• INCLUSION CRITERIA

Ethnicity: Caucasian, due to the cross-sectional analysis, upon which the present longitudinal study is based, being made up of Caucasian subjects and the lack of normative data in other racial and ethnic groups

Age 18-45 years, to minimize the confounding role of the well-known effects of aging on brain tissue composition. There is, in fact, compelling evidence from post mortem and in vivo studies that the brain shrinks with age. Neuropathological and CT and MRI morphometric studies indicated that aging predominantly and substantially affects the GM. In addition, deep WM lesions are seen on MRIs in approximately one-third of asymptomatic elderly subjects. Blood pressure also rises with increasing age and can affect brain morphology.

Several studies provided evidence of specific patterns in the structural brain correlates of aging, not only globally, between GM and WM compartments, but also locally, within regions of the brain. Therefore, to limit the confounding effect of aging on brain tissue composition, which could theoretically overlap with and confound those of weight loss, the age limit for entering the study will be 45 years.

BMI greater than or equal to 35 kg/m(2) for group 1 and less than 25 kg/m(2) for group 2.

Weight less than or equal to 150 kg (maximum weight allowed on the MRI scanning tables by the manufacturers).

EXCLUSION CRITERIA

History or clinical manifestation of:

• Current smoking
• Type 2 diabetes (according to the World Health Organization diagnostic criteria (63))
• Endocrine disorders, such as Cushing's disease, pituitary disorders, and hypo- and hyperthyroidism
• Pulmonary disorders, including chronic obstructive pulmonary disease that would limit ability to follow the protocol (investigator judgment) and obstructive sleep apnea syndrome; only subjects with mild or exercise-induced asthma on no medications or on beta-adrenergic agonists only (such as albuterol) will be allowed to enter the study
• Cardiovascular diseases, including coronary heart disease, heart failure, arrhythmias, and peripheral artery disease
• Hypertension, as diagnosed and treated by an outside physician or by sitting blood pressure measurement, using an appropriate cuff, higher than 140/90 mmHg on two or more occasions
• Gastrointestinal disease, including inflammatory bowel diseases (e.g. Crohn's disease and ulcerative colitis), malabsorption syndromes (e.g. celiac disease), gastric ulcer (active); only subjects with gastro-esophageal reflux will be allowed to enter the study
• Liver disease, including cirrhosis, active hepatitis B or C, and AST or ALT greater than or equal to 3x normal
• Renal disease, as defined by serum creatinine concentrations greater than or equal to 1.5 mg/dl and/or proteinuria greater than 300 mg/day (200 microgram/min)
• Central nervous system disease, including previous history of cerebrovascular accidents, dementia, and neurodegenerative disorders
• Cancer requiring treatment in the past five years, except for non-melanoma skin cancers or cancers that have clearly been cured or in the opinion of the investigator carry an excellent prognosis (e.g., Stage 1 cervical cancer)
• Conditions not specifically mentioned above may serve as criteria for exclusion at the discretion of the investigators

Personal and/or family history of major psychiatric disorders based upon the DSM-IV (64), including depression, schizophrenia, and psychosis, which may affect brain tissue composition independent of obesity.

Medications acting on the central nervous system and steroidal drugs within 2 months of the baseline study.

Non-steroidal anti-inflammatory drugs (NSAID), proton pump inhibitors, and anti-acids will be allowed but discontinued 3 or more days before the admission.

Alcohol and/or drug abuse (more than 3 drinks per day and use of drugs, such as amphetamines, cocaine, heroin, or marijuana).

Contra-indications for MRI, including pacemakers and/or ferromagnetic implants and claustrophobia.

Pregnancy or lactation.

All subjects will be fully informed of the aim, nature, and risks of the study prior to giving written informed consent.