0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

In Vivo Brain Concentrations of N-Acetyl Compounds, Creatine, and Choline in Alzheimer Disease FREE

Adolf Pfefferbaum, MD; Elfar Adalsteinsson, PhD; Daniel Spielman, PhD; Edith V. Sullivan, PhD; Kelvin O. Lim, MD
[+] Author Affiliations

From the Neuropsychiatry Program, SRI International, Menlo Park (Dr Pfefferbaum); Departments of Psychiatry and Behavioral Sciences (Drs Pfefferbaum and Sullivan) and Radiology (Drs Adalsteinsson and Spielman), Stanford University School of Medicine, Stanford, Calif; and the Nathan Kline Institute, Orangeburg, NY (Dr Lim).


Arch Gen Psychiatry. 1999;56(2):185-192. doi:10.1001/archpsyc.56.2.185.
Text Size: A A A
Published online

Background  Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging.

Objective  To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation.

Method  Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing.

Results  Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD.

Conclusion  Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.

Figures in this Article

ALZHEIMER DISEASE (AD) results in substantial loss of brain tissue.115 This decline is attributable to deterioration of cell processes, shrinkage of neurons, and perhaps neuronal death.10,1620 Healthy elderly individuals show an age-related gray matter volume decline in the neocortex2124 (see Guttman et al25) but their volume loss may not be accompanied by neuronal death.2629 At issue is the functionality of the tissue remaining in the brains of healthy elderly patients and patients with AD.

In vivo proton magnetic resonance spectroscopic imaging (1H MRSI) allows examination of brain tissue integrity. TheN-acetyl (NAc) peak is composed of several NAc compounds, including NAc aspartate, that are present only in living, mature neurons and not glia.30 Many studies have reported lower NAc signals in patients with AD compared with healthy elderly individuals 3133; some,3437 but not others,3843 have reported age-related decline in brain NAc in healthy people. Most studies have employed single-voxel spectroscopy31 and have expressed NAc as a ratio4447 of 1 or 2 other metabolites: creatine plus phosphocreatine (Cr), which reflects high-energy phosphate metabolism, and choline (Cho), which increases in signal intensity with membrane synthesis and degradation.48,49 Many proton spectroscopy studies assume that neither age nor AD seriously affects Cr or Cho levels and thus express data as ratios.

We developed an MRSI method to estimate absolute proton metabolite signal intensities in gray matter and white matter separately.38 Concentration, expressed as institutional signal intensity units per tissue volume, revealed more NAc in gray matter than white matter, consistent with many, 34,5056 but not all,5760 studies. Despite significant gray matter volume deficits in elderly healthy individuals, the young and elderly groups had equivalent concentrations of NAc in gray matter and white matter. By contrast, Cr and Cho concentrations demonstrated significant age effects. Cho concentrations were greater in gray matter in older controls; Cr concentrations were greater in gray matter and white matter in older subjects. These observations draw into question the use of Cr and Cho as appropriate referents for determining NAc concentration.

We applied our MRSI method to patients with AD and compared their results with those from our study of normal aging.38 We expected the patients with AD, unlike the healthy elderly controls, to have abnormally low NAc concentrations in gray matter and white matter. We also anticipated that Cho levels would be even higher in patients with AD than they were in healthy elderly controls.

The 3 study groups included 15 young controls (all men; mean [±SD] age, 25.3±2.9 years), 19 healthy elderly controls (9 men, 10 women; mean age, 73.3±4.1 years), and 16 patients with AD (6 men, 10 women; mean age, 73.4±6.0 years). All analyses were performed blind to subject identity.

The patients with AD were recruited from the Geriatric Psychiatry Rehabilitation Unit and the National Institute of Mental Health Aging Clinical Research Center at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif (Table 1). These centers have a 90.2% autopsy-confirmed AD success rate of patients who in life had a diagnosis of probable AD. Patients met National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease.61,62 Controls were recruited from the local community. Subjects were excluded if they had any significant history of psychiatric or neurological disorder unrelated to their diagnosis (stroke, closed head injury), current alcohol or other drug abuse or dependence, or a life-threatening medical condition. Screening included a psychiatric interview and medical examination; informed consent was obtained from all participants (Table 1).

Table Graphic Jump LocationTable 1. Characteristics of Patients With Alzheimer Disease

The elderly control and AD groups were matched in age and sex, were comparable in years of education (elderly control mean [±SD], 16.3±2.2 years; AD mean, 15.4±2.0 years), and achieved similar scores on the National Adult Reading Test, an estimate of premorbid intelligence (elderly control mean [±SD], 115.6±5.8; AD mean, 110.6±9.5). Patients with AD (mean [±SD] score, 19.8±4.6) had significantly lower scores than the elderly controls (mean score, 28.5±1.2) on the Mini-Mental State Examination.63

NEUROPSYCHOLOGICAL TESTS

Cognitive data were collected within 3 months (0-84 days) of magnetic resonance imaging. Brain-behavior relationships were based on tests assessing verbal and nonverbal recognition and word finding. The Warrington Recognition Test64 assessed memory for words and faces, and the modified Boston Naming Test65 assessed confrontation naming.

IMAGE ACQUISITION

In vivo proton MRSI and structural magnetic resonance imaging scans were acquired using a quadrature head coil on a 1.5-T magnetic resonance imaging scanner (5.6 System software; GE Signa, Milwaukee, Wis) with echo-speed gradient hardware (GE Medical Systems; Milwaukee, Wis) (2.2-G/cm maximum gradient amplitude, and 185-µs minimum rise time). Data were obtained with oblique anatomic prescriptions parallel to the anteroposterior commissure (AC-PC) line identified from midsagittal structural images. The image acquisition protocol and analysis are given in other studies.38

Spectroscopic Image Acquisition

A modified version of a 3-dimensional MRSI sequence using a time-varying readout gradient in the slice selection direction was used to image multiple contiguous slices.66 Excitation was accomplished with a pair of spin-echo, spectral-spatial pulses preceded by an adiabatic inversion as described in other studies.38 Collection parameters were repetition time (TR), 2 seconds; inversion time (TI), 170 milliseconds; echo time (TE), 144 milliseconds. The nominal voxel size was 1.1 cm3 and the total MRSI time was 17 minutes. Data reconstruction and metabolite estimation were performed as described elsewhere.66 Corrections for receiver gain and coil loading were made when images were reconstructed to allow comparability of metabolite signal levels between subjects.41 The final metabolite images were 16 images of 32×32 pixels each.

Shimming and Fieldmap Acquisition

An automated shimming procedure67,68 with 3 linear terms and 6 nonlinear terms was used to minimize main field variations. A final 3-dimensional fieldmap was collected at a resolution of 64×64×32 voxels (TR, 40 milliseconds; and TE, 10 milliseconds; flip angle, 20°; effective slice thickness, 6.4 mm; and field of view, 24 cm) to measure residual field inhomogeneities.

Structural Image Acquisition

A midsagittal, gradient-recalled echo image was used to compute slice positions with 0.5-mm accuracy for all 3 scans in this protocol (anatomical, fieldmap, and MRSI). Anatomic images were acquired with an axial fast-spin echo protocol (TR, 3000 milliseconds; and TE, 20/80 milliseconds; echo train length, 8; 3-mm skip, 0.2 mm; 256 × 256 pixels matrix; field of view, 24 cm; number of excitations, 1; and time, 3 minutes 18 seconds). Sixteen slices were collected, the most inferior slice beginning at the anteroposterior commissure line, corresponding to the 8 middle spectroscopic slices and providing 2 anatomical slices for each MRSI slice. Twelve of these high-resolution images, corresponding to 6 slices of metabolite data, were used in the structure/metabolite analysis.

