A Case for Reward-Based Episodic Encoding

Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items—which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning

The ToMenovela – A Photograph-Based Stimulus Set for the Study of Social Cognition with High Ecological Validity

We present the ToMenovela, a stimulus set that has been developed to provide a set of normatively rated socio-emotional stimuli showing varying amount of characters in emotionally laden interactions for experimental investigations of (i) cognitive and (ii) affective Theory of Mind (ToM), (iii) emotional reactivity, and (iv) complex emotion judgment with respect to Ekman’s basic emotions (happiness, anger, disgust, fear, sadness, surprise, Ekman and Friesen, 1975). Stimuli were generated with focus on ecological validity and consist of 190 scenes depicting daily-life situations. Two or more of eight main characters with distinct biographies and personalities are depicted on each scene picture. To obtain an initial evaluation of the stimulus set and to pave the way for future studies in clinical populations, normative data on each stimulus of the set was obtained from a sample of 61 neurologically and psychiatrically healthy participants (31 female, 30 male; mean age 26.74 ± 5.84), including a visual analog scale rating of Ekman’s basic emotions (happiness, anger, disgust, fear, sadness, surprise) and free-text descriptions of the content of each scene. The ToMenovela is being developed to provide standardized material of social scenes that are available to researchers in the study of social cognition. It should facilitate experimental control while keeping ecological validity high

Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study

BackgroundWhite matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and A beta positivity on WMH, and their impact on cognition.MethodsWe analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years;178 female;NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (Delta PACC5).ResultsSubjects with hypertension or A beta positivity presented the largest WMH volumes (p(FDR) < 0.05), with spatial overlap in the frontal (hypertension: 0.42 +/- 0.17;A beta: 0.46 +/- 0.18), occipital (hypertension: 0.50 +/- 0.16;A beta: 0.50 +/- 0.16), parietal lobes (hypertension: 0.57 +/- 0.18;A beta: 0.56 +/- 0.20), corona radiata (hypertension: 0.45 +/- 0.17;A beta: 0.40 +/- 0.13), optic radiation (hypertension: 0.39 +/- 0.18;A beta: 0.74 +/- 0.19), and splenium of the corpus callosum (hypertension: 0.36 +/- 0.12;A beta: 0.28 +/- 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (p(FDR) < 0.05). A beta positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 +/- 0.08, p(FDR) < 0.001;executive: - 0.21 +/- 0.08, p(FDR) < 0.001;PACC5: - 0.29 +/- 0.09, p(FDR) = 0.006;Delta PACC5: - 0.34 +/- 0.04, p(FDR) < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 +/- 0.02, p(FDR) = 0.029;executive: - 0.04 +/- 0.02, p(FDR) = 0.067;PACC5: - 0.05 +/- 0.02, p(FDR) = 0.030;Delta PACC5: - 0.09 +/- 0.03, p(FDR) = 0.043) and WMH in the optic radiation partially mediated that between A beta positivity and memory (indirect effect-memory: - 0.05 +/- 0.02, p(FDR) = 0.029).ConclusionsPosterior white matter is susceptible to hypertension and A beta accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

Background and ObjectivesTo determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI).MethodsThis study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-beta (A beta)42/A beta 40, phosphorylated tau (p-tau181), total tau and A beta 42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M +/- SD: 40.6 +/- 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD.ResultsIn our sample (N = 672, mean age: 70.7 +/- 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215;HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups.DiscussionOur results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD

Brain reserve contributes to distinguishing preclinical Alzheimer's stages 1 and 2

BackgroundIn preclinical Alzheimer's disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions.MethodsWe tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol.ResultsIn asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Ass42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs.ConclusionsThese data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, A beta 42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295);a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM;n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological A beta when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity

Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum

Background: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODEcohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in A beta(42)/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to A beta(42) and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples