Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study.

Background and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course. Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Age-related neural changes during memory conjunction errors.

Human behavioral studies demonstrate that healthy aging is often accompanied by increases in memory distortions or errors. Here we used event-related fMRI to examine the neural basis of age-related memory distortions. We used the memory conjunction error paradigm, a laboratory procedure known to elicit high levels of memory errors. For older adults, right parahippocampal gyrus showed significantly greater activity during false than during accurate retrieval. We observed no regions in which activity was greater during false than during accurate retrieval for young adults. Young adults, however, showed significantly greater activity than old adults during accurate retrieval in right hippocampus. By contrast, older adults demonstrated greater activity than young adults during accurate retrieval in right inferior and middle prefrontal cortex. These data are consistent with the notion that age-related memory conjunction errors arise from dysfunction of hippocampal system mechanisms, rather than impairments in frontally mediated monitoring processes.

Age-related changes in the episodic simulation of future events.

Episodic memory enables individuals to recollect past events as well as imagine possible future scenarios. Although the episodic specificity of past events declines as people grow older, it is unknown whether the same is true for future events. In an adapted version of the Autobiographical Interview, young and older participants generated past and future events. Transcriptions were segmented into distinct details that were classified as either internal (episodic) or external. Older adults generated fewer internal details than younger adults for past events, a result replicating previous findings; more important, we show that this deficit extends to future events. Furthermore, the number of internal details and the number of external details both showed correlations between past and future events. Finally, the number of internal details generated by older adults correlated with their relational memory abilities, a finding consistent with the constructive-episodic-simulation hypothesis, which holds that simulation of future episodes requires a system that can flexibly recombine details from past events into novel scenarios.

Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration.

People can consciously re-experience past events and pre-experience possible future events. This fMRI study examined the neural regions mediating the construction and elaboration of past and future events. Participants were cued with a noun for 20s and instructed to construct a past or future event within a specified time period (week, year, 5-20 years). Once participants had the event in mind, they made a button press and for the remainder of the 20s elaborated on the event. Importantly, all events generated were episodic and did not differ on a number of phenomenological qualities (detail, emotionality, personal significance, field/observer perspective). Conjunction analyses indicated the left hippocampus was commonly engaged by past and future event construction, along with posterior visuospatial regions, but considerable neural differentiation was also observed during the construction phase. Future events recruited regions involved in prospective thinking and generation processes, specifically right frontopolar cortex and left ventrolateral prefrontal cortex, respectively. Furthermore, future event construction uniquely engaged the right hippocampus, possibly as a response to the novelty of these events. In contrast to the construction phase, elaboration was characterized by remarkable overlap in regions comprising the autobiographical memory retrieval network, attributable to the common processes engaged during elaboration, including self-referential processing, contextual and episodic imagery. This striking neural overlap is consistent with findings that amnesic patients exhibit deficits in both past and future thinking, and confirms that the episodic system contributes importantly to imagining the future.