An average imaging session with the above-described protocol took about 1 hour.

IMAGE ANALYSIS
Spectroscopic Images

Six MRSI slices were used, beginning with the slice 12.8 mm above the anteroposterior commissure line and extending superiorly (Figure 1). These slices were chosen because they had the least amount of signal loss and artifacts due to field inhomogeneity. Within these 6 slices, only pixels with good homogeneity (B0 shifts within the range of ±5 Hz) were included for analysis. These slices were also manually edited to remove regions, usually outside of the brain, of obvious lipid and/or water artifacts. To further guard against the possibility that incompletely suppressed water signal contaminated the MRSI data, especially for Cho and Cr concentrations in the medial frontal region, an exclusion region roughly corresponding to the cingulate gyrus was constructed for each slice by proportionate geometric positioning. The metabolite signals were calculated as magnitude values, so the noise in the metabolite maps had a nongaussian (Rician) noise distribution in the low signal-to-noise ratio range. To account for the effects of this nongaussian noise distribution, a bias correction was applied to the metabolite signal intensity values.69

Place holder to copy figure label and caption
Figure 1.

Left, Brain images of a 73-year-old male control. Right, Brain images of a 75-year-old male patient with Alzheimer disease. Superior to inferior brain slices are shown from left to right. Segmented image: the fast spin-echo magnetic resonance structural images are segmented into cerebrospinal fluid (dark gray), gray matter (medium gray), and white matter (light gray). Low-pass tissue image: The tissue image after low-pass filtering matches the spatial frequency characteristics of the metabolite images. The white outlines on these and the specific metabolite images below are taken from the perimeter of the structural images and indicate the registration of the metabolite image with the structural image. Images of N-acetyl compounds, creatine, and choline are of signal intensities that contribute to the quantification of each metabolite concentration.

Graphic Jump Location
Structural Images

Nonbrain (ie, dura, skull, and scalp) tissue was removed. The images were converted into segmentation maps, with each pixel designated as gray matter, white matter, or cerebrospinal fluid, and volumes were derived for each compartment. The data from each of the 2 segmented, high-resolution, structural slices corresponding to a metabolite slice were combined to provide 128 (8×8×2) segmented voxels underlying each metabolite voxel. Brain tissue composition of each subject was computed, with and without the voxels excluded in the metabolite analysis (Figure 1).

Structural and Metabolite Image Analysis

The segmented structural data were filtered to yield the same spatial frequency characteristics as the MRSI data. The optimum gray matter and white matter NAc, Cr, and Cho levels were found using a robust, least absolute deviation–regression algorithm.38 The metabolite spectrum in each voxel was assumed to be a combination of signals from tissue compartments of gray matter and white matter. The gray matter and white matter tissue composition of each spectroscopic voxel was calculated from the segmented structural data. Given this information, the signal intensity of both gray matter and white matter was estimated for each subject and each metabolite.

STATISTICAL ANALYSIS

Group differences were tested with repeated-measures analysis of variance and Student t tests. We performed exploratory correlations between metabolite measures and cognitive test scores with Pearson product-moment correlations. We report correlations that reached P<.05 or less (1 tailed), with predictions that better performance would be associated with higher concentrations of NAc and lower concentrations of Cr and Cho; family-wise Bonferonni adjustment for 3 comparisons (3 tests for each metabolite) requiredP<.03. Correlations were done for the AD and elderly control groups independently to avoid the possibility that the results would merely reflect group differences.

BRAIN TISSUE VOLUMES

The patients with AD had smaller gray matter volumes than the elderly controls, who had smaller volumes than the young controls (F2,49=115.904,P=.001). Cerebrospinal fluid volumes showed a complementary step-wise group effect (F2,49=70.966, P=.001). The overall group difference was significant for white matter (F2,49=3.476,P=.04), but only the AD group exhibited a volume deficit relative to the young and the elderly control groups (Figure 2). The pattern of group differences was virtually identical when examining only those structural voxels that corresponded to the spectroscopic voxels meeting the inclusion criteria (Table 2).

Place holder to copy figure label and caption
Figure 2.

Volumes, without metabolite criteria imposed, derived from the segmented magnetic resonance imaging structural data for each of the compartments. The 3 groups showed a stepwise increase in brain cerebrospinal fluid volume, where the young controls had the smallest volume and the patients with Alzheimer disease (AD) the largest volume; all pairwise differences were significant. Gray matter volume showed the complementary pattern of group differences. White matter volume, however, was deficient only in the AD group relative to the young and elderly control groups. Error bars indicate SEMs (young vs elderly* P≤.001; elderly vs AD †P≤.001, ‡P =.06). Please refer to Table 2 for t test results.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Structural Composition (mL) of Brain Generating Magnetic Resonance Spectroscopy Signal (Mean ± SE)
METABOLITE CONCENTRATION AND TISSUE TYPE

Despite the significant tissue volume deficit in patients with AD, the number of spectroscopic voxels meeting criteria for analysis did not differ significantly among the 3 groups (F2,49=2.399,P=.10). The concentration estimation model provided separate metabolite concentration estimates for gray matter and white matter (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Concentrations in gray matter and white matter for each brain metabolite measured. Relative to the elderly control group, the Alzheimer disease (AD) group had lower N-acetyl compounds concentrations in gray matter (*t33=2.771,P=.01) but not white atter (t33=1.419, P=.17). Creatine was higher in the gray matter of elderly controls (†t32=4.647,P=.0001) and patients with AD (‡t29=4.804, P=.001) and in the white matter of elderly controls (§t32=3.603,P=.002) and patients with AD(∥t29=2.133, P=.04) relative to the young controls, showing an age effect. Choline showed an additive age and disease effect for gray matter (¶ young vs elderly:t32=3.847, P=.02; #elderly vs AD:t33=2.552, P=.005). Error bars indicate SEMs.

Graphic Jump Location

A repeated-measures analysis of variance (3 groups by 2 tissue types) for NAc concentration yielded significant effects of group (F2,47=6.913,P=.002) and tissue type (F2,47=234.108, P=.001) but no interaction (F2,47=1.708,P=.19). The overall group difference was significant in gray matter (F2,49=5.283, P=.008); the AD group had significantly lower gray matter NAc levels than the young (P=.03) and elderly (P=.009) control groups, which did not differ from each other. The ratio of gray to white matter NAc concentration was similar for the 3 groups (young control ratio=1.31; elderly control ratio=1.38; and patients with AD ratio=1.30) (F2,49=1.024,P=.37).

For Cr concentration, a repeated-measures analysis of variance (3 groups by 2 tissue types) yielded significant group (F2,47=21.25,P=.001) and tissue-type effects (F1,47=884.214, P=.001) and interaction (F2,47=3.934,P=.03). For both tissue types, the elderly controls and patients with AD had higher Cr concentrations than the young controls (elderly vs young controls for gray matter: t32=4.678,P=.001, and for white matter: t32=3.935,P=.001; patients with AD vs young controls for gray matter: t29=4.619, P=.001, and for white matter:t29=2.572, P=.02). By contrast, the elderly control and AD groups did not differ significantly from each other in either gray matter (t33=1.065,P=.29) or white matter (t33=1.386, P=.18) Cr concentrations. Again, the ratio of gray matter to white matter Cr concentration was similar for the 3 groups (young control group ratio=1.98; elderly control group ratio=1.95; and AD group ratio=2.12) (F2,49=1.503,P=.23).

For Cho concentrations, a repeated-measures analysis of variance (3 groups by 2 tissue types) yielded a significant group effect (F2,47=10.964,P=.001) and interaction (F2,47=12.073, P=.001) and trend toward a tissue-type effect (F1,47=3.691,P=.06). Gray matter Cho concentrations were lowest in the young controls and highest in the patients with AD, and all group-paired comparisons were significant (young vs elderly: t32 =3.925,P=.001; elderly vs patients with AD: t33=2.506,P=.02; young vs patients with AD: t29=4.993,P=.001). As indicated by the interaction, white matter Cho showed a different pattern from gray matter; only the comparison between the elderly controls and patients with AD reached significance; the elderly group had higher Cho concentrations than the AD group (t33=3.074, P=.004). Unlike NAc and Cr, the ratio of gray matter to white matter for Cho concentration showed a group difference, with the value for the AD group higher (ratio=1.20) than values for the young (ratio=.79,t29=4.061, P=.001) and elderly control (ratio=.91,t33=3.362, P=.002) groups; the young and elderly controls did not differ significantly from each other (t32=1.351,P=.19).

The 3 group-by-metabolite analyses of variance were recalculated excluding women, because the younger group was composed of men only. The results were the same without the women, except that the group-by-Cr interaction was no longer significant in the men-only analysis.

CORRELATIONS BETWEEN METABOLITE CONCENTRATIONS AND COGNITIVE TEST SCORES

As expected, the AD group was impaired on the 3 cognitive measures compared with the elderly controls (Table 3). There were several brain-behavior correlations in the predicted direction. In elderly controls, face recognition scores were positively correlated with gray matter NAc concentration (r=0.80,P=.001, n=13). In patients with AD, higher Cr gray matter concentrations were related to lower word-recognition scores (r=−0.67, P=.03, n=11), and higher Cho gray matter concentrations were related to lower face recognition scores (r=−0.70,P=.02, n=11).

Independent estimation of the concentrations of NAc, Cr, and Cho revealed different patterns across the groups: NAc showed a disease effect, Cr showed an age effect, and Cho showed disease and age effects. N-Acetyl compounds concentration was significantly reduced only in AD in gray matter but not white matter, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young controls. Both the elderly healthy and AD groups had an excess of Cr in gray matter. Choline concentration in gray matter was notably higher in the elderly than in the young control group, and the AD values were even higher than those measured in the elderly controls.

While neuronal soma and processes may shrink, the current consensus is that little if any loss of neuronal cell numbers occurs in normal aging.2629 Gray matter volume deficits without NAc concentration deficit suggests normal cell integrity in the healthy elderly. Like postmortem studies,10,1620,28 the current in vivo study revealed severe gray matter volume deficits and an accompanying deficit in gray matter NAc concentration in AD.

For literature comparison, we calculated whole brain raw signal intensity NAc/Cr ratio values of 1.382, 1.274, and 1.225 for the young, elderly, and AD groups, respectively. Concentration-corrected ratios of NAc/Cr for gray matter only presented a similar pattern of 1.38, 1.229, and 1.098 for the young, elderly, and AD groups, whereas for white matter only the pattern was 2.073, 1.734, 1.743. Thus, the NAc/Cr ratio differences seen in whole-brain mixed gray-white tissue represent a decrease in the NAc/Cr ratio with aging but no additional AD effect in white matter and a further decrease in this ratio in the AD group in gray matter.

Consistent with other in vivo31,4447,7072 and ex vivo or postmortem33,54,73,74 reports, NAc concentration, whether expressed as a ratio of Cr or Cho or in absolute terms, was substantially lower in patients with AD than in age-matched controls. Kwo-On-Yeun et al54 also noted substantially more reduction in NAc in gray matter than in white matter in comparing patients with AD to controls. As in other studies, NAc signal intensity was greater in gray matter than white matter for all 3 groups in our study.

Across all 3 groups, the calculated Cr concentration in gray matter was almost twice that in white matter, whereas the Cho concentration was more uniformly distributed between gray and white matter. Given these age- and disease-related differences in metabolite concentrations for gray and white matter, it is clear that neither Cr nor Cho concentration is constant, and, thus, they should not be used without regard to age and disease effects as referents in ratio expression of the NAc signal. The 3 group comparisons—young controls, elderly controls, and elderly patients with AD—help to disentangle disease effects from effects of normal aging. The former should be superimposed on the latter. Patients with AD did not significantly differ from the elderly controls in the volume of Cr in either gray or white matter, but both groups differed from the young controls. This pattern indicates that increased Cr concentration in patients with AD is attributable to advanced age rather than to the disease. The elevated gray matter Cho concentration in AD, however, seems to be the result of the additive effects of advanced age plus disease. Chang et al39 noted decreased brain water content (noncerebrospinal fluid) with age, which could explain a relative decrease in cortical volume with the same number of cells, leading to increased metabolite concentration. Miller et al49 reported that increased choline reflects degree of cellular density in brain tumors. Adding gliosis to this aging effect could explain the additional increase in Cho level we observed in patients with AD. White matter Cho concentration showed the opposite pattern, ie, no increase with age but a decrease with AD. Moats et al71 observed age-related increases in Cho levels in normal elderly but no further differences between normal elderly and patients with AD. Our observed increased Cho concentration in gray matter may be the result of cell membrane turnover.

Pettegrew et al,75 using in vitro phosphorus 31 (31P) MRS, found elevated phosphomonoester levels in patients with AD. Brown et al76 showed that phosphomonoester, phosphomonoester/phosphodiesther, and inorganic phosphate levels were elevated in patients with AD compared with controls, whereas no significant differences in any 31P indexes were found by Bottomley et al.77 Similar findings were reported by Murphy et al.78 More recently, Gonzalez et al79 reported a 50% increase in phosphomonoester/phosphoiesther levels in patients with AD, but unchanged β-nucleoside 5‘-triphosphate, phosphocreatine, and inorganic phosphate levels in AD, speculating that the phosphodiesther difference reflected changes in the biophysical state of membrane phospholipids. Using quantitative 31P and 1H perchloric acid extracts, Klunk et al80 found increased myoinositol, aspartate, L-glutamate, alanine, phosphocholine, and phosphodiester levels, and decreased phosphoetanolamine and NAc-L-aspartate levels. They concluded that compounds related to membrane degradation and excitatory neurotransmission increased in patients with AD, while those related to neuronal integrity and inhibitory neurotransmission decreased. Pettegrew et al81 reported increased phosphomonoesther and phosphocreatine levels that preceded dementia for 1 subject.

The proton Cr signal is a combination of phosphocreatine and creatine.82 Thus, one cannot separate the contribution of creatine and phosphocreatine to the total Cr signal or relate findings directly to phosphorus spectroscopy studies, which, for instance, report a decreased ratio of phosphocreatine to inorganic orthophosphate in AD.83 Similarly, several Cho-containing compounds contribute to the Cho peak in proton magnetic resonance spectroscopy. As reviewed by Michaelis et al82 Cho plasmogen (0.6 mmol/kg), glycerophosphorylcholine (0.4 mmol/kg), phosphorylcholine (0.4 mmol/kg), cytedinediphosphate-choline (0.05 mmol/kg), acetylcholine (0.03 mmol/kg), and choline (0.02 mmol/kg) contribute to the 1MRS choline signal. Contributions from 15- to 18-mmol/L lipid-soluble phosphatidylcholine are minor.49,82 In vivo 31P MRS could clearly play an important role in identifying the sources of the observed Cho as well as Cr signals in1H MRSI.

A limitation of our method is imposed by the inhomogeneity of the main magnetic field. While we applied second-order, nonlinear shims to improve the homogeneity, the remaining field inhomogeneities, particularly in the more inferior and frontal brain regions, limit the useful extent of the observed volume. Because we apply a late-echo acquisition, metabolites with short T2 relaxation times, such as myoinositol, are not observed.

