Alzheimer's disease (AD) is a progressive neurological condition that results in the irreversible loss of neurons, particularly in the cortex and hippocampus. The clinical hallmarks are progressive impairment in memory, judgment, decision making, orientation to physical surroundings, and language. In 1906, Alois Alzheimer defined the clinicopathological syndrome that bears his name at a meeting in Munich. When he described the disorder in a woman in her early 50s, neither he nor his audience recognized that AD might ultimately turn out to be indistinguishable from common senile dementia (1, 2). Indeed, AD became generally accepted as the most common basis for senile dementia only after Blessed, Tomlinson and Roth (3) disclosed their work. 1H Magnetic Resonance Spectroscopy (MRS) is an application of Magnetic Resonance (MR) that allows in vivo noninvasive assessment of several local metabolite levels in brain tissue, such as, N-Acetylaspartate (NAA), mobile Choline moieties (Cho), Creatine (Cr) and Phosphocreatine (PCr), Glutamine/Glutamate complex (Glx), myo-inositol (mI), Lactate (Lac) and Lipids (Lip). NAA is mainly found in neurons within the central nervous system, but not in glial cells or other nonneuronal tissue. Although its exact metabolism remains unclear, NAA is generally thought to represent a marker of neuronal function (4, 5). The NAA level decreases in cases of neuronal loss or damage. The mI, a pentose sugar, appears to be a more specific marker for some types of dementia than NAA. The mI signal consists of glial metabolites that are responsible for osmoregulation. (6, 7). Elevated mI levels may mark gliosis, membrane dysfunction, cytoskeleton abnormalities and correlate with glial proliferation in inflammatory central nervous system demyelination (8). Another metabolite of interest for MRS is Cho. In the brain, the largest amount of Cho is found in the Choline-bound membrane phospholipids, which are the precursors for choline and acetylcholine synthesis. High Cho levels may reflect cellular proliferation, as in neoplasia, or myelin breakdown (9, 10). NAA decreases in a variety of neurological disorders, including AD (11-15). A decrease of the NAA/Cr ratio could indicate regional variations in AD (16-18). In patients with mild to moderate AD, NAA/Cr levels are lower than normal at the posterior cingulate gyrus, whereas they are normal at the medial occipital lobe, including the visual cortex (17). These regional patterns agree with the distribution of the neurofibrillary pathology and the associated neuronal loss, demonstrating that regional NAA/Cr levels are potential indicators of AD progression. Performing MRS assessment of the temporal lobe may be particularly useful as it is affected in the early course of disease progression (19-20). Since the medial temporal lobe, especially the hippocampus usually shows marked pathological changes in AD patients (21-23), this is likely to be the site where the greatest metabolic changes occur. In fact, extensive hippocampus pathology leading to early atrophy of this structure may be noticed during the pre-symptomatic phase of AD (24-25). Ross et al. (26-27) carried out the first study in which absolute concentrations of NAA, Cho and Cr, corrected for tissue atrophy, correlated with cognitive scores and hippocampus volume measurements. As well, Schuff et al. (28) demonstrated that the combination of hippocampus volume and hippocampus [NAA] discriminates AD more accurately than either measurement alone. It is well-known that the ratio of neurons to glial cells changes as a consequence of atrophy (29-30). MRS studies have consistently reported decreased brain NAA levels and increased mI levels in some brain regions in subjects with AD. Kantarci et al. performed MRS in healthy subjects (control group), probable AD patients and patients who showed Mild Cognitive Impairment (MCI) to measure metabolite ratios at the posterior cingulate, the left superior temporal lobe and the medial occipital lobe (17). Reduced NAA/Cr ratio and increased mI/Cr levels were found at the superior temporal lobe and posterior cingulate, in AD patients. However, an elevation of mI/Cr ratio at the posterior cingulate was the only significant discovery that resulted from comparing the MCI group with controls. These findings coincide with the pattern of development of AD (21). High mI levels have been reported suggesting an increase of glial content or membrane abnormalities in subjects with AD (31-35). It is thought that the elevation of the mI peak is related to glial proliferation and astrocytic activation in AD (31, 33, 36). Parnetti et al. reported that the increase of mI correlated with dementia severity and its duration (35). Therefore, NAA/Cr and mI/NAA ratios combination may provide