Klaus Fliessbach

With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer’s disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer’s dementia patients, first-degree relatives of patients with Alzheimer’s dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets. In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer’s Disease Assessment Scale—cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected. The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration. German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

Errorless learning (EL) is a method for optimizing learning, which uses feed-forward instructions in order to prevent people from making mistakes during the learning process. The majority of previous studies on EL taught patients with dementia artificial tasks of little or no relevance for their daily lives. Furthermore, only a few controlled studies on EL have so far been performed and just a handful of studies have examined the long-term effects of EL. Tasks were not always trained in the patients’ natural or home environment, limiting the external validity of these studies. This multicenter parallel randomized controlled trial examines the effects of EL compared with trial and error learning (TEL) on the performance of activities of daily living in persons with Alzheimer’s or mixed-type dementia living at home. Patients received nine 1-hour task training sessions over eight weeks using EL or TEL. Task performance was measured using video observations at week 16. Secondary outcome measures were task performance measured at week 26, satisfaction with treatment, need for assistance, challenging behavior, adverse events, resource utilization and treatment costs. A total of 161 participants were randomized, of whom 71 completed the EL and 74 the TEL arm at week 11. Sixty-nine EL patients and 71 TEL patients were assessed at the 16-week follow-up (the primary measurement endpoint). Intention-to-treat analysis showed a significantly improved task performance in both groups. No significant differences between the treatment groups were found for primary or secondary outcomes. Structured relearning improved the performance of activities of daily living. Improvements were maintained for 6 months. EL had no additional effect over TEL. German Register of Clinical Trials DRKS00003117 . Registered 31 May 2011.

Our decisions often have consequences for other people. Hence, self-interest and other-regarding motives are traded off in many daily-life situations. Interindividually, people differ in their tendency to behave prosocial. These differences are captured by the concept of social value orientation (SVO), which assumes stable, trait-like tendencies to act selfish or prosocial. This study investigates group differences in prosocial decision making and addresses the question of whether prosocial individuals act intuitively and selfish individuals instead need to control egoistic impulses to behave prosocially. We address this question via the interpretation of neuronal and behavioural indicators. In the present fMRI-study participants were grouped into prosocial- and selfish participants. They made decisions in multiple modified Dictator-Games (DG) that addressed self- and other-regarding motives to a varying extent (self gain, non-costly social gain, mutual gain, costly social gain). Selfish participants reacted faster than prosocial participants in all conditions, except for decisions in the non-costly social condition, in which selfish participants displayed the longest decision times. In the total sample we found enhanced neural activity in the ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC / BA 9) during decisions that resulted in non-costly social benefits. These areas have been implicated in cognitive control processes and deliberative value integration. Decisively, these effects were stronger in the group of selfish individuals. We believe that selfish individuals require more explicit and deliberative processing during prosocial decisions. Our results are compatible with the assumption that prosocial decisions in prosocials are more intuitive, whereas they demand more active reflection in selfish individuals.

Humans often evaluate their abilities by comparing their personal performance with that of others. For this process, it is critical whether the comparison turns out in one’s favor or against it. Here, we investigate how social comparisons of performance are encoded and integrated on the neural level. We collected functional magnetic resonance images while subjects answered questions in a knowledge quiz that was related to their profession. After each question, subjects received a feedback about their personal performance, followed by a feedback about the performance of a reference group who had been quizzed beforehand. Based on the subjects’ personal performance, we divided trials in downward and upward comparisons. We found that upward comparisons correlated with activity in the dorsolateral prefrontal cortex and the anterior insula. Downward comparisons were associated with increased activation in the ventral striatum (VS), the medial orbitofrontal cortex and the ventral anterior cingulate cortex (ACC). The extent to which subjects outperformed the reference group modulated the activity in the VS and in the dorsal ACC. We suggest that the co-activation of the VS and the dorsal ACC contributes to the integration of downward comparisons into the evaluation of personal performance.

It is ecologically adaptive that the amount of effort invested to achieve a reward increases the relevance of the resulting outcome. Here, we investigated the effect of effort on activity in reward and loss processing brain areas by using functional magnetic resonance imaging. In total, 28 subjects were endowed with monetary rewards of randomly varying magnitude after performing arithmetic calculations that were either difficult (high effort), easy (low effort) or already solved (no effort). Subsequently, a forced donation took place, where a varying part of the endowment was transferred to a charity organization, causing a loss for the subject. Results show that reward magnitude positively modulates activity in reward-processing brain areas (subgenual anterior cingulate cortex and nucleus accumbens) only in the high effort condition. Furthermore, anterior insular activity was positively modulated by loss magnitude only after high effort. The results strongly suggest an increasing relevance of outcomes with increasing previous effort.

In this paper we study neural responses to inequitable distributions of rewards despite equal performance. We specifically focus on differences between advantageous (AI) and disadvantageous inequity (DI). AI and DI were realized in a hyperscanning fMRI experiment with pairs of subjects simultaneously performing a task in adjacent scanners and observing both subjects' rewards. Results showed i) hypoactivation of the ventral striatum under DI but not under AI; ii) inequity induced activation of medial and dorsolateral prefrontal regions, that were stronger under DI than AI; iii) correlations between subjective evaluations of DI and amygdala activity, and between AI evaluation and right ventrolateral prefrontal activity. Our study provides neurophysiological evidence for different cognitive processes that occur when exposed to DI and AI, respectively. Our data is compatible with the assumption that any form of inequity represents a norm violation, but that important differences between AI and DI emerge from an asymmetric involvement of status concerns.

The motives underlying prosocial behavior, like charitable donations, can be related either to actions or to outcomes. To address the neural basis of outcome orientation in charitable giving, we asked 33 subjects to make choices affecting their own payoffs and payoffs to a charity organization, while being scanned by functional magnetic resonance imaging (fMRI). We experimentally induced a reward prediction error (RPE) by subsequently discarding some of the chosen outcomes. Co-localized to a nucleus accumbens BOLD signal corresponding to the RPE for the subject's own payoff, we observed an equivalent RPE signal for the charity's payoff in those subjects who were willing to donate. This unique demonstration of a neuronal RPE signal for outcomes exclusively affecting unrelated others indicates common brain processes during outcome evaluation for selfish, individual and nonselfish, social rewards and strongly suggests the effectiveness of outcome-oriented motives in charitable giving.