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Review

Obesity and brain illness: from cognitive and psychological evidences to obesity paradox

, , , , , , , , & show all
Pages 473-479 | Published online: 21 Nov 2017

Abstract

Recent findings showed that obesity represents an additional risk factor to developing brain illness such as cognitive impairments and psychopathological disorders. However, some benefits of overweight in the elderly have been identified and an “obesity paradox” has been shown. Currently, it is still unknown how obesity and brain functioning could be linked, and the process by which body fat independently injures cognitive abilities and psychological well-being remains unclear. To establish the independent role of obesity on cognitive abilities and mental health, clarifying the role played by several factors and understanding their interaction is essential. In this review, we discuss the relationship between obesity and brain illness and underline the role played by confounders and other covariates to determine this link.

Introduction

In the past decades, worldwide obesity gradually increased and World Health Organization formally recognized this condition as a global epidemic.Citation1,Citation2

Recent readings estimate worldwide incidence of obese adults at 10.8% for men and 14.9% for women, increasing from 857 million in 1980 to 2.1 billion in 2013 for both developing and developed countries. In the same time frame, overweight people increased from 28.8% to 36.9% (men) and from 29.8% to 38% (women). However, different sex and age patterns between countries are observed. The prevalence is also rising in children and adolescents, increasing from 8.1% in 1980 to 12.9% in 2013 in boys and 8.4% to 13.4% in girls.Citation3

Obesity negatively affects most bodily systems and boosts the risk of many chronic diseases, including type 2 diabetes, metabolic syndrome, hypertension, dyslipidemia, hyperinsulinemia, coronary artery disease, cardiovascular disease, osteoarthritis, chronic kidney disease, many forms of cancer (e.g., endometrial, esophageal, renal cell, pancreatic, ovarian, breast, colorectal, thyroid, malignant melanoma, etc.), nonalcoholic steatohepatitis, sleep apnea, depression and other psychiatric disorders.Citation4Citation9

Furthermore, recent findings showed that obesity may also affect cognitive function, and higher body mass index (BMI), especially in midlife, might increase the risk of developing dementia, or other cognitive impairments, later in life.Citation10Citation13

However, despite these findings, some benefits of overweight in the elderly have been identified,Citation14 and an “obesity paradox” in the past years has been shown.Citation15

Currently, it is still unknown how weight increase and brain functioning could be linked, and the process by which obesity injures cognitive abilities and psychological well-being remains unclear.

To establish the independent role of obesity on brain physiology, it is necessary to clarify the role played by several factors and understand their interaction, which is essential to plan future studies.

This review, conducted in line with the American Psychiatric Association practice guidelines, focuses on the relationship between obesity, cognitive decline (CD) and psychological disorders and underlines the role played by confounders and other covariates to determine this link.

Obesity and CD

To better understand the role played by obesity to affect cognitive functioning is essential to examine how weight increase interacts with brain physiology.

Structural integrity is reflected by brain substructure volumes and represents a major hallmark of underlying neuronal health. Tissue loss occurs with normal aging, but it is more marked in dementia cases.Citation16,Citation17

Recent findings showed that obesity additively afflicts the brain structure of cognitively impaired patients and is linked to poor brain volumes even in cognitively normal elderly subjects.Citation18

In a longitudinal study group from overweight and obese female patients, temporal lobe atrophy was estimated from 13% to 16% for each BMI unit increase.Citation19 In a structural brain mapping cohort study of 700 cognitively impaired patients (mild cognitive impairment [MCI] and Alzheimer’s disease [AD]), higher BMI was related to decreased brain volume in frontal, temporal, parietal, and occipital lobe regions, proving an additional burden on the brain structure. Further, whole brain analysis estimated brain tissue reduction from 0.5% to 1.5% for each BMI unit increase, even after controlling for relevant confounders (i.e., sex, age, level of education), and AD caused widespread brain volume deficits and ventricular expansion (other features of brain tissue loss) compared with MCI.Citation20

Brain scanning studies demonstrated that obese individuals had significantly lower gray matter density in the post-central gyrus, frontal lobe, putamen, and middle frontal gyrus when compared with normal weight.Citation21

Greater body adiposity in otherwise healthy subjects was related with lower brain volumes in hippocampus area, orbital frontal cortex and parietal lobes.

