Jörg Magerkurth

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 Q10 (CoQ10) is a physiological cofactor of complex I. Therefore, we evaluated the short‐term effects of CoQ10 in PSP. We performed a double‐blind, randomized, placebo‐controlled, phase II trial, including 21 clinically probable PSP patients (stage ≤ III) to receive a liquid nanodispersion of CoQ10 (5 mg/kg/day) or matching placebo. Over a 6‐week period, we determined the change in CoQ10 serum concentration, cerebral energy metabolites (by 31P‐ and 1H‐magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Åsberg Depression Scale). CoQ10 was safe and well tolerated. In patients receiving CoQ10 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 CoQ10 treatment compared to placebo. Since CoQ10 appears to improve cerebral energy metabolism in PSP, long‐term treatment might have a disease‐modifying, neuroprotective effect.

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 Parkinsons disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinsons 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 Parkinsons disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinsons disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinsons 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 Parkinsons disease which occurs early in the course of the disease.

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

1H 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 1H MRSI and 1H‐decoupled 31P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined 1H and 31P 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 1H 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 31P MRS. The origin of this residual choline fraction remains to be investigated. Copyright

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.

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.

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 (1H) and phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1H and 1H-decoupled 31P 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 1H 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.

Cortical–basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives

Structural brain changes are amongst the most robust biological alterations in schizophrenia, and their investigation in unaffected relatives is important for an assessment of the contribution of genetic factors. In this cross-sectional morphometry study we investigated whether volume changes in SZ are linked with genetic vulnerability and whether these effects are separated from secondary illness effects. We compared density of grey and white matter using high-resolution 3D-anatomical MRI imaging data in 31 SZ patients, 29 first-degree relatives and 38 matched healthy controls, using Voxel-Based Morphometry (VBM) with SPM8. Volume of basal ganglia was also compared by manual segmentation. We found increased grey matter in the striatum, globus pallidus internus and thalamus and decreased grey matter in the parahippocampal and cingulate gyri both in SZ patients and relatives. Additionally, SZ patients had decreased volume of temporal, frontal and limbic grey and white matter in comparison with relatives and controls. Relatives showed intermediate values in many of these areas. Increased volume in the thalamus and parts of the basal ganglia and decreased volume of cortical areas and underlying white matter were thus associated with schizophrenia and its genetic vulnerability. These results suggest that brain morphological changes associated with SZ are in part determined by genetic risk factors and are not entirely explained by effects of medication or changes secondary to illness.

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.

Age-Related Changes of Cerebral Autoregulation: New Insights with Quantitative T2′-Mapping and Pulsed Arterial Spin-Labeling MR Imaging

BACKGROUND AND PURPOSE: Cerebral perfusion and O2 metabolism are affected by physiologic age-related changes. High-resolution motion-corrected quantitative T2′-imaging and PASL were used to evaluate differences in deoxygenated hemoglobin and CBF of the gray matter between young and elderly healthy subjects. Further combined T2′-imaging and PASL were investigated breathing room air and 100% O2 to evaluate age-related changes in cerebral autoregulation. MATERIALS AND METHODS: Twenty-two healthy volunteers 60–88 years of age were studied. Two scans of high-resolution motion-corrected T2′-imaging and PASL-MR imaging were obtained while subjects were either breathing room air or breathing 100% O2. Manual and automated regions of interest were placed in the cerebral GM to extract values from the corresponding maps. Results were compared with those of a group of young healthy subjects previously scanned with the identical protocol as that used in the present study. RESULTS: There was a significant decrease of cortical CBF (P < .001) and cortical T2′ values (P < .001) between young and elderly healthy subjects. In both groups, T2′ remained unchanged under hyperoxia compared with normoxia. Only in the younger but not in the elderly group could a significant (P = .02) hyperoxic-induced decrease of the CBF be shown. CONCLUSIONS: T2′-mapping and PASL in the cerebral cortex of healthy subjects revealed a significant decrease of deoxygenated hemoglobin and of CBF with age. The constant deoxyHb level breathing 100% O2 compared with normoxia in young and elderly GM suggests an age-appropriate cerebral autoregulation. At the younger age, hyperoxic-induced CBF decrease may protect the brain from hyperoxemia.

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.