Preservation of cortical sortilin protein levels in MCI and Alzheimer's disease

The nerve growth factor (NGF) precursor protein proNGF is the predominant NGF moiety found in the human neocortex and exhibits pro-apoptotic properties when bound to the p75^NTR neurotrophin receptor in the presence of sortilin, a Vps10p domain trafficking protein. Recently studies have shown that proNGF levels increase in the cortex of people who died with early stage Alzheimer's disease (AD) or with mild cognitive impairment (MCI), a putative prodromal AD stage. In contrast, cortical levels of the high-affinity, pro-survival NGF receptor TrkA are reduced in AD despite stable levels of p75^NTR. These data suggest a stoichiometric shift in proNGF and its receptors which favors proNGF binding of p75^NTR. Whether cortical levels of sortilin are altered during the progression of AD remains unknown. Therefore, we measured sortilin protein levels in postmortem superior frontal and superior temporal cortical tissues derived from Religious Orders Study subjects clinically diagnosed antemortem with no cognitive impairment (NCI), MCI or AD. No changes in frontal or temporal cortical sortilin protein levels occurred across the clinical groups. There was no association between sortilin levels and antemortem cognitive test scores. However, there was a positive association between temporal cortex sortilin levels and severity of neuropathology by Braak and NIA-Reagan diagnoses. The stability of cortical sortilin levels in the face of stable p75^NTR, increased proNGF, and reduced TrkA levels may favor pro-apoptotic proNGF:p75^NTR:sortilin trimeric interactions within the cortex during the earliest stages of AD. These findings are relevant to the development of NGF drug therapy for the treatment of dementia.     

Characterization of Potential Outcome Measures for Future Clinical Trials in Fragile X Syndrome

Clinical trials targeting recently elucidated synaptic defects in fragile X syndrome (FXS) will require outcome measures capable of assessing short-term changes in cognitive functioning. Potentially useful measures for FXS were evaluated here in a test–retest setting in males and females with FXS (N = 46). Good reproducibility, determined by an interclass correlation (ICC) or weighted kappa (κ) of 0.7–0.9 was seen for RBANS List and Story Memory, NEPSY Tower, Woodcock–Johnson Spatial Relations and the commissions score from the Carolina Fragile X Project Continuous Performance Test (CPT). This study demonstrates the feasibility of generating test profiles containing reliability data, ability levels required for test performance, and refusal rates to assist with choice of outcome measures in FXS and other cohorts with cognitive disability.