a basis for a MRS-diagnose for AD (12, 37-38). Some studies have reported high Cho and Cho/Cr levels. The elevation of Cho peak may be explained as a consequence of membrane phosphatidylcholine catabolism that provides free choline for the chronically deficient acetylcholine production in AD (39-40). The alterations of membrane biochemistry that accompany AD have profound effects on the concentration of various choline-containing compounds. An increase in Cho resonance has been observed in gray matter (31, 40-41), while decreased Cho resonance has been reported in white matter (42). This raise in gray matter Cho levels has been associated with decreases in memory function (40) and regional cerebral metabolism (43). However, other studies have reported no significant changes in the Cho resonance by proton MRS performed in subjects with AD (44-45). On the other hand, according to the cholinergic hypothesis of AD, memory impairments result from the death of cholinergic neurons in the basal forebrain (46). Cholinergic neurons may be selectively vulnerable in AD, because they require choline for the synthesis of both, the neurotransmitter acetylcholine and the membrane structural component phosphatidylcholine. The autocannibalism hypothesis suggests that cholinergic neurons degrade membrane phosphatidylcholine to compensate the deficiency of free choline used for acetylcholine synthesis in AD patients (39). This hypothesis is supported by studies performed in postmortem brain tissue from AD patients that showed higher than normal cellular levels of glycerophosphocholine, a phospholipids catabolic intermediate (47, 48). Structural changes of the neuronal membrane due to degradation of membrane phosphatidylcholine may lead to cell dysfunction and death (49). Phosphomonoesters like phosphoethanolamine and phosphocholine are considered anabolic precursors of membrane phospholipids, whereas phosphodiesters like glycerol-3-phosphoethanolamine and glycerol-3-phosphocholine are known as catabolic products from the breakdown of phospholipids (50). 31P MRS performed in AD patients showed a larger-than-normal concentration of phosphomonoesters in the temporoparietal cortex (51). This observation is an evidence that phosphomonoesters and phosphodiesters ratios are abnormal in the postmortem brain tissue from AD patients (50), suggesting that regenerative processes involving phospholipids occur early in AD, whereas degenerative processes occur later. The PCr/Inorganic Phosphorus (PCr/Pi) ratio measured by 31P MRS has been lately used to distinguish AD subjects from vascular dementia patients (51). Disturbed phospholipids metabolism in AD is also suggested by MRS evidences of increased mI/Cr ratio (by 11?22%) at the parietal and occipital cortices in AD patients in comparison to controls, as the neuronal marker NAA/Cr ratio was reduced by 5?11% (36). As mI is part of the phosphatidylinositol molecule, its increased brain concentration in AD patients could reflect accelerated breakdown of phosphatidylinositol and other phospholipids. Metabolite levels correlate with cognitive scores and dementia severity (33). Therefore, metabolite levels may be used as a diagnostic tool to help differentiating AD patients from those with other forms of dementia and age-matched control subjects. Shonk et al. (12) determined that changes in the NAA/mI ratio would help to distinguish AD patients from control subjects with 83% sensitivity and 98% specificity. Likewise, he established that changes in the mI/Cr and mI/PCr ratios would help to distinguish AD subjects from elder patients with other forms of dementia with 82% sensitivity and 64% specificity. MRS has been used to predict cognitive scores at 1-year follow-up studies (37). Controlled studies have used MRS to monitor treatment effects in AD. Decreases in the Cho/Cr and Cho/PCr ratios have been demonstrated in AD patients in response to Xanomeline administration, a muscarinic agonist (52-53). Also, increases in the NAA/mI ratio have been detected in response to Donepezil, a cholinesterase inhibitor (54). Rivastigmine is a cholinesterase inhibitor with proven therapeutic efficacy in AD (4). Doraiswamy et al. concluded on his review about the role of MRS in the drug development for dementia, that MRS measurements of NAA levels combined with hippocampal volumetry could provide highly useful surrogate markers of AD progression in the trials of neuroprotective agents (4). Our study was designed to determine the usefulness of Temporal Lobe (TL) and Frontal Lobe (FL) MRS in assessing brain metabolic changes that could result from treating moderate AD patients with Rivastigmine and to correlate those changes with the modifications of the cognitive function measured by the Mini-Mental Status Exam (MMSE) (55).