The level of brain metabolite concentration seen with 1H MRSI appears to have functional significance, given the correlations found with cognitive measures. The metabolite concentration–memory test correlations are consistent with our previous work, which showed a selective relationship between these tests and degree of hippocampal volume loss in patients with AD.3,6 Together, these results lend support to the hypothesis that the prominent disease-related increase in gray matter Cho concentration marks cellular degeneration resulting in reduced NAc concentration and poorer cognitive function in AD.

Accepted for publication October 2, 1998.

This work was supported by grants AG11427, AA05965, and MH30854 (Dr Pfefferbaum), AA10723 and MH40041 (Dr Sullivan), and RR09784 and CA48269 (Dr Spielman) from the National Institutes of Health, Bethesda, Md.

We thank the the State of California Alzheimer's Disease Research Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif, for providing subjects for the study.

Corresponding author: Adolf Pfefferbaum, MD, Neuropsychiatry Program (BN166), SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025 (e-mail: dolf@synapse.sri.com).

Tanabe  JLAmend  DSchuff  NDiSclafani  VEzekiel  FNorman  DFein  GWeiner  MW Tissue segmentation of the brain in Alzheimer disease. AJNR Am J Neuroradiol. 1997;18115- 123
Rusinek  HDe Leon  MJGeorge  AEStylopoulos  LAChandra  RSmith  GRand  TMourino  MKowalski  H Alzheimer disease: measuring loss of cerebral gray matter with MR imaging. Radiology. 1991;178109- 114
Fama  RSullivan  EVShear  PKMarsh  LYesavage  JATinklenberg  JRLim  KOPfefferbaum  A Selective cortical and hippocampal volume correlates of Mattis Dementia Rating Scale in Alzheimer disease. Arch Neurol. 1997;54719- 728
Link to Article
Jernigan  TLSalmon  DPButters  NShults  CWHesselink  JR Specificity of brain-structural changes in Alzheimer's, Huntington's, and Parkinson's diseases. J Clin Exp Neuropsychol. 1990;12410
De Leon  MJGeorge  AEStylopoulos  LASmith  GMiller  DC Early marker for Alzheimer's disease: the atrophic hippocampus. Lancet. 1989;2672- 673
Link to Article
Cahn  DASullivan  EVShear  PKMarsh  LFama  RLim  KOYesavage  JATinklenberg  JRPfefferbaum  A Structural MRI correlates of recognition memory in Alzheimer's disease. J Int Neuropsychol Soc. 1998;4106- 114
Link to Article
Soininen  HSPartanen  KPitkanen  AVainio  PHanninen  THallikainen  MKoivisto  KRiekkinen  PJ Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurology. 1994;441660- 1668
Link to Article
Seab  JPJagust  WJWong  STSRoos  MSReed  BRBudinger  TF Quantitative NMR measurements of hippocampal atrophy in Alzheimer's disease. Magn Reson Med. 1988;8200- 208
Link to Article
Bouras  CHof  PRMorrison  JH Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett. 1993;153131- 135
Link to Article
Kemper  TL Neuroanatomical and neuropathological changes during aging and dementia. Albert  ML,Knoefel  JE, edsClinical Neurology of Aging. New York, NY Oxford University Press1994;
Brun  AEnglund  E The pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology. 1981;5549- 564
Link to Article
Brun  AGustafson  LEnglund  E Subcortical pathology of Alzheimer's disease. Alzheimer Dis Assoc Disord. 1990;5173- 77
Braak  HBraak  E Alzheimer's disease affects limbic nuclei of the thalamus. Acta Neuropathol (Berl). 1991;81261- 268
Link to Article
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82239- 259
Link to Article
Hof  PR Morphology and neurochemical characteristics of the vulnerable neurons in brain aging and Alzheimer's disease. Eur Neurol. 1997;3771- 81
Link to Article
Arnold  SEHyman  BTVan Hoesen  G Neuropathological changes of the temporal pole in Alzheimer's disease and Pick's disease. Arch Neurol. 1994;51145- 150
Link to Article
Mufson  EJ Lack of neocortical nerve cell loss in Alzheimer's disease: reality or methodological artifact. Neurobiol Aging. 1994;15361- 362
Link to Article
Braak  HBraak  E Morphological criteria for the recognition of Alzheimer's disease and the distribution pattern of cortical changes related to this disorder. Neurobiol Aging. 1994;15355- 356
Link to Article
Regeur  LJensen  GBPakkenberg  HEvans  SMPakkenberg  B No global neocortical nerve cell loss in brains from patients with senile dementia of Alzheimer's type. Neurobiol Aging. 1994;15347- 352
Link to Article
Swaab  DFHofman  MALucassen  PJSalehi  AUylings  HBM Neuronal atrophy, not cell death, is the main hallmark of Alzheimer's disease. Neurobiol Aging. 1994;15369- 371
Link to Article
Pfefferbaum  AMathalon  DHSullivan  EVRawles  JMZipursky  RBLim  KO A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol. 1994;51874- 887
Link to Article
Raz  NGunning  FMHead  DDupuis  JHMcQuain  JBriggs  SDLoken  WJThornton  AEAcker  JD Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex. 1997;7268- 282
Link to Article
Blatter  DDBigler  EDGale  SDJohnson  SCAnderson  CBurnett  BMParker  NKurth  SHorn  S Quantitative volumetric analysis of brain MRI: normative database spanning 5 decades of life. Am J Neuroradiol. 1995;16241- 245
Jernigan  TLArchibald  SLBerhow  MTSowell  ERFoster  DSHesselink  JR Cerebral structure on MRI, I: localization of age-related changes. Biol Psychiatry. 1991;2955- 67
Link to Article
Guttmann  CRGJolesz  FAKikinis  RKilliany  RJMoss  MBSandor  TAlbert  MS White matter changes with normal aging. Neurology. 1998;50972- 978
Link to Article
Tang  YNyengaard  JRPakkenberg  BGundersen  HJG Age-induced white-matter changes in the human brain: a stereological investigation. Neurobiol Aging. 1997;18609- 615
Link to Article
Flood  DGColeman  PD Hippocampal plasticity in normal aging and decreased plasticity in Alzheimer's disease. Storm-Mathisen  JZimmer  JOtterson  OPedsProgress in Brain Research Understanding the Brain Through the Hippocampus. Amsterdam, the Netherlands Elsevier Science Publishers1990;83435- 443
Flood  DG Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease, II: subiculum. Brain Res. 1991;54083- 95
Link to Article
Flood  DG Critical issues in the analysis of dendritic extent in aging humans, primates, and rodents. Neurobiol Aging. 1993;14649- 654
Link to Article
Tallan  HH Studies on the distribution ofN-acetyl-L-aspartate acid in brain. J Biol Chem. 1956;22441- 45
Ernst  TChang  LMelchor  RMehringer  CM Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 NTR spectroscopy. Radiology. 1997;203829- 836
