Eight moderate AD patients successfully completed the study protocol meeting the criteria of spectral quality. In Table 1, the data are displayed as means ± standard deviation. Neither mI/Cr nor Cho/Cr ratios show differences in any of the four brain regions studied 16 weeks after Rivastigmine administration as compared with the baseline measure performed on week 0. However, two metabolite averaged ratios show significant differences as compared with their baseline measures. As Table 1 shows, the NAA/Cr ratio raised from 1.46 ± 0.21 to 1.96 ± 0.46 at the RFL (p<0.05) and the NAA/mI ratio increased from 1.67 ± 0.51 to 2.70 ± 1.21 at the LTL (p<0.05). Some authors have reported decreased NAA levels at the Medial Temporal Lobe in AD patients (16, 33-34, 59). Nevertheless, our results show an increase of the NAA/mI ratio at the LTL after Rivastigmine administration. The elevation of the NAA/mI ratio may reflect a decrease of the mI signal as an effect of the Rivastigmine administration instead of an increase of the NAA signal as Figure 3 shows (MRS from the AD patient identified with the number 1). In 1993, Ross and coworkers reported a 22% increase in mI levels and an 11% decrease in NAA residues at the parietal (white matter) and occipital (gray matter) cortices in AD patients as compared with healthy subjects (60). They conclude that the elevation of mI levels in mild to moderate AD patients suggests that abnormalities inherent to the inositol polyphosphate messenger pathway may occur early in the natural history of AD. Therefore, the detection of high mI and low NAA levels through the MRS examination promise to be an early diagnostic test for AD. Later, in 1995, the same research team reported that reduced levels of NAA and increased levels of mI at the occipital region (gray matter) characterized AD as compared with the significantly reduced levels of NAA but normal levels of mI found in patients with other forms of dementia (61). Finally, they proposed that the mI/NAA ratio could be used to distinguish an AD brain from a healthy brain with 83% sensitivity and 98% specificity. Recently, Renshaw et al. (62) found a reduction of the NAA levels at the anterior temporal lobe in patients diagnosed with probable AD using a short MRS test. This change was not observed in patients whose memory loss and other cognitive declines were not attributed to AD suggesting that its detection may help to diagnose AD. The research team led by Renshaw did not observe changes in NAA/mI or mI/Cr ratios. For them, the large variances within the mI values reported in the literature may be due to measurement errors, changes in the metabolite levels per se or limitations inherent to the echo time used during the studies. On the other hand, Huang et al. (34) reported increases in absolute concentration of mI at the right and left parietal lobes in mild, moderate and severe AD patients in comparison with control subjects. More recently, Herminghaus et al. (63) reported decreased total NAA levels and increased mI levels as a common hallmark for Vascular Dementia (VD) and AD, which are considered the two most common types of dementia. These authors also reported a significant increase of the mI/total Cr ratio at the mid-parietal gray matter, the parietal white matter and the superior and medial temporal gyrus from the dominant hemisphere according to the handedness of each AD patient. Chantal et al. (64) reported a statistically significant increase of the mI/H2O ratio at the right parietotemporal cortex in AD patients as compared with those who showed MCI and control subjects. The meaning of the increased mI levels in the course of AD is a fertile ground for MRS-linked research. The hypothesis proposed by Wurtman et al. (39, 49) explains the pathogenesis of AD based on cholinergic neuronal damage. However, it is possible to consider a role of mI in the course of AD that can be sustained by many evidences. For example, Stokes and Hawthome (65) noticed a marked depletion of phosphatidylinositol (PI) ? a membrane lipid ? in the postmortem brain tissue from AD patients. They granted it to a defective biosynthesis of PI. Jolles et al. (66) described a diminution in the activity of the inositol polyphosphate enzyme called phosphatidylinositol kinase. Likewise, he identified a specific defect within the inositol polyphosphate cascade in brain tissue from AD patients that may explain the impairments registered in the cholinergic activity. Other research teams (60-61, 67) reported a 20% to 30% increase in the concentration of mI (the polyol found at highest concentrations in brain tissue among other inositol-linked metabolites) in mild-to-moderate AD patients, which was not detected in other forms of dementia (61). Shonk and Ross (68) performed MRS in adults with Down's Syndrome and observed that a significant elevation of mI levels occurs before each onset of dementia without any concomitant reduction of the neuronal marker NAA. In 1999, the research team led by Huang and Rapoport corroborated these results posing that the approximately 50% higher mI levels found at the occipital and parietal regions in adults with Downís Syndrome suggest a gene dose effect from the extra 21st chromosome, where the human osmoregulatory Na+/mI cotransport gene is located (69). However, what causes the increase of mI levels in AD remains unclear. An excessive activity of the inositol monophosphatase early in AD course could result in the conversion of Inositol-1-Phosphate (IP) to mI. Inositol monophosphatase now appears to be the most intensely regulated enzyme within the IP cascade (70). An enhanced activity of the Na+/mI transporter placed on the membrane of glial cells could produce higher steady-state mI concentrations. On the other hand, an inhibition of the enzymatic conversion of mI to Phosphatidyl Inositol (PI) may explain the reduced PI levels found in the postmortem brain tissue from AD patients and the increased mI levels, as well. Figure 4 shows the individual increases of the NAA/mI ratio measured in moderate AD patients after Rivastigmine treatment. The AD patient identified with the number 8 showed no change in NAA/mI ratio between the two measurements. Only the AD patient identified with the number 7 showed a decrease in NAA/mI ratio after completing the treatment. An additional evaluation was performed in this patient on week 20, where worse cognitive status was found as compared with the other 7 patients who successfully completed the study. Therefore, the NAA/mI ratio could be used to predict the pharmacological response from AD patients to Rivastigmine. However, further investigations involving a larger number of patients are required to verify this hypothesis. Figure 5 shows the correlation between MMSE improvements and the increase of the NAA/mI ratio. A significant association between these two variables was obtained according to the Spearman rank correlation (p<0.004). Our results agree with the previous reports from several research teams, such as the ones led by Jessen et al. (71), Chantal et al. (72) and Kantarci et al. (73). Wadman and Rai (74) carried out a study that fortifies the characteristic association between decreased NAA levels and increased mI levels found at the parieto-occipital region, and cognitive impairments linked to AD. Martínez-Bisbal research team (75) reported that NAA/mI ratio provides the best area under the ROC curve for diagnosing AD with the highest sensitivity (82,5%) and specificity (72,7%). So that, exploring the benefits of using a cholinesterase inhibitor in AD patients to reduce mI levels seems to be pertinent at this point (76-80). Nowadays, it is difficult to establish a relation between the high mI levels observed in AD patients and the pathophysiology of the disease itself. Abnormal mI concentrations alter the physiology of the brain in AD patients due to the changes in the enzymatic equilibrium and the concentration of metabolites within the inositol polyphosphate cascade. These changes are, in turn, caused by variations in the mechanisms of hormone receptors, the hormone sensitivity, the hormone response or the adaptative modifications of the cellular events that require inositol-linked metabolites as second messengers. Therefore, modifying brain mI concentrations could have a beneficial effect for AD patients according to the progression of the disease. Figure 6 shows the MR spectra from the AD patient identified with the number 4. It is clearly noticeable the increase in NAA/Cr ratio measured at the RFL between the two observations (Week 0 and Week 16). The variation of the NAA/Cr ratio could be the result of an apparent recovery of the NAA signal due to the Rivastigmine administration. Previous studies have reported decreased NAA/Cr ratios and reduced absolute NAA concentrations at the hippocampus, parietal and temporal lobes in AD patients. These results coincide with the anatomic location of the damaged areas identified during the autopsies of the brain tissue from AD patients (11-12,18,20,28-30,34,37). The study of the Frontal Lobe is closely related to MCI and