Proton magnetic resonance spectroscopy of the substantia nigra in schizophrenia.

BACKGROUND: Converging evidence in schizophrenia points to disruption of the dopamine and glutamate neurotransmitter systems in the pathophysiology of the disorder. Dopamine is produced in the substantia nigra, but few neuroimaging studies have specifically targeted this structure. In fact, no studies of the substantia nigra in schizophrenia have used proton magnetic resonance spectroscopy (MRS). We sought to demonstrate the feasibility of acquiring single-voxel MRS measurements at 3T from the substantia nigra and to determine which metabolites could be reliably quantified in schizophrenia patients and healthy controls. METHODS: We used a turbo spin echo sequence with magnetization transfer contrast to visualize the substantia nigra and single-voxel proton MRS to quantify levels of N-acetylaspartate, glutamate and glutamine (Glx), and choline in the left substantia nigra of 35 people with schizophrenia and 22 healthy controls. RESULTS: We obtained spectra from the substantia nigra and quantified neurometabolites in both groups. We found no differences in levels of N-acetylaspartate/creatine, Glx/creatine, or choline/creatine between the groups. We found a significant correlation between Glx/creatine and overall cognitive performance, measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), in controls but not patients, a difference that was statistically significant. CONCLUSIONS: Our study demonstrates the feasibility of obtaining single-voxel MRS data from the substantia nigra in schizophrenia. Such measurements may prove useful in understanding the biochemistry underlying cellular function in a region implicated in the pathophysiology of schizophrenia.

MRI volume of the medial frontal cortex predicts financial capacity in patients with mild Alzheimer's disease.

Persons with mild Alzheimer's disease (AD) have significant deficits in financial abilities. This study examined the relationship between brain structure volumes, cognition, and financial capacity in patients with mild AD. Sixteen mild AD patients and 16 older adult comparisons completed the Financial Capacity Instrument (FCI), a psychometric measure of financial abilities, and also underwent magnetic resonance imaging (MRI) to obtain volumes of the bilateral hippocampi, angular gyri, precunei, and medial and dorsolateral frontal cortices. Mild AD patients performed significantly below comparisons on the FCI and had significantly smaller hippocampi. Among mild AD patients, FCI performance was moderately correlated with frontal (medial and dorsolateral frontal cortex) and posterior (angular gyri and precunei) cortical volumes. Stepwise regression demonstrated that medial frontal cortex volume predicted FCI score. The relationship between medial frontal cortex volume and overall FCI score was partially mediated by two measures of simple attention (DRS Attention, DRS Construction). The findings suggest that medial frontal cortex atrophy and associated declines in simple attention play an increasingly important role in declining financial skills in patients with mild AD.

Magnetic transfer contrast accurately localizes substantia nigra confirmed by histology.

BACKGROUND: Magnetic resonance imaging (MRI) has multiple contrast mechanisms. Like various staining techniques in histology, each contrast type reveals different information about the structure of the brain. However, it is not always clear how structures visible in MRI correspond to structures previously identified by histology. The purpose of this study was to determine if magnetic transfer contrast (MTC) or T2 contrast MRI was better at delineating the substantia nigra (SN). METHODS: MRI scans were acquired in vivo from two nonhuman primates (NHPs). The NHPs were subsequently euthanized, perfused, and their brains sectioned for histologic analyses. Each slice was photographed before sectioning. Each brain was sectioned into approximately 500 sections, 40 µm each, encompassing most of the cortex, midbrain, and dorsal parts of the hindbrain. Levels corresponding to anatomic MRI images were selected. From these, adjacent sections were stained using Kluver-Barrera (myelin and cell bodies) or tyrosine hydroxylase (dopaminergic neurons) immunohistochemistry. The resulting images were coregistered to the block-face images using a moving least squares algorithm with similarity transformations. MR images were similarly coregistered to the block-face images, allowing the structures on MRI to be identified with structures on the histologic images. RESULTS: We found that hyperintense (light) areas in MTC images were coextensive with the SN as delineated histologically. The hypointense (dark) areas in T2-weighted images were not coextensive with the SN but extended partially into the SN and partially into the cerebral peduncles. CONCLUSIONS: MTC is more accurate than T2-weighting for localizing the SN in vivo.

Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging.

BACKGROUND: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS: We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Tendon length and joint flexibility are related to running economy.