Schuff  NAmend  DEzekiel  FSteinman  SKTanabe  JNorman  DJagust  WKramer  JHMastrianni  JAFein  GWeiner  MW Changes of hippocampalN-acetyl aspartate and volume in Alzheimer's disease: a proton MR spectroscopic imaging and MRI study. Neurology. 1997;491513- 1521
Link to Article
Klunk  WEPanchalingam  KMoossy  JMcClure  RJPettegrew  JW N-acetyl-L-aspartate and other amino acid metabolites in Alzheimer's disease brain: a preliminary proton nuclear magnetic resonance study. Neurology. 1992;421578- 1585
Link to Article
Lim  KOSpielman  DM Estimating NAA in cortical gray matter with applications for measuring changes due to aging. Magn Reson Med. 1997;37372- 377
Link to Article
Charles  HCLazeyras  FKrishnan  KRRBoyko  OBPatterson  LJDoraiswamy  PMMcDonald  WM Proton spectroscopy of human brain: effects of age and sex. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18995- 1004
Link to Article
Fukuzako  HHashiguchi  TSakamoto  YOkamura  HDoi  WTakenouchi  KTakigawa  M Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects. Psychiatry Clin Neurosci. 1997;51261- 263
Link to Article
Christiansen  PToft  PLarsson  HBWStubgaard  MHenriksen  O The concentration of N-acetyl aspartate, creatine+phosphocreatine, and choline in different parts of the brain in adulthood and senium. Magn Reson Imaging. 1993;11799- 806
Link to Article
Pfefferbaum  ASullivan  EAdalsteinsson  ASpielman  DLim  KO In vivo quantification of N-acetyl aspartate, creatine and choline from large volumes of gray and white matter on magnetic resonance spectroscopic imaging: application to normal aging. Magn Reson Med. 1999;41276- 294
Link to Article
Chang  LErnst  TPoland  REJenden  DJ In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci. 1996;582049- 2056
Link to Article
Meyerhoff  DJMacKay  SConstans  JMNorman  DVan Dyke  CFein  GWeiner  MW Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol. 1994;3640- 47
Link to Article
Soher  BJvan Zijl  PCMDuyn  JHBarker  PB Quantitative proton MR spectroscopic imaging of the human brain. Magn Reson Med. 1996;35356- 363
Link to Article
Kreis  RErnst  TRoss  BD Absolute quantitation of water and metabolites in the human brain, II: metabolite concentrations. J Magn Reson. 1993;1029- 19
Link to Article
Saunders  DEHowe  FAvan den Boogaart  AGriffith  JRBrown  MM Aging of the human adult brain: in vivo quantification of metabolic content with proton magnetic resonance spectroscopy [abstract]. Proc Soc Magn Reson. 1995;31804
Parnetti  LTarducci  RPresciutti  OLowenthal  DTPippi  MPalumbo  BGobbi  GPelliccioli  GPSenin  U Proton magnetic resonance spectroscopy can differentiate Alzheimer's disease from normal aging. Mech Ageing Dev. 1997;979- 14
Link to Article
Frederick  BDSatlin  AYurgelun-Todd  DARenshaw  PF In vivo proton magnetic resonance spectroscopy of Alzheimer's disease in the parietal and temporal lobes. Biol Psychiatry. 1997;42147- 150
Link to Article
Kattapong  VJBrooks  WMWesley  MHKodituwakku  PWRosenberg  GA Proton magnetic resonance spectroscopy of vascular- and Alzheimer-type dementia. Arch Neurol. 1996;53678- 680
Link to Article
Tedeschi  GBertolino  ALundbom  NBonavita  SPatronas  NJDuyn  JHMetman  LVChase  TNDi Chiro  G Cortical and subcortical chemical pathology in Alzheimer's disease as assessed by multislice proton magnetic resonance spectroscopic imaging. Neurology. 1996;47696- 704
Link to Article
Tedeschi  GLundbom  NRaman  RBonavita  SDuyn  JAlger  JDi Chiro  G Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg. 1997;87516- 524
Link to Article
Miller  BLChang  LBooth  RErnst  TCornford  MNikas  DMcBride  DJenden  DJ In vivo H-1 MRS choline: correlation with in vitro chemistry histology. Life Sci. 1996;581929- 1935
Link to Article
Moyher  SENelson  SJWald  LLHenry  RGKurhanewicz  JVigneron  DB High-spatial resolution MRS and segmented MRI to study NAA in cortical gray matter and white matter of the human brain [abstract]. Proc Soc Magn Reson. 1995;1332
Narayana  PAFotedar  LKJackson  EFBohan  TPButler  IJWolinsky  JS Regional in vivo proton magnetic resonance spectroscopy of brain. J Magn Reson. 1989;8344- 52
Wang  YLi  S-J Differentiation of metabolic concentrations between gray matter and white matter of human brain by in vivo 1H magnetic resonance spectroscopy. Magn Reson Med. 1998;3928- 33
Link to Article
Doyle  TJBeddell  BJNarayana  PA Relative concentration of proton MR visible neurochemicals in gray and white matter in human brain. Magn Reson Med. 1995;33755- 759
Link to Article
Kwo-0n-Yuen  PFNewmark  RDBudinger  TFKaye  JABall  MJJagust  WJ Brain N-acetyl-L-aspartic acid in Alzheimer's disease: a proton magnetic resonance spectroscopy study. Brain Res. 1994;667167- 174
Link to Article
Petroff  OASpencer  DDAlger  JRPrichard  JW High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology. 1989;391197- 1202
Link to Article
Petroff  OACPleban  LASpencer  DD Symbiosis between in vivo and in vitro NMR spectroscopy: the creatine, N-acetylaspartate, glutamate and GABA content of the epileptic human brain. Magn Reson Imaging. 1995;131197- 1211
Link to Article
Tedeschi  GBertolino  ARighini  ACampbell  GRaman  RDuyn  JHMoonen  CTWAlger  JRDi Chiro  G Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopic imaging. Neurology. 1995;451384- 1391
Link to Article
Pouwels  PJWFrahm  J Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med. 1998;3953- 60
Link to Article
Hetherington  HPPan  JWMason  GFAdams  DVaughn  MJTweig  DBPohost  GM Quantitative 1H spectroscopic imaging of human brain at 4.1 T using image segmentation. Magn Reson Med. 1996;3621- 29
Link to Article
Knufman  NMJBerkelbach  Not Availablevan der Sprenkel  JWTulleken  CAF N-Acetyl-aspartate differences between gray and white matter as observed by proton spectroscopic imaging in normal subjects [abstract]. Proc Soc Magn Reson. 1992;1905
McKhann  GDrachman  DFolstein  MKatzman  R Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease Neurology. 1984;37939- 944
Link to Article
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105
Link to Article
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Link to Article
Warrington  E Recognition Memory Test Manual.  Windsor, England Nelson Publishing Co1984;
Huff  FJCollins  CCorkin  SRosen  TJ Equivalent forms of the Boston Naming Test. J Clin Exp Neuropsychol. 1986;8556- 562
