1H-MRS evaluation of metabolism in Alzheimer's disease and vascular dementia

Proton magnetic resonance spectroscopy (1H-MRS) allows major metabolites to be measured noninvasively in defined regions of the living brain, and can detect biochemical abnormalities where conventional structural imaging appears normal. MRS can be performed in 10 min as part of a clinical MRI examination. Biochemical abnormalities in Alzheimer's Disease (AD), vascular dementia (VaD) and other primary degenerative dementias have been investigated using MRS. Characteristic and consistent abnormalities in AD are decreased N-acetyl aspartate (NAA) and elevated myo-inositol (mI) in the mesial temporal and parieto-occipital cortex. These are thought to represent neuronal loss/dysfunction and gliosis, in anatomic distributions which reflect early pathological involvement and atrophy patterns in AD. Less consistent disturbances of glutamine and glutamate (Glx) and choline-containing compounds (Cho) have also been reported. Similar changes are seen in VaD; mostly in white matter, whereas in AD they predominate in cortical grey matter. The regional distribution of grey matter involvement may differ between AD and other degenerative dementias. Hence, both the nature and anatomic distribution of metabolite abnormalities contribute to diagnostic discrimination with MRS. NAA/mI ratios from short echo time spectra of the posterior cingulate region cortex discriminate reliably between AD subjects, normal individuals and those with VaD, and provides a useful clinical test, as an adjunct to structural imaging. Elevated mI is detected in mild cognitive impairment (MCI) and quantitative metabolite measures correlate with degrees of cognitive impairment in AD; these suggest a possible role for MRS in early diagnosis and for surrogate biochemical markers for monitoring disease progression and therapeutic response.     

A decrease in N-acetylaspartate and an increase in myoinositol in the anterior cingulate gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease

BACKGROUND AND PURPOSE: The cognitive decline in Alzheimer's disease (AD) patients has been reported to involve alterations in the medial temporal lobe and the posterior cingulate gyrus. On the other hand, the neurochemical pathologies of the behavioral and psychological symptoms of dementia (BPSD) have not been sufficiently discussed. The aim of this study was to clarify the pathologies of BPSD in AD patients. METHODS: Thirty patients with probable AD were included and underwent the following assessments: Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Story Recall Test (SRT), Behavioral pathology in Alzheimer's disease (BEHAVE-AD) and proton MRS ((1)H-MRS). None of them had been medicated for BPSD. RESULTS: The MRS study revealed that MMSE, CDT, and SRT scores were positively related to N-acetyl-aspartate (NAA)/creatine(Cr) and negatively related to myoinositol (mI)/Cr in the posterior cingulate gyrus, but not in the anterior cingulate gyrus. On the other hand, the scores obtained in two categories of BEHAVE-AD (delusional thought/ activity disturbances) were negatively related with NAA/Cr and positively related with mI/Cr in the anterior cingulate gyrus, but not in the posterior cingulate gyrus. CONCLUSION: We conclude that BPSD and the decline in cognitive function in AD might have separate pathologies.     

The progression of Alzheimer's disease from limbic regions to the neocortex: clinical, radiological and pathological relationships

Alzheimer's disease (AD) is characterised by the gradual accumulation of neurofibrillary pathology in selected regions of the brain. Earlier studies indicate that the accumulation of neurofibrillary tangles is associated both with decline in patient's cognitive performance as well as with medial temporal lobe atrophy on CT scans. There are also indications that progression through the pathological stages of AD is associated with decline in cognitive functions. The results of this study indicate that progression of disease, especially beyond the boundaries of the limbic regions, is associated with marked decline in the cognitive performance of patients suffering from AD. However the clinical manifestations of early pathological stages are not so well defined. We also found that the atrophy of the medial temporal lobe on CT scans is related to the progression of pathology. Atrophy is most apparent when the disease reaches its isocortical stages and is not marked in the limbic stages of the disease. The additive effect of pathologies co-existing with AD is apparent in reduced cognitive scores, while the atrophy of limbic structures, as measured on CT scans, seems to be mainly attributable to AD-related pathology.     

Cognitive impairment: classification by 1H magnetic resonance spectroscopy.

