Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

Objective: We aimed to evaluate the combined effects of HIV and APOE e4 allele(s) on glial metabolite levels, and on known cognitive deficits associated with either condition, across the ages. Results: Frontal white matter myo-inositol was elevated in subjects with HIV across the age span but showed age-dependent increase in seronegative subjects, especially in APOE e41 carriers. In contrast, only seronegative APOE e41 subjects showed elevated myo-inositol in parietal cortex. All APOE e41 subjects had lower total creatine in basal ganglia. While all HIV subjects showed greater cognitive deficits, HIV1 APOE e41 subjects had the poorest executive function, fluency memory, and attention/working memory. Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE e41 subjects, and worse fluency in HIV1 APOE e41 subjects. Methods Conclusions:In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE e4 on neuroinflammation. APOE e4 negatively affects energy metabolism in brain regions rich in dopaminergic synapses. The combined effects of HIV infection and APOE e4 may lead to greater cognitive deficits, especially in those with greater neuroinflammation. APOE e4 allele(s) may be a useful genetic marker to identify white and mixed-race HIV subjects at risk for cognitive decline. Neurology ® 2014;82:2213-2222 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; ARV 5 antiretroviral; cART 5 combination antiretroviral therapy; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAND 5 HIV-associated neurocognitive disorders; IL 5 interleukin; MI 5 myo-inositol; MP-RAGE 5 magnetization-prepared rapid-acquisition gradient echo; MRS 5 magnetic resonance spectroscopy; SN 5 seronegative; tCr 5 total creatine; TE 5 echo time; TR 5 repetition time.