PURPOSE: The purpose of study was to determine whether quadriceps/patella and Achilles tendon length and flexibility of the knee extensors and plantar flexors are related to walking and running economy. METHODS: Twenty-one male distance runners were subjects. Quadriceps/patella and Achilles tendon length were measured by magnetic resonance imaging; body composition was measured DXA; oxygen uptake at rest while seated, walking (3 mph), and running (6 and 7 mph) were measured by indirect calorimetry; knee and ankle joint flexibility were measured by goniometry; and leg lengths were measured by anthropometry while seated. Correlations were used to identify relationships between variables of interest. RESULTS: Net VO2 (exercise VO2 - rest VO2) for walking (NVOWK) and running at 6 and 7 mph (NVO6 and NVO7, respectively) was significantly related to Achilles tendon length (r varying from -0.40 to -0.51, P all < 0.04). Achilles tendon cross section was not related to walking or running economy. Quadriceps/patella tendon length was significantly related to NVO7 (r = -0.43, P = 0.03) and approached significance for NVO6 (r = -0.36, P = 0.06). Flexibility of the plantar flexors was related to NVO7 (+0.38, P = 0.05). Multiple regression showed that Achilles tendon length was independently related to NVO6 and NVO7 (partial r varying from -0.53 to -0.64, all P < 0.02) independent of lower leg length, upper leg length, quadriceps/patella tendon length, knee extension flexibility, or plantarflexion flexibility. CONCLUSIONS: These data support the premise that longer lower limb tendons (especially Achilles tendon) and less flexible lower limb joints are associated with improved running economy.

Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia.

BACKGROUND: Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. METHODS: We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. RESULTS: In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. CONCLUSIONS: Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.

Brain metabolic correlates of decision making in amnestic mild cognitive impairment.

Persons with amnestic mild cognitive impairment (MCI) have subtle impairments in medical decision-making capacity (MDC). We examined the relationship between proton magnetic resonance spectroscopy (MRS) and MDC in MCI. Twenty-nine MCI patients and 42 controls underwent MRS to obtain ratios of N-acetylaspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, and myo-Inositol (mI)/Cr of the posterior cingulate. They also completed the Capacity to Consent to Treatment Instrument (CCTI), a vignette-based instrument measuring decisional standards of expressing choice, appreciating consequences of choice, providing rational reasons for choice, and understanding treatment choices. Patients showed abnormal MRS ratios of mI/Cr and Cho/Cr compared to controls, and impairments on the CCTI understanding and reasoning Standards. Performance on the reasoning standard of the CCTI was correlated with NAA/Cr (r = .46, p < .05). The relationship of NAA/Cr with decision-making suggests a role for posterior cortical neuronal functioning in performance of complex IADLs in MCI.

Magnetic resonance imaging volume of the angular gyri predicts financial skill deficits in people with amnestic mild cognitive impairment.

OBJECTIVES: To better understand how brain atrophy in amnestic mild cognitive impairment (MCI) as measured using magnetic resonance imaging (MRI) volumetrics could affect instrumental activities of daily living (IADLs) such as financial abilities. DESIGN: Controlled, matched-sample, cross-sectional analysis regressing MRI volumetrics with financial performance measures. SETTING: University medical and research center. PARTICIPANTS: Thirty-eight people with MCI and 28 older adult controls. MEASUREMENTS: MRI volumetric measurement of the hippocampi, angular gyri, precunei, and medial frontal lobes. Participants also completed neuropsychological tests and the Financial Capacity Instrument (FCI). RESULTS: Correlations were performed between FCI scores and MRI volumes in the group with MCI. People with MCI performed significantly below controls on the FCI and had significantly smaller hippocampi. Among people with MCI, performance on the FCI was moderately correlated with angular gyri and precunei volumes. Regression models demonstrated that angular gyrus volumes were predictive of FCI scores. Tests of mediation showed that measures of arithmetic and possibly attention partially mediated the relationship between angular gyrus volume and FCI score. CONCLUSION: Impaired financial abilities in amnestic MCI correspond with volume of the angular gyri as mediated by arithmetic knowledge. The findings suggest that early neuropathology within the lateral parietal region in MCI leads to a breakdown of cognitive abilities that affect everyday financial skills. The findings have implications for diagnosis and clinical care of people with MCI and AD.

Proton magnetic resonance spectroscopy in dementias and mild cognitive impairment.

With the anticipated increase in dementias due to the aging demographic of industrialized nations, biomarkers for neurodegenerative diseases are increasingly important as new therapies are being developed for clinical trials. Proton MR spectroscopy ((1)H MRS) appears poised to be a viable means of tracking brain metabolic changes due to neurodegenerative diseases and potentially as a biomarker for treatment effects in clinical therapeutic trials. This review highlights the body of literature investigating brain metabolic abnormalities in Alzheimer's disease, amnestic mild cognitive impairment, frontotemporal dementia, vascular dementia, Lewy body dementia, and Parkinson's disease dementia. In particular, the review addresses the viability of (1)H MRS to discriminate among dementias, to measure disease progression, and to measure the effects of pharmacological treatments. While findings to date are encouraging, more study is needed in longitudinal patterns of brain metabolic changes, correspondence with changes in clinical markers of disease progression, and sensitivity of (1)H MRS measures to treatment effects. Such developments will hopefully benefit the search for effective treatments of dementias in the twenty-first century.

Brain metabolism differs in Alzheimer's disease and Parkinson's disease dementia.

BACKGROUND: Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimer's disease (AD) and in Parkinson's disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS). METHODS: Twelve patients with idiopathic PDD, 22 patients with probable mild AD, and 61 healthy older controls underwent posterior cingulate MRS. RESULTS: Patients with AD exhibited reduced N-acetyl aspartate (NAA)/creatine (Cr) (P < .05) and increased choline (Cho)/Cr (P < .05) and myo-inositol (mI)/Cr (P < .01) compared with controls. Patients with PDD exhibited reduced NAA/Cr (P < .05) and glutamate (Glu)/Cr (P < .01) compared with controls. There was reduced Glu/Cr in PDD compared with AD (P < .01). CONCLUSIONS: Patients with AD and patients with PDD exhibited distinct brain metabolic MRS profiles. Findings suggest that comparison of brain MRS profiles across dementias provides useful direction for future study.

Brain N-acetylaspartate is reduced in Parkinson disease with dementia.

Persons with Parkinson disease (PD) are at risk of developing dementia. Of the dementias affecting patients with PD, PD with dementia (PDD) is not well understood, although brain imaging studies to date have observed characteristic patterns of brain atrophy. Metabolic differences have been observed in magnetic resonance spectroscopy (MRS) studies comparing patients with PDD to nondemented PD patients, although it is unclear whether PDD patients have abnormally low MRS ratios compared with healthy age-matched adults. In this study, 12 patients with PDD, 12 patients with PD and no dementia, and 12 age-matched healthy older adults underwent MRS of the posterior cingulate gyrus. Patients with PDD showed lower N-acetylaspartate/creatine (NAA/Cr) compared with controls (P=0.004) and compared with nondemented PD patients (P=0.003). No abnormalities were observed in choline/Cr or myo-Inositol/Cr. NAA/Cr was correlated with mental status in patients with PD and in patients with PDD (r=0.56; P=0.029). The findings suggest that reduced NAA/Cr of the posterior cingulate could be used as a marker for dementia in patients with PD. Future studies investigating the utility of brain MRS as a predictor of dementia in PD and comparing brain metabolism in PDD with other dementias seem warranted.

High-resolution chemical shift imaging for the assessment of intramuscular lipids.

A new high-resolution MRSI technique was used to measure extracellular lipids (EMCL), intracellular lipids (IMCL), and total muscle lipids (TML). The purpose of this study was to assess the feasibility and reproducibility of this new technique. This study also compared results obtained from small regions of interest (ROIs) vs. a summation of a large ROI of voxels representing the total soleus or anterior tibialis (TA) muscles. Eight volunteers were studied with the use of a conventional single-slice MR spectroscopic imaging (MRSI) sequence run with the following parameters: TR = 145.9 ms, FOV = 16 cm, slice thickness = 1 cm, and 64 x 64 phase encodes. EMCL, IMCL, and TML values from the small ROIs proved to be reproducible (coefficient of variation (CV) = 7.8-13.8% for soleus, and 8.2-18% for TA). EMCL, IMCL, and TML values from the larger soleus ROI proved to be reproducible (CV = 7.3-16.1%), whereas the larger TA ROIs were less reproducible. The small and larger soleus ROIs produced statistically equivalent measures of EMCL and TML per unit area. However, the small soleus and TA ROIs showed a trend toward yielding different IMCL contents as compared to the larger ROIs. This study demonstrates that high-resolution 1H MRSI of the calf muscle is feasible and can reproducibly measure EMCL, IMCL, and TML.

Elevated brain scyllo-inositol concentrations in patients with Alzheimer's disease.

in vivo (1)H MRS reveals reduced N-acetylaspartate (NAA) and elevated myo-inositol (mI) in patients with mild Alzheimer's disease (AD) and patients with amnestic mild cognitive impairment (MCI). We are unaware of studies that have documented abnormal scyllo-inositol (sI) levels in patients with AD or patients with MCI, although a previous MRS study in older adults has indicated that sI is a peak of interest to measure in AD. Fifteen patients with mild AD, 26 patients with amnestic MCI, and 19 healthy older adults were recruited to this study. All underwent (1)H MRS of the posterior cingulate gyrus of the brain using a 3 T MRI scanner. Increases in the sI/creatine (Cr) ratio were observed in patients with mild AD (P < 0.05). The mI/Cr ratio was raised in patients with mild AD (P < 0.01) and MCI (P < 0.05). Reduced NAA/Cr was detected in patients with mild AD (P < 0.05). The sI/Cr ratio correlated negatively (r = -0.60, P < 0.05) with a measure of clock drawing in patients with mild AD, indicating that impaired cognitive ability in AD is associated with higher concentrations of sI/Cr. In vivo measurement of sI/Cr in the posterior cingulate gyrus of patients with mild AD revealed increases compared with cognitively healthy older adults. Further research on the mechanisms of sI increase in AD is needed. Future studies on the longitudinal course of sI/Cr in MCI and AD appear warranted.

In vivo GABA detection with improved selectivity and sensitivity by localized double quantum filter technique at 4.1T.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter for the normal function of mammal and human brain. It is difficult to detect GABA signal with the conventional single quantum technique due to its relatively low concentration and overlapping with other signals from creatine (Cr), glutathione (GSH), as well as macromolecules. Using a high-selective read pulse, DANTE, and at the facility of increased sensitivity and chemical shift resolution at high-field 4.1T, GABA editing by double quantum filter (DQF) with robust suppression of Cr and GSH was achieved. Our editing efficiency of 40-50% was achievable on a GABA phantom (50 mM GABA and 61 mM choline). Furthermore, GABA editing spectra were acquired with echo time TE = 77 ms, and any possible macromolecular contamination to GABA editing spectra was found to be negligible. This high-field DQF setup was applied to 11 healthy volunteers, and the mean GABA level was measured to be 1.12 +/- 0.15 mM in the occipital lobe in reference to 7.1 mM Cr concentration.

Cardiac transplant patients response to the (31)P MRS stress test.

BACKGROUND: Previous studies showed low resting phosphocreatine/adenosine triphosphate (PCr/ATP) ratios within this patient population compared with controls; however, these low PCr/ATP did not correlate with endomyocardial biopsy rejection. One possible explanation is the presence of cardiac allograft vasculopathy (CAV), which might be manifested as a transient ischemic event in the mildly stressed transplanted heart. If transient ischemia is invoked through the (31)P magnetic resonance spectroscopy (MRS) stress test, monitoring of such an event should be achievable and thus implicating possible ischemic involvement. METHODS: Heart transplant patients (n = 25) and normal controls (n = 11) were studied using the (31)P MRS stress test; 10 patients tested positive (> 2 standard deviations [SDs] from control values). Patients also were monitored for heart rate and blood pressure with the handgrip exercise generating a small increase in the rate-pressure product. RESULTS: The percent change (%Delta) in the PCr/ATP ratio in the control group was 1.50% +/- 10.6; the transplant population showed an overall change of -6.7% +/- 18.5. The responders, those that were at or below the 2 SD line from control, had a -25.6 +/- 3.6% Delta PCr/ATP; whereas the non-responders reflect a 5.1 +/- 13.4%. The responders' response is quite striking when considering the threshold for an abnormal PCr/ATP %Delta in response to stress testing was -19.7%, which was the 2 SD mark below the mean value for the reference population. DISCUSSION: The (31)P MRS stress test showed that a possible transient ischemic event occurred in a subset of patients, thus implicating possible CAV in the cardiac transplant patient. Such an approach may provide an early diagnosis of this disease.