help reinforce ways to help reverse, well what I hope to reverse, the effects of damage already done.

Bit more carrot a little less stick? Seems to get a little more traction with my patients.

G
#11 geatteGrano
September 25, 2010

so informative, thanks to tell us.
#12 Miriam Gordon
April 1, 2011

Thanks, Mo, for another fascinating post. Obviously you saw from Twitter that I have a keen interest in the science of obesity. I have a Ph.D. in developmental and molecular biology, and have since also turned science writer.

As a biological scientist who has struggled with my weight for many years, I’ve come to accept my body as it is, and do what I can to keep myself healthy. Of all the stuff I’ve learned over the last few years, inflammation does indeed have very serious consequences in obesity. I’ve also learned, as you mentioned in the last sentence of your post, that physical activity is KEY to maintaining good health in obese people. It literally reverses insulin resistance, and has a remarkably efficient effect on visceral fat, which is by far the most dangerous fat tissue in the body.

I attended a weight loss program, from 2004 – 2007, at Columbia University/St. Luke’s New York Obesity Research Center. It is run by 3 people: a dietitian, an exercise physiologist, and a cognitive psychologist. At one of our weekly meetings, the exercise physiologist, Rich Weil, showed us a pair of remarkable human abdominal CT scans taken just before and one half hour after moderate cardiovascular exercise – after exercise, the visceral fat was reduced by about 75%. I will never forget this image. Visceral fat is extremely sensitive to exercise. So there are many good reasons for obese people to have hope for a healthy life, even in old age. Waist circumference is an easy, cheap, and very poor substitute for measuring visceral fat. Many health professionals figure that most “people of girth” don’t exercise anyway, so they take if for granted that these people have disproportionately high levels of visceral fat. If these people are indeed sedentary, then that’s probably true. But it’s not true if they exercise regularly. Lifestyle changes, including learning to eat healthier and increasing self-esteem regardless of body size goes a long way to improve health in general.

The reason I’m so passionate about this topic is not only for my own self-interest, but to combat the extreme prejudice that obese people encounter in Western society. The stress from this alone is a huge factor in decreasing the mental and physical health of fat people. Rebecca Puhl of the Rudd Center for Obesity at Yale has done some terrific work on this. Scientists in the field of obesity research are realizing that no matter how much they may have attributed obesity to sloth and gluttony on the part of the individual, there is much more that is as yet unknown. In our obesogenic society, those who are genetically predisposed to obesity will become obese despite their most valiant, repeated efforts at weight loss (and the more “yo-yo dieting cycles, the worse the obesity gets.

This society wrongly believes that anyone can be thin if they try hard enough. Generations of experience tell us otherwise. Rudy Leibel, one of the scientists who first cloned the leptin gene, confirmed this. There is much work to be done. Hopefully we will all move toward a society that is healthier for all of us, with the help of objective scientific inquiry.

Thanks for getting me juiced up for more blogging! I haven’t posted anything on my Fat Science blog for over a year. I might just start up again!
#13 George
April 28, 2011

This is ridiculous journalism, although I give credit for using the word “association”. This does not mean obesity causes temporal lobe or any other brain anomaly. What if the anomaly caused people to eat more trying to self medicate? Way too premature and irresponsible to highlight these so-called studies and allow suggestive headlines to be written!