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, Aß42/40 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 Aß 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.

tDCS-Induced Modulation of GABA Levels and Resting-State Functional Connectivity in Older Adults.

Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults, in whom the majority of studies have been conducted, cannot be easily transferred to older populations. Here, we investigated tDCS-induced effects in older adults (N = 48; age range, 50-79 years) using magnetic resonance spectroscopy to quantify GABA levels as well as resting-state functional magnetic resonance imaging to assess sensorimotor network strength and interhemispheric connectivity. In a randomized, counterbalanced, crossover design, we applied anodal tDCS (atDCS), cathodal tDCS (ctDCS), and sham tDCS (stDCS) over the left sensorimotor region. We observed a significant reduction of GABA levels after atDCS compared with stDCS, reflecting the preserved neuromodulatory effect of atDCS in older adults. Moreover, resting-state functional coupling was decreased during atDCS compared with stDCS, most likely indicating augmented efficiency in brain network functioning. Increased levels of interhemispheric connectivity with age were diminished by atDCS, suggesting stimulation-induced functional decoupling. Further, the magnitude of atDCS-induced local plasticity was related to baseline functional network strength. Our findings provide novel insight into the neuronal correlates underlying tDCS-induced neuronal plasticity in older adults and thus might help to develop tDCS interventions tailored to the aging brain.SIGNIFICANCE STATEMENT Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults cannot be easily transferred to older populations. We used a systematic multimodal imaging approach to investigate the neurophysiological effects of tDCS in older adults and found stimulation-induced effects on GABA levels, reflecting augmented local plasticity and functional connectivity, suggesting modulation of network efficiency. Our findings may help to reconcile some of the recent reports on the variability of tDCS-induced effects, not only implicating age as a crucial modulating factor, but detailing its specific impact on the functionality of neural networks.

Investigating the neural mechanisms of transcranial direct current stimulation effects on human cognition: current issues and potential solutions.

Transcranial direct current stimulation (tDCS) has been studied extensively for its potential to enhance human cognitive functions in healthy individuals and to treat cognitive impairment in various clinical populations. However, little is known about how tDCS modulates the neural networks supporting cognition and the complex interplay with mediating factors that may explain the frequently observed variability of stimulation effects within and between studies. Moreover, research in this field has been characterized by substantial methodological variability, frequent lack of rigorous experimental control and small sample sizes, thereby limiting the generalizability of findings and translational potential of tDCS. The present manuscript aims to delineate how these important issues can be addressed within a neuroimaging context, to reveal the neural underpinnings, predictors and mediators of tDCS-induced behavioral modulation. We will focus on functional magnetic resonance imaging (fMRI), because it allows the investigation of tDCS effects with excellent spatial precision and sufficient temporal resolution across the entire brain. Moreover, high resolution structural imaging data can be acquired for precise localization of stimulation effects, verification of electrode positions on the scalp and realistic current modeling based on individual head and brain anatomy. However, the general principles outlined in this review will also be applicable to other imaging modalities. Following an introduction to the overall state-of-the-art in this field, we will discuss in more detail the underlying causes of variability in previous tDCS studies. Moreover, we will elaborate on design considerations for tDCS-fMRI studies, optimization of tDCS and imaging protocols and how to assure high-level experimental control. Two additional sections address the pressing need for more systematic investigation of tDCS effects across the healthy human lifespan and implications for tDCS studies in age-associated disease, and potential benefits of establishing large-scale, multidisciplinary consortia for more coordinated tDCS research in the future. We hope that this review will contribute to more coordinated, methodologically sound, transparent and reproducible research in this field. Ultimately, our aim is to facilitate a better understanding of the underlying mechanisms by which tDCS modulates human cognitive functions and more effective and individually tailored translational and clinical applications of this technique in the future.

Long-term environmental enrichment is associated with better fornix microstructure in older adults.

Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults. Methods: N = 201 cognitively unimpaired participants (≥ 60 years of age) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) baseline cohort were included. Two groups of participants with higher (n = 104) or lower (n = 97) long-term EE were identified, using the self-reported frequency of diverse physical, intellectual, and social leisure activities between the ages 13 to 65. White matter (WM) microstructure was measured by fractional anisotropy (FA) and mean diffusivity (MD) in the fornix, uncinate fasciculus, and parahippocampal cingulum using diffusion tensor imaging. Long-term EE groups (lower/higher) were compared with adjustment for potential confounders, such as education, crystallized intelligence, and socio-economic status. Results: Reported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized ß = 0.117, p = 0.033) and lower MD (ß = -0.147, p = 0.015). Greater fornix microstructure was indirectly associated (FA: unstandardized B = 0.619, p = 0.038; MD: B = -0.035, p = 0.026) with better memory function through higher long-term EE. No significant effects were found for the other WM tracts. Conclusion: Our findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.