Cross-sectional studies showed that elevated waist–hip ratio and greater BMI were linked to reduced hippocampal volume and tissue loss of temporal lobe.Citation22Citation24

A further analysis in over 1400 healthy Japanese showed negative correlation between brain volume and obesity, highlighting lower brain gray matter ratio of temporal, occipital and frontal lobes and the anterior lobe of cerebellum.Citation25

Several studies have found that obesity in midlife is related with an increased risk of CD in the elderly, and, according to these findings, consistent neuropathological studies showed either hippocampal brain atrophy or executive disfunction.Citation26;Citation116Citation119 It is well recognized that hippocampal formation played a key role in learning and memory,Citation27,Citation28 it is particularly affected by agingCitation29Citation31 and that low volume of this region predicts cognitive impairment and dementia in general people.Citation32Citation37

However, the exact underlying mechanisms by which obesity increases the risk of AD remains to be fully understood, but some explanations are available.

Neuropathological features of AD, such as amyloid plaques and neurofibrillary tangles,Citation38 are even more stated in elderly obese people when compared with normal-weight subjects. In a cohort study, greater levels of β-amyloid, the main component of amyloid plaques, protein precursor and expression of tau, were present in the hippocampal region of morbidly obese patients without cognitive damage when compared with non-obese controls.Citation39

A possible connection between midlife obesity and development of AD in the elderly is represented by increased levels of adipose tissue, which could modify β-amyloid metabolism. Plasma amyloid proteins have been found in obesity,Citation40,Citation41 and it is suggestive of increased risk of AD.Citation42

Furthermore, high-fat diet may independently increase either body fat or dementia risk.Citation43 In a prospective study from 939 individuals aged ≥65 years, greater caloric intake was related to higher AD risk in the subsequent 6.3-year follow-up.Citation44 High-fat diet (fatty acids and sugars) may also interact with brain physiology, harming the integrity of blood–brain barrier (BBB),Citation45 which plays a key role in protecting the central nervous system (CNS) from blood-borne toxins.Citation46 AD and vascular dementia (VaD) are linked with BBB dysfunction,Citation47 and longitudinal study showed that midlife obesity was also correlated with lower BBB integrity.Citation48

Higher levels of white adipose tissue could increase systemic inflammation and may provide CD and dementia.Citation49 Adipocytes, lymphocytes and macrophages leading to production of pro-inflammatory cytokines and subsequent increase in tumor necrosis factor-α.Citation50Citation53,Citation115 Indeed, central inflammation is observed after high-fat feeding, especially in the hypothalamus region.Citation54 Further, systemic inflammation has been shown to be linked to vascular disease,Citation55 obesity, poorer cognitive performance and dementia.Citation56,Citation57 It was demonstratedCitation58 that the outcomes of metabolic syndrome on cognitive performance were mediated by inflammation, and that combined effects of high inflammation and metabolic syndrome had a greater risk of CD. However, the direction of the associations between inflammation and dementia is unclear.Citation59

Finally, the effects of obesity on brain physiology are further observed in principal mediators of the CNS, such as microglia and astrocytes.

Obesity and psychopathology

Several studies suggest that subjects with severe psychiatric disorders are more likely than general population to be obese.Citation60 However, the link between body fat and psychiatric illness is widely discussed.

There are several studies that account for the risk of psychiatric disorders in obese individuals such as mood disorders, anxiety disorders, low self-esteem, body dissatisfaction, eating disorders and emotional problems.Citation61,Citation62 However, an extensive body of literature shows that mood disorders are most frequently related to obesity, and the incident risk of lifetime depression is significantly higher in obese persons when compared with non-obese peers, with a range from 29% to 56%.Citation63Citation65

In a study performed with more than 40,000 people, the relationship between obesity and depression varied by sex and obese men, compared with normal-weight people, reported less symptoms of major depression and suicidal ideation. A different pattern was seen for women that was 37% more likely to report depressive symptom when compared with normal-weight peers.Citation66

However, with regard to the direction of relationships between obesity and psychopathology, the studies failed to find clinically significant results. Studies that investigated whether obesity precedes depression or whether an existing mood disturbance predisposed to weight increase showed conflicting results.

In a nationally representative adolescent sample, obesity condition did not increase depression incidence 1 year later. However, depression at baseline doubled the risk of developing obesity at follow-up.Citation67

Apparently, results from longitudinal studies suggest that depression precedes obesity in adolescent girls, but not boys, and that obesity precedes depression in older adults. In a sample of 1037 New Zealanders, boys who were depressed at age 18 or 21 were less likely to be obese at age 26. Girls with late adolescent depression, however, were twice as likely to be obese at age 26.Citation68

However, other studies showed that obesity is not strongly associated with depression, or any abnormal personality characteristics and psychological traits are more widely varied within the population of obese individuals than between obese and non-obese.Citation69Citation73

The reason for controversial results seems to be a lack of consensus about how to measure psychological functioning, and a growing body of studies reminds us of the importance of considering the role played by co-morbidity of morbid obesity.

