Quantitative T2, T2*, and T2' MR imaging in patients with ischemic leukoaraiosis might detect microstructural changes and cortical hypoxia.

INTRODUCTION: Quantitative MRI with T2, T2*, and T2' mapping has been shown to non-invasively depict microstructural changes (T2) and oxygenation status (T2* and T2') that are invisible on conventional MRI. Therefore, we aimed to assess whether T2 and T2' quantification detects cerebral (micro-)structural damage and chronic hypoxia in lesions and in normal appearing white matter (WM) and gray matter (GM) of patients with ischemic leukoaraiosis (IL). Measurements were complemented by the assessment of the cerebral blood flow (CBF) and the degree of GM and WM atrophy. METHODS: Eighteen patients with IL and 18 age-matched healthy controls were included. High-resolution, motion-corrected T2, T2*, and T2' mapping, CBF mapping (pulsed arterial spin labeling, PASL), and segmentation of GM and WM were used to depict specific changes in both groups. All parameters were compared between patients and healthy controls, using t testing. Values of p < 0.05 were accepted as statistically significant. RESULTS: Patients showed significantly increased T2 in lesions (p < 0.01) and in unaffected WM (p = 0.045) as well as significantly increased T2* in lesions (p = 0.003). A significant decrease of T2' was detected in patients in unaffected WM (p = 0.027), while no T2' changes were observed in GM (p = 0.13). Both unaffected WM and GM were significantly decreased in volume in the patient-group (p < 0.01). No differences of PASL-based CBF could be shown. CONCLUSION: Non-invasive quantitative MRI with T2, T2*, and T2' mapping might be used to detect subtle structural and metabolic changes in IL. Assessing the grade of microstructural damage and hypoxia might be helpful to monitor disease progression and to perform risk assessment.

Association of microstructural white matter abnormalities with cognitive dysfunction in geriatric patients with major depression.

Major depression disorder (MDD) is one of the most common causes of disability in people over 60years of age. Previous studies have linked affective and cognitive symptoms of MDD to white matter (WM) disruption in limbic-cortical circuits. However, the relationship between clinical cognitive deficits and loss of integrity in particular WM tracts is poorly understood. Fractional anisotropy (FA) as a measure of WM integrity was investigated in 17 elderly MDD subjects in comparison with 18 age-matched controls using tract-based spatial statistics (TBSS) and correlated with clinical and cognitive parameters. MDD patients revealed significantly reduced FA in the right posterior cingulate cluster (PCC) compared with controls. FA in the right PCC (but not in the left PCC) showed a significant positive correlation with performance in a verbal naming task, and showed a non-significant trend toward a correlation with verbal fluency and episodic memory performance. In control subjects, no correlations were found between cognitive tasks and FA values either in the right or left PCC. Results provide additional evidence supporting the neuronal disconnection hypothesis in MDD and suggest that cognitive deficits are related to the loss of integrity in WM tracts associated with the disorder.

T2'- and PASL-based perfusion mapping at 3 Tesla: influence of oxygen-ventilation on cerebral autoregulation.

PURPOSE: To use T2'-mapping together with Pulsed Arterial Spin Labeling (PASL) providing quantitative information of deoxygenation level and cerebral blood flow (CBF) in the cerebral gray matter to obtain simultaneous information about the cerebral oxygen metabolism and the resulting cerebral vasoreactivity under normoxic and hyperoxic conditions. MATERIALS AND METHODS: Twelve young, healthy volunteers underwent MRI under normoxic and hyperoxic conditions performing PASL and high-resolution, motion-corrected T2* and T2-mapping to calculate T2'values. Regions of interest (ROI) were placed in the frontoparietal cortex and thalamus by manual and automatic segmentation. For each ROI, mean normoxic T2'- and CBF values were extracted and compared with the same parameters assessed under hyperoxic ventilation. RESULTS: A hyperoxic-induced decrease of the CBF could be shown in the frontoparietal cortex (P = 0.009). The T2 values of frontoparietal cortex decreased under hyperoxic inhalation compared with normoxia (P = 0.01), whereas T2' remained unchanged. CONCLUSION: Motion-corrected high-resolution T2'-maps can be used together with PASL to evaluate the DeoxyHb content in relation to CBF in the cerebral gray matter. We could show that cortical CBF decreases under hyperoxic inhalation in healthy young subjects, whereas the T2' values remained constant. These data suggest that hyperoxic-induced vasoconstriction may protect the brain against hyperoxemia.

Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives.

In this study, we investigate whether aberrant integrity of white matter (WM) fiber tracts represents a genetically determined biological marker of schizophrenia (SZ), and its relation with clinical symptoms. We collected brain DTI data from 28 SZ patients, 18 first-degree relatives and 22 matched controls and used voxel-based analysis with tract-based spatial statistics (TBSS) in order to compare fractional anisotropy (FA) between groups. Mean voxel-based FA values from the entire skeleton of each group were compared. We did a multiple regression analysis, followed by single post-hoc contrasts between groups. FA values were extracted from the statistically significant areas. The results showed significantly smaller FA values for SZ patients in comparison with controls in cortico-spinal tracts, in commissural fibers, in thalamic projections, in association fibers and in cingulum bundles. A significant increase of FA in SZ patients in comparison with healthy controls was only found in the arcuate fasciculus. Relatives had intermediate values between patients and controls which were deemed significant in the comparison to patients and controls in association fibers, arcuate fasciculus and cingulum bundles. Lower FA values in association fibers were significantly associated with predisposition toward hallucinations (in SZ patients and relatives), with higher PANSS scores of positive symptoms and with duration of illness (SZ patients). Our results suggest that clinical and subclinical presentations of psychotic symptoms are associated with aberrant integrity of multiple WM tracts. This association may represent an endophenotype of schizophrenia, since it is present in unaffected relatives as well. Such endophenotypes may serve as quantitative traits for future genetic studies and as candidate markers for early and preclinical identification of subjects at risk.

GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure.

OBJECTIVE: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton ((1)H) and phosphorus ((31)P) magnetic resonance spectroscopic imaging (MRSI) in vivo. METHODS: (1)H and (1)H-decoupled (31)P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. RESULTS: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from (1)H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. CONCLUSION: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

T2' imaging within perfusion-restricted tissue in high-grade occlusive carotid disease.

BACKGROUND AND PURPOSE: Quantitative T2' imaging presumably detects regional changes in the relation of oxygenated and deoxygenated hemoglobin. Regional differences in hemoglobin oxygenation might reflect areas with increased oxygen extraction for compensation of reduced perfusion pressure. We investigated quantitative T2' imaging in patients with high-grade stenoses of brain-supplying arteries and hypothesized that T2' values are lower in perfusion-restricted areas as compared with normally perfused tissue. METHODS: Eighteen patients (15 men; mean age±SD, 54±12.8 years) with unilateral symptomatic or asymptomatic high-grade extracranial or intracranial internal carotid artery or proximal middle cerebral artery stenosis/occlusion were included. MR examination included perfusion-weighted imaging and quantitative, motion-corrected mapping of T2' time. Time-to-peak and mean transit time maps were thresholded for different degrees of perfusion delays (eg, >0 seconds, ≥2 seconds) compared with the contralateral hemisphere. Mean T2' values in areas of impaired perfusion were compared with T2' values in corresponding contralateral or ipsilateral, normoperfused areas. RESULTS: Mean size of perfusion-impaired areas in time-to-peak maps (time-to-peak delay>0 seconds) was 10.8 mL (±6.3) and 11.5 mL (±6.4) in mean transit time maps (mean transit time delay>0 seconds). T2' values were significantly (P<0.01) lower in all perfusion-restricted compared with corresponding contralateral brain areas (ipsilateral versus contralateral). For time-to-peak delay >0 seconds, T2' values were 115 ms (±9) versus 125 ms (±12). For mean transit time delay>0 seconds, T2' values were 115 ms (±9) versus 128 ms (±10). Differences in T2' values increased with the severity of the perfusion delay. Ipsilateral T2' values outside the perfusion-disturbed areas did not differ from contralateral T2' values. CONCLUSIONS: Motion-corrected T2' imaging presumably detects areas with increased oxygen extraction within perfusion-restricted tissue in patients with high-grade occlusive vessel disease.

Neural correlates of autobiographical memory in amnestic Mild Cognitive Impairment.

