Proton magnetic resonance spectroscopy can differentiate Alzheimer's disease from normal aging

doi:10.1016/S0047-6374(97)01877-0

Mechanisms of Ageing and Development

Volume 97, Issue 1, July 1997, Pages 9-14

https://doi.org/10.1016/S0047-6374(97)01877-0 Get rights and content

Abstract

In order to evaluate the pattern of proton magnetic resonance spectroscopy (¹H-MRS) in the gray and white matter of patients with Alzheimer's disease (AD) and healthy controls, a cross-sectional study was carried out on 13 consecutive AD patients and 7 healthy older subjects who were referred to the Day-Hospital for diagnostic assessment. All examinations were performed on a 1.5 Tesla whole-body scanner. Volumes of interest were selected in both the gray (temporal region) and the white (frontal region) matter. N-acetyl group, total creatine, total choline and myo-inositol were quantified referring the metabolite peak area to the unsuppressed water peak area acquired under the same conditions, and the ratio was expressed in arbitrary units. A significant decrease in N-acetyl–aspartate (NAA) in both gray and white matter and an increase in myo-inositol (mI) in gray matter of AD patients were observed. The gray matter NAA/mI ratio clearly separated the two groups. White matter mI was significantly associated with severity and duration of dementia. No association with age was documented. It can be concluded that in vivo ¹H-MRS can contribute to the knowledge of pathophysiology of AD, giving neurochemical details of both gray and white matter. In particular, the gray matter NAA/mI ratio seems to be able to differentiate normal cerebral aging from Alzheimer's disease.

Introduction

The use of proton magnetic resonance spectroscopy (¹H-MRS) in clinical settings has increased remarkably over the last decade. The non-invasive nature of this technique opens up many opportunities for studying different age-related neuropsychiatric disorders, such as Alzheimer's disease (AD), which do not have satisfactory animal models. Although biochemical data needed to interpret ¹H-MRS findings are not fully known—in contrast to the clearcut anatomic database of MR imaging—¹H-MRS has the possibility to correlate metabolite alterations with measurements of neuropathologic and clinical severity. Many neurobiological aspects of physiological and pathological aging brain do overlap, being mainly distinguishable on a quantitative basis; the lack of positive indicators of AD is also documented by clinical diagnostic procedures merely based on the exclusion of other causes of dementia. The issue of differentiating normal aging from AD, i.e. the possibility of diagnosing AD in its very early phase, has also been evaluated by means of ¹H-MRS. Some in vivo 1, 2, 3and in vitro 4, 5studies show a decrease of N-acetyl–aspartate (NAA) and an increase of myo-inositol (mI) in AD patients with respect to age matched controls. ¹H-MRS also gives the opportunity to study in vivo, separately, gray matter and white matter neurochemical characteristics. This aspect is of interest since white matter alterations seem to play an important role in the pathogenesis of age related neurodegenerative disorders, namely AD, as also shown by recent neuroradiological and histopathologic investigations [6].

With the aim of further contributing to the knowledge of the in vivo neurochemical pattern of normal aging and AD, we carried out the present investigation performing ¹H-MRS on both gray and white matter of AD patients and age-matched controls.

Section snippets

Subjects

Thirteen consecutive patients (3 male, 10 female, mean age 73.6±6, range 62–83 years) consecutively referred to our Aging Brain Centre fulfilling the NINCDS-ADRDA criteria [7]for probable AD entered the study. The stage of dementia, as assessed by means of global deterioration scale (GDS) [8]ranged from mild (GDS: 3) to severe (GDS: 6); the degree of cognitive impairment, evaluated by Mini Mental State Examination [9]ranged from mild (MMSE score: 23) to severe (MMSE score: 4); mean MMSE score

Results

Table 1 gives mean (±S.D.) values of brain metabolites measured in gray and white matter of AD patients and controls. AD patients showed a significant decrease in both gray (P<0.001) and white (P<0.02) matter NAA. mI was higher in AD patients only in gray matter (P<0.02). Creatine and choline levels were similar in the two groups. The ratio NAA/mI in gray matter was significantly different (P<0.001) in the two groups, without any overlap (range in AD group: 0.9–1.6; range in controls: 1.8–2.2,

Discussion

Proton magnetic resonance spectroscopy offers the opportunity to study separately in vivo, gray matter and white matter neurochemical characteristics, thus contributing to the knowledge of the molecular basis and progression of AD.

In our ¹H-MRS study a significant decrease of NAA both in gray and white matter, together with a significant increase of mI, was found. Gray matter NAA/mI ratio neatly separated AD patients from controls, and the increase of mI in white matter was associated with

Acknowledgements

This work was supported by Consiglio Nazionale delle Ricerche, Targeted Project on Aging.

References (16)

L.B. Miller, R.A. Moats, T. Shonk, T. Ernst, S. Woolley and B.D. Ross, Alzheimer disease: depiction of increased...
R.A. Moats, T. Ernst, T.K. Shonk and B.D. Ross, Abnormal cerebral metabolite concentrations in patients with probable...
L. Parnetti, D.T. Lowenthal, O. Presciutti et al. 1H-MRS, MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in...
W.E. Klunk, K. Panchalingam, J. Moossy, R.J. McClure and J.W. Pettegrew, N-acetyl-L-aspartate and other amino acid...
W.E. Klunk, C.J. Xu and K. Panchalingam, Analysis of magnetic resonance spectra by mole percent: comparison to absolute...
Ph. Scheltens, K. Barkhof, D. Leys, E. Wolters, R. Ravid and W. Kamphorst, Histopathologic correlates of white matter...
G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price and E.M. Stadlan, Clinical diagnosis of Alzheimer disease:...
B. Reisberg, S.H. Ferris, M.J. De Leon and T. Crook, The global deterioration scale for assessment of primary...

There are more references available in the full text version of this article.

Cited by (109)

