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Background: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis., Methods: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis., Results: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression., Conclusions: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Objective: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing., Methods: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury., Results: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy., Conclusions: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS., (© 2014 American Academy of Neurology.)

Purpose: To evaluate circulating cytokines and chemokines as correlates of the degree of brain injury in individuals with advanced human immunodeficiency virus (HIV) infection., Experimental Design: Study participants included ten well-characterized subjects in advanced stage HIV infection. High-throughput multiplexed analysis was used to quantify markers of interest at baseline and 3 years later in the clinical course. Objective measurements of the brain were derived in vivo with quantitative magnetic resonance segmentation algorithms and with diffusion tensor imaging., Results: Of the markers examined, monocyte chemoattractant protein-1 (MCP-1 or CCL-2) was the most prominent correlate of brain injury. Elevated MCP-1 levels correlated with brain white matter alterations at the initial assessment. The relationship to injury was more extensive 3 years later; elevated MCP-1 was significantly correlated with measures of brain microstructural alterations and of abject atrophy., Conclusions and Clinical Relevance: The findings build on our prior observations that elevated MCP-1 levels may be a useful predictive marker for HIV-associated neurocognitive disorder. As a potent chemoattractant, MCP-1 may mediate injury through participation in self-reinforcing cycles of chronic immune activation and cytokine/chemokine-mediated neurotoxicity., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Circulating levels of specific matrix metalloproteinases (MMPs; 1 and 7) were evaluated as correlates of brain injury in eight individuals in advanced human immunodeficiency virus (HIV) infection. Neurological status was quantified in vivo with automated segmentation algorithms and with diffusion tensor imaging. Both metalloproteinases correlated with microstructural brain alterations and the degree of atrophy. MMPs may influence neurological outcome through involvement in neuroimmune response, blood-brain barrier permeability, leukocyte migration, and MMP-mediated neurotoxicity.

Background and Purpose: Patients infected with human immunodeficiency virus (HIV) are susceptible to cognitive deterioration. This study investigated the utility of magnetization transfer (MT) imaging for quantification of brain tissue alterations associated with cognitive deficits in patients with HIV., Materials and Methods: MT ratios (MTR) were derived for whole brain and for regions of interest (ROIs) in the basal ganglia and white matter in 11 HIV and 12 control subjects. Relationships with severity of cognitive impairment and specific neuropsychological deficits were also evaluated., Results: MTR values for normalized whole brain histogram peak height, whole brain histogram mean, and all examined ROIs were reduced in the HIV subjects. Normalized histogram peak height and mean for whole brain, as well as means for the corpus callosum, basal ganglia, and frontal white matter (FWM), were significantly correlated with severity of cognitive impairment. MTR values for white matter regions (corpus callosum, FWM, and centrum semiovale) were correlated with specific cognitive deficits., Conclusion: Quantitative MTR measurements, determined for the whole brain and for vulnerable ROIs, are sensitive to neuropathologic changes associated with cognitive impairment in HIV-infected patients.

Background and Purpose: More than 85% of brain traumas are classified as "mild"; MR imaging findings are minimal if any and do not correspond to clinical symptoms. Our goal, therefore, was to quantify the global decline of the neuronal marker N-acetylaspartate (NAA), as well as gray (GM) and white matter (WM) atrophy after mild traumatic brain injury (mTBI)., Materials and Methods: Twenty patients (11 male, 9 female; age range, 19-57 years; median, 35 years) with mTBI (Glasgow Coma Scale score 13-15 with loss of consciousness for at least 30 seconds) and 19 age- and sex-matched control subjects were studied. Seven patients were studied within 9 days of TBI; the other 13 ranged from 1.2 months to 31.5 years (average and median of 4.6 and 1.7 years, respectively) after injury. Whole-brain NAA (WBNAA) concentration was obtained in all subjects with nonlocalizing proton MR spectroscopy. Brain volume and GM and WM fractions were segmented from T1-weighted MR imaging and normalized to the total intracranial volume, suitable for intersubject comparisons. The data were analyzed with least squares regression., Results: Patients with mTBI exhibited, on average, a 12% WBNAA deficit that increased with age, compared with the control subjects (p<.05). Adjusted for age effects, patients also suffered both global atrophy (-1.09%/year; P=.029) and GM atrophy (-0.89%/year; P=.042). Patients with and without visible MR imaging pathology, typically punctate foci of suspected shearing injury, were indistinguishable in both atrophy and WBNAA., Conclusion: WBNAA detected neuronal/axonal injury beyond the minimal focal MR-visible lesions in mTBI. Combined with GM atrophy, the findings may provide further, noninvasive insight into the nature and progression of mTBI.

