Hippocampal Proton MR Spectroscopy in Early Alzheimer��s Disease and Mild Cognitive Impairment

Proton magnetic resonance spectroscopy ((1)H-MRS) studies have previously reported reduced brain N-acetyl aspartate (NAA) and increased myo-inositol (mI) in people with established Alzheimer's disease (AD). The earliest structure affected by AD is the hippocampus but relatively few studies have examined its neuronal integrity by MRS in AD and fewer still in people with amnestic mild cognitive impairment (MCI). We measured the hippocampal concentration of NAA, mI, choline (Cho) and creatine?+?phosphocreatine (Cr?+?PCr) in 39 patients with AD, 21 subjects with MCI and 38 age matched healthy elderly controls. Patients with AD had a significantly lower hippocampal [NAA] than controls, with subjects with MCI intermediate between the other two groups. [NAA] was positively correlated with memory in the impaired groups. Using mean hippocampal [NAA] and [Cr?+?PCr] we correctly classified 72% of people with AD, and 75% of controls. Reductions in [NAA] can be detected in the hippocampi of subjects with MCI and hippocampal [NAA] and [Cr?+?PCr] can distinguish between mild AD and normal elderly controls.     

Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) defines a group of otherwise healthy elderly subjects with a markedly elevated risk of developing Alzheimer's disease (AD). In the search for biomarkers of MCI, we assessed whether MCI shares neurochemical abnormalities with AD in areas affected early in the course of the disease. As a secondary study aim, we tested to what extent neurochemical findings reflect neuropsychological deficits. Proton spectroscopy was performed in 19 MCI patients, 18 AD patients and 22 age and gender matched controls (CON) within the parietal gray and white matter (PWM and PGM) and the hippocampus (HIP). The cognitive test battery used included measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The N-acetyl-aspartate to creatine ratio (NAA/Cr) was significantly reduced in the HIP of MCI and AD compared with CON (p < 0.05). Only AD patients showed parietal abnormalities, namely significantly elevated myoinositol (mI/Cr and mI/NAA) in PGM, reduced NAA/Cr and elevated mI/NAA in PWM. MCI subjects were significantly impaired in categorical verbal fluency (VF) (p < 0.001) and delayed verbal recall (DVR) (p < 0.001). VF was positively correlated with hippocampal NAA/Cr (p < 0.05) and parietal mI/NAA (p < 0.05). In summary, this study demonstrates shared neurobiological hippocampal abnormalities in MCI and AD, whereas parietal lobe neurochemical profiles and functions were normal in MCI. Thus, biological evidence is provided that MCI represents a precursor stage of AD. Moreover, multivoxel 1H MRS may enable an objective staging of the neurodegenerative process underlying the age-dependent cognitive deficits eventually leading to dementia.     

Reduced hippocampal glutamate in Alzheimer disease

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using ¹H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE = 46 ms) ¹H spectra were acquired at 4 T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p < 0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.     

Conversion of MCI to dementia: Role of proton magnetic resonance spectroscopy

Mild cognitive impairment (MCI) represents a heterogeneous group of cognitive disturbances at high risk of dementia. The amnestic subtype (aMCI) might be a prodromal state of Alzheimer's disease (AD). The aim of this study is the identification, by proton magnetic resonance spectroscopy (1H MRS), of modifications in brain metabolites able to detect subjects with aMCI at risk of conversion towards AD. Twenty-five subjects with aMCI and 29 normal elderly were enrolled; they underwent a comprehensive clinical and instrumental assessment, a cerebral 1H MRS scan to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI) and creatine (Cr) in the paratrigonal white matter, bilaterally. After 1 year, 5 MCI subjects became demented (progressive MCI, pMCI). Their baseline levels of metabolites were compared with those evaluated in stable MCI (sMCI) and in controls. We observed a significant difference of the NAA/Cr ratio between pMCI (1.48+/-0.08) and sMCI (1.65+/-0.12) and between pMCI and controls (1.63+/-0.16) in the left hemisphere, suggesting that this metabolic alteration can be detected before the clinical appearance of dementia.     

