Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies.

Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB.

Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate.

Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.

Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging.

OBJECTIVES: Impaired cardiac function has been confirmed in patients with chronic fatigue syndrome (CFS). Magnetic resonance cardiac tagging is a novel technique that assesses myocardial wall function in vivo. We hypothesized that patients with CFS may have impaired development and release of myocardial torsion and strain. METHODS: Cardiac morphology and function were assessed using magnetic resonance imaging and cardiac tagging methodology in 12 CFS patients (Fukuda) and 10 matched controls. RESULTS: Compared to controls, the CFS group had substantially reduced left ventricular mass (reduced by 23%), end-diastolic volume (30%), stroke volume (29%) and cardiac output (25%). Residual torsion at 150% of the end-systolic time was found to be significantly higher in the patients with CFS (5.3 ± 1.6°) compared to the control group (1.7 ± 0.7°, P = 0.0001). End-diastolic volume index correlated negatively with both torsion-to-endocardial-strain ratio (TSR) (r = -0.65, P = 0.02) and the residual torsion at 150% end-systolic time (r = -0.76, P = 0.004), so decreased end-diastolic volume is associated with raised TSR and torsion persisting longer into diastole. Reduced end-diastolic volume index also correlated significantly with increased radial thickening (r = -0.65, P = 0.03) and impaired diastolic function represented by the ratio of early to late ventricular filling velocity (E/A ratio, r = 0.71, P = 0.009) and early filling percentage (r = 0.73, P = 0.008). CONCLUSION: Patients with CFS have markedly reduced cardiac mass and blood pool volumes, particularly end-diastolic volume: this results in significant impairments in stroke volume and cardiac output compared to controls. The CFS group appeared to have a delay in the release of torsion.

Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging.

RATIONALE: One of the key targets of psychopharmacology research is to determine the potential sites of action of antidepressants in order to characterise their underlying mechanism of action. OBJECTIVE: Using blood oxygenation level-dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), the neuroanatomical target-sites of reboxetine (a selective noradrenaline reuptake inhibitor) and bupropion (an antidepressant with stimulatory effects on dopamine and potentially on noradrenaline) were mapped. METHODS: Separate groups of rats were challenged acutely or chronically (daily injections for 14 days) with saline or psychoactive compounds and scanned. Subsequent statistical parametric mapping of the main effects of the drug was performed by identifying changes in the BOLD signal. RESULTS: Acute reboxetine challenge at a low dose (10 mg/kg i.p.) produced positive BOLD responses specifically in the hypothalamus, whereas a larger dose (30 mg/kg i.p.) produced activations in the hypothalamus, anterior hippocampus and prefrontal cortex. Chronic reboxetine (30 mg/kg i.p.) treatment induced increased BOLD responses in the posterior hippocampus and prefrontal cortex, while no significant contrast changes were observed in the hypothalamus and a significant decrease was apparent in the amygdala. In contrast, acute bupropion (15 and 30 mg/kg i.p.) challenge in both doses produced no significant contrast changes in the regions of interest. However, chronic bupropion treatment (30 mg/kg i.p.) produced robust increases in BOLD responses in the hippocampus, amygdala and prefrontal cortex. CONCLUSION: In summary, this study demonstrates that reboxetine and bupropion evoke a significant increase in BOLD functional activity in specific regions of the brain, including the hypothalamus, hippocampus, prefrontal cortex and amygdala. Furthermore, the study illustrates the potential value of pharmacological MRI in rodents to delineate pharmacologically induced changes in regional brain function.

Cerebral blood flow by arterial spin labeling in poststroke dementia.

OBJECTIVE: To investigate the relationship between cerebral blood flow and dementia in older stroke survivors and subjects with Alzheimer disease (AD). METHODS: This cohort study used arterial spin labeling MRI at 3 T to examine cerebral blood flow (CBF). We scanned 39 patients 6 years after stroke. They were older than 75 years at the time of stroke and free of dementia 3 months poststroke, with 8 subsequently developing dementia. We also scanned 17 subjects with AD and 29 healthy control subjects. We determined the perfusion in regions of interest (ROIs). Hippocampal volume was also measured using a previously validated automated procedure. RESULTS: The gray matter/white matter CBF ratio was reduced globally in the poststroke dementia (PSD) group (1.55 SD = 0.12) relative to control subjects (1.78 SD = 0.18; p = 0.03). The CBF ratio in a parietal ROI was reduced in the AD (1.34 SD = 0.31; p = 0.003), PSD (1.32 SD = 0.22; p = 0.041), and poststroke no-dementia (PSND) (1.44 SD = 0.34; p = 0.014) groups relative to that of control subjects (1.70 SD = 0.32). In subjects without stroke, the best predictor of dementia was hippocampus volume, whereas in the stroke group, it was the global CBF gray matter/white matter ratio. Hippocampus volume was not significantly different between the AD and PSD groups, and both had reduced hippocampi relative to those of control subjects and the PSND group. CONCLUSIONS: We found evidence for both vascular and AD pathology in PSD, suggesting that both the direct impact of the stroke and subsequent development of AD-type changes play a role in the etiology of PSD.

Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.

Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR). Here, using a combination of functional magnetic resonance imaging (fMRI) and electrophysiology we demonstrate regional heterogeneity in the mechanisms underlying neurovascular coupling. Direct electrical stimulation of the rat hindpaw sensorimotor cortex induces blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) fMRI responses in several anatomically distinct cortical and subcortical structures. Following intraperitoneal administration of the type 5 mGluR antagonist, MPEP, both BOLD and CBV responses to cortical stimulation were significantly reduced, whilst the local field potential (LFP) responses remained largely constant. Spatially, the degree of reduction in fMRI responses varied between cortical and subcortical regions (primary cortex approximately 18% vs. striatum approximately 66%), and also between primary and secondary cortical areas ( approximately 18% vs. approximately 55%). Similarly, greater decreases in response amplitude were seen in the contralateral secondary cortex ( approximately 91%) and ipsilateral striatum (approximately 70%), compared to the primary cortex (approximately 44%). Following MPEP, a negative component of the BOLD and CBV responses became more apparent, suggesting that different mechanisms mediate vasodilatory and vasoconstrictory responses. Interestingly, under baseline conditions the quantitative relationship between fMRI and LFP responses in cortical and subcortical regions was markedly different. Our data indicate that coupling between neuronal and fMRI responses is neither empirically nor mechanistically consistent across the brain.

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome.

OBJECTIVES: To examine muscle acid handling following exercise in chronic fatigue syndrome (CFS/ME) and the relationship with autonomic dysfunction. DESIGN: Observational study. SETTING: Regional fatigue service. SUBJECTS & INTERVENTIONS: Chronic fatigue syndrome (n = 16) and age and sex matched normal controls (n = 8) underwent phosphorus magnetic resonance spectroscopy (MRS) to evaluate pH handling during exercise. Subjects performed plantar flexion at fixed 35% load maximum voluntary contraction. Heart rate variability was performed during 10 min supine rest using digital photophlethysmography as a measure of autonomic function. RESULTS: Compared to normal controls, the CFS/ME group had significant suppression of proton efflux both immediately postexercise (CFS: 1.1 +/- 0.5 mmol L(-1) min(-1) vs. normal: 3.6 +/- 1.5 mmol L(-1) min(-1), P < 0.001) and maximally (CFS: 2.7 +/- 3.4 mmol L(-1) min(-1) vs. control: 3.8 +/- 1.6 mmol L(-1) min(-1), P < 0.05). Furthermore, the time taken to reach maximum proton efflux was significantly prolonged in patients (CFS: 25.6 +/- 36.1 s vs. normal: 3.8 +/- 5.2 s, P < 0.05). In controls the rate of maximum proton efflux showed a strong inverse correlation with nadir muscle pH following exercise (r(2) = 0.6; P < 0.01). In CFS patients, in contrast, this significant normal relationship was lost (r(2) = 0.003; P = ns). In normal individuals, the maximum proton efflux following exercise were closely correlated with total heart rate variability (r(2) = 0.7; P = 0.007) this relationship was lost in CFS/ME patients (r(2) < 0.001; P = ns). CONCLUSION: Patients with CFS/ME have abnormalities in recovery of intramuscular pH following standardised exercise degree of which is related to autonomic dysfunction. This study identifies a novel biological abnormality in patients with CFS/ME which is potentially open to modification.

The technology of MRI--the next 10 years?

MRI is the most flexible of our diagnostic imaging modalities, possessing the ability to characterize a wide range of parameters in the living subject and provide exquisite spatial resolution. Here we first review the rise of MRI to its current clinical "state-of-the-art" status and then consider the future directions for this technique. The long-term impact on clinical practice of recent innovations in MRI scanner hardware and sequence design are also considered. Key changes in clinical practice that we predict for the coming 10 years include: a widespread shift to higher field imaging (3T); further improvements in MRI coil technology, including further increases in the number of channels; the introduction of ultra-short echo-time imaging; the introduction of combined modality methods (e.g. positron emission tomography (PET)-MRI and single photon emission CT (SPECT)-MRI); and significant advances in molecular MRI agents. Even after 30 years of continuing developments in human MRI, the coming decade will provide further major advances in diagnostic MRI.

Association between cortical metabolite levels and clinical manifestations of migrainous aura: an MR-spectroscopy study.

