Faculty Bibliography

OBJECTIVES: As approximately 40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. METHODS: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16x16x4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) ( approximately 35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. RESULTS: The mean (+/- standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 +/- 0.9, 7.2 +/- 0.4 and 0.9 +/- 0.1 mM, respectively; these concentrations increased 28% (p approximately 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 +/- 0.6 mM pre-infection vs. 7.3 +/- 0.8 mM post-infection; p approximately 0.37). The mean cortex volume was also unchanged (8.1 +/- 1.1 cm(3) pre-infection vs. 8.3 +/- 0.5 cm(3) post-infection; p approximately 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex.

PURPOSE: To design a proton MR spectroscopy (1 H-MRS) localization sequence that combines the signal-to-noise-ratio (SNR) benefits of point resolved spectroscopy (PRESS) with the high pulse bandwidths, low chemical shift displacements (CSD), low specific absorption rates (SAR), short echo times (TE), and superior radiofrequency transmit field (B1+ ) immunity of stimulated echo acquisition mode (STEAM), by simultaneously refocusing and acquiring both the double-spin and stimulated echo coherence pathways from the volume of interest. THEORY AND METHODS: We propose a family of 1 H-MRS sequences comprising three orthogonal spatially selective pulses with flip angles 90 degrees < alpha, beta, gamma < 128 degrees . The stimulated and double-spin echo are refocused in-phase simultaneously by altering the pulses' phases, flip angles and timing, as well as the interpulse gradient spoiling moments. The approximately 90 degrees nutations of alpha, beta, gamma provide STEAM-like advantages (lower SAR, in-plane CSD and TE; greater B1+ immunity), but with SNRs comparable with PRESS. RESULTS: Phantom and in vivo brain experiments show that 83-100% of the PRESS SNR (metabolite-dependent) is achieved at under 75% of the SAR and 66% lower in-plane CSD. CONCLUSION: The advantages of STEAM can be augmented with the higher SNR of PRESS by combining the spin and stimulated echoes. Quantification, especially of J-coupled resonances and intermediate and long TEs, must be carefully considered. Magn Reson Med, 2014. (c) 2014 Wiley Periodicals, Inc.

Background: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients. Objective: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. Methods: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 +/- 8.4 years old (mean +/- standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. Results: WBNAA concentration of MCI and AD patients (10.5 +/- 3.0 and 10.1 +/- 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25-29% lower than the 14.1 +/- 2.4 mM of normal matched controls (p < 10-4). The fBPV of MCI and AD patients (72.9 +/- 4.9 and 69.9 +/- 4.7%) differed significantly from each other (4%, p = 0.02) and both were significantly lower than the 74.6 +/- 4.4% of normal elderly (2%, p = 0.003 for MCI; 6%, p < 10-4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV. Conclusion: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology.

Concentration of the neuronal marker, N-acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole-head proton (1 H)-MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and whole-head 1 H-MRS from 18 healthy young adults were examined. Non-localized, whole-head 1 H-MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T1 -weighted MRI) to yield WBNAA. A paired-sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical (12.8 +/- 2.5 mm for integration, 12.8 +/- 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within-subject variability was 11.7% (+/-1.3 mm) for integration versus 7.0% (+/-0.8 mm) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds below 0.1% and vanishingly small (experimental - fitted) residuals. Modeling of the whole-head 1 H-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders

PURPOSE: To reduce the specific-absorption-rate (SAR) and chemical shift displacement (CSD) of three-dimensional (3D) Hadamard spectroscopic imaging (HSI) and maintain its point spread function (PSF) benefits. METHODS: A 3D hybrid of 2D longitudinal, 1D transverse HSI (L-HSI, T-HSI) sequence is introduced and demonstrated in a phantom and the human brain at 3 Tesla (T). Instead of superimposing each of the selective Hadamard radiofrequency (RF) pulses with its N single-slice components, they are cascaded in time, allowing N-fold stronger gradients, reducing the CSD. A spatially refocusing 180 degrees RF pulse following the T-HSI encoding block provides variable, arbitrary echo time (TE) to eliminate undesirable short T2 species' signals, e.g., lipids. RESULTS: The sequence yields 10-15% better signal-to-noise ratio (SNR) and 8-16% less signal bleed than 3D chemical shift imaging of equal repetition time, spatial resolution and grid size. The 13 +/- 6, 22 +/- 7, 24 +/- 8, and 31 +/- 14 in vivo SNRs for myo-inositol, choline, creatine, and N-acetylaspartate were obtained in 21 min from 1 cm3 voxels at TE approximately 20 ms. Maximum CSD was 0.3 mm/ppm in each direction. CONCLUSION: The new hybrid HSI sequence offers a better localized PSF at reduced CSD and SAR at 3T. The short and variable TE permits acquisition of short T2 and J-coupled metabolites with higher SNR. Magn Reson Med, 2013. (c) 2013 Wiley Periodicals, Inc.

Evidence suggests that normal pressure hydrocephalus (NPH) is underdiagnosed in day to day radiologic practice, and differentiating NPH from cerebral atrophy due to other neurodegenerative diseases and normal aging remains a challenge. To better characterize NPH, we test the hypothesis that a prediction model based on automated MRI brain tissue segmentation can help differentiate shunt-responsive NPH patients from cerebral atrophy due to Alzheimer disease (AD) and normal aging. Brain segmentation into gray and white matter (GM, WM), and intracranial cerebrospinal fluid was derived from pre-shunt T1-weighted MRI of 15 shunt-responsive NPH patients (9 men, 72.6 +/- 8.0 years-old), 17 AD patients (10 men, 72.1 +/- 11.0 years-old) chosen as a representative of cerebral atrophy in this age group; and 18 matched healthy elderly controls (HC, 7 men, 69.7 +/- 7.0 years old). A multinomial prediction model was generated based on brain tissue volume distributions. GM decrease of 33 % relative to HC characterized AD (P < 0.005). High preoperative ventricular and near normal GM volumes characterized NPH. A multinomial regression model based on gender, GM and ventricular volume had 96.3 % accuracy differentiating NPH from AD and HC. In conclusion, automated MRI brain tissue segmentation differentiates shunt-responsive NPH with high accuracy from atrophy due to AD and normal aging. This method may improve diagnosis of NPH and improve our ability to distinguish normal from pathologic aging.

OBJECTIVE: To obtain quantitative neurometabolite measurements, specifically myoinositol (mI) and glutamate plus glutamine (Glx), markers of glial and neuronal excitation, in deep gray matter structures after mild traumatic brain injury (mTBI) using proton magnetic resonance spectroscopy (1H-MRS) and to compare these measurements against normal healthy control subjects. METHODS: This study approved by the institutional review board is Health Insurance Portability and Accountability Act compliant. T1-weighted MRI and multi-voxel 1H-MRS imaging were acquired at 3 tesla from 26 patients with mTBI an average of 22 days postinjury and from 13 age-matched healthy controls. Two-way analysis of variance was used to compare patients and controls for mean N-acetylaspartate, choline, creatine (Cr), Glx, and mI levels as well as the respective ratios to Cr within the caudate, globus pallidus, putamen, and thalamus. RESULTS: Quantitative putaminal mI was higher in patients with mTBI compared with controls (p = 0.02). Quantitative neurometabolite ratios of putaminal mI and Glx relative to Cr, mI/Cr, and Glx/Cr were also higher among patients with mTBI compared with controls (p = 0.01 and 0.02, respectively). No other differences in neurometabolite levels or ratios were observed in any other brain region evaluated. CONCLUSION: Increased putaminal mI, mI/Cr, and Glx/Cr in patients after mTBI compared with control subjects supports the notion of a complex glial and excitatory response to injury without concomitant neuronal loss, evidenced by preserved N-acetylaspartate levels in this region.

BACKGROUND AND OBJECTIVE: To examine whether clinically benign multiple sclerosis patients (BMS) show similar losses of their global N-acetylaspartate (NAA) neuronal marker relative to more clinically disabled patients of similar disease duration. METHODS: The whole-brain NAA concentration (WBNAA) was acquired with whole-head non-localizing proton MR spectroscopy. Fractional brain parenchymal volume (fBPV), T2 and T1 lesion loads, were obtained from the MRI in: (i) 24 BMS patients: 23.1+/-7.2 years disease duration, median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 0-3); (ii) 26 non-benign MS patients (non-BMS), 24.5+/-7.4 years disease duration, median EDSS of 4.0 (range: 3.5-6.5); (iii) 15 healthy controls. RESULTS: Controls' 12.4+/-2.3mM WBNAA was significantly higher than the BMS's and non-BMS's 10.5+/-2.4 and 9.9+/-2.1mM (both p<0.02), but the difference between the patients' groups was not (p>0.4). Likewise, the controls' 81.2+/-4.5% fBPV exceeded the BMS and non-BMS's 77.0+/-5.8% and 76.3+/-8.6% (p<0.03), which were also not different from one another (p>0.7). BMS patients' T1-hypointense lesion load, 2.1+/-2.2cm(3), was not significantly different than the non-BMS's 4.1+/-5.4cm(3) (p>0.08) and T2-hyperintense loads: 6.0+/-5.7cm(3) and 8.7+/-7.8cm(3), were also not different (p>0.1). CONCLUSIONS: WBNAA differentiates normal controls from MS patients but does not distinguish BMS from more disabled MS patients of similar disease duration. Nevertheless, all MS patients who remain RR for 15+ years suffered WBNAA loss similar to the average RR MS population at fourfold shorter disease duration suggesting relative global neuronal sparing or leveling-off of the neurodegeneration rate.