Actually, further research on this issue is needed.

The obesity paradox

Several studies have provided empirical evidence that obesity in midlife represents a risk factor for cognitive diseases later in life, such as MCI, VaD and AD.Citation74Citation78

Higher midlife BMI is heavily predictive of both AD and VaD, independent of other comorbidities (e.g., stroke, cardiovascular diseases and diabetes), and compared with normal-weight individuals, obesity at age 40–45 years increases the risk of developing dementia by 74% in the elderly.

In a prospective cohort study, high BMI assessed in middle age was independently linked with cognitive impairment in a sample aged 33–62 years in the subsequent 5-year follow-up,Citation79 and subjects with BMI above the third quartile during middle age had 59% greater risk of suffering dementia during old age.

These results collectively suggest that midlife obesity is a strong predictor of dementia in the elderly, and being obese in middle age may increase the risk for functional impairment and brain pathology.Citation80

Despite these findings,Citation81,Citation82 other studies have shown no association or even negative correlations between obesity and cognitive impairment in the elderly.Citation83Citation85

A substantial part of scientific literature in this area underlines that body fat, traditionally considered dangerous for health, might predict survival in the elderly and that even low BMI during middle age could be linked to CD in old age.Citation86Citation88

Some findings support this dissociation, highlighting an “obesity paradox”.Citation89

Continuous BMI was not linked to cognitive impairment in some studies,Citation90Citation93 and high BMI, assessed in late life, was not related to increased risk of CD.Citation94 In a sample of 169 adults aged ≥68 years, greater BMI reduced risk of CD when compared with lower BMI subjects (<23) in a 5-year follow-up.Citation95 In a sample of 1393 elderly subjects, continuous BMI and MCI were not linked.Citation96 In an 8-year prospective investigation of 1351 subjects, higher BMI was not associated with increased dementia risk.Citation97 In a research study of 1302 patients (mean age 77.71±6.86 years), of which 905 (69.5%) without CD and 397 (30.5%) had CD, higher BMI scores reduced the risk of cognitive disorder.Citation98 Finally, underweight condition in late life (BMI <20) increased dementia risk by 60%, while being obese (BMI >30) was linked with a reduced risk of cognitive impairments.

To summarize, the studies performed in middle age show a relationship between high BMI and dementia risk, whereas those in the elderly differ. Apparently, risk estimates in middle age reversed when assessed in late life.

A recent meta-analyses performed with extensive follow-up (ranging from 3.2 to 36.0 years) showed that low BMI in midlife, compared with normal BMI, increased 1.96 times the risk of developing AD in the elderly. The relative risk to develop AD for obese midlife BMI was 2.04. Furthermore, compared with normal BMI, overweight midlife could be associated with 35% increased risk of developing AD and 33% of developing VaD in late life. These findings overall suggest that underweight, overweight and obesity in midlife increase dementia risk and that predictive ability of BMI varied over time.

Consistent with previous systematic reviews and meta-analysis from body weight and dementia,Citation99 the risks appear higher for underweight and obese BMI, suggesting a U-shaped relationship, a curvilinear association between midlife BMI and late-life dementia.

However, these inconsistencies and paradoxical findings may have several explanations.

According to Clinical Guidelines on the identification, evaluation and treatment of overweight and obesity in adults (1998), BMI ≤18.5 kg/m2 underweight condition, from 18.5 to 24.9 kg/m2 normal- or healthy-weight condition, from 25 to 29.9 kg/m2 overweight, ≥30 kg/m2 obesity and ≥40 kg/m2 morbid obesity. This index was first described by Adolphe Quetelet but involved some limitations.Citation100

Ethnicity and age, for example, affect this index because fat-free mass ratio decreases with age, especially among women.Citation101 Aging process implied that lean body mass decreases, while adipose tissue increases without weight gain. Therefore, this ratio may not be captured by BMI and not represent, in the elderly, a reliable index of adiposity.Citation102,Citation103 In other words, BMI may underestimate adiposity because with aging, lean body mass is replaced by fat.Citation104 Thus, this index is a better measure of adiposity only for younger people while, during old age, it is possible to report low BMI despite relatively high body fat. The link between increased adiposity and dementia may be weaker among older subjects who may have more body fat despite low body weight and cloud the relationship between obesity and dementia in older samples.