Impact of COMT val158met on tDCS-induced cognitive enhancement in older adults.

BACKGROUND: Previous studies suggest that genetic polymorphisms and aging modulate inter-individual variability in brain stimulation-induced plasticity. However, the relationship between genetic polymorphisms and behavioral modulation through transcranial direct current stimulation (tDCS) in older adults remains poorly understood. OBJECTIVE: Link individual tDCS responsiveness, operationalized as performance difference between tDCS and sham condition, to common genetic polymorphisms in healthy older adults. METHODS: 106 healthy older participants from five tDCS-studies were re-invited to donate blood for genotyping of apoliproprotein E (APOE: ε4 carriers and ε4 non-carriers), catechol-O-methyltransferase (COMT: val/val, val/met, met/met), brain-derived neurotrophic factor (BDNF: val/val, val/met, met/met) and KIdney/BRAin encoding gene (KIBRA: C/C, C/T, T/T). Studies had assessed cognitive performance during tDCS and sham in cross-over designs. We now asked whether the tDCS responsiveness was related to the four genotypes using a linear regression models. RESULTS: We found that tDCS responsiveness was significantly associated with COMT polymorphism; i.e., COMT val carriers (compared to met/met) showed higher tDCS responsiveness. No other significant associations emerged. CONCLUSION: Using data from five brain stimulation studies conducted in our group, we showed that only individual variation of COMT genotypes modulated behavioral response to tDCS. These findings contribute to the understanding of inherent factors that explain inter-individual variability in functional tDCS effects in older adults, and might help to better stratify participants for future clinical trials.

Dentate Gyrus Volume Mediates the Effect of Fornix Microstructure on Memory Formation in Older Adults.

Age-related deterioration in white and gray matter is linked to cognitive deficits. Reduced microstructure of the fornix, the major efferent pathway of the hippocampus, and volume of the dentate gyrus (DG), may cause age-associated memory decline. However, the linkage between these anatomical determinants and memory retrieval in healthy aging are poorly understood. In 30 older adults, we acquired diffusion tensor and T1-weighted images for individual deterministic tractography and volume estimation. A memory task, administered outside of the scanner to assess retrieval of learned associations, required discrimination of previously acquired picture-word pairs. The results showed that fornix fractional anisotropy (FA) and left DG volumes were related to successful retrieval. These brain-behavior associations were observed for correct rejections, but not hits, indicating specificity of memory network functioning for detecting false associations. Mediation analyses showed that left DG volume mediated the effect of fornix FA on memory (48%), but not vice versa. These findings suggest that reduced microstructure induces volume loss and thus negatively affects retrieval of learned associations, complementing evidence of a pivotal role of the fornix in healthy aging. Our study offers a neurobehavioral model to explain variability in memory retrieval in older adults, an important prerequisite for the development of interventions to counteract cognitive decline.

tDCS-induced episodic memory enhancement and its association with functional network coupling in older adults.

Transcranial direct current stimulation (tDCS) augments training-induced cognitive gains, an issue of particular relevance in the aging population. However, negative outcomes have been reported as well, and few studies so far have evaluated the impact of tDCS on episodic memory formation in elderly cohorts. The heterogeneity of previous findings highlights the importance of elucidating neuronal underpinnings of tDCS-induced modulations, and of determining individual predictors of a positive response. In the present study, we aimed to modulate episodic memory formation in 34 older adults with anodal tDCS (1 mA, 20 min) over left temporoparietal cortex. Participants were asked to learn novel associations between pictures and pseudowords, and episodic memory performance was subsequently assessed during immediate retrieval. Prior to experimental sessions, participants underwent resting-state functional magnetic resonance imaging. tDCS led to better retrieval performance and augmented learning curves. Hippocampo-temporoparietal functional connectivity was positively related to initial memory performance, and was positively associated with the magnitude of individual tDCS-induced enhancement. In sum, we provide evidence for brain stimulation-induced plasticity of episodic memory processes in older adults, corroborating and extending previous findings. Our results demonstrate that intrinsic network coupling may determine individual responsiveness to brain stimulation, and thus help to further explain variability of tDCS responsiveness in older adults.

Role of Sensorimotor Cortex in Gestural-Verbal Integration.

Action comprehension that is related to language or gestural integration has been shown to engage the motor system in the brain, thus providing preliminary evidence for the gestural-verbal embodiment concept. Based on the involvement of the sensorimotor cortex (M1) in language processing, we aimed to further explore its role in the cognitive embodiment necessary for gestural-verbal integration. As such, we applied anodