Association of white matter microstructural integrity with cognition and dementia.

Late-life measures of white matter (WM) microstructural integrity may predict cognitive status, cognitive decline, and incident mild cognitive impairment (MCI) or dementia. We considered participants of the Atherosclerosis Risk in Communities study who underwent cognitive assessment and neuroimaging in 2011-2013 and were followed through 2016-2017 (n = 1775 for analyses of prevalent MCI and dementia, baseline cognitive performance, and longitudinal cognitive change and n = 889 for analyses of incident MCI, dementia, or death). Cross-sectionally, both overall WM fractional anisotropy and overall WM mean diffusivity were strongly associated with baseline cognitive performance and risk of prevalent MCI or dementia. Longitudinally, greater overall WM mean diffusivity was associated with accelerated cognitive decline, as well as incident MCI, incident dementia, and mortality, but WM fractional anisotropy was not robustly associated with cognitive change or incident cognitive impairment. Both cross-sectional and longitudinal associations were attenuated after additionally adjusting for likely downstream pathologic changes. Increased WM mean diffusivity may provide an early indication of dementia pathogenesis.

Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (beta glycan) knockout mice.

Betaglycan (Tgfbr3) is a coreceptor for transforming growth factor-beta (TGFB) superfamily ligands. In the current study, a defect in seminiferous cord formation was detected in 12.5-13.5 days postcoitum (dpc) beta glycan null murine testis. Immunohistochemistry with antibodies against cell-specific markers revealed defects in somatic cell populations. To confirm these data, quantitative real-time PCR was performed to determine changes in the expression levels of genes involved in fetal testis cell differentiation and function. The expression levels of the Leydig cell markers Insl3, Cyp17a1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12.5 dpc. Whole mount in situ hybridization confirmed that Cyp11a1 expression was reduced in the null testis, but its distribution pattern was unchanged. Apoptosis was not affected by the loss of beta glycan, but proliferation within the interstitium was reduced at 14.5 dpc. However, morphometric analysis showed no changes in Leydig cell counts between the wild-type and the knockout testes at 14.5 dpc, indicating that fetal Leydig function, rather than number, was affected by the loss of beta glycan. The expression levels of Sertoli cell markers Dhh, Sox9, and Amh were also reduced in the knockout testis at 14.5 dpc. However, the expression of fetal germ cell markers Pou5f1 and DDX4 were not changed across the genotypes at any age examined. Our data show that the presence of beta glycan is required for normal cord formation, normal fetal Leydig cell development, and the establishment of fetal testis endocrine function, thus implicating TGFB superfamily members as regulators of early fetal testis structure and function.

ETV5 is required for continuous spermatogenesis in adult mice and may mediate blood testes barrier function and testicular immune privilege.

The transcription factor Ets-variant gene 5 (ETV5) is essential for spermatogonial stem cell (SSC) self-renewal, as the targeted deletion of the Etv5 gene in mice (Etv5(-/-)) results in only the first wave of spermatogenesis. Reciprocal transplants of neonatal germ cells from wild-type (WT) and Etv5(-/-) testes were performed to determine the role of ETV5 in Sertoli cells and germ cells. ETV5 appears to be needed in both cell types for normal spermatogenesis. In addition, Etv5(-/-) recipients displayed increased interstitial inflammation and tubular involution after transplantation. Preliminary studies suggest that the blood-testis barrier (Sertoli-Sertoli tight junctional complex) is abnormal in the Etv5(-/-) mouse.