Alternative anthropometric tools to assess obesity in the elderly could be more effective. It has been reported that the highest quintile of sagittal abdominal diameter, evaluated in midlife, was related with a three fold increased dementia risk. Waist circumference and waist: hip ratio have been proposed as a better adiposity marker in old ageCitation105 and are also related to higher dementia risk.Citation44 Therefore, it has been suggested that low late-life BMI and waist circumference represent potentially useful preclinical markers for MCI and AD.Citation106

Another possible explanation of conflicting results is that rapid weight loss could precede diagnosis of AD and general cognitive impairment by several years.Citation107Citation109 Clinical data suggest that weight loss precedes dementia diagnosisCitation92,Citation93 and in dementia onset, obese patients lose ~50% of their pre-dementia weight.Citation110,Citation111 This implies that BMI effects on dementia may be more accurately estimated at midlife than in old ageCitation7,Citation24 because it would reflect a more valid perspective of a person’s lifelong exposure to body fat.Citation59

It is now known that underlying neuropathological changes characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles may be observed many years in advance of the onset of clinical symptoms of AD. As a result of AD, BMI may decrease and emerge earlier than cognitive symptoms.

Furthermore, weight loss occurs with a lot of comorbidities in older ageCitation112Citation114 and reflects poor health. Higher midlife BMI increases dementia risk; in old age, increased BMI could be a global marker of decreased risk. In agreement with these hypotheses, being overweight and obese in later life seems to be a protective factor from dementia. Nevertheless, many studies are required.

Conclusion

It is unclear whether obesity increases cognitive impairments independently from other risk factors, given that some experimental studies are limited by study design, variable follow-up and limited account of comorbidities.

Although previous findings have shown negative association between obesity and age-related CD, studies performed with appropriate exclusion criteria and accurate adjustment for potential collinearity seem to support the relationship.

Given the need to achieve synergies between research activities, future studies should focus on the independent role of obesity on brain functioning, taking into account a large number of covariates, such as sex, lifestyle factors (diet, physical activity, level of education, smoking, alcohol consumption), neurological disorders, mental diseases, vascular diseases, inflammatory processes, hypertension, diabetes and leptin dysregulation.

To better understand the exclusive role of obesity in enhancing CD and psychological diseases, there is a need to improve the study design by implementing clear exclusion criteria, adequate comparison groups, multivariate statistical technique and appropriate assessment of cognitive domains and psychological functions.

In this paper, we provided some insights about confounders and emphasized the need for more multivariate research.

