Faculty Bibliography

BACKGROUND: Clinical outcomes were associated with immune response of HLA-A2+ patients enrolled in a randomized phase 2 trial of ICT-107. METHODS: 124 patients (77 HLA-A2+), randomized 2:1, received ICT-107 (autologous DCs incubated with 6 synthetic peptide CTL epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Ra2) or matching control (un-incubated DC). Immune response was determined by a functional ELISPOT assay pre and post-treatment (ICT-107 30.5% vs. 15.5% in controls). Determination of p-values and significance between dependent variables and overall survival (OS) or progression-free survival (PFS) was performed using log-rank test. Fisher's exact tests were performed for association between extended overall survival (EOS: OS > 22.2 months) and extended progression-free survival (EPFS: PFS > 16.5 months) and the same variables. RESULTS: HLA-A2+ patients showed evidence of immune response being associated with both OS and PFS. After determining HLA-A2 ELISPOT responders (responders) using a comprehensive scoring system, responders had a median OS of 23.1 months versus 13.7 for non-responders (p = 0.0673). Similarly, responders had an EOS percentage of 52% versus 29% non-responders (p = 0.0615). Further, responders had a significantly higher percentage of EPFS (41% versus 15%, p = 0.0259). When censored to 7.5 months post-treatment, immune response was found to significantly improve OS (median 17.6 months versus 13.7, p = 0.0018). Level of IL-12 production can be linked to survival. High IL-12 producers had a median OS of 20.6 compared to 15.4 for low producers (p = 0.0515). Within the treatment group, the difference was larger, with medians of 23.3 months versus 15.2 (p = 0.0654), and high producers had a significantly higher percentage of EOS (54% versus 31%, p = 0.0426) and EPFS (43% versus 19%, p = 0.0293). CONCLUSIONS: The associations identified between clinical outcomes of OS and PFS with immunologic response provide support for the efficacy of ICT-107 in HLA-A2+ patients due to a biologic T cell response

The objective of this study was to test the hypothesis that corticosteroid and nonsteroidal anti-inflammatory drug (NSAID) medications are associated with less global and regional Alzheimer's disease (AD) neuropathology. This postmortem study was based on 694 brains of subjects from the Mount Sinai School of Medicine Brain Bank who did not have neuropathologies other than neuritic plaques (NPs), neurofibrillary tangles (NFTs), or cerebrovascular disease. Densities of NPs and of NFTs were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Counts of NPs in several neocortical regions were also assessed. For each neuropathology measure, analyses of covariance controlling for age at death and sex compared subjects who received only corticosteroids (n = 54) or those who received only NSAIDs (n = 56) to the same comparison group, subjects who received neither (n = 576). Subjects receiving corticosteroids had significantly lower ratings and counts of NPs for all neuropathological measures, and NFTs overall and in the cerebral cortex and amygdala. In contrast, no measures were significant for subjects who received NSAIDs. Use of corticosteroids was associated with approximately 50% fewer NPs and NFTs in most brain regions examined, compared with nonmedicated subjects. In contrast, use of NSAIDs was not substantially associated with the reductions in hallmark lesions of AD. Because corticosteroids have anti-inflammatory as well as a myriad of other neurobiological effects, more direct studies in model systems could reveal novel therapeutic targets and mechanisms for AD lesion reduction.

Cardiovascular risk factors including hypertension (HTN) have been shown to increase the risk of Alzheimer disease. The current study investigated whether individuals with HTN are more susceptible to increased cognitive decline and whether the influence of HTN on cognitive decline varied as a function of dementia severity. A total of 224 nursing home and assisted living residents, with a mean age of 84.9 (+/-7.6) years, were assessed longitudinally with Mini Mental State Exams (MMSEs) and Clinical Dementia Ratings (CDR). Baseline dementia status was defined by the CDR score. As described in , MMSE scores in persons with HTN and questionable dementia (CDR = 0.5) declined significantly faster than nonhypertensive questionably demented persons. Hypertensive participants did not decline significantly faster than nonhypertensive participants in persons with intact cognition (CDR = 0) or frank dementia (CDR >/= 1). These results suggest an increased risk of subsequent cognitive decline in hypertensive individuals who are especially vulnerable to developing dementia and raises the possibility that avoiding or controlling HTN might reduce the rate of cognitive decline in cognitively vulnerable individuals, potentially delaying their conversion to full-fledged dementia.

OBJECTIVES: This study examines the effect of age on rate of cognitive decline in different stages of dementia, of nursing home and assisted-living residents. METHODS: In this longitudinal study, the Mini Mental State Examination (MMSE) was used to measure rate of cognitive decline in subjects who were nondemented [Clinical Dementia Rating (CDR)=0; n=353], questionably demented (CDR=0.5; n=121), or frankly demented (CDR>/=1; n=213) at baseline. RESULTS: A generalized estimating equation was used to model the MMSE scores over time (mean follow-up 2.9+/-2.0 y). The generalized estimating equation model had the MMSE scores at successive follow-up time points as dependent variables and had linear and quadratic age, follow-up time from baseline, CDR at baseline, and all the interactions among them as independent variables, controlling for MMSE at baseline, sex, race, and education. The mean age of the entire sample was 85.2+/-7.4 years at baseline. There were no significant interactions of linear age effects with rate of cognitive decline. The analysis of interaction of quadratic age with rate of cognitive decline showed complex relationships: in the nondemented group, there was no substantial quadratic association of age with the rate of cognitive decline (P=0.13); in the questionable demented group, the oldest subjects declined relatively faster (P=0.02); and in the demented group, the youngest and oldest subjects tended to decline relatively less than subjects in the intermediate ages (P=0.07). CONCLUSIONS: This study adds an additional aspect to the complexity of the association between age and rate of cognitive decline, showing that the direction and amplitude of this effect differs according to the stage along the course of cognitive decline.

Elevated serum total cholesterol (TC) has been considered a risk factor for Alzheimer's disease (AD), but conflicting results have confused understanding of the relationships of serum lipids to the presence of AD in the elderly.Methods: To clarify these issues, we evaluated correlations of admission TC, low-density (LDL) and high-density (HDL)cholesterol directly with the densities of Alzheimer hallmarks--neuritic plaques (NP) and neurofibrillary tangles (NFT)--in nursing home residents (n=281). Results: Significant positive associations of TC and LDL with NP densities were found in both the neocortex (TC: r=0.151, p=0.013 and LDL: r=0.190, p=0.005) and the hippocampal/entorhinal (allocortical)region (TC: r=0.182, p=0.002 and LDL: r=0.203, p=0.003). Associations of HDL with NP were less strong but also significant.In contrast, after adjustment for confounders, no correlations of NFT with any lipid were significant.When subjects with any non-AD neuropathology (largely vascular) were excluded, the TC-plaque and LDL-plaque associations for the remaining "Pure AD" subgroup were consistently stronger than for the full sample. The TC- and LDL-plaque correlations were also stronger for the subgroup of 87 subjects with an APOE epsilon4 allele. Conclusions: The findings indicate that serum TC and LDL levels clearly relate to densities of NP, but not to densities of NFT. The stronger associations found in the subgroup that excluded all subjects with non-AD neuropathology suggest that cerebrovascular involvement does not explain these lipid-plaque relationships. Since the associations of TC/LDL with NP were particularly stronger in epsilon4 carriers, varying prevalence of this allele may explain some discrepancies among prior studies.