Link to Article
Adalsteinsson  EIrarrazabal  PSpielman  DMMacovski  A Three-dimensional spectroscopic imaging with time-varying gradients. Magn Reson Med. 1995;33461- 466
Link to Article
Spielman  DAdalsteinsson  ELim  KO Quantitative analysis of improved homogeneity using linear versus higher order shims for CSF of the brain [abstract].  Abstracts of the Fifth Scientific Meeting of the International Society for Magnetic Resonance in Medicine April 12-18, 1997 Vancouver, British Columbia
Webb  PMacovski  A Rapid, fully-automatic, arbitrary volume, in-vivo shimming. Magn Reson Med. 1991;20113- 122
Link to Article
Gudbjartsson  HPatz  S The Rician distibution of noisy MRI data. Magn Reson Med. 1995;34910- 914
Link to Article
MacKay  SMeyerhoff  DJConstans  JMNorman  DFein  GWeiner  MW Regional gray and white matter metabolite differences in subjects with AD, with subcortical ischemic vascular dementia, and elderly controls with H-1 magnetic resonance spectroscopic imaging. Arch Neurol. 1996;53167- 174
Link to Article
Moats  RAErnst  TShonk  TKRoss  BD Abnormal cerebral metabolite concentrations in patients with probable Alzheimer's disease. Magn Reson Med. 1994;32110- 115
Link to Article
Mohanakrishnan  PFowler  AHVonsattel  JPJolles  PRHusain  MMLiem  PMyers  LKomoroski  RA Regional metabolic alterations in Alzheimer's disease: an in vitro H-1 NMR study of the hippocampus and cerebellum. J Gerontol A Biol Sci Med Sci. 1997;52B111- B117
Link to Article
Jaarsma  DVeenma van der Duin  LKorf  J N-acetylaspartate and N-acetylaspartylglutamate levels in Alzheimer's disease post-mortem brain tissue. J Neurol Sci. 1994;127230- 233
Link to Article
Mohanakrishnan  PFowler  AHVonsattel  JPHusain  MMJolles  PRLiem  PKomoroski  RA An in vitro H-1 nuclear magnetic resonance study of the temporoparietal cortex of Alzheimer brains. Exp Brain Res. 1995;102503- 510
Link to Article
Pettegrew  JMoossy  JWithers  GMcKeag  DPanchalingam  K 31P nuclear magnetic resonance study of the brain in Alzheimer's disease. J Neuropathol Exp Neurol. 1988;47235- 248
Link to Article
Brown  GLevine  SGorell  JPettegrew  JGdowski  JBueri  JHelpern  JWelch  K In vivo 31P NMR profiles of Alzheimer's disease and multiple subcortical infarct dementia. Neurology. 1989;391423- 1427
Link to Article
Bottomley  PACousins  JPPendrey  DLWagle  WAHardy  CJEames  FAMcCaffrey  RJThompson  DA Alzheimer dementia: quantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy. Radiology. 1992;183695- 699
Murphy  DGMBottomley  PASalerno  JADeCarli  CMentis  MJGrady  CLTeichberg  DGiacometti  KRRosenberg  JMHardy  CJSchapiro  MBRapoport  SIAlger  JRHorwitz  B An in vivo study of phosphorus and glucose metabolism in Alzheimer's disease using magnetic resonance spectroscopy and PET. Arch Gen Psychiatry. 1993;50341- 349
Link to Article
Gonzalez  RGGuimaraes  ARMoore  GJCrawley  ACupples  LAGrowdon  JH Quantitative in vivo P-31 magnetic resonance spectroscopy of Alzheimer disease. Alzheimer Dis Assoc Dis. 1996;1046- 52
Klunk  WEXu  CPanchalingam  KMcClure  RJPettegrew  JW Quantitative H-1 and P-31 MRS of PCA extracts of postmortem Alzheimer's disease brain. Neurobiol Aging. 1996;17349- 357
Link to Article
Pettegrew  JWKlunk  WEKanal  EPanchalingam  KMcClure  RJ Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia. Neurobiol Aging. 1995;16973- 975
Link to Article
Michaelis  TMerboldt  KDBruhn  HHanicke  WFrahm  J Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra. Radiology. 1993;187219- 227
Smith  CDPettigrew  LCAvison  MJKirsch  JETinkhtman  AJSchmitt  FAWermeling  DPWekstein  DRMarkesberry  WR Frontal lobe phosphorus metabolism and neuropsychological function in aging and in Alzheimer's disease. Ann Neurol. 1995;38194- 201
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Left, Brain images of a 73-year-old male control. Right, Brain images of a 75-year-old male patient with Alzheimer disease. Superior to inferior brain slices are shown from left to right. Segmented image: the fast spin-echo magnetic resonance structural images are segmented into cerebrospinal fluid (dark gray), gray matter (medium gray), and white matter (light gray). Low-pass tissue image: The tissue image after low-pass filtering matches the spatial frequency characteristics of the metabolite images. The white outlines on these and the specific metabolite images below are taken from the perimeter of the structural images and indicate the registration of the metabolite image with the structural image. Images of N-acetyl compounds, creatine, and choline are of signal intensities that contribute to the quantification of each metabolite concentration.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Volumes, without metabolite criteria imposed, derived from the segmented magnetic resonance imaging structural data for each of the compartments. The 3 groups showed a stepwise increase in brain cerebrospinal fluid volume, where the young controls had the smallest volume and the patients with Alzheimer disease (AD) the largest volume; all pairwise differences were significant. Gray matter volume showed the complementary pattern of group differences. White matter volume, however, was deficient only in the AD group relative to the young and elderly control groups. Error bars indicate SEMs (young vs elderly* P≤.001; elderly vs AD †P≤.001, ‡P =.06). Please refer to Table 2 for t test results.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Concentrations in gray matter and white matter for each brain metabolite measured. Relative to the elderly control group, the Alzheimer disease (AD) group had lower N-acetyl compounds concentrations in gray matter (*t33=2.771,P=.01) but not white atter (t33=1.419, P=.17). Creatine was higher in the gray matter of elderly controls (†t32=4.647,P=.0001) and patients with AD (‡t29=4.804, P=.001) and in the white matter of elderly controls (§t32=3.603,P=.002) and patients with AD(∥t29=2.133, P=.04) relative to the young controls, showing an age effect. Choline showed an additive age and disease effect for gray matter (¶ young vs elderly:t32=3.847, P=.02; #elderly vs AD:t33=2.552, P=.005). Error bars indicate SEMs.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of Patients With Alzheimer Disease
Table Graphic Jump LocationTable 2. Structural Composition (mL) of Brain Generating Magnetic Resonance Spectroscopy Signal (Mean ± SE)