Author contributions

All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

References

  • Caballero B The global epidemic of obesity: an overview Epidemiol Rev 2007 29 1 5 17569676
  • Mitchell NS Catenacci VA Wyatt HR Hill JO Obesity: overview of an epidemic Psychiatr Clin North Am 2011 34 717 732 22098799
  • Ng M Fleming T Robinson M Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013 Lancet 2014 384 9945 766 781 24880830
  • World Health Organization Obesity and Overweight [Fact Sheet] 2011
  • Qiu C Winblad B Fratiglioni L The age-dependent relation of blood pressure to cognitive function and dementia Lancet Neurol 2005 4 8 487 499 16033691
  • Panza F D’Introno A Colacicco AM Lipid metabolism in cognitive declineand dementia Brain Res Rev 2006 51 2 275 292 16410024
  • Whitmer RA Gunderson EP Barrett-Connor E Quesenberry CPJr Yaffe K Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study BMJ 2005 330 7504 1360 15863436
  • Grimley EJ Areosa SA Effect of the treatmentof type II diabetes mellitus on the development of cognitive impairment and dementia Cochrane Database Syst Rev 2003 1 CD003804
  • Marra L Cantile M Scognamiglio G Deregulation of HOX B13 expression in urinary bladder cancer progression Curr Med Chem 2013 20 6 833 839 23276138
  • Gustafson D Rothenberg E Blennow K Steen B Skoog I An 18-year follow-up of overweight and risk of Alzheimer disease Arch Intern Med 2003 163 13 1524 1528 12860573
  • Rosengren A Skoog I Gustafson D Wilhelmsen L Body mass index, other cardiovascular risk factors, and hospitalization for dementia Arch Intern Med 2005 165 3 321 326 15710796
  • Whitmer RA Gustafson DR Barrett-Connor E Haan MN Gunderson EP Yaffe K Central obesity and increased risk of dementia more than three decades later Neurology 2008 71 14 1057 1064 18367704
  • Beydoun MA Beydoun HA Wang Y Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis Obes Rev 2008 9 3 204 218 18331422
  • Atti AR Palmer K Volpato S Winblad B De Ronchi D Fratiglioni L Late-life body mass index and dementia incidence: nine-year follow-up data from the Kungsholmen Project J Am Geriatr Soc 2008 56 1 111 116 18028342
  • Fitzpatrick AL Kuller LH Lopez OL Midlife and late-life obesity and the risk of dementia: cardiovascular health study Arch Neurol 2009 66 3 336 342 19273752
  • Chieffi S La Marra M Messina G De Luca V Messina A Monda M β-amyloid peptide in pathogenesis of Alzheimer’s disease Curr Topics Peptide Protein Res 2011 12 65 69
  • Chieffi S La Marra M Viggiano A Messina G De Luca V Monda M. Caffeine protection against β-amyloid peptide toxicity in Alzheimer’s disease Current Topics in Peptide and Protein Research 2011 12 71 75
  • Raji CA Ho AJ Parikshak NN Brain structure and obesity Hum Brain Mapp 2010 31 353 364 19662657
  • Gustafson D Lissner L Bengtsson C Bjorkelund C Skoog I A 24-year follow-up of body mass index and cerebral atrophy Neurology 2004 63 1876 1881 15557505
  • Ho AJ Raji CA Becker JT Cardiovascular Health Study, ADNI Obesity is linked with lower brain volume in 700 AD and MCI patients Neurobiol Aging 2010 31 8 1326 1339 20570405
  • Pannacciulli N Del Parigi A Chen K Le DS Reiman EM Brain abnormalities in human obesity: a voxel-based morphometric study Neuroimage 2006 31 1419 1425 16545583
  • Jagust W Harvey D Mungas D Haan M Central obesity and the aging brain Arch Neurol 2005 62 10 1545 1548 16216937
  • Ward MA Carlsson CM Trivedi MA Sager MA Johnson SC The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study BMC Neurol 2005 5 23 16321166
  • Gorospe EC Dave JK The risk of dementia with increased body mass index Age Aging 2007 36 1 23 29
  • Taki Y Kinomura S Sato K Relationship between body mass index and gray matter volume in 1,428 healthy individuals Obesity (Silver Spring) 2008 16 119 124 18223623
  • Debette S Seshadri S Beiser A Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline Neurology 2011 77 5 461 468 21810696
  • Messina G Palmieri F Monda V Exercise causes muscle Glut4 translocation in an insulin-independent manner Biol Med 2015 7 006
  • Messina G Viggiano A Tafuri D Role of orexin in obese patients in the intensive care unit J Anesth Clin Res 2014 5 1000395
  • Jack CRJr Petersen RC Xu Y Rates of hippocampal atrophy correlate with change in clinical status in aging and AD Neurology 2000 55 484 489 10953178
  • Raji CA Lopez OL Kuller LH Carmichael OT Becker JT Age, Alzheimer disease, and brain structure Neurology 2009 73 1899 1905 19846828
  • Chieffi S Messina G La Marra M Distractor interference in visual motor tasks Costa A Villalba E Horizon in Neuroscience Research 2014 13 151 160
