HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Correspondence to:

ARTICLES: R. A. Whitmer, D. R. Gustafson, E. Barrett-Connor, M. N. Haan, E. P. Gunderson, and K. Yaffe Central obesity and increased risk of dementia more than three decades later Neurology 2008; 0: 01.wnl.0000306313.89165.efv1 [Abstract]

Correspondence: Submit a response to this article

Correspondence published:

Central obesity and increased risk of dementia more than three decades later

Emanuele Cereda, Manuela Chiara Sacchi (Division of Clinical Nutrition, Niguarda Ca’ Granda Hospital, Milan, Italy) Alexis Elias Malavazos (Endocrinology Unit, Department of Medical and Surgical Sciences, University of Milan, IRCCS Policlinico San Donato, Milan, Italy)   (26 June 2008)

Central obesity and increased risk of dementia more than three decades later

Azeez Farooki   (26 June 2008)

Central obesity and increased risk of dementia more than three decades later

Nikolaos Tezapsidis, Mark A. Smith (Case Western Reserve University), J. Wes Ashford (Stanford University)   (26 June 2008)

Reply from the authors

Rachael A. Whitmer, D. R. Gustafson, E. Barrett-Connor, M. N. Haan, E. P. Gunderson, and K. Yaffe   (26 June 2008)