Picks Dementia (Frontal Lobe dementia) rather than to AD. However, in 1995, Christiansen et al. (81) used fully relaxed water signal as an internal standard in a STEAM experiment to measure [NAA], [Cho], [Cr] and [Cr + PCr] at the Frontal Lobe in 12 probable AD patients. The NAA concentration was significantly lower in probable AD patients as compared with the healthy volunteers. No significant differences were found in other metabolite concentrations. Figure 7 shows the individual increases in NAA/Cr ratio measured at the RFL after Rivastigmine treatment. Increased NAA/Cr ratio only registered at the RFL could reflect an apparent recovery of the NAA signal at the Right Hemisphere of the Brain in AD patients. Krishnan et al. (82) reported that treating AD patients with placebo was associated to relative declines in neuronal concentrations of NAA, relative loss of hippocampal volume and relative cognitive impairments. While treating them with Donepezil was associated to relative increases in neuronal NAA concentrations at certain brain regions (between Week 6 and Week 18) and a greater preservation of hippocampal volume. Figure 8 shows the improvements in the cognitive status measured in AD patients 16 weeks after Rivastigmine administration. As well, it illustrates the correlation between MMSE changes and the NAA/Cr ratio at the RFL. A significant association between these two variables was obtained according to the Spearman rank correlation (p<0.002). Once again, our data agree with the previous results reported by Krishan, who demonstrated that treating AD patients with a cholinesterase inhibitor (Donepezil) causes improvements in cognition as compared with the effects of the placebo-based treatment measured several times throughout the study. It is important to mention that decreases in NAA concentration at the Frontal Lobe have been previously reported in other conditions that may precede or coexist with AD. In 1997, Ernst and coworkers reported a 28% reduction of N-acetyl compounds at the frontal lobe in patients with frontotemporal dementia (33). More recently, Kizu et al. (83) reported decreased NAA/Cr ratios in both sides of the frontal lobe in patients with frontotemporal dementia. But, NAA levels naturally decrease at the frontal lobe as an age sign in healthy people. Brooks et al. (84) registered a 12% decrease in NAA concentration at the FL between the third and seventh decades of life in healthy subjects. Likewise, Sijens et al. (85) reported significant decreases of the NAA concentration in healthy men and women according to age correlation analyses. From now on, future research projects must go deeper into the mechanisms involved in the increase of NAA signal (NAA/Cr ratio) and the possibility of slowing down the progression of AD using Rivastigmine. These investigations must focus on verifying the hypothesis concerning how cholinesterase inhibitors, such as Rivastigmine and Donepezil, may delay the neurodegeneration or AD progression. However, we are well aware that the multiple difficulties related to the understanding of AD pathophysiology should be solved first, because the neuronal loss mechanisms still remain unclear. The results published in this report are preliminaries and must be registered again using a larger number of AD patients. For the time being, we can pose that preventing or reversing the accumulation of mI in the brain tissue from AD patients may conserve the neuronal function by inhibiting the secondary loss of NAA. mI levels at the TL appear to be a pretty specific surrogate marker for AD, although its biochemical meaning in this context is uncertain. Our results emphasize the importance of short TE measurements, which allow the evaluation of mI levels. Short echo time MRS may become a potential strong, accessible and cost-effective tool to assist the physicians in the management of patients with memory problems. It is likely to be particularly useful for the early diagnosis of AD in cases where the clinical features are not quite definitive during AD initial presentation. In fact, in 2005, Modrego et al. (86) reported that MRS is capable of predicting the conversion from MCI to probable AD. In conclusion, MRS may provide a useful tool for monitoring the therapeutic response from AD patients to Rivastigmine. The link between the Rivastigmine monitoring by MRS and the MMSE?s AD Assessment Scale Scores changes may also provide a fertile ground for developing a Rivastigmine-based therapy and predicting its efficacy to improve the cognitive status in AD patients.