Evidence of neurodegeneration in brains of older adults who do not yet fulfill MCI criteria

We sought to determine whether there are structural and metabolic changes in the brains of older adults with cognitive complaints yet who do not meet MCI criteria (i.e., preMCI). We compared the volumes of regional lobar gray matter (GM) and medial temporal lobe structures, including the hippocampus, entorhinal cortex (ERC), fusiform and parahippocampal gyri, and metabolite ratios from the posterior cingulate in individuals who had a Clinical Demetia Rating (CDR) of 0.5, but who did not meet MCI criteria (preMCI, N=17), patients with mild cognitive impairment (MCI, N=13), and cognitively normal controls (N=18). Controls had more ERC, fusiform, and frontal gray matter volume than preMCI and MCI subjects and greater parahippocampal volume and more posterior cingulate N-acetylaspartate (NAA)/myoinosotil (mI) than MCI. There were no significant differences between MCI and preMCI subjects on any of these measures. These findings suggest there are neurodegenerative changes in the brains of older adults who have cognitive complaints severe enough to qualify for CDR=0.5 yet show no deficits on formal neuropsychological testing. The results further support the hypothesis that detection of individuals with very mild forms of Alzheimer's disease (AD) may be facilitated by use of the CDR, which emphasizes changes in cognition over time within individuals rather than comparison with group norms.     

Regional proton magnetic resonance spectroscopy patterns in dementia with Lewy bodies

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.     

Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer's disease

Magnetic resonance (MR)-based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Longitudinal changes in (1)H MR spectroscopy ((1)H MRS) metabolite markers have not been characterized in MCI subjects. Our objective was to determine the longitudinal (1)H MRS metabolite changes in patients with MCI, and AD, and to compare (1)H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/creatine ratio declined in MCI and AD patients compared to cognitively normal elderly. The change in (1)H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that (1)H MRS metabolite ratios may be useful markers for the progression of AD. Choline/creatine ratio declined in stable MCI, compared to converter MCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in MCI patients who did not to progress to AD.     

Regionally specific atrophy of the corpus callosum in AD, MCI and cognitive complaints

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer's disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.     

Metabolite alterations in autistic children: a 1H MR spectroscopy study

PurposeThe purpose of this study was to assess the role of proton magnetic resonance spectroscopy (1H MRS) in the detection of changes in cerebral metabolite levels in autistic children.Material and methodsStudy group consisted of 12 children, aged 8–15 years, who were under the care of Pediatric Neurology Department and Pediatric Rehabilitation Department of Medical University of Bialystok. The diagnosis of autism was established by neurologist, psychiatrist and psychologist in every case. All patients matched the clinical criteria of the disease according to International Statistical Classification of Diseases and Related Health Problems (ICD-10). The control group included 16 healthy children aged 7–17. ¹H MRS was performed with a single-voxel method (TE-36, TR-1500, NEX-192). The volume of interest (VOI) was located in the frontal lobe regions, separately on each side.ResultsWe showed lower N-acetylaspartate/creatine (NAA/Cr), γ-aminobutyric acid /creatine (GABA/Cr) and glutamate/creatine (Glx/Cr) in the frontal lobes in the study group comparing with healthy controls. The ratio of myoinositol/creatine (mI/Cr) was increased in autistic children. No differences in choline/creatine (Cho/Cr) ratio in study group and controls were found. There was a correlation between age and NAA/Cr in autistic children (R=0.593 p=0.041). No significant differences in metabolite ratios between right and left hemisphere in ASD and controls were found.Conclusions¹H MRS can provide important information regarding abnormal brain metabolism. Differences in NAA/Cr, GABA/Cr, Glx/Cr and mI/Cr may contribute to the pathogenesis of autism.     

Aerobic Fitness and the Brain: Increased N-Acetyl-Aspartate and Choline Concentrations in Endurance-Trained Middle-Aged Adults

Engagement in regular aerobic exercise is associated with cognitive benefits, but information on the mechanisms governing these changes in humans is limited. The goal of the current study was to compare neurometabolite concentrations relating to cellular metabolism, structure, and viability in endurance-trained and sedentary middle-aged adults. Twenty-eight endurance-trained and 27 sedentary adults, aged 40–65 years, underwent general health assessment, cardiorespiratory fitness measurement, neuropsychological testing, and proton magnetic resonance spectroscopy (¹H MRS). ¹H MRS was used to examine N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in frontal and occipitoparietal grey matter. Group differences in concentrations of NAA, Cho, mI, and Glu, calculated as ratios over Cr, were explored using ANOVA. There were no significant differences in global cognitive function, memory, and executive function performance between the groups. In comparison to sedentary adults, the endurance-trained group displayed significantly higher NAA/Cr in the frontal grey matter (F(1, 53) = 5.367, p = 0.024) and higher Cho/Cr in the occipitoparietal grey matter (F(1, 53) = 5.138, p = 0.028). Within our middle-aged sample, endurance-trained adults demonstrated higher levels of NAA/Cr in the frontal grey matter and higher Cho/Cr in the occipitoparietal grey matter. Higher levels of NAA may indicate greater neuronal integrity and higher cerebral metabolic efficiency in association with cardiorespiratory fitness, whereas increased Cho may represent increased phospholipid levels secondary to neural plasticity.     

