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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.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.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.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.