References

Tanabe  JLAmend  DSchuff  NDiSclafani  VEzekiel  FNorman  DFein  GWeiner  MW Tissue segmentation of the brain in Alzheimer disease. AJNR Am J Neuroradiol. 1997;18115- 123
Rusinek  HDe Leon  MJGeorge  AEStylopoulos  LAChandra  RSmith  GRand  TMourino  MKowalski  H Alzheimer disease: measuring loss of cerebral gray matter with MR imaging. Radiology. 1991;178109- 114
Fama  RSullivan  EVShear  PKMarsh  LYesavage  JATinklenberg  JRLim  KOPfefferbaum  A Selective cortical and hippocampal volume correlates of Mattis Dementia Rating Scale in Alzheimer disease. Arch Neurol. 1997;54719- 728
Link to Article
Jernigan  TLSalmon  DPButters  NShults  CWHesselink  JR Specificity of brain-structural changes in Alzheimer's, Huntington's, and Parkinson's diseases. J Clin Exp Neuropsychol. 1990;12410
De Leon  MJGeorge  AEStylopoulos  LASmith  GMiller  DC Early marker for Alzheimer's disease: the atrophic hippocampus. Lancet. 1989;2672- 673
Link to Article
Cahn  DASullivan  EVShear  PKMarsh  LFama  RLim  KOYesavage  JATinklenberg  JRPfefferbaum  A Structural MRI correlates of recognition memory in Alzheimer's disease. J Int Neuropsychol Soc. 1998;4106- 114
Link to Article
Soininen  HSPartanen  KPitkanen  AVainio  PHanninen  THallikainen  MKoivisto  KRiekkinen  PJ Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurology. 1994;441660- 1668
Link to Article
Seab  JPJagust  WJWong  STSRoos  MSReed  BRBudinger  TF Quantitative NMR measurements of hippocampal atrophy in Alzheimer's disease. Magn Reson Med. 1988;8200- 208
Link to Article
Bouras  CHof  PRMorrison  JH Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett. 1993;153131- 135
Link to Article
Kemper  TL Neuroanatomical and neuropathological changes during aging and dementia. Albert  ML,Knoefel  JE, edsClinical Neurology of Aging. New York, NY Oxford University Press1994;
Brun  AEnglund  E The pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology. 1981;5549- 564
Link to Article
Brun  AGustafson  LEnglund  E Subcortical pathology of Alzheimer's disease. Alzheimer Dis Assoc Disord. 1990;5173- 77
Braak  HBraak  E Alzheimer's disease affects limbic nuclei of the thalamus. Acta Neuropathol (Berl). 1991;81261- 268
Link to Article
Braak  HBraak  E Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82239- 259
Link to Article
Hof  PR Morphology and neurochemical characteristics of the vulnerable neurons in brain aging and Alzheimer's disease. Eur Neurol. 1997;3771- 81
Link to Article
Arnold  SEHyman  BTVan Hoesen  G Neuropathological changes of the temporal pole in Alzheimer's disease and Pick's disease. Arch Neurol. 1994;51145- 150
Link to Article
Mufson  EJ Lack of neocortical nerve cell loss in Alzheimer's disease: reality or methodological artifact. Neurobiol Aging. 1994;15361- 362
Link to Article
Braak  HBraak  E Morphological criteria for the recognition of Alzheimer's disease and the distribution pattern of cortical changes related to this disorder. Neurobiol Aging. 1994;15355- 356
Link to Article
Regeur  LJensen  GBPakkenberg  HEvans  SMPakkenberg  B No global neocortical nerve cell loss in brains from patients with senile dementia of Alzheimer's type. Neurobiol Aging. 1994;15347- 352
Link to Article
Swaab  DFHofman  MALucassen  PJSalehi  AUylings  HBM Neuronal atrophy, not cell death, is the main hallmark of Alzheimer's disease. Neurobiol Aging. 1994;15369- 371
Link to Article
Pfefferbaum  AMathalon  DHSullivan  EVRawles  JMZipursky  RBLim  KO A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol. 1994;51874- 887
Link to Article
Raz  NGunning  FMHead  DDupuis  JHMcQuain  JBriggs  SDLoken  WJThornton  AEAcker  JD Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex. 1997;7268- 282
Link to Article
Blatter  DDBigler  EDGale  SDJohnson  SCAnderson  CBurnett  BMParker  NKurth  SHorn  S Quantitative volumetric analysis of brain MRI: normative database spanning 5 decades of life. Am J Neuroradiol. 1995;16241- 245
Jernigan  TLArchibald  SLBerhow  MTSowell  ERFoster  DSHesselink  JR Cerebral structure on MRI, I: localization of age-related changes. Biol Psychiatry. 1991;2955- 67
Link to Article
Guttmann  CRGJolesz  FAKikinis  RKilliany  RJMoss  MBSandor  TAlbert  MS White matter changes with normal aging. Neurology. 1998;50972- 978
Link to Article
Tang  YNyengaard  JRPakkenberg  BGundersen  HJG Age-induced white-matter changes in the human brain: a stereological investigation. Neurobiol Aging. 1997;18609- 615
Link to Article
Flood  DGColeman  PD Hippocampal plasticity in normal aging and decreased plasticity in Alzheimer's disease. Storm-Mathisen  JZimmer  JOtterson  OPedsProgress in Brain Research Understanding the Brain Through the Hippocampus. Amsterdam, the Netherlands Elsevier Science Publishers1990;83435- 443
Flood  DG Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease, II: subiculum. Brain Res. 1991;54083- 95
Link to Article
Flood  DG Critical issues in the analysis of dendritic extent in aging humans, primates, and rodents. Neurobiol Aging. 1993;14649- 654
Link to Article
Tallan  HH Studies on the distribution ofN-acetyl-L-aspartate acid in brain. J Biol Chem. 1956;22441- 45
Ernst  TChang  LMelchor  RMehringer  CM Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 NTR spectroscopy. Radiology. 1997;203829- 836
Schuff  NAmend  DEzekiel  FSteinman  SKTanabe  JNorman  DJagust  WKramer  JHMastrianni  JAFein  GWeiner  MW Changes of hippocampalN-acetyl aspartate and volume in Alzheimer's disease: a proton MR spectroscopic imaging and MRI study. Neurology. 1997;491513- 1521
Link to Article
Klunk  WEPanchalingam  KMoossy  JMcClure  RJPettegrew  JW N-acetyl-L-aspartate and other amino acid metabolites in Alzheimer's disease brain: a preliminary proton nuclear magnetic resonance study. Neurology. 1992;421578- 1585
Link to Article
Lim  KOSpielman  DM Estimating NAA in cortical gray matter with applications for measuring changes due to aging. Magn Reson Med. 1997;37372- 377
Link to Article
Charles  HCLazeyras  FKrishnan  KRRBoyko  OBPatterson  LJDoraiswamy  PMMcDonald  WM Proton spectroscopy of human brain: effects of age and sex. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18995- 1004
Link to Article
Fukuzako  HHashiguchi  TSakamoto  YOkamura  HDoi  WTakenouchi  KTakigawa  M Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects. Psychiatry Clin Neurosci. 1997;51261- 263
Link to Article
Christiansen  PToft  PLarsson  HBWStubgaard  MHenriksen  O The concentration of N-acetyl aspartate, creatine+phosphocreatine, and choline in different parts of the brain in adulthood and senium. Magn Reson Imaging. 1993;11799- 806
Link to Article
Pfefferbaum  ASullivan  EAdalsteinsson  ASpielman  DLim  KO In vivo quantification of N-acetyl aspartate, creatine and choline from large volumes of gray and white matter on magnetic resonance spectroscopic imaging: application to normal aging. Magn Reson Med. 1999;41276- 294
Link to Article
Chang  LErnst  TPoland  REJenden  DJ In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci. 1996;582049- 2056
Link to Article
Meyerhoff  DJMacKay  SConstans  JMNorman  DVan Dyke  CFein  GWeiner  MW Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol. 1994;3640- 47
Link to Article
Soher  BJvan Zijl  PCMDuyn  JHBarker  PB Quantitative proton MR spectroscopic imaging of the human brain. Magn Reson Med. 1996;35356- 363
Link to Article
Kreis  RErnst  TRoss  BD Absolute quantitation of water and metabolites in the human brain, II: metabolite concentrations. J Magn Reson. 1993;1029- 19
Link to Article
Saunders  DEHowe  FAvan den Boogaart  AGriffith  JRBrown  MM Aging of the human adult brain: in vivo quantification of metabolic content with proton magnetic resonance spectroscopy [abstract]. Proc Soc Magn Reson. 1995;31804