Reduced brain glutamate in patients with Parkinson's disease

An understanding of the role played by glutamate (Glu) in idiopathic Parkinson's disease (PD) has remained somewhat elusive. Animal models of PD suggest that over-activity of Glu receptors complicates the motor symptoms of PD and that Glu blockade may be a pharmacologic target in PD, whereas patient autopsy studies have proved less convincing for changes in Glu. No previous 1H MRS patient studies have documented changes in glutamate. All but one of these previous studies were performed at 1.5 T. We performed 3 T 1H MRS of the posterior cingulate gyrus in 12 non-demented patients with PD and 12 age-matched, neurologically normal control participants. Glu, N-acetylaspartate (NAA) and choline-containing compounds (Cho) measured in reference to creatine + phosphocreatine (Cr) were determined from single-voxel proton MR spectra measured by PRESS at TE of 80 ms. The results show that the Glu/Cr ratio was reduced in patients with PD compared with controls (t = 2.54; P = 0.019), whereas no differences were observed in NAA/Cr or Cho/Cr ratios. These findings suggest that a reduction in Glu occurs in the cerebral cortex of patients with PD. (1)H MRS at 3 T should be investigated in future studies as a means of tracking the course of metabolic brain changes in association with progression of disease in patients with PD.     

Focal posterior cingulate atrophy in incipient Alzheimer's disease

Severe posterior cingulate cortex hypometabolism is a feature of incipient, sporadic Alzheimer's disease (AD). The aim was to test the hypothesis that this region is focally atrophic in very early disease by studying AD patients at the mild cognitive impairment (MCI) stage, and, if so, to determine whether the amount of atrophy was comparable to that of the hippocampus. Twenty-four patients meeting criteria for amnestic MCI, who all subsequently progressed to fulfil AD criteria, and 28 age-matched controls, were imaged with volumetric MRI. Four regions of interest were manually traced in each hemisphere: two posterior cingulate regions (BA 23 and BA 29/30), the hippocampus (as a positive control) and the anterior cingulate (as a negative control). BA 23 and BA 29/30 were both significantly atrophic and this atrophy was comparable to that found in the hippocampus, in the absence of anterior cingulate cortex (ACC) atrophy. Contrary to previous reports, there was no evidence that posterior cingulate atrophy is specifically associated with early-onset AD. The results indicate that posterior cingulate cortex atrophy is present from the earliest clinical stage of sporadic AD and that this region is as vulnerable to neurodegeneration as the hippocampus.     

Activation of brain regions vulnerable to Alzheimer's disease: the effect of mild cognitive impairment

This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.     

Proton magnetic resonance spectroscopy in children with spastic diplegia

The objective of this prospective study was the application of proton magnetic resonance spectroscopy in children with spastic diplegia (SD) to determine the metabolite profile of SD children in the left basal ganglia, and to assess the relationship of this profile with motor and mental development. Patients with SD showed reduced ratios of N-acetylaspartate (NAA)/creatine (Cr), NAA/choline (Cho), NAA/myo-inositol (mI), Cho/NAA, Cho/Cr and Cho/mI in the basal ganglia compared to a well-matched control group. On the other hand, we noted increased Cr/NAA, Cr/Cho and mI/NAA ratios in the SD patients as compared with controls. NAA/mI ratios were positively correlated with the severity scale of cerebral palsy in SD children. There was also a significant correlation between Cr/NAA and mental retardation. Increased Cr/NAA, Cr/Cho and mI/NAA ratios in SD children may suggest the existence of the compensatory mechanisms in these patients. The NAA/mI ratio could be used as an additional marker of SD severity and Cr/NAA as a marker of the mental retardation.     

Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), brain lesions are marked by severe neuronal loss and retinal degeneration was previously mentioned in affected patients. Mild cognitive impairment (MCI) is a clinical syndrome that could be an early phase of AD. In this study, using optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) thickness was assessed in patients with mild AD, moderate to severe AD, amnestic MCI and control subjects. The results show that RNFL thickness is statistically reduced in patients with MCI, mild AD or moderate to severe AD compared to controls. In addition, no statistical difference was found between the results in MCI patients and mild AD patients. The RNFL seems to be involved early during the course of amnestic MCI and OCT tests could be carried out in patients with cognitive troubles.     

Mild cognitive impairment as predictor for Alzheimer's disease in clinical practice: effect of age and diagnostic criteria

BACKGROUND: We investigated whether the predictive accuracy of mild cognitive impairment (MCI) for Alzheimer-type dementia (AD) in a clinical setting is dependent on age and the definition of MCI used. METHOD: Non-demented subjects older than 40 (n=320) who attended a memory clinic of a university hospital were reassessed 5 years later for the presence of AD. MCI was diagnosed according to the criteria of amnestic MCI, mild functional impairment (MFI), ageing-associated cognitive decline (AACD), and age-associated memory impairment (AAMI). The main outcome measure was the area under the curve (AUC) of a receiver operating characteristic (ROC) curve. Analyses were conducted on the entire sample and on subgroups of subjects aged 40-54, 55-69 and 70-85 years. RESULTS: A diagnosis of AD at follow-up was made in 58 subjects. Four of them were in the 40-54 age group, 29 in the 55-69 age group and 25 in the 70-85 age group. The diagnostic accuracy in the entire sample was low to moderately high with AUCs ranging from 0.56 (AACD) to 0.75 (amnestic MCI). A good predictive accuracy with an AUC >0.80 was only observed in subjects aged 70-85 using the criteria of amnestic MCI (AUC=0.84). CONCLUSIONS: The predictive accuracy of MCI for AD is dependent on age and the definition of MCI used. The predictive accuracy is good only for amnestic MCI in subjects 70-85 years. As subjects with prodromal AD are often younger than 70, the usefulness of MCI as predictor of AD in clinical practice is limited.     

Verbal fluency performance in amnestic MCI and older adults with cognitive complaints

Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimer's disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n = 37), cognitive complaints (CC, n = 37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n = 33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

Comparison of reproducibility of single voxel spectroscopy and whole‐brain magnetic resonance spectroscopy imaging at 3T

To date, single voxel spectroscopy (SVS) is the most commonly used MRS technique. SVS is relatively easy to use and provides automated and immediate access to the resulting spectra. However, it is also limited in spatial coverage. A new and very promising MRS technique allows for whole‐brain MR spectroscopic imaging (WB‐MRSI) with much improved spatial resolution. Establishing the reproducibility of data obtained using SVS and WB‐MRSI is an important first step for using these techniques to evaluate longitudinal changes in metabolite concentration. The purpose of this study was to assess and directly compare the reproducibility of metabolite quantification at 3T using SVS and WB‐MRSI in ‘hand‐knob’ areas of motor cortices and hippocampi in healthy volunteers. Ten healthy adults were scanned using both SVS and WB‐MRSI on three occasions one week apart. N‐acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo‐inositol (mI) were quantified using SVS and WB‐MRSI with reference to both Cr and H₂O. The reproducibility of each technique was evaluated using the coefficient of variation (CV), and the correspondence between the two techniques was assessed using Pearson correlation analysis. The measured mean (range) intra‐subject CVs for SVS were 5.90 (2.65‐10.66)% for metabolites (i.e. NAA, Cho, mI) relative to Cr, and 8.46 (4.21‐21.07)% for metabolites (NAA, Cr, Cho, mI) relative to H₂O. The mean (range) CVs for WB‐MRSI were 7.56 (2.78‐11.41)% for metabolites relative to Cr, and 7.79 (4.57‐14.11)% for metabolites relative to H₂O. Significant positive correlations were observed between metabolites quantified using SVS and WB‐MRSI techniques when the Cr but not H₂O reference was used. The results demonstrate that reproducibilities of SVS and WB‐MRSI are similar for quantifying the four major metabolites (NAA, Cr, Cho, mI); both SVS and WB‐MRSI exhibited good reproducibility. Our findings add reference information for choosing the appropriate ¹H‐MRS technique in future studies.     

连线测验(中文修订版)在早期识别阿尔茨海默病中的作用

目的：中文修订版的连线测验（TMT）在识别轻度认知功能障碍（MCI）和轻度阿尔茨海默病（AD）中的作用。方法：对正常老人94名．遗忘型MCI组107例和轻度AD组54例进行MMSE、TMT在内的8种神经心理测验。结果：正常老人与MCI组TMT完成率均高于轻度AD组。年龄与教育程度对TMT—B的影响比TMT—A更大。TMT-A、B与MMSE、CFT模仿、CWCR、CFT回忆、AVLT延迟回忆均有显著相关性。完成TMT—A、B测验．NC组、MCI组与轻度AD组两两比较均有显著差异，TMT可以清楚的区分三组。结论：TMT对MCI病人有一定的辅助识别作用，对轻度AD病人有较强的辅助识别作用．