Faculty Bibliography

BACKGROUND AND PURPOSE: Although NAA is often used as a marker of neuronal health and integrity in neurologic disorders, its normal response to physiologic challenge is not well-established and its changes are almost always attributed exclusively to brain pathology. The purpose of this study was to test the hypothesis that the neuronal cell marker NAA, often used to assess neuronal health and integrity in neurologic disorders, is not confounded by (possibly transient) physiologic changes. Therefore, its decline, when observed by using 1H-MR spectroscopy, can almost always be attributed exclusively to brain pathology. MATERIALS AND METHODS: Twelve healthy young male adults underwent a transient hypercapnia challenge (breathing 5% CO2 air mixture), a potent vasodilator known to cause a substantial increase in CBF and venous oxygenation. We evaluated their whole-brain NAA by using nonlocalizing proton MR spectroscopy, venous oxygenation with T2-relaxation under spin-tagging MR imaging, CBF with pseudocontinuous arterial spin-labeling, and the cerebral metabolic rate of oxygen, during normocapnia (breathing room air) and hypercapnia. RESULTS: There was insignificant whole-brain NAA change (P = .88) from normocapnia to hypercapnia and back to normocapnia in this cohort, as opposed to highly significant increases: 28.0 +/- 10.3% in venous oxygenation and 49.7 +/- 16.6% in global CBF (P < 10-4); and a 6.4 +/- 10.9% decrease in the global cerebral metabolic rate of oxygen (P = .04). CONCLUSIONS: Stable whole-brain NAA during normocapnia and hypercapnia, despite significant global CBF and cerebral metabolic rate of oxygen changes, supports the hypothesis that global NAA changes are insensitive to transient physiology. Therefore, when observed, they most likely reflect underlying pathology resulting from neuronal cell integrity/viability changes, instead of a response to physiologic changes.

Homotopy reflects the intrinsic functional architecture of the brain through synchronized spontaneous activity between corresponding bilateral regions, measured as voxel mirrored homotopic connectivity (VMHC). Hypercapnia is known to have clear impact on brain hemodynamics through vasodilation, but have unclear effect on neuronal activity. This study investigates the effect of hypercapnia on brain homotopy, achieved by breathing 5% carbon dioxide (CO2 ) gas mixture. A total of 14 healthy volunteers completed three resting state functional MRI (RS-fMRI) scans, the first and third under normocapnia and the second under hypercapnia. VMHC measures were calculated as the correlation between the BOLD signal of each voxel and its counterpart in the opposite hemisphere. Group analysis was performed between the hypercapnic and normocapnic VMHC maps. VMHC showed a diffused decrease in response to hypercapnia. Significant regional decreases in VMHC were observed in all anatomical lobes, except for the occipital lobe, in the following functional hierarchical subdivisions: the primary sensory-motor, unimodal, heteromodal, paralimbic, as well as in the following functional networks: ventral attention, somatomotor, default frontoparietal, and dorsal attention. Our observation that brain homotopy in RS-fMRI is affected by arterial CO2 levels suggests that caution should be used when comparing RS-fMRI data between healthy controls and patients with pulmonary diseases and unusual respiratory patterns such as sleep apnea or chronic obstructive pulmonary disease. Hum Brain Mapp, 2015. (c) 2015 Wiley Periodicals, Inc.

Background: Vascular involvement in multiple sclerosis (MS) perivascular cuffing and thickened vein walls were described decades ago. Recently, a reduced (periventricular) venous density was reported in MS, and intra-lesional venous shrinking was suggested as an in vivo marker following inflammation. Vascular abnormalities on 7T MRI images have not been investigated in neuromyelitis optica (NMO). Objective: To compare periventricular venous density in NMO, healthy controls and MS using ultra-high field (7T) MRI. Methods: 18 patients with NMO (18 female; age mean+/-SD, range: 48+/-15, 22-71 years), 18 relapsing remitting MS patients (13 female; age mean+/-SD, range: 41+/-9, 20-53 years), and 18 healthy controls (7 female; age mean+/-SD, range: 44+/-14, 20-70 years) were investigated at 7T MRI including T2*-weighted (T2*w) and fluid-attenuated inversion recovery (FLAIR) imaging to calculate the periventricular venous area (PVA in mm²) by a blinded investigator. Results: In total, we detected 131 white matter lesions in 18 NMO patients, 368 white matter lesions were visualized in MS patients, and 139 white matter lesions were depicted in HC. We did not observe any differences in periventricular venous density measured by PVA in NMO (mean+/-SD, range: 132,33+/-24,08, 97-176 mm²) versus HC (Mann-Whitney U test, p=0.171; mean+/-SD, range: 143,33+/-27,30, 88-196 mm²). Contrarily, PVA was significantly reduced in MS (Mann-Whitney U test, p=0.019; mean+/-SD, range: 118,81+/-29,63, 61-170 mm²) compared to HC as described previously. Conclusions: The periventricular venous system appeared - in contrast to

Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

OBJECTIVE: The analysis of the MR phase provides additional information on the tissue microstructure. In multiple sclerosis (MS) lesions phase alterations may reflect different stages of inflammatory activity. Here we investigated lesion morphology in MS patients with short and long disease duration on T2* weighted, phase, magnitude and susceptibility weighted imaging (SWI) at 7 Tesla (T). METHODS: 17 MS or clinically isolated syndrome patients with short (<60 months) and 11 with long (>60 months) disease duration underwent 7T MRI. Lesions were subsequently analyzed side-by-side with regard to morphology and visibility on T2* weighted, SWI, magnitude and SWI-filtered phase images. RESULTS: 126 of 192 T2* weighted lesions (65.6%) were characterized by a phase alteration pattern, and hence could be differentiated on phase images. In detail, a significantly reduced proportion of lesions showing phase alterations was detectable in patients with longer disease duration (mean+/-SD 51+/-37%, range 0-100%) compared to patients with short disease duration (mean+/-SD 90+/-19.5%, range 50-100%, p = 0.003). CONCLUSION: This cross-sectional study identified different patterns of phase changes in lesions of MS patients with short and long standing disease. Longitudinal studies are warranted to prove that MR phase imaging is useful in determining the activity and the developmental stage of individual MS plaques.