1H magnetic resonance spectroscopy (MRS) allows accurate and non-invasive in vivo metabolic study, and is a useful tool for the diagnosis of different forms of dementias. Cognitive impairment pathologies have been almost exclusively studied with MRS by comparison with healthy without a global comparison amongst Alzheimer disease (AD), vascular dementia, mild cognitive impairment (MCI) and major depression patients with cognitive impairment. Whereas decrease of N-acetylaspartate (NAA) and increase myo-Inositol (mI) at different brain locations by 1H MRS are common features of AD, Choline (Cho) alterations have been inconclusive. In our study, 64 patients with cognitive impairment were evaluated by 1H MRS using two echo times (31 and 136 ms). There were statistical differences between dementia (AD and vascular dementia) and non-dementia (MCI and depression) spectra at posterior cingulate gyrus. Cho/Cr, mI/Cr and NAA/Cr have been valuables for the differentiation amongst the different cognitive impairment entities. NAA/mI provides the best area under the ROC curve with the highest sensitivity (82.5%) and specificity (72.7%) in diagnosing AD. NAA/mI and mI/Cr ratios differed amongst the four cognitive impairment degenerative pathologies. Metabolic MRS differences found amongst patients with cognitive impairment entities can be useful to differentiate between AD, vascular dementia, MCI and depression.     

MRS in relation to hippocampal volume in the oldest old

The MRS brain metabolite ratio N-acetylaspartate (NAA)/myo-inositol (mI) is reported to be decreased in AD. MRS was used to study medial temporal and parietal regions in 60 cognitively healthy subjects older than 85 years. Subjects with small hippocampal volumes, a putative risk factor for dementia, had significantly lower NAA/mI in parietal and temporal lobes compared with other subjects. Neuropsychological tests and APOE genotype did not correlate with MRS ratios. MRS measures are candidate biomarkers for dementia risk.     

Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study

BACKGROUND: Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. METHODS: The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. RESULTS: The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. CONCLUSION: These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.     

MRI and MRS alterations in the preclinical phase of murine prion disease: association with neuropathological and behavioural changes

Prion diseases are fatal chronic neurodegenerative diseases. Previous qualitative magnetic resonance imaging (MRI) and spectroscopy (MRS) studies report conflicting results in the symptomatic stages of the disease, but little work has been carried out during the earlier stages of the disease. Here we have used the murine ME7 model of prion disease to quantitatively investigate MRI and MRS changes during the period prior to the onset of overt clinical signs (20+ weeks) and have correlated these with pathological and behavioural abnormalities. Using in vivo MRI, at the later stages of the preclinical period (18 weeks) the diffusion of tissue water was significantly reduced, coinciding with significant microglial activation and behavioural hyperactivity. Using in vivo MRS, we found early (12 weeks) decreases in the ratio of N-acetyl aspartate to both choline (NAA/Cho) and creatine (NAA/Cr) in the thalamus and hippocampus, which were associated with early behavioural deficits. Ex vivo MRS of brain extracts confirmed and extended these findings, showing early (8-12 weeks) decreases in both the neuronal metabolites NAA and glutamate, and the metabolic metabolites lactate and glucose. Increases in the glial metabolite myo-inositol were observed at later stages when microglial and astrocyte activation is substantial. These changes in MRI and MRS signals, which precede overt clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.     

Functional investigation of bilateral posterior cingulate gyri using multivoxel MR spectroscopy

The exact functional correlation of each hemisphere's posterior cingulate gyrus with the symptoms of Alzheimer's disease (AD) remains unknown. We attempted to evaluate the relationship between metabolite ratios in each hemisphere's posterior cingulate gyrus and cognitive deficits, using multivoxel magnetic resonance spectroscopy (MRS). We recruited 23 patients with AD, 16 patients with amnestic mild cognitive impairment and 22 cognitively normal subjects. All patients underwent multivoxel MRS in the bilateral posterior cingulate gyri. We statistically analyzed correlations between the N-acetylaspartate/creatine ratio (NAA/Cr) in each posterior cingulate gyrus and patients' raw scores on neuropsychological tests. The NAA/Cr of each posterior cingulate gyrus correlated well with the verbal learning test scores on immediate recall and delayed recall tasks. We found that the only cognitive domain to correlate with the NAA/Cr of each posterior cingulate gyrus was verbal memory. Our results did not show any significant functional difference between right and left posterior cingulate gyri.     