  • Elias MF Beiser A Wolf PA Au R White RF D’Agostino RB The preclinical phase of alzheimer disease: a 22-year prospective study of the Framingham Cohort Arch Neurol 2000 57 6 808 813 10867777
  • Amieva H Jacqmin-Gadda H Orgogozo JM The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study Brain 2005 128 Pt 5 1093 1101 15774508
  • Iavarone A Patruno M Galeone F Chieffi S Carlomagno S Brief report: error pattern in an autistic savant calendar calculator J Autism Dev Disord 2007 37 4 775 779 16900402
  • Francavilla G Abrignani MG Braschi A Physical exercise and sport activities in patients with and without coronary heart disease Monaldi Arch Chest Dis 2007 68 2 87 95 Italian 17886769
  • Francavilla VC Abricnani M Braschi A Francavilla C Utility of QT dispersion in sports medicine Medicina Dello Sport 2008 61 477 485
  • Chieffi S Messina G Villano I Exercise influence on hippocampal function: possible involvement of Orexin-A Front Physiol 2017 8 85 28261108
  • Serrano-Pozo A Frosch MP Masliah E Hyman BT Neuropathological alterations in Alzheimer disease Cold Spring Harb Perspect Med 2011 1 a006189 22229116
  • Mrak RE Alzheimer-type neuropathological changes in morbidly obese elderly individuals Clin Neuropathol 2009l 28 40 45 19216219
  • Lee YH Martin JM Maple RL Tharp WG Pratley RE Plasma amyloid-beta peptide levels correlate with adipocyte amyloid precursor protein gene expression in obese individuals Neuroendocrinology 2009 90 4 383 390 19672057
  • Jahangiri A Wilson PG Hou TF Brown A King VL Tannock LR Serum amyloid A is found on ApoB-containing lipoproteins in obese humans with diabetes Obesity (Silver Spring) 2013 21 5 993 996 23784902
  • Moroz N Tong M Longato L Xu H de la Monte SM Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus J Alzheimers Dis 2008 15 29 44 18780965
  • Anstey N Cherbuin M Budge M Young J Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies Obes Rev 2011 12 426 437
  • 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 17353383
  • Nguyen JC Killcross AS Jenkins TA Obesity and cognitive decline: role of inflammation and vascular changes Front Neurosci 2014 8 375 25477778
  • Ballabh P Braun A Nedergaard M The blood-brain barrier: an overview: structure, regulation, and clinical implications Neurobiol Dis 2004 16 1 13 15207256
  • Skoog I Wallin A Fredman P A population study on blood-brain barrier function in 85-year-olds: relation to Alzheimer’s disease and vascular dementia Neurology 1998 50 4 966 971 9566380
  • Gustafson DR Karlsson C Skoog I Rosengren L Lissner L Blennow K Mid-life adiposity factors relate to blood-brain barrier integrity in late life J Intern Med 2007 262 643 650 17986201
  • Odegaard JI Chawla A Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis Science 2013 339 6116 172 177 23307735
  • Hotamisligil GS Shargill NS Spiegelman BM Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance Science 1993 259 5091 87 91 7678183
  • Visser M Bouter LM McQuillan GM Wener MH Harris TB Elevated C reactive protein levels in overweight and obese adults JAMA 1999 282 22 2131 2135 10591334
  • Yudkin JS Stehouwer CD Emeis JJ Coppack SW C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999 19 4 972 978 10195925
  • Ouchi N Parker JL Lugus JJ Walsh K Adipokines in inflammation and metabolic disease Nat Rev Immunol 2011 11 2 85 97 21252989
  • Miller AA Spencer SJ Obesity and neuroinflammation: a Pathway to cognitive impairment Brain Behav Immun 2014 42 10 21 24727365
  • Pradhan AD Manson JE Rifai N Buring JE Ridker PM C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus JAMA 2001 286 3 327 334 11466099
  • Bruun JM Pedersen SB Kristensen K Richelsen B Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro Mol Cell Endocrinol 2002 190 1–2 91 99 11997182
  • Trayhurn P Wood IS Adipokines: inflammation and the pleiotropic role of white adipose tissue Br J Nutr 2004 92 3 347 355 15469638
  • Yaffe K Metabolic syndrome and cognitive decline Curr Alzheimer Res 2007 4 2 123 126 17430234
  • Hassing Overweight in midlife and risk of dementia: a 40-year follow-up study Int J Obes (Lond) 2009 33 8 893 898 19506566
  • McElroy SL Kotwal R Malhotra S Nelson EB Keck PE Nemeroff CB Are mood disorders and obesity related? A review for the mental health professional J Clin Psychiatry 2004 65 5 634 651 15163249
  • Onyike CU Crum RM Lee HB Lyketsos CG Eaton WW Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey Am J Epidemiol 2003 158 12 1139 1147 14652298
  • Amann B Mergl R Torrent C Abnormal temperament in patients with morbid obesity seeking surgical treatment J Affect Disord 2009 118 1–3 155 160 19243838
  • Glinski J Wetzler S Goodman E The psychology of gastric bypass surgery Obes Surg 2001 11 581 588 11594099