Episodic memory dysfunction, commonly assessed with word list recall, is the main characteristic of amnestic Mild Cognitive Impairment (aMCI). While brain pathology underlying this kind of memory impairment is well established in aMCI, little is known about the effect of neurodegeneration on autobiographical memory. The present study investigated neuronal correlates of autobiographical memory in aMCI patients (n=12) and healthy elderly controls (n=13) using functional magnetic resonance imaging (fMRI). Additionally, voxel-based morphometry (VBM) was employed to reveal brain pathology in aMCI patients. Neuropsychological assessment showed significant impairment in episodic memory tasks (immediate and delayed word list recall) in aMCI patients. Moreover, VBM revealed significantly reduced gray matter concentration, which was most pronounced in the temporal lobes of aMCI patients. Despite episodic memory impairment and atrophy in areas that are associated with encoding and recall of episodic memories, aMCI patients showed no alterations in brain activation associated with autobiographical memory retrieval. These findings could suggest that autobiographical memory is subserved by a different neuronal network than episodic memory and that the two memory systems are differently affected by aMCI.

Bevacizumab impairs oxidative energy metabolism and shows antitumoral effects in recurrent glioblastomas: a 31P/1H MRSI and quantitative magnetic resonance imaging study.

Bevacizumab shows unprecedented rates of response in recurrent glioblastomas (GBM), but the detailed mechanisms are still unclear. We employed in vivo magnetic resonance spectroscopic imaging (MRSI) and quantitative magnetic resonance imaging to investigate whether bevacizumab alters oxygen and energy metabolism and whether this effect has antitumoral activity in recurrent GBM. (31)P and (1)H MRSI, apparent diffusion coefficient (ADC), and high-resolution T2 and T2' mapping (indirect marker of oxygen extraction) were investigated in 16 patients with recurrent GBM at 3 Tesla before and 1.5-2 months after initiation of therapy with bevacizumab. Changes of metabolite concentrations and of the quantitative values in the tumor and normal appearing brain tissue were calculated. The Wilcoxon signed-ranks test was used to evaluate differences for tumor/edema versus control as well as changes before versus after commencement of therapy. Survival analyses were performed for significant parameters. Tumor T2', pH, ADC, and T2 decreased significantly in patients responding to bevacizumab therapy (n = 10). Patients with at least 25% T2' decrease during treatment showed longer progression-free and overall survival durations. Levels of high-energy metabolites were lower at baseline; these persisted under therapy. Glycerophosphoethanolamine as catabolic phospholipid metabolite increased in responders. The MRSI data support the hypothesis that bevacizumab induces relative tumor hypoxia (T2' decrease) and affects energy homeostasis in recurrent GBM, suggesting that bevacizumab impairs vascular function. The antiangiogenic effect of bevacizumab is predictive of better outcome and seems to induce antitumoral activity in the responding GBMs.

Combined (1)H and (31)P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis.

(1)H MRSI has evolved as an important tool to study the onset and progression of brain damage in multiple sclerosis. Abnormal increases in total creatine, total choline and myoinositol have been noted in multiple sclerosis. However, the pathobiochemical mechanisms related to these changes are still largely unclear. The combination of (1)H MRSI and (1)H-decoupled (31)P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined (1)H and (31)P MRSI data were obtained at 3 T in 22 patients with multiple sclerosis and in 23 healthy controls, and aligned with structural MRI to allow for correction for partial volume effects caused by cerebrospinal fluid and lesion load. A significant increase in total creatine was found in multiple sclerosis, and this was attributed to equal changes in the phosphorylated and unphosphorylated components. The concentrations of the putative glial markers total creatine and myoinositol in lesion-free (1)H MRSI voxels correlated with the global lesion load. We conclude that changes in total creatine are not related to altered energy metabolism, but rather indicate gliosis. Together with the increase in myoinositol, total creatine can be considered as a biomarker for disease severity. A significant total choline increase was mainly a result of choline components not visible by (31)P MRS. The origin of this residual choline fraction remains to be investigated.

Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease.

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.

In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy.

Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N=21; PSP stages II to III) and healthy controls (N=9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (=ATP+phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.

Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial.

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q(10) (CoQ(10)) is a physiological cofactor of complex I. Therefore, we evaluated the short-term effects of CoQ(10) in PSP. We performed a double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients (stage < or = III) to receive a liquid nanodispersion of CoQ(10) (5 mg/kg/day) or matching placebo. Over a 6-week period, we determined the change in CoQ(10) serum concentration, cerebral energy metabolites (by (31)P- and (1)H-magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Asberg Depression Scale). CoQ(10) was safe and well tolerated. In patients receiving CoQ(10) compared to placebo, the concentration of low-energy phosphates (adenosine-diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high-energy phosphates to low-energy phosphates (adenosine-triphosphate to adenosine-diphosphate, phospho-creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ(10) treatment compared to placebo. Since CoQ(10) appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.