Central obesity and increased risk of dementia more than three decades later 26 June 2008
Emanuele Cereda, International Center for the Assessment of Nutritional Status (ICANS), University of Milan, Italy. via Botticelli 21, 20133 Milan, Italy, Manuela Chiara Sacchi (Division of Clinical Nutrition, Niguarda Ca’ Granda Hospital, Milan, Italy) Alexis Elias Malavazos (Endocrinology Unit, Department of Medical and Surgical Sciences, University of Milan, IRCCS Policlinico San Donato, Milan, Italy) Send Correspondence to journal: Re: Central obesity and increased risk of dementia more than three decades later emanuele.cereda{at}virgilio.it Emanuele Cereda, et al.	We read with interest the recent article by Whitmer et al. who provide evidence of a longitudinal link between middle-life visceral obesity and dementia risk. [1] It is now apparent that intra-abdominal fat may play a role in other health complications in addition to cardiovascular disease (CVD). Unfortunately, the underlying mechanisms are still unclear. To explain the observations that overall adiposity is linked both to cognitive decline and CVD and that concurrent CVD is often seen in older dementia patients, we recently reviewed current physiopathologic theories. [2,3] We concluded that visceral adipose tissue (VAT) is consistently implicated in cognitive decline rather than body mass index. In addition, women who experience changes in body composition and fat distribution after menopause transition are at an increased risk of AD. This is due to a stronger link to vascular factors (pro-inflammatory molecules) and metabolic complications (insulin resistance, dyslipidemia, hypertension). [3] Luchsinger et al. have hypothesized that in people over 65, a short-term (5-year follow-up) prospective association seems modified by age and is different depending on the anthropometric measure. [4] However, a life course contribution to chronic diseases is recognized. [2] The study by Whitmer et al. [1] supports the previously suggested theory [2,3] particularly when multiple adjustments for concurrent VAT-related complications (diabetes, hypertension, hyperlipidemia and CVDs) are considered. In this respect, the role of VAT as endocrine organ, which is able to release a number of mediators, appears fundamental. The confounding effect of insulin resistance should be recognized but it should also be noted that a chronic low-grade inflammation is a precondition associated with obesity duration. Reduction in VAT, particularly through physical activity, is efficacious in improving metabolic profile and inflammation. However, long-term results are difficult to maintain and protective effects are still unclear. [3] It is possible that further adjustment for physical activity would have strengthened the authors’ evidence. This warrants further investigation and anthropometric data is not readily available. Despite this study’s limitations, the suggested use of available surrogates of visceral adiposity other than sagittal abdominal diameter in a neurological setting is justified. [2] References 1. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008; (in press) 2. Cereda E, Sansone V, Meola G, Malavazos AE. Increased visceral adipose tissue rather than BMI as a risk factor for dementia. Age Ageing 2007;36:488-491. 3. Cereda E, Battezzati A, Bertoli S, Malavazos AE, Testolin G. A life-course contribution of nutrition to future cognitive decline. In: Bernhardt NE and Kasko AM editors. Nutrition for the Middle-Aged and Elderly. Hauppauge NY: Nova Science Publishers; 2008 (in press). 4. Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007;64:392-398. Disclosure: The authors report no disclosures.
Central obesity and increased risk of dementia more than three decades later 26 June 2008
Azeez Farooki, Memorial Sloan Kettering Cancer Center 1275 York Ave Box 296, New York, NY 10065 Send Correspondence to journal: Re: Central obesity and increased risk of dementia more than three decades later farookia{at}mskcc.org Azeez Farooki	I read with interest the longitudinal study [1] of US patients which adds dementia to the other well known negative outcomes associated with visceral obesity. [5] I would like to add a useful caveat: waist circumference is most accurately interpreted in the context of ethnicity. Current ATP-III criteria for metabolic syndrome define abdominal obesity as a waist circumference in men >102 cm (40 in) and in women >88 cm (35 in). [6] The International Diabetes Foundation created definitions for four different ethnic groups and may include three more groups when data become available. [7] Using ATP-III criteria, a patient of Asian origin, for example, might be misclassified as having “normal” waist circumference. For many patients with visceral obesity, losing weight through diet control and exercise is difficult but this study provides yet another motivation to pursue these therapeutic lifestyle changes. References 5. Lapidus L, Bengtsson C, Larsson B, et al. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J (Clin Res Ed) 1984;10:289:1257-1261. 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. 7. George, K, Alberti, MM, Zimmet, P, et al. The metabolic syndrome - a new worldwide definition. Lancet 2005;336:1059. Disclosure: The author reports no disclosures.
Central obesity and increased risk of dementia more than three decades later 26 June 2008
Nikolaos Tezapsidis, Neurotez, Inc. 991 Highway 22, Suite 200A, Bridgewater, NJ 08807, Mark A. Smith (Case Western Reserve University), J. Wes Ashford (Stanford University) Send Correspondence to journal: Re: Central obesity and increased risk of dementia more than three decades later ntezapsidis{at}neurotez.com Nikolaos Tezapsidis, et al.	Whitmer et al. demonstrated a significant correlation between mid-life obesity and dementia later in life and suggested that visceral adipocyte-derived factors may be neurotoxic, contributing to the slow deterioration of the CNS. [1] However, it has been shown that some of these factors including leptin may be beneficial to neurons. Leptin is capable of reducing the brain Aß load [8], is neuroprotective and improves cognitive performance of aged rodents. [9] Obesity is often characterized by some form of leptin resistance that may be attributable to CRP (C-reactive protein), which is elevated in obesity. [10] CRP can bind to leptin preventing its binding to the leptin receptor. Therefore, obese subjects may be deprived from leptin's beneficial action, propagating obesity and neurodegeneration. It has also been documented that obese individuals who eventually developed AD may experience a loss in weight prior to the onset of dementia. [11] A gradual selective neuronal loss in the hippocampus, hypothalamus, or both due to the absence of centrally acting leptin may lead to disturbances in appetite. In AD patients, leptin levels are reduced whereas blood CRP levels are normal so leptin therapy may benefit AD patients. Additional benefits may include ability to increase insulin sensitivity and alleviate insulin resistance which are common in AD. References 8. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. Faseb J 2004;18:1870-1878. 9. Harvey J. Leptin: a diverse regulator of neuronal function. J Neurochem 2007;100:307-313. 10. Chen K, Li F, Li J, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 2006;12:425-432. 11. Gustafson S. Adiposity indices and dementia. Lancet Neurol 2006;5:713-720. Disclosure: Dr. Tezapsidis is the founder of Neurotez, Inc., a private CNS biotechnology corporation (www.neurotez.com) that is pursuing leptin as a novel therapeutic for AD. Drs. Mark Smith and Wes Ashford are affiliated with Neurotez, Inc.
Reply from the authors 26 June 2008
Rachael A. Whitmer, Kaiser Permanente Division of Research Oakland, CA, D. R. Gustafson, E. Barrett-Connor, M. N. Haan, E. P. Gunderson, and K. Yaffe Send Correspondence to journal: Re: Reply from the authors Rachel.Whitmer{at}nsmtp.kp.org Rachael A. Whitmer, et al.	We thank Drs. Cereda, Farooki, and Tezapsidis for their comments on our article. [1] We agree with Cereda et al. that obesity and central obesity confers with it a state of inflammation and this may also contribute to cognitive impairment and dementia risk. Unfortunately measures of physical activity were not available so it is unknown what effect this would have on the association between midlife central obesity status and dementia risk. We also concur that visceral adipose tissue itself is the likely culprit in the association between central obesity and increased dementia risk. Hopefully, future studies will investigate possible actions of visceral adipocytes on the brain and effects of an altered adipokine milieu on cognitive status. [12] Regarding comments from Farooki et al., ethnic specific anthropometric measurements are the most precise. Although there are standard ethnic specific guidelines for waist circumference in defining central obesity, there are not published ethnic specific guidelines for sagittal abdominal diameter, the anthropometric measurement used in our study. Future studies examining central obesity and disease outcomes should incorporate these guidelines. With respect to comments from Tezapsidis concerning leptin as a possible therapeutic for patients with AD, leptin has been shown to be beneficial to neurons. However, obesity is associated with ‘leptin resistance’ so it is possible that obese individuals may not respond to possible neuroprotective effects of leptin. However, a recent study in non-demented elders demonstrated that higher serum leptin levels are associated with better cognitive performance independent of total body weight and total body fat. [13] More work is needed on how states of leptin resistance as induced by chronic obesity may contribute to brain aging. References 12. Whitmer, RA. Epidemiology of Adiposity and Dementia, Current Alzheimer’s Research, 2007;4:117-122 13. Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K; for the Health ABC study. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study.Neurobiol Aging. 2008 Mar 19. [Epub ahead of print]. Disclosure: The authors report no disclosures.