  • Hsu LK Benotti PN Dwyer J Nonsurgical factors that influence the outcome of bariatric surgery: a review Psychosomat Med 1998 60 3 338 346
  • Kolotkin RL Crosby RD Pendleton R Stong M Gress RE Adams T Healthrelated quality of life in patients seeking gastric bypass surgery vs non-treatment-seeking controls Obes Surg 2003 13 3 371 377 12841896
  • Carpenter KM Hasin DS Allison DB Faith MS Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study Am J Public Health 2000 90 2 251 257 10667187
  • Goodman E Whitaker RC A prospective study of the role of depression in the development and persistence of adolescent obesity Pediatrics 2002 110 3 497 504 12205250
  • Richardson LP Davis R Poulton R A longitudinal evaluation of adolescent depression and adult obesity Arch Pediatr Adolesc Med 2003 157 8 739 745 12912778
  • Maddi SR Fox SR Khoshaba DM Harvey RH Lu JL Persico M Reduction in psychopathology following bariatric surgery for morbid obesity Obes Surg 2001 11 6 680 685 11775564
  • Black DW Goldstein RB Mason EE Prevalence of mental disorder in 88 morbidly obese bariatric clinic patients Am J Psychiatry 1992 149 2 227 234 1734744
  • Papageorgiou GM Papakonstantinou A Mamplekou E Terzis I Melissas J Pre- and postoperative psychological characteristics in morbidly obese patients Obes Surg 2002 12 4 534 539 12194547
  • Assari SJ Association between obesity and depression among American Blacks: role of ethnicity and gender J Racial Ethn Health Disparities 2014 1 36
  • Kim JY Chang HM Cho JJ Yoo SH Kim SY Relationship between obesity and depression in the Korean working population J Korean Med Sci 2010 25 11 1560 1567 21060743
  • Bramanti V Bronzi D Tomassoni D Effect of choline-containing phospholipids on transglutaminase activity in primary astroglial cell cultures Clin Exp Hypertens 2008 30 798 807 19021029
  • Bramanti V Grasso S Tomassoni D Effect of growth factors and steroid hormones on heme oxygenase and cyclin D1 expression in primary astroglial cell cultures J Neurosci Res 2015 93 521 529 25388553
  • Bramanti V Tomassoni D Grasso S Cholinergic precursors modulate the expression of heme oxigenase-1, p21 during astroglial cell proliferation and differentiation in culture Neurochem Res 2012 37 2795 2804 22956150
  • Cacopardo B Pinzone MR Berretta S Localized and systemic bacterial infections in necrotizing pancreatitis submitted to surgical necrosectomy or percutaneous drainage of necrotic secretions BMC Surg 2013 13 Suppl 2 S50 24267612
  • Viggiano A Chieffi S Tafuri D Laterality of a second player position affects lateral deviation of basketball shooting J Sports Sci 2014 32 1 46 52 23876006
  • Viggiano A Nicodemo U Viggiano E Mastication overload causes an increase in O2 - production into the subnucleus oralis of the spinal trigeminal nucleus Neuroscience 2010 166 2 416 421 20045451
  • Istvan J Zavela K Weidner G Body weight and psychological distress in NHANES I Int J Obes Relat Metlab Discord 1992 16 12 999 1003
  • Moscatelli F Valenzano A Petito A Relationship between blood lactate and cortical excitability between taekwondo atlete and non-athletes after hand-grip exercise Somatosens Mot Res 2016 33 2 137 144 27412765
  • Messina G Monda V Moscatelli F Role of orexin system in obesity Biol Med 2015 7 248
  • Ruberto M Precenzano F Parisi L Visuomotor integration skills in children affected by obstructive sleep apnea syndrome: a case-control study Acta Medica Mediterranea 2016 32 1659 1663
  • Roberts RE Deleger S Strawbridge WJ Kaplan GA Prospective association between obesity and depression: evidence from the Alameda County Study Int J Obes 2003 27 4 514 521
  • Roccella M Salerno M Parisi L Borderline intellectual functioning and parental stress: an italian case-control study Acta Medica Mediterranea 2016 32 1762 1765
  • Cerretani D Bello S Cantatore S Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver Pharmacol Res 2011 64 5 517 527 21864684
  • Turillazzi E Greco P Neri M Pomara C Riezzo I Fineschi V Anaphylactic latex reaction during anaesthesia: the silent culprit in a fatal case Forensic Sci Int 2008 179 1 e5 8 18468822
  • Solfrizzi V Panza F Colacicco AM Italian Longitudinal Study on Aging Working Group Vascular risk factors, incidence of MCI, and rates of progression to dementia Neurology 2004 63 10 1882 1891 15557506
  • Gustafson DR Backman K Joas E 37 years of body mass index and dementia: observations from the prospective population study of women in Gothenburg, Sweden J Alzheimers Dis 2012 28 163 171 21965312
  • Besser LM Gill DP Monsell SE Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease Alzheimer Dis Assoc Disord 2014 28 36 43 24126214
