Summary A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11+/−). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2+) and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. Electrophysiological recordings of Drd2+ MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11+/− mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11+/− mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

Background Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared to that of healthy aging. Methods We examined longitudinal structural brain MRI atrophy rates employing region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants over age 60 years (n=38) compared to age-matched HIV-uninfected healthy and cognitively normal controls (n=24). Results The mean age of participants was 63 years, the mean estimated duration of infection was 21 years and the median of duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, p=0.016), caudate (0.74% vs. 0.03%, p=0.012), frontal lobe (0.48% vs. 0.01%, p=0.034), total cortical gray matter (0.65% vs. 0.16%, p=0.027), brain stem (0.31% vs. 0.01%, p=0.026), and pallidum (0.73% vs. 0.39%, p=0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. Conclusion Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared to healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

BACKGROUND There are contradicting reports on the associations between Apolipoprotein E4 (ApoE ε4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups. METHODS We assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain MRI and diffusion tensor imaging (DTI). RESULTS The median age of the participants was 64 years (range: 60–84) and the median estimated duration of HIV infection was 22 years. Apo ε4 carriers (n=19) were similar to non-carriers (n=57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE ε4 carriers demonstrated greater deficits in cognitive performance in the executive domain (p=0.045) and had reduced fractional anisotropy (FA) and increased mean diffusivity (MD) throughout large white matter tracts within the brain compared to non-carriers. Tensor Based Morphometry (TBM) analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE ε4 carriers compared to ε4-non-carriers. CONCLUSION In this sample of older HIV-infected individuals, having at least one ApoE ε4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus and brainstem. This pattern of cognitive deficit, atrophy and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded.

Introduction: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)‐antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti–muscle‐specific kinase (MuSK)‐MG. Methods: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK‐MG. Results: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post‐intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12–1.53, P = 0.19). Discussion: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK‐MG patients. Muscle Nerve 59:404–410, 2019