Previous studies suggest an abnormal cerebral cortical energy metabolism in migraineurs. If causally related to the pathophysiology of migraine, these abnormalities might show a dose-response relationship with the duration and severity of aura symptoms. While such a trend has been suggested in phosphorus spectroscopy (31P-MRS) studies, it has not been considered in proton spectroscopy (1H-MRS) studies and it has not been studied in cerebral white matter. We aimed to determine whether for any of the metabolites measured by 31P-MRS or 1H-MRS there was a dose-response relationship with aura duration and severity, and whether such an association was also present in cerebral white matter. We studied patients with migraine with aura and healthy controls with 31P-MRS and with 1H-MRS. We measured metabolite ratios in grey and in white matter and in the patients, we related metabolite levels to the clinical characteristics and duration of the aura. In patients, the phosphocreatine/phosphate (PCr/Pi) ratio decreased significantly with increasing aura duration and was significantly lower in patients with hemiplegic migraine than in patients with non-motor aura. Overall the metabolite ratios did not differ significantly between patients and controls, but compared with controls the PCr/Pi ratio in patients with hemiplegic migraine and in patients with persistent aura >7 days was significantly lower. These changes were only present in grey matter. Results for 1H-MRS did not differ significantly between patients and controls, and they showed no association with duration or severity of symptoms. In this study, metabolite ratios differed significantly between patients with different aura phenotypes and with increasing aura duration. In addition, only in some patient subgroups were metabolite ratios significantly different from controls. These findings support the concept that migraine with aura is a heterogeneous disorder with distinct pathophysiological subtypes. They further suggest that rather than determining the susceptibility to developing a migraine attack, changes in cortical energy metabolism may determine the clinical manifestations of the migrainous aura once an attack has started.

MRS reveals additional hexose N-acetyl resonances in the brain of a mouse model for Sandhoff disease.

Sandhoff disease, one of several related lysosomal storage disorders, results from the build up of N-acetyl-containing glycosphingolipids in the brain and is caused by mutations in the genes encoding the hexosaminidase beta-subunit. Affected individuals undergo progressive neurodegeneration in response to the glycosphingolipid storage. (1)H magnetic resonance spectra of perchloric acid extracts of Sandhoff mouse brain exhibited several resonances ca 2.07 ppm that were not present in the corresponding spectra from extracts of wild-type mouse brain. High-performance liquid chromatography and mass spectrometry of the Sandhoff extracts post-MRS identified the presence of N-acetylhexosamine-containing oligosaccharides, which are the likely cause of the additional MRS resonances. MRS of intact brain tissue with magic angle spinning also showed additional resonances at ca 2.07 ppm in the Sandhoff case. These resonances appeared to increase with disease progression and probably arise, for the most part, from the stored glycosphingolipids, which are absent in the aqueous extracts. Hence in vivo MRS may be a useful tool for detecting early-stage Sandhoff disease and response to treatment.

Detection of the inhibitory neurotransmitter GABA in macrophages by magnetic resonance spectroscopy.

Macrophages are key components of the inflammatory response to tissue injury, but their activities can exacerbate neuropathology. High-resolution magnetic resonance spectroscopy was used to identify metabolite levels in perchloric acid extracts of cultured cells of the RAW 264.7 murine macrophage line under resting and lipopolysaccharide-activated conditions. Over 25 metabolites were identified including gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter not previously reported to be present in macrophages. The presence of GABA was also demonstrated in extracts of human peripheral blood monocyte-derived macrophages. This finding suggests that there may be communication between damaged central nervous system (CNS) tissue and recruited macrophages and resident microglia, which could help orchestrate the immune response. On activation, lactate, glutamine, glutamate, and taurine levels were elevated significantly, and GABA and alanine were reduced significantly. Strong resonances from glutathione, evident in the macrophage two-dimensional 1H spectrum, suggest that this may have potential as a noninvasive marker of macrophages recruited to the CNS, as it is only present at low levels in normal brain. Alternatively, a specific combination of spectroscopic changes, such as lactate, alanine, glutathione, and polyamines, may prove to be the most accurate means of detecting macrophage recruitment to the CNS.

Confounding effects of anesthesia on functional activation in rodent brain: a study of halothane and alpha-chloralose anesthesia.

Functional magnetic resonance imaging (fMRI) in animal models provides a platform for more extensive investigation of drug effects and underlying physiological mechanisms than is possible in humans. However, it is usually necessary for the animal to be anesthetized. In this study, we have used a rat model of direct cortical stimulation to investigate the effects of anesthesia in rodent fMRI. Specifically, we have sought to answer two questions (i) what is the relationship between baseline neuronal activity and the BOLD response to stimulation under halothane anesthesia? And (ii) how does the BOLD response change after transferring from halothane to the commonly used anesthetic alpha-chloralose? In the first set of experiments, we found no significant differences in the amplitude of the BOLD response at the different halothane doses studied, despite electroencephalography (EEG) recordings indicating a dose-dependent reduction in baseline neuronal activity with increasing halothane levels. In the second set of experiments, a reduction in the spatial extent of the BOLD response was apparent immediately after transfer from halothane to alpha-chloralose anesthesia, although no change in the peak signal change was evident. However, several hours after transfer to alpha-chloralose, a significant increase in both the spatial extent and peak height of the BOLD response was observed, as well as an increased sensitivity to secondary cortical and subcortical activation. These findings suggest that, although alpha-chloralose anesthesia is associated with a greater BOLD response for a fixed stimulus relative to halothane, there is substantial variation in the extent and magnitude of the response over time that could introduce considerable variability in studies using this anesthetic.