  • Kivipelto M Ngandu T Fratiglioni L Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease Arch Neurol 2005 62 1556 1560 16216938
  • Whitmer RA Gunderson EP Quesenberry CP Zhou J Yaffe K Body mass index in midlife and risk of Alzheimer disease and vascular dementia Curr Alzheimer Res 2007 4 103 109 17430231
  • Cournot M Marquie JC Ansiau D Martinaud C Fonds H Ferrieres J Ruidavets JB Relation between body mass index and cognitive function in healthy middle-aged men and women Neurology 2006 67 7 1208 1214 17030754
  • Yaffe K Kanaya A Lindquist K The metabolic syndrome, inflammation, and risk of cognitive decline JAMA 2004 292 18 2237 2242 15536110
  • Elias MF Elias PK Sullivan LM Wolf PA D’Agostino RB Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study Int J Obes Relat Metab Disord 2003 27 2 260 268 12587008
  • Gustafson DR Backman K Waern M Adiposity indicators and dementia over 32 years in Sweden Neurology 2009 73 19 1559 1566 19901247
  • Buchman AS Wilson RS Bienias JL Shah RC Evans DA Bennett DA Change in body mass index and risk of incident Alzheimer disease Neurology 2005 65 892 897 16186530
  • Stewart R Masaki K Xue QL A 32 year prospective study of change in body weight and incident dementia: the Honolulu-Asia aging study Arch Neurol 2005 62 55 60 15642850
  • Nourhashemi F Deschamps V Larrieu S Body mass index and incidence of dementia: the PAQUID study Neurology 2003 60 117 119 12525731
  • Freedman DM Ron E Ballard-Barbash R Doody MM Linet MS Body mass index and all-cause mortality in a nationwide US cohort Int J Obes (Lond) 2006 30 5 822 829 16404410
  • Curtis JP Selter JG Wang Y The obesity paradox: body mass index and outcomes in patients with heart failure Arch Intern Med 2005 165 55 61 15642875
  • Kalantar-Zadeh K Abbott KC Salahudeen AK Kilpatrick RD Horwich TB Survival advantages of obesity in dialysis patients Am J Clin Nutr 2005 82 3 909 910 16210724
  • Johnson DK Wilkins CH Morris JC Accelerated weight loss may precede diagnosis in Alzheimer disease Arch Neurol 2006 63 9 1312 1317 16966511
  • Yaffe K Fiocco AJ Lindquist K Predictors of maintaining cognitive function in older adults: the Health ABC study Neurology 2009 72 23 2029 2035 19506226
  • Komulainen P Lakka TA Kivipelto M Metabolic syndrome and cognitive function: a population-based follow-up study in elderly women Dement Geriatr Cogn Disord 2007 23 1 29 34 17068394
  • Sturman MT Mendes de Leon CF Bienias JL Morris MC Wilson RS Evans DA Body mass index and cognitive decline in a biracial community population Neurology 2008 70 360 367 17881716
  • Hughes TF Borenstein AR Schofield E Wu Y Larson EB Association between late-life body mass index and dementia: the Kame Project Neurology 2009 72 1741 1746 19451529
  • Dahl AK Lopponen M Isoaho R Berg S Kivela SL Overweight and obesity in old age are not associated with greater dementia risk J Am Geriatr Soc 2008 56 2261 2266 19093925
  • Deschamps V Astier X Ferry M Rainfray M Emeriau JP Barberger-Gateau P Nutritional status of healthy elderly persons living in Dordogne, France, and relation with mortality and cognitive or functional decline Eur J Clin Nutr 2002 56 4 305 312 11965506
  • Scarmeas N Luchsinger JA Schupf N Physical activity, diet, and risk of Alzheimer disease JAMA 2009 302 627 637 19671904
  • West NA Haan MN Body adiposity in late life and risk of dementia or cognitive impairment in a longitudinal communitybased study J Gerontol A Biol Sci Med Sci 2009 64 1 103 109 19168781
  • Doruk H Naharci MI Bozoglu E Isik AT Kilic S The relationship between body mass index and incidental mild cognitive impairment, Alzheimer’s disease and vascular dementia in elderly J Nutr Health Aging 2010 14 10 834 838 21125201
  • Messina G Di Bernardo G Viggiano A Exercise increases the level of plasma orexin A in humans J Basic Clin Physiol Pharmacol 2016 27 6 611 616 27665420
  • Villano I Messina A Valenzano A Basal Forebrain Cholinergic System and Orexin Neurons: effects on attention Front Behav Neurosci 2017 11 10 28197081
  • Franco R Zappavigna S Gigantino V Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion J Exp Clin Cancer Res 2014 33 48 24893613
  • Chieffi S Iavarone A Iaccarino L Age-related differences in distractor interference on line bisection Exp Brain Res 2014 32 11 3659 3664
  • Messina G Viggiano A Chieffi S Interaction between leptin and fat and its relationship to menopause Curr Topics Peptide Protein Res 2011 12 77 81
  • Chieffi S Villano I Iavarone A Asymmetries of Visuospatial Attention in Schizophrenia J Psychiatry 2016 19 388
  • Chieffi S Iavarone A La Marra M Memory for proprioceptive targets in bulimia nervosa J Psychiatry 2015 18 297