Cardiovascular risk and encoding-related hippocampal connectivity in older adults.

BACKGROUND: Cardiovascular conditions contribute to brain volume loss, reduced cerebrovascular health, and increased dementia risk in aging adults. Altered hippocampal connectivity has also been observed in individuals with cardiovascular conditions, yet the functional consequences of these changes remain unclear. In the present study, we collected functional magnetic resonance imaging data during memory encoding and used a psychophysiological interaction analysis to examine whether cardiovascular burden, indexed using the Framingham risk score, was associated with encoding-related hippocampal connectivity and task performance in cognitively-intact older adults between 65 and 85 years of age. Our goal was to better understand the early functional consequences of vascular and metabolic dysfunction in those at risk for cognitive decline. RESULTS: High Framingham risk scores were associated with lower total brain volumes. In addition, those with high Framingham risk scores showed an altered relationship between left hippocampal-medial prefrontal coupling and task performance compared to those with low Framingham risk scores. Specifically, we found a significant interaction of Framingham risk and learning on connectivity between the left hippocampus and primarily left midline prefrontal regions comprising the left ventral anterior cingulate cortex and medial prefrontal cortex. Those with lower Framingham risk scores showed a pattern of weaker connectivity between left hippocampal and medial prefrontal regions associated with better task performance. Those with higher Framingham risk scores showed the opposite pattern; stronger connectivity was associated with better performance. CONCLUSIONS: Findings from the current study show that amongst older adults with cardiovascular conditions, higher Framingham risk is associated with lower brain volume and altered left hippocampal-medial prefrontal coupling during task performance compared to those with lower Framingham risk scores. This may reflect a compensatory mechanism in support of memory function and suggests that older adults with elevated cardiovascular risk are vulnerable to early Alzheimer disease-like dysfunction within the episodic memory system.

Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs.

A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.

The Impact of Memory Change on Daily Life in Normal Aging and Mild Cognitive Impairment.

PURPOSE OF THE STUDY: Older adults with age-normal memory changes and those with amnestic mild cognitive impairment (aMCI) report mild memory difficulties with everyday problems such as learning new names or remembering past events. Although the type and extent of memory changes in these populations have been well documented, little is known about how memory changes impact their everyday lives. DESIGN AND METHODS: Using a qualitative research design, data were collected from three focus groups of older adults with normal memory changes (n = 23) and two focus groups of older adults with aMCI (n = 14). A thematic analysis using the constant comparative method was used to identify the impacts of memory change on key life domains. RESULTS: Four major themes emerged from the two groups, including changes in feelings and views of the self, changes in relationships and social interactions, changes in work and leisure activities, and deliberate increases in compensatory behaviors. Participants described both positive and negative consequences of memory change, and these were more substantial and generally more adverse for individuals with aMCI than for those with age-normal memory changes. IMPLICATIONS: There are similarities and important differences in the impact of mild memory change on the everyday lives of older adults with age-normal memory changes and those with aMCI. Findings underscore the need for clinical interventions that aim to minimize the emotional impact of memory changes and that increase leisure and social activity in individuals with aMCI.

Dynamic working memory performance in individuals with single-domain amnestic mild cognitive impairment.

Previous studies have observed poorer working memory performance in individuals with amnestic mild cognitive impairment than in healthy older adults. It is unclear, however, whether these difficulties are true only of the multiple-domain clinical subtype in whom poorer executive functioning is common. The current study examined working memory, as measured by the self-ordered pointing task (SOPT) and an n-back task, in healthy older adults and adults with single-domain amnestic mild cognitive impairment (aMCI). Individuals with single-domain aMCI committed more errors and required longer to develop an organizational strategy on the SOPT. The single-domain aMCI group did not differ from healthy older adults on the 1-back or 2-back, but had poorer discrimination on the 3-back task. This is, to our knowledge, the first characterization of dynamic working memory performance in a single-domain aMCI group. These results lend support for the idea that clinical amnestic MCI subtypes may reflect different stages on a continuum of progression to dementia and question whether standardized measures of working memory (span tasks) are sensitive enough to capture subtle changes in performance.

Associative recognition in mild cognitive impairment: relationship to hippocampal volume and apolipoprotein E.

Associative memory involves remembering relations between items of information and is critically dependent on the hippocampus, a brain structure that shows early changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. We examined associative and item memory in aMCI with a focus on the role of medial-temporal lobe regions and genetic risk for Alzheimer's disease. Twenty-four individuals with aMCI and 21 demographically matched healthy older adults underwent associative recognition testing, structural brain imaging, and apolipoprotein E (ApoE) genotyping. A significant interaction between group and recognition type indicated poorer associative recognition than item recognition across tasks in the aMCI group relative to controls. Within the aMCI group, associative but not item recognition showed sizable and significant correlations with hippocampal volume (but not with other medial temporal-lobe structures) and with number of ApoE ε4 alleles. Correlations were smaller and generally not significant in the control group. Our findings replicate and extend previous studies by showing an associative recognition impairment in aMCI that is not accounted for by an item recognition deficit, is related to structural integrity of the hippocampus, and increases with genetic risk for Alzheimer's disease.