In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer's disease

PURPOSE: Prior proton magnetic resonance spectroscopy (MRS) studies have consistently reported decreased brain n-acetyl aspartate (NAA) levels and increased myo-inositol (mI) levels in subjects with Alzheimer's disease (AD) relative to healthy comparison subjects. These studies have usually been conducted in small and homogeneous populations of patients with established Alzheimer's disease. Few studies have tested the usefulness of this finding in a general population seeking evaluation for memory loss and other cognitive declines. We designed a study to evaluate the significance of single-voxel proton MRS findings in these patients with memory loss and other cognitive declines. GENERAL METHOD: Thirty-five subjects with a primary complaint of memory loss and other cognitive declines were consecutively referred over a period of 13 months to a specialty clinic. Patients with a diagnosis of mild to moderate probable Alzheimer's disease (N = 22), non-Alzheimer's dementia (depression, multiinfarct dementia, Parkinson's Disease, Korsakoff's Psychosis, and bipolar disorder; N = 13), and healthy comparison subjects (N = 18) were examined with respect to possible differences in metabolites using proton MRS in a 3.4-ml anterior temporal lobe voxel. FINDINGS: The Alzheimer's disease group had 10.7% lower NAA/creatine (Cr) ratios relative to the healthy comparison group and 9.4% lower NAA/creatine relative to the non-Alzheimer's dementia group (15.0% lower NAA/creatine relative to the depression subgroup of the non-Alzheimer's dementia group). There were no significant differences in choline (Cho) or myo-inositol ratios among the groups. There were significant correlations between NAA/creatine ratios and mini-mental status exam (MMSE) scores in subjects with Alzheimer's disease (t = 2.41, p = 0.032) but not in subjects with non-Alzheimer's dementia or in its depression subgroup. CONCLUSIONS: This study found a reduction in the neuronal marker NAA in the anterior temporal lobe of patients diagnosed with probable Alzheimer's disease, using a short add-on proton MRS exam. This change was not observed in patients whose memory loss and other cognitive declines were not attributed to Alzheimer's disease, suggesting that it may aid in the diagnosis or detection of Alzheimer's disease.     

Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment

Alterations in synaptic protein stoichiometry may contribute to neocortical synaptic dysfunction in Alzheimer disease (AD). Whether perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remain unclear. We examined protein levels of synaptophysin (SYP), synaptotagmin (SYT), and drebrin (DRB) in 5 neocortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual) of people clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Normalized SYP levels were decreased approximately 35% in the superior temporal and inferior parietal cortex in severe AD compared with NCI. SYT levels were unchanged across clinical diagnosis in the cortical regions. Levels of DRB, a dendritic spine plasticity marker, were reduced approximately 40% to 60% in all cortical regions in AD compared with NCI. DRB protein was also reduced approximately 35% in the superior temporal cortex of MCI subjects, and DRB and SYP levels in the superior temporal cortex correlated with Mini-Mental State Examination and Braak scores. In contrast, DRB levels in the superior frontal cortex increased approximately 30% in MCI subjects. The differential changes in DRB expression in the frontal and temporal cortex in MCI suggest a disparity of dendritic plasticity within these regions that may contribute to the early impairment of temporal cortical functions subserving memory and language compared with the relative preservation of frontal cortical executive function during the initial stages of cognitive decline.     

Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease

Structures of the medial temporal lobes are recognized to play a central role in memory processing and to be the primary sites of deterioration in Alzheimer disease (AD). Mild cognitive impairment (MCI) represents potentially an intermediate state between normal aging and AD. Proton magnetic resonance spectroscopy (MRS) was used to examine brain metabolic changes in patients with AD and MCI in the medial temporal lobes (MTLs), parietotemporal cortices (PTCs) and prefrontal cortices (PFCs). Fourteen patients with MCI, 14 patients with mild AD and 14 age- and sex-matched control subjects were studied. Patients with AD and MCI demonstrated significant reductions of NAA/H(2)O and Cho/H(2)O in the left MTL relative to control subjects. Patients with AD showed mI/H(2)O increases relative to patients with MCI and control subjects in all six regions investigated, and a statistically significant mI/H(2)O increase was measured in the right PTC. Patients with AD and MCI demonstrated the same metabolic pattern in the left MTL, suggesting a similar pathological process underlying memory impairment. Increased mI signal appears to be a neurochemical abnormality associated mostly with AD and the dementia process. Some interhemispheric metabolite asymmetries were increased in AD patients.     

Memantine versus donepezil in mild to moderate Alzheimer’s disease: a randomized trial with magnetic resonance spectroscopy

Background and purpose: To compare memantine with the most prescribed cholinesterase inhibitor (donepezil) from a clinical viewpoint when administered in early phases of Alzheimer disease (AD), and to find out whether memantine may produce changes in brain metabolite concentrations in comparison with donepezil. Methods: In this comparative rater‐blinded parallel group randomized trial we recruited a consecutive sample of patients with probable mild to moderate AD. At baseline we carried out neuropsychological assessment with mini‐mental, Clinical Dementia Rating Scale (CDR), Blessed Dementia Rating Scale, Alzheimer’s Disease Assessment Scale, cognitive part (ADAS‐cog), neuropsychiatric inventory (NPI), and disability assessment for dementia (DAD), as well as ¹H magnetic resonance spectroscopy (MRS) in several areas of the brain. Patients were randomized to receive either donepezil or memantine for 6 months. After this elapse of time we repeated the same procedures and observed the changes in clinical scales (ADAS‐cog, NPI, DAD), as well as the changes in metabolite levels in every area of exploration (temporal, pre‐frontal, posterior cingulated (PCG), and occipital), especially those of N‐acetyl‐aspartate (NAA) which is regarded as a surrogate marker of neuronal density. Results: A total of sixty‐three patients completed the trial. We did not see significant differences in clinical scales and metabolite levels between those on donepezil (n = 32) and those on memantine (n = 31). In general, more patients worsened than improved on either of the drugs. The changes in the NAA/creatine ratio in the PCG correlated significantly with the changes in the ADAS‐cog (P = 0.004). Conclusions: Donepezil and memantine have similar modest clinical and spectroscopic effect on mild to moderate AD. MRS could be useful to monitor progression of the disease.     

Proton MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis.

The concentration of the metabolite N-acetyl aspartate (NAA), thought to be a marker of axonal loss or damage, has been shown to be reduced in lesions, as demonstrated by high signal areas on T2-weighted MRI, and in normal-appearing white matter (NAWM) in established multiple sclerosis (MS). The stage of the disease when these changes first appear is not known. To try to determine this we studied 20 patients with clinically isolated syndromes, many of whom will be at the earliest clinical stages of MS, and 20 age- and sex-matched controls with single-voxel proton magnetic spectroscopy (MRS). MRS was performed using a General Electric 1.5T Signa EchoSpeed scanner (TR 3000 ms, TE 30 ms, PRESS). Absolute metabolite concentrations were determined using the LCModel fitting software. No significant reduction of NAA concentration was evident in the NAWM of the patients (patients: median 7.3 mM; controls: median 7.7 mM; P=0.19). There was, however, a significantly lower concentration of NAA in lesions (median 6.6 mM, P=0.015). Absolute values of choline-containing compounds, creatine and myo-inositol were significantly raised in the lesions (P=0.007, P=0.011 and P=0.002 respectively). The low NAA in lesions is consistent with axonal loss, damage or dysfunction occurring focally at the earliest clinical phase of the disease. The lack of any significant reduction in NAA in patient NAWM demonstrates that more widespread axonal changes are not yet detectable at this early clinical stage. A larger cohort and follow-up will be necessary to determine whether or not MRS findings have any prognostic significance for individual patients or sub-groups. This will also enable the clarification of the time course, pathogenesis and pathophysiological significance of the development of the low NAA, which is found in the NAWM of many patients with established MS.     

1H magnetic resonance spectroscopy, cognitive function, and apolipoprotein E genotype in normal aging, mild cognitive impairment and Alzheimer's disease.

The aim of this study was to examine the associations of apolipoprotein E (APOE) genotype, metabolic changes in the posterior cingulate detected by 1H magnetic resonance spectroscopy (MRS), and neuropsychologic measures of memory and cognition both in normally aging elderly, and in patients with mild cognitive impairment (MCI) and AD. We studied 67 controls, 18 MCI and 33 AD patients. We used the Dementia Rating Scale total score (DRSTOT) as a measure of general cognitive function and the total learning from the Auditory Verbal Learning Test (AVTOT) as a measure of memory performance. No differences were noted on 1H-MRS metabolite ratios or cognitive measures across APOE genotype within control and patient groups. In controls, age was a significant predictor of both cognitive test scores, and NAA/Cr was a univariate associate of DRSTOT. All 3 1H-MRS metabolite ratios, N-acetylaspartate (NAA)/creatine (Cr), myoinositol (MI)/Cr, and NAA/MI, were univariate associates of AVTOT and DRSTOT scores in the combined MCI and AD group. In stepwise regression analyses in the combined patient group only NAA/MI entered the models. These data suggest NAA/Cr could be a modest predictor of general cognitive function in both healthy elderly and impaired patients, while MI/Cr is a more specific marker for neuropsychologic dysfunction associated with neurodegenerative disease. Among 1H-MRS measurements, the NAA/MI ratio maybe the most efficient predictor of memory and cognitive function in patients with MCI and AD.     

Regional hyperperfusion in older adults with objectively-defined subtle cognitive decline

Although cerebral blood flow (CBF) alterations are associated with Alzheimer’s disease (AD), CBF patterns across prodromal stages of AD remain unclear. Therefore, we investigated patterns of regional CBF in 162 Alzheimer’s Disease Neuroimaging Initiative participants characterized as cognitively unimpaired (CU; n = 80), objectively-defined subtle cognitive decline (Obj-SCD; n = 31), or mild cognitive impairment (MCI; n = 51). Arterial spin labeling MRI quantified regional CBF in a priori regions of interest: hippocampus, inferior temporal gyrus, inferior parietal lobe, medial orbitofrontal cortex, and rostral middle frontal gyrus. Obj-SCD participants had increased hippocampal and inferior parietal CBF relative to CU and MCI participants and increased inferior temporal CBF relative to MCI participants. CU and MCI groups did not differ in hippocampal or inferior parietal CBF, but CU participants had increased inferior temporal CBF relative to MCI participants. There were no CBF group differences in the two frontal regions. Thus, we found an inverted-U pattern of CBF signal across prodromal AD stages in regions susceptible to early AD pathology. Hippocampal and inferior parietal hyperperfusion in Obj-SCD may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain cognitive functioning relative to MCI participants, yet is also reflective of early cognitive inefficiencies that distinguish Obj-SCD from CU participants.     

Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer’s disease

Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer’s disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.     

Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD

BACKGROUND: The reduction of N-acetylaspartate (NAA) detected by proton MR spectroscopy (1H-MRS) represents a robust but unspecific marker for neuronal loss or dysfunction. OBJECTIVE: To apply 1H-MRS in two brain regions that reflect the characteristic spatial distribution of neuronal loss in AD. These regions are the medial temporal lobe (MTL), which is affected early in AD, and the primary motor and sensory cortex (central region), which is affected late in the disease and might serve as an intraindividual control region in mild to moderate disease stages. METHODS: Twenty patients and 18 volunteers underwent 1H-MRS in both brain areas. The metabolic ratios of NAA/creatine and choline/creatine were determined. Additionally, the metabolic ratios of the MTL were divided by the ratios of the central region to assess the relative change in the MTL in individual subjects. All ratios were correlated with psychometric test scores. RESULTS: A significant reduction of NAA/creatine and choline/creatine ratios was detected in the MTL of patients with AD. In the central region, no significant difference between the groups was found. NAA/creatine (MTL/central region) was reduced in patients with AD and showed a correlation with the Mini-Mental State Examination and the cognitive part of the Alzheimer Disease Assessment Scale scores. Choline/creatine (MTL/central region) did not show a significant difference between groups. CONCLUSION: Assessing the distribution of NAA/creatine reduction guided by the expected neuropathologic change can improve the role of 1H-MRS in the assessment of AD. The disease severity can be monitored by relative reduction of NAA/creatine in the MTL in comparison with an intraindividual unaffected control region.     