Electrical status epilepticus in sleep: The role of thalamus in etiopathogenesis
2021, Seizure
In patients diagnosed with epilepsy, decreased ratio of N-acetyl aspartate to creatine (NAA/Cr) measured in magnetic resonance spectroscopy (MRS) has been accepted as a sign of neuronal cell loss or dysfunction. In this study, we aimed to determine whether a similar neuronal cell loss is present in a group of encephalopathy with electrical status epilepticus in sleep (ESES) patients
We performed this case-control study at a tertiary pediatric neurology center with patients with ESES. Inclusion criteria for the patient group were as follows: 1) a spike-wave index of at least 50%, 2) acquired neuropsychological regression, 3) normal cranial MRI. Eventually, a total of 21 patients with ESES and 17 control subjects were enrolled in the study. MRI of all control subjects was also within normal limits. 3D Slicer program was used for the analysis of thalamic and brain volumes. LCModel spectral fitting software was used to analyze single-voxel MRS data from the right and left thalamus of the subjects.
The mean age was 8.0 ± 1.88 years and 8.3 ± 1.70 years in ESES patients and the control subjects. After correcting for the main potential confounders (age and gender) with a linear regression model, NAA/Creatine ratio of the right thalamus was significantly lower in the ESES patient group compared to the healthy control group (p = 0.026). Likewise, the left thalamus NAA/Cr ratio was significantly lower in the ESES patient group than the healthy control group (p = 0.007). After correcting for age and gender, right thalamic volume was not statistically significantly smaller in ESES patients than in healthy controls (p = 0.337), but left thalamic volume was smaller in ESES patients than in healthy controls (p = 0.024).
In ESES patients, the NAA/Creatine ratio, which is an indicator of neuronal cell loss or dysfunction in the right and left thalamus, which appears regular on MRI, was found to be significantly lower than the healthy control group. This metabolic-induced thalamic dysfunction, which was reported for the first time up to date, may play a role in ESES epileptogenesis.
MR approaches in neurodegenerative disorders
2018, Progress in Nuclear Magnetic Resonance Spectroscopy
Citation Excerpt :
Exceptions to the finding of reduced NAA in AD are studies of occipital lobe [113], fronto-parietal cortical surface [117] and frontal grey matter voxels where NAA is reported as normal in AD [115]. These metabolic changes have been associated with clinical status with elevated mI inversely correlating to MMSE [114] and reduced NAA correlating with MMSE [117]. It must be noted for completeness that a small number of studies have failed to find any metabolic changes in AD versus controls [123,124], but studies with such negative findings are few in number.
Neurodegenerative disease is the umbrella term which refers to a range of clinical conditions causing degeneration of neurons within the central nervous system leading to loss of brain function and eventual death. The most prevalent of these is Alzheimer’s disease (AD), which affects approximately 50 million people worldwide and is predicted to reach 75 million by 2030. Neurodegenerative diseases can only be fully diagnosed at post mortem by neuropathological assessment of the type and distribution of protein deposits which characterise each different condition, but there is a clear role for imaging technologies in aiding patient diagnoses in life. Magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques have been applied to study these conditions for many years. In this review, we consider the range of MR-based measurements and describe the findings in AD, but also contrast these with the second most common dementia, dementia with Lewy bodies (DLB).
The most definitive observation is the major structural brain changes seen in AD using conventional T1-weighted (T1w) MRI, where medial temporal lobe structures are notably atrophied in most symptomatic patients with AD, but often preserved in DLB. Indeed these findings are sufficiently robust to have been incorporated into clinical diagnostic criteria. Diffusion tensor imaging (DTI) reveals widespread changes in tissue microstructure, with increased mean diffusivity and decreased fractional anisotropy reflecting the degeneration of the white matter structures. There are suggestions that there are subtle differences between AD and DLB populations. At the metabolic level, atrophy-corrected MRS demonstrates reduced density of healthy neurons in brain areas with altered perfusion and in regions known to show higher deposits of pathogenic proteins.
As studies have moved from patients with advanced disease and clear dysfunction to patients with earlier presentation such as with mild cognitive impairment (MCI), which in some represents the first signs of their ensuing dementia, the ability of MRI to detect differences has been weaker and further work is still required, ideally in much larger cohorts than previously studied.
The vast majority of imaging research in dementia populations has been univariate with respect to the MR-derived parameters considered. To date, none of these measurements has uniquely replicated the patterns of tissue involvement seen by neuropathology, and the ability of MR techniques to deliver a non-invasive diagnosis eludes us. Future opportunities may lie in combining MR and nuclear medicine approaches (position emission tomography, PET) to provide a more complete view of structural and metabolic changes. Such developments will require multi-variate analyses, possibly combined with artificial intelligence or deep learning algorithms, to enhance our ability to combine the array of image-derived information, genetic, gender and lifestyle factors.
The impact of acute and short-term methamphetamine abstinence on brain metabolites: A proton magnetic resonance spectroscopy chemical shift imaging study
2018, Drug and Alcohol Dependence
Citation Excerpt :
In the 1H MRS literature, increased mI is suggested to reflect glial proliferation (Brand et al., 1993; Bertholdo et al., 2013; Soares and Law, 2009), which is associated with neuroinflammatory response of neuroinflammatory and neurodegenerative disorders (Moats et al., 1994, Chang et al., 1997, 1999; Bertholdo et al., 2013; Chang et al., 2013). Importantly, the relationship between mI and NAA, higher mI/Cr + PCr with lower NAA/Cr + PCr, is suggested to specifically reflect neuroinflammatory processes related to neurodegeneration and not neuronal proliferation/regeneration (Berman et al., 2008; Chang et al., 1999, 1997; Ernst et al., 2000; Moats et al., 1994) The relationships found suggest that increased mI, or degree of neuroinflammation, are contingent on the duration of MA used in MAA (Gruber et al., 2008; Parnetti et al., 1997). The effects of time on acute to short-term MAA, related to within-participant changes over time, showed compromised neuronal function, integrity, bioenergetics and osmosis (Baslow, 2003; Govindaraju et al., 2000; Moffett et al., 2007; Patel and Clark, 1979; Tsai and Coyle, 1995) specifically in the right FWM.
Abuse of methamphetamine (MA) is a global health concern. Previous ¹H-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites.
Adults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift ¹H-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 ± 0.6 weeks, n = 31) and short-term MAA (5.1 ± 0.8 weeks, n = 22). The change in ¹H-MRS metabolites over time (n = 19) was also investigated. Standard ¹H-MRS metabolites are reported relative to Cr + PCr.
Acute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM.
In acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first ¹H-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA.
Lower brain and blood nutrient status in Alzhiemer's disease: Results from meta-analyses
2017, Alzheimer's and Dementia: Translational Research and Clinical Interventions
Alzheimer's disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Recently, we showed the results of the meta-analyses indicating lower plasma levels of vitamins A, B₁₂, C, E, and folate in AD patients compared with cognitively intact elderly controls (controls). Now, additional and more extensive literature searches were performed selecting studies which compare blood and brain/cerebrospinal fluid (CSF) levels of vitamins, minerals, trace elements, micronutrients, and fatty acids in AD patients versus controls.
The literature published after 1980 in Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases was systematically analyzed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to detect studies meeting the selection criteria. Search terms used are as follows: AD patients, Controls, vitamins, minerals, trace elements, micronutrients, and fatty acids. Random-effects meta-analyses using a linear mixed model with correction for age differences between AD patients and controls were performed when four or more publications were retrieved for a specific nutrient.
Random-effects meta-analyses of 116 selected publications showed significant lower CSF/brain levels of docosahexaenoic acid (DHA), choline-containing lipids, folate, vitamin B₁₂, vitamin C, and vitamin E. In addition, AD patients showed lower circulatory levels of DHA, eicosapentaenoic acid, choline as phosphatidylcholine, and selenium.
The current data show that patients with AD have lower CSF/brain availability of DHA, choline, vitamin B₁₂, folate, vitamin C, and vitamin E. Directionally, brain nutrient status appears to parallel the lower circulatory nutrient status; however, more studies are required measuring simultaneously circulatory and central nutrient status to obtain better insight in this observation. The brain is dependent on nutrient supply from the circulation, which in combination with nutrient involvement in AD-pathophysiological mechanisms suggests that patients with AD may have specific nutritional requirements. This hypothesis could be tested using a multicomponent nutritional intervention.
Imaging Approaches to Cerebral Cortex Pathology
2017, The Cerebral Cortex in Neurodegenerative and Neuropsychiatric Disorders: Experimental Approaches to Clinical Issues
Although many advances in understanding the cellular and molecular mechanisms for Alzheimer’s disease have been made in the past decades, drug development has failed to significantly improve drug treatment of the disease. This is partly because failed clinical trials have focused on efficacy in terms of cognitive improvement rather than the rigorous evaluation of putative disease mechanisms and the effect of the tested drugs on these mechanisms. The use of imaging biomarkers of neurodegenerative disease, especially those from magnetic resonance imaging (MRI) and positron emission tomography (PET), could substantially accelerate the development of novel therapeutics by providing quantitative metrics of disease progression that relate directly to the underlying pathology. Herein, new MRI and PET imaging techniques relevant to neurodegeneration are briefly introduced.
On the early diagnosis of Alzheimer's Disease from multimodal signals: A survey
2016, Artificial Intelligence in Medicine
The number of Alzheimer's Disease (AD) patients is increasing with increased life expectancy and 115.4 million people are expected to be affected in 2050. Unfortunately, AD is commonly diagnosed too late, when irreversible damages have been caused in the patient.
An automatic, continuous and unobtrusive early AD detection method would be required to improve patients’ life quality and avoid big healthcare costs. Thus, the objective of this survey is to review the multimodal signals that could be used in the development of such a system, emphasizing on the accuracy that they have shown up to date for AD detection. Some useful tools and specific issues towards this goal will also have to be reviewed.
An extensive literature review was performed following a specific search strategy, inclusion criteria, data extraction and quality assessment in the Inspec, Compendex and PubMed databases.
This work reviews the extensive list of psychological, physiological, behavioural and cognitive measurements that could be used for AD detection. The most promising measurements seem to be magnetic resonance imaging (MRI) for AD vs control (CTL) discrimination with an 98.95% accuracy, while electroencephalogram (EEG) shows the best results for mild cognitive impairment (MCI) vs CTL (97.88%) and MCI vs AD distinction (94.05%). Available physiological and behavioural AD datasets are listed, as well as medical imaging analysis steps and neuroimaging processing toolboxes. Some issues such as “label noise” and multi-site data are discussed.
The development of an unobtrusive and transparent AD detection system should be based on a multimodal system in order to take full advantage of all kinds of symptoms, detect even the smallest changes and combine them, so as to detect AD as early as possible. Such a multimodal system might probably be based on physiological monitoring of MRI or EEG, as well as behavioural measurements like the ones proposed along the article. The mentioned AD datasets and image processing toolboxes are available for their use towards this goal. Issues like “label noise” and multi-site neuroimaging incompatibilities may also have to be overcome, but methods for this purpose are already available.

View all citing articles on Scopus

View full text