We report the findings from whole-brain proton MR spectroscopy, quantifying the neuronal marker N-acetylaspartate (NAA), for 2 presurgical meningioma patients and 10 healthy controls. The patients' whole-brain NAA (WBNAA) concentrations were considerably elevated (3+ SDs) compared with healthy controls when excluding the tumors from brain volume; WBNAA levels normalized following correction to approximate "preneoplastic" brain size. These results suggest global neuronal preservation in these 2 patients while their brains were compressed by large, slowly growing, extra-axial masses.

Diffusion tensor imaging (DTI) was used to derive in vivo tissue status measurements of subcortical brain regions that are vulnerable to injury in human immunodeficiency virus (HIV)-infected patients. Quantitative measurements, including the mean diffusivity (MD) and fractional anisotropy (FA), were determined in lateralized basal ganglia (caudate and putamen) and centrum semiovale in 11 well-characterized HIV patients and in 11 control subjects. DTI measurements were examined for patterns of relationship with markers of clinical and cognitive progression. DTI measures acquired in subcortical regions were significantly correlated with loss of function in specific cognitive domains. Significant relationships were identified between measures for putamen and verbal memory (MD), visual memory (FA), working memory (FA), and overall cognitive impairment (MD). Measures for caudate (FA) were significantly correlated with visual memory. Measures for centrum semiovale were significantly correlated with visual memory deficits (MD) and visuoconstruction (FA). Relationships between anisotropy measures and anemia (basal ganglia) and CD4 counts (centrum semiovale) were also observed. Findings from this investigation indicate that DTI is a sensitive tool for correlating neuroanatomic pathologic features with specific cognitive deficits in patients with HIV infection.

Objective: To study whole-brain MR measures derived from diffusion tensor imaging and magnetization transfer imaging (MTI) for the in vivo assessment of cumulative neuropathologic changes in HIV and to evaluate the quantitative imaging strategies with respect to cognitive status measures including the severity of dementia and the degree of impairment in specific cognitive domains including attention, memory, constructional abilities, and motor speed., Methods: Quantitative whole-brain measurements, including fractional anisotropy (FA), apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR), were derived from histograms and compared in HIV and control participants. Relationships between the MR and cognitive status measures were examined., Results: Whole-brain FA and MTR were reduced in patients with HIV and correlated with dementia severity. Whole-brain MTR and ADC were correlated with psychomotor deficits. Evaluation of relationships between the studied MR measures indicated a correlation between ADC and MTR; FA was not correlated with either ADC or MTR., Conclusions: Findings from this investigation support the use of quantitative whole-brain MR measures for evaluation of disease burden in HIV. Reductions in whole-brain fractional anisotropy and magnetization transfer ratio (MTR) distinguished HIV and control subjects, and these measures were associated with dementia severity. Relationships were identified between whole-brain MTR and apparent diffusion coefficient and psychomotor deficits. Combining these quantitative strategies in neuroimaging examinations may provide more comprehensive information concerning ongoing changes in the brains of HIV patients.

Magnetic resonance (MR) scans were performed as part of a prospective neuropsychological study within the Multicenter AIDS Cohort Study. Fifty HIV-1-seronegative men, 85 HIV-1-seropositive men without constitutional symptoms, and 14 with symptomatic HIV disease underwent MR imaging using a uniform protocol. Scans were rated by neuroradiologists blinded to all clinical details except age. The majority of MR scans were normal in all of the clinical groups and no covert mass lesions or diffuse white matter abnormalities were identified. Focal hyperintensities in the white matter were observed in 24% of the HIV-1 seronegatives, 26% of HIV-1 asymptomatic seropositives (CDC II/III), and 17% of those with ARC/AIDS. No significant associations were noted between the white matter hyperintensities and HIV-1 serostatus, neurological abnormalities, CD4 count, alcohol or drug use, hypertension, or smoking. In one individual classified with early HIV-1 dementia, MR demonstrated several hyperintensities in the deep parietal white matter, but at autopsy no microscopic abnormalities corresponding to the MR findings were identified. Our studies imply that focal white matter hyperintensities identified on MR are not specific for HIV-1 infection and are probably incidental and of no clinical significance.