Parnetti  LTarducci  RPresciutti  OLowenthal  DTPippi  MPalumbo  BGobbi  GPelliccioli  GPSenin  U Proton magnetic resonance spectroscopy can differentiate Alzheimer's disease from normal aging. Mech Ageing Dev. 1997;979- 14
Link to Article
Frederick  BDSatlin  AYurgelun-Todd  DARenshaw  PF In vivo proton magnetic resonance spectroscopy of Alzheimer's disease in the parietal and temporal lobes. Biol Psychiatry. 1997;42147- 150
Link to Article
Kattapong  VJBrooks  WMWesley  MHKodituwakku  PWRosenberg  GA Proton magnetic resonance spectroscopy of vascular- and Alzheimer-type dementia. Arch Neurol. 1996;53678- 680
Link to Article
Tedeschi  GBertolino  ALundbom  NBonavita  SPatronas  NJDuyn  JHMetman  LVChase  TNDi Chiro  G Cortical and subcortical chemical pathology in Alzheimer's disease as assessed by multislice proton magnetic resonance spectroscopic imaging. Neurology. 1996;47696- 704
Link to Article
Tedeschi  GLundbom  NRaman  RBonavita  SDuyn  JAlger  JDi Chiro  G Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg. 1997;87516- 524
Link to Article
Miller  BLChang  LBooth  RErnst  TCornford  MNikas  DMcBride  DJenden  DJ In vivo H-1 MRS choline: correlation with in vitro chemistry histology. Life Sci. 1996;581929- 1935
Link to Article
Moyher  SENelson  SJWald  LLHenry  RGKurhanewicz  JVigneron  DB High-spatial resolution MRS and segmented MRI to study NAA in cortical gray matter and white matter of the human brain [abstract]. Proc Soc Magn Reson. 1995;1332
Narayana  PAFotedar  LKJackson  EFBohan  TPButler  IJWolinsky  JS Regional in vivo proton magnetic resonance spectroscopy of brain. J Magn Reson. 1989;8344- 52
Wang  YLi  S-J Differentiation of metabolic concentrations between gray matter and white matter of human brain by in vivo 1H magnetic resonance spectroscopy. Magn Reson Med. 1998;3928- 33
Link to Article
Doyle  TJBeddell  BJNarayana  PA Relative concentration of proton MR visible neurochemicals in gray and white matter in human brain. Magn Reson Med. 1995;33755- 759
Link to Article
Kwo-0n-Yuen  PFNewmark  RDBudinger  TFKaye  JABall  MJJagust  WJ Brain N-acetyl-L-aspartic acid in Alzheimer's disease: a proton magnetic resonance spectroscopy study. Brain Res. 1994;667167- 174
Link to Article
Petroff  OASpencer  DDAlger  JRPrichard  JW High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy. Neurology. 1989;391197- 1202
Link to Article
Petroff  OACPleban  LASpencer  DD Symbiosis between in vivo and in vitro NMR spectroscopy: the creatine, N-acetylaspartate, glutamate and GABA content of the epileptic human brain. Magn Reson Imaging. 1995;131197- 1211
Link to Article
Tedeschi  GBertolino  ARighini  ACampbell  GRaman  RDuyn  JHMoonen  CTWAlger  JRDi Chiro  G Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopic imaging. Neurology. 1995;451384- 1391
Link to Article
Pouwels  PJWFrahm  J Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med. 1998;3953- 60
Link to Article
Hetherington  HPPan  JWMason  GFAdams  DVaughn  MJTweig  DBPohost  GM Quantitative 1H spectroscopic imaging of human brain at 4.1 T using image segmentation. Magn Reson Med. 1996;3621- 29
Link to Article
Knufman  NMJBerkelbach  Not Availablevan der Sprenkel  JWTulleken  CAF N-Acetyl-aspartate differences between gray and white matter as observed by proton spectroscopic imaging in normal subjects [abstract]. Proc Soc Magn Reson. 1992;1905
McKhann  GDrachman  DFolstein  MKatzman  R Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease Neurology. 1984;37939- 944
Link to Article
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105
Link to Article
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Link to Article
Warrington  E Recognition Memory Test Manual.  Windsor, England Nelson Publishing Co1984;
Huff  FJCollins  CCorkin  SRosen  TJ Equivalent forms of the Boston Naming Test. J Clin Exp Neuropsychol. 1986;8556- 562
Link to Article
Adalsteinsson  EIrarrazabal  PSpielman  DMMacovski  A Three-dimensional spectroscopic imaging with time-varying gradients. Magn Reson Med. 1995;33461- 466
Link to Article
Spielman  DAdalsteinsson  ELim  KO Quantitative analysis of improved homogeneity using linear versus higher order shims for CSF of the brain [abstract].  Abstracts of the Fifth Scientific Meeting of the International Society for Magnetic Resonance in Medicine April 12-18, 1997 Vancouver, British Columbia
Webb  PMacovski  A Rapid, fully-automatic, arbitrary volume, in-vivo shimming. Magn Reson Med. 1991;20113- 122
Link to Article
Gudbjartsson  HPatz  S The Rician distibution of noisy MRI data. Magn Reson Med. 1995;34910- 914
Link to Article
MacKay  SMeyerhoff  DJConstans  JMNorman  DFein  GWeiner  MW Regional gray and white matter metabolite differences in subjects with AD, with subcortical ischemic vascular dementia, and elderly controls with H-1 magnetic resonance spectroscopic imaging. Arch Neurol. 1996;53167- 174
Link to Article
Moats  RAErnst  TShonk  TKRoss  BD Abnormal cerebral metabolite concentrations in patients with probable Alzheimer's disease. Magn Reson Med. 1994;32110- 115
Link to Article
Mohanakrishnan  PFowler  AHVonsattel  JPJolles  PRHusain  MMLiem  PMyers  LKomoroski  RA Regional metabolic alterations in Alzheimer's disease: an in vitro H-1 NMR study of the hippocampus and cerebellum. J Gerontol A Biol Sci Med Sci. 1997;52B111- B117
Link to Article
Jaarsma  DVeenma van der Duin  LKorf  J N-acetylaspartate and N-acetylaspartylglutamate levels in Alzheimer's disease post-mortem brain tissue. J Neurol Sci. 1994;127230- 233
Link to Article
Mohanakrishnan  PFowler  AHVonsattel  JPHusain  MMJolles  PRLiem  PKomoroski  RA An in vitro H-1 nuclear magnetic resonance study of the temporoparietal cortex of Alzheimer brains. Exp Brain Res. 1995;102503- 510
Link to Article
Pettegrew  JMoossy  JWithers  GMcKeag  DPanchalingam  K 31P nuclear magnetic resonance study of the brain in Alzheimer's disease. J Neuropathol Exp Neurol. 1988;47235- 248
Link to Article
Brown  GLevine  SGorell  JPettegrew  JGdowski  JBueri  JHelpern  JWelch  K In vivo 31P NMR profiles of Alzheimer's disease and multiple subcortical infarct dementia. Neurology. 1989;391423- 1427
Link to Article
Bottomley  PACousins  JPPendrey  DLWagle  WAHardy  CJEames  FAMcCaffrey  RJThompson  DA Alzheimer dementia: quantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy. Radiology. 1992;183695- 699
Murphy  DGMBottomley  PASalerno  JADeCarli  CMentis  MJGrady  CLTeichberg  DGiacometti  KRRosenberg  JMHardy  CJSchapiro  MBRapoport  SIAlger  JRHorwitz  B An in vivo study of phosphorus and glucose metabolism in Alzheimer's disease using magnetic resonance spectroscopy and PET. Arch Gen Psychiatry. 1993;50341- 349
Link to Article
Gonzalez  RGGuimaraes  ARMoore  GJCrawley  ACupples  LAGrowdon  JH Quantitative in vivo P-31 magnetic resonance spectroscopy of Alzheimer disease. Alzheimer Dis Assoc Dis. 1996;1046- 52
Klunk  WEXu  CPanchalingam  KMcClure  RJPettegrew  JW Quantitative H-1 and P-31 MRS of PCA extracts of postmortem Alzheimer's disease brain. Neurobiol Aging. 1996;17349- 357
Link to Article
Pettegrew  JWKlunk  WEKanal  EPanchalingam  KMcClure  RJ Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia. Neurobiol Aging. 1995;16973- 975
Link to Article
Michaelis  TMerboldt  KDBruhn  HHanicke  WFrahm  J Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra. Radiology. 1993;187219- 227
Smith  CDPettigrew  LCAvison  MJKirsch  JETinkhtman  AJSchmitt  FAWermeling  DPWekstein  DRMarkesberry  WR Frontal lobe phosphorus metabolism and neuropsychological function in aging and in Alzheimer's disease. Ann Neurol. 1995;38194- 201
Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 94

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario