Faculty Bibliography

Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De upper left and right quadrants), axonal water fraction (AWF), and tortuosity (alpha) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy (1H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, alpha, and fractional anisotropy; negative correlations between NAA and De, upper left and right quadrants and the overall radial diffusivity (D upper left and right quadrants). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De upper left and right quadrants, AWF, and alpha).

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.

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

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.

There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale score of 14.7), 18-56 years old, 3 - 55 days post injury and 13 controls. All were scanned at 3 Tesla with T1-and T2-weighted MRI and 3D 1H-MRSI (480 voxels over 360 cm3, ~30% of the brain). On scan day patients completed a symptom questionnaire and those indicating at least one of the most common acute/subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray- and white matter (GM/WM) absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in the PCS-positive and PCS-negative patients were compared to age- and gender-matched controls using two-way analysis of variance. The results showed that the PCS-negative group (n=11) and controls (n=8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n=15), however, had lower WM NAA than the controls (n=12): 7.0+/-0.6 mM (mean+/- standard deviation) versus 7.9+/-0.5mM (p=0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in individuals with mostly normal neuroimaging as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking.

To test the hypotheses that global decreased neuro-axonal integrity reflected by decreased N-acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo-inositol (mI), present in a CD8-depleted rhesus macaque model of HIV-associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 x 16 x 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre- and 4-6 weeks post-simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm(3) spatial resolution over ~35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6 +/- 0.4 to 6.0 +/- 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 +/- 0.2 to 1.0 +/- 0.1 mM (p < 0.003); global mI increased 11%: 5.7 +/- 0.4 to 6.5 +/- 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response

OBJECTIVE: To characterize and follow the diffuse gray and white matter (GM/WM) metabolic abnormalities in early relapsing-remitting multiple sclerosis using proton magnetic resonance spectroscopic imaging ((1)H-MRSI). METHODS: Eighteen recently diagnosed, mildly disabled patients (mean baseline time from diagnosis 32 months, mean Expanded Disability Status Scale [EDSS] score 1.3), all on immunomodulatory medication, were scanned semiannually for 3 years with T1-weighted and T2-weighted MRI and 3D (1)H-MRSI at 3 T. Ten sex- and age-matched controls were followed annually. Global absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) were obtained for all GM and WM in the 360 cm(3) (1)H-MRSI volume of interest. RESULTS: Patients' average WM Cr, Cho, and mI concentrations (over all time points), 5.3 +/- 0.4, 1.6 +/- 0.1, and 5.1 +/- 0.7 mM, were 8%, 12%, and 11% higher than controls' (p