Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

Objective Subjective cognitive complaints are often used in the diagnosis of memory and other cognitive impairment. This study examined whether cognitive complaints are associated with longitudinal changes in cognition and cross-sectional differences in regional brain function during memory performance in 98 participants with a mean age of 75. Method The Cognitive Failures Questionnaire (CFQ) assessed cognitive complaints and mixed effects regression models were used to determine whether mean CFQ scores predicted rates of change in cognitive function over a period of 11.5 years. Results Higher CFQ scores, reflecting increased subjective complaints, were associated with steeper rates of decline in immediate and delayed recall on the California Verbal Learning Test. Voxel-based regression analysis was used to determine the cross-sectional relationship between CFQ scores and regional cerebral blood flow measured by PET during a resting condition and during verbal and figural memory tasks. Higher levels of cognitive complaints were associated with increased activity in insular, lingual and cerebellar areas during memory tasks. Conclusions These findings offer some support for the validity of subjective cognitive complaints as markers of age related changes in memory and brain activity.

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ObjectiveTo assess the contribution of education to cognitive reserve.MethodsAnalyses are based on older participants in a longitudinal clinical-pathologic cohort study who had annual cognitive testing (n = 2,899) and subgroups that developed incident dementia (n = 696), died, and underwent a neuropathologic examination from which 10 neurodegenerative and cerebrovascular markers were derived (n = 752), or both (n = 405). Cognitive test scores were converted to a standard scale and averaged to yield composite measures of cognition.ResultsParticipants had a mean of 16.3 years of education (SD = 3.7, range 0–30). In all participants, education was associated with initial level of global cognition but not rate of cognitive change. In those who developed dementia, rate of global cognitive decline accelerated a mean of 1.8 years before the diagnosis, but education was not related to the onset or rate of accelerated decline. In the deceased, rate of global cognitive decline accelerated a mean of 3.4 years before death, but higher educational attainment was related to earlier (not later) onset of accelerated decline and unrelated to rate of acceleration. Higher education was associated with lower likelihood of gross and microscopic cerebral infarcts but not with other neuropathologic markers. Education was not related to global cognitive change not attributable to neuropathologic burden and did not decrease the association of higher neuropathologic burden with more rapid cognitive decline.ConclusionThe results suggest that the contribution of education to cognitive reserve is limited to its association with level of cognitive function before old age.

A group of 94 nondemented patients self-referred to an outpatient memory clinic for memory diffi culties were studied to determine the incidence of single versus multi-domain mild cognitive impairment (MCI) using Petersen criteria. Fifty-fi ve community dwelling normal controls (NC) participants without memory complaints also were recruited. Tests assessing executive control, naming/lexical retrieval, and declarative memory were administered. Thirty-four patients exhibited single-domain MCI, 43 patients presented with multi-domain MCI. When the entire MCI sample ( n = 77) was subjected to a cluster analysis, 14 patients were classifi ed with amnesic MCI, 21 patients with dysexecutive MCI, and 42 patients were classifi ed into a mixed/multi-domain MCI group involving low scores on tests of letter fl uency, "animal" fl uency, and delayed recognition discriminability. Analyses comparing the three cluster-derived MCI groups versus a NC group confi rmed the presence of memory and dysexecutive impairment for the amnesic and dysexecutive MCI groups. The mixed MCI group produced lower scores on tests of letter fl uency compared with the amnesic MCI and NC groups and lower scores on tests of naming and memory compared with the NC group. In summary, multi-domain MCI is quite common. These data suggest that MCI is a highly nuanced and complex clinical entity. ( JINS , 2010, 16, 84-93.)