Quantitative proton magnetic resonance spectroscopy of the cervical spinal cord.

Proton MR spectroscopy ((1)H-MRS) provides indices of neuronal damage in the central nervous system (CNS); however, it has not been extensively applied in the spinal cord. This work describes an optimized proton spectroscopy protocol for examination of the human cervical spinal cord. B(0) field mapping of the cord revealed periodic inhomogeneities due to susceptibility differences with surrounding tissue. By combining field maps and experimental data, we found that the optimum voxel size was 9 x 7 x 35 mm(3) placed with the inferior end of the voxel above vertebral body C2. Metabolite concentrations were determined in the cervical cord in six healthy controls by short-echo point-resolved spectroscopy (PRESS) volume localization. The results were compared with metabolite concentrations in the brainstem, cerebellum, and cortex in the same individuals. The concentrations in the cervical cord were as follows: N-acetyl-aspartate (NAA) 17.3 +/- 0.5, creatine (Cr) 9.5 +/- 0.9, and choline 2.7 +/- 0.5 mmol/l. The NAA concentration was significantly lower in the cord than in the brainstem (Mann-Whitney, P < 0.025), and higher than in the cortex (P < 0.005) and cerebellum (P < 0.005). Cr was significantly lower in the cord than in the cerebellum (P < 0.05). There were no significant differences between Cr concentrations in the spinal cord compared to the cortex and brainstem.

Differences in the BOLD fMRI response to direct and indirect cortical stimulation in the rat.

Functional MRI (fMRI) exploits a relationship between neuronal activity, metabolism, and cerebral blood flow to functionally map the brain. We have developed a model of direct cortical stimulation in the rat that can be combined with fMRI and used to compare the hemodynamic responses to direct and indirect cortical stimulation. Unilateral electrical stimulation of the rat hindpaw motor cortex, via stereotaxically positioned carbon-fiber electrodes, yielded blood oxygenation level-dependent (BOLD) fMRI signal changes in both the stimulated and homotypic contralateral motor cortices. The maximal signal intensity change in both cortices was similar (stimulated = 3.7 +/- 1.7%; contralateral = 3.2 +/- 1.0%), although the response duration in the directly stimulated cortex was significantly longer (48.1 +/- 5.7 sec vs. 19.0 +/- 5.3 sec). Activation of the contralateral cortex is likely to occur via stimulation of corticocortical pathways, as distinct from direct electrical stimulation, and the response profile is similar to that observed in remote (e.g., forepaw) stimulation fMRI studies. Differences in the neuronal pool activated, or neurovascular mediators released, may account for the more prolonged BOLD response observed in the directly stimulated cortex. This work demonstrates the combination of direct cortical stimulation in the rat with fMRI and thus extends the scope of rodent fMRI into brain regions inaccessible to peripheral stimulation techniques.

Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis.

Progression of disability in multiple sclerosis (MS) appears related to axonal damage, which is at least in part associated with white matter lesions. Beta-interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of axonal injury. To test the generalisability of this conclusion, particularly in a population with relatively active disease, we used magnetic resonance spectroscopy measures to test whether BIFN can reverse or arrest progression of axonal injury in patients with MS. Eleven patients with a history of active (median, 1.5 relapses/year) relapsing-remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel magnetic resonance spectroscopic measurements of relative concentrations of brain N-acetylaspartate (NAA), a measure of axonal integrity from a central, predominantly white matter brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and white matter water T2 relaxation time (p = 0.047) over 12 months. Also consistent with a treatment effect, white matter T2-hyperintense lesion loads did not increase. However, the central white matter NAA/creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02). For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006). These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of axonal injury. Nonetheless, there appears to be a relationship between the rate of progression of axonal injury and relapse rate over the previous two years. The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.

Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives.

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.

Reversible brain injury in a head-injured patient identified by magnetic resonance imaging and spectroscopy.

Serial MRI studies of a severely head-injured patient showed extensive diffusion abnormalities lasting for 40 days. These were related to initial perfusion abnormalities and improved in parallel with clinical status. Spectroscopy showed diffuse damage and pH changes. Together these data support a role for ischaemia in head injury.