Introduction and purpose: Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin... Show moreIntroduction and purpose: Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HIP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NM) and creatine using 7-Tesla (7 T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers. Methods: A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7 day wash-out period. After administration of the oral 5-HTP function test. ACTH and cortisol were measured over 4 h and MRS scans at 71 were performed every 30 min over 3 h measuring Glx: Creatine, Chol:Creatine and NAA:Creatine ratios. Results: In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NM levels over 180 min but induced a significant decrease of Glx at 60 min on post-hoc analysis. 5-Hip-induced significant ACTH release reaching an E-max of 60.2 ng/L at 80 min followed by cortisol with an E-max, of 246.4 ng/mL at 110 min. Conclusions: The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area. (C) 2010 Elsevier Inc. All rights reserved. Show less
Jurgens, C.K.; Bos, R.; Luyendijk, J.; Witjes-Ane, M.N.W.; Grond, J. van der; Middelkoop, H.A.M.; Roos, R.A.C. 2010
To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in 'premanifest' carriers of the Huntington's disease (HD) gene mutation. Furthermore... Show moreTo investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in 'premanifest' carriers of the Huntington's disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity. Show less
Es, A.C.G.M. van; Grond, J. van der; Dam, V.H. ten; Craen, A.J.M. de; Blauw, G.J.; Westendorp, R.G.J.; ... ; PROSPER Study Grp 2010
Background and Purpose: Although total cerebral blood flow (tCBF) is known to be related to age, less is known regarding the associations between tCBF and the morphologic changes of the brain... Show moreBackground and Purpose: Although total cerebral blood flow (tCBF) is known to be related to age, less is known regarding the associations between tCBF and the morphologic changes of the brain accompanying cerebral aging. The purpose of this study was to investigate whether total cerebral blood flow (tCBF) is related to white matter hyperintensity (WMH) volume and/or cerebral atrophy. Furthermore, we investigate whether tCBF should be expressed in mL/min, as was done in all previous MR studies, or in mL/100 mL/min, which yielded good results in precious SPECT, PET and perfusion MRI studies investigating regional cerebral blood flow. Materials and Methods: Patients were included from the nested MRI sub-study of the PROSPER study. Dual fast spin echo and FLAIR images were obtained in all patients. In addition, single slice phase contrast MR angiography was used for flow measurements in the internal carotids and vertebral arteries. tCBF was expressed in both mL/min and mL/100 mL/min. Results: We found a significant correlation between tCBF in mL/min and both age (r = -.124; p = p <=.001) and parenchymal volume (r = 0.430; p <=.001). We found no association between tCBF in mL/min and %-atrophy (r = -.077; p <=.103) or total WMH volume (r = -.069; p =.148). When tCBF was expressed in mL/100 mL/min the correlation between tCBF and age was no longer found (r = -.001; p =.985). Multivariate regression analyses corrected for age showed a significant correlation between tCBF in mL/100 mL/min and WMH volume (r = -.106; p =.044). No significant association between tCBF in mL/100 mL/min and %- atrophy was found. Conclusion: From this study we conclude that, when evaluating tCBF alterations due to various pathologies, tCBF should in mL/100 mL/min instead of mL/min. Furthermore, changes or differences in WMH volume should be accounted for. Show less
Schoonman, G.G.; Oosterhout, W.P.J. van; Ferrari, M.D.; Grond, J. van der 2010
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke,... Show moreCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke, cognitive decline, psychiatric disturbances and migraine. The prevalence of migraine in CADASIL is slightly higher than in the general population, and the proportion of migraine with aura is much higher. The pathophysiological mechanism that leads to increased aura prevalence in CADASIL is unknown. Possible mechanisms of the excess of migraine with aura are an increased susceptibility to cortical spreading depression (CSD) or a different expression of CSD. It is also possible that the brainstem migraine area is involved in CADASIL. Last, it is possible that the NOTCH3 mutation acts as a migraine aura susceptibility gene by itself. In this narrative review we summarize the literature about migraine in CADASIL, with a special focus on what CADASIL might teach us about the pathophysiology of migraine. PMID: 21038489 [PubMed - in process] Show less