A review of 1H MR spectroscopy findings in Alzheimer's disease

Hydrogen-1 MR spectroscopy (MRS) studies demonstrate metabolic differences between patients who have Alzheimer's disease (AD) and cognitive normal age-matched controls. Clinical MRS also shows regional variations in metabolites between patients who have AD and those who have other dementias. Single-voxel and volumetric standard MRS techniques and automated data processing software are available for clinical MR scanners. Improvements in specificity and sensitivity of AD diagnosis, using MRS techniques as an adjunct to clinical imaging, are under evaluation. Multiparametric data analyses show, however, that metabolite changes correlate with in-vitro, postmortem, and metabolic changes and to changes in or predictions of cognitive scores.     

Brain metabolite concentration and dementia severity in Alzheimer's disease: a (1)H MRS study

OBJECTIVE: (1)H-MRS studies have shown abnormalities in brain levels of myo-inositol (mI) and N-acetyl aspartate (NAA) in AD, but the relation of these abnormalities with dementia severity was not examined. The authors sought to determine whether altered brain levels of mI and other metabolites occur in mild AD and whether they change as dementia severity worsens. METHODS: The authors used (1)H-MRS with external standards to measure absolute brain concentrations of mI, NAA, total creatine (Cr), and choline (Cho)-containing compounds in 21 subjects with AD and 17 age- and sex-matched controls in occipital and left and right parietal regions. RESULTS: Concentrations of NAA were significantly decreased, whereas mI and Cr concentrations were significantly increased in all three brain regions in subjects with AD compared with controls. Higher concentrations of mI and Cr occurred even in mild AD. A discriminant analysis of the (1)H-MRS data combined with CSF volume measurements distinguished subjects with AD, ranging from mild to severe dementia, from controls with 100% correct classification. NAA concentration, though not other metabolites, was positively correlated with Mini-Mental State Examination score. CONCLUSION: The measurements with (1)H-MRS of absolute metabolite concentrations in the neocortex showed abnormal concentrations of brain metabolites in AD; these metabolite concentrations do not necessarily correlate with disease severity. Although changes in myo-inositol and creatine occur in the early stages of AD, abnormalities of N-acetyl aspartate do not occur in mild AD but progressively change with dementia severity. Further, subjects with mild AD can be differentiated from controls with (1)H-MRS.     

Decreased glutamate + glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T

OBJECTIVE: To determine whether glutamate + glutamine (GLX) levels in the brain as measured in vivo with proton MRS at 0.5 tesla (T) distinguish between probable Alzheimer's disease and normal aging. BACKGROUND: Glutamatergic markers had been measured previously in postmortem brain tissue. Conventional proton MRS at 1.5 T cannot reliably detect the GLX resonance in vivo. The authors developed a technique at 0.5 T that is sensitive to the GLX resonance. METHODS: Metabolite ratios using creatine and phosphocreatine resonance as an internal standard were acquired from the cingulate region of 18 patients with AD and 12 healthy controls. The major resonances in the spectrum were examined: N-acetylaspartate (NAA), choline-containing compounds, myo-inositol, and GLX. The Mini-Mental State Examination (MMSE) was used to assess cognitive status. The Instrumental Activities of Daily Living Scale (Instrumental ADL) was used to assess functional status. RESULTS: Reduced ratios of GLX (-10%, p = 0.001) and NAA (-12%, p = 0.000) were found in patients with AD. Increased ratios of myo-inositol in patients with AD approached significance (+14%). GLX ratios of patients with AD were correlated with MMSE (r = 0.61, p = 0.007) and Instrumental ADL (r = 0.59, p = 0.01) scores. The combined sensitivity of NAA and myo-inositol in correctly diagnosing AD was 78%. The addition of GLX to NAA and myo-inositol increased the sensitivity to 89%. Overall diagnostic accuracy improved from 80 to 83% with the addition of GLX. CONCLUSIONS: Glutamate + glutamine reduction may be a biologic marker for AD and may be a potential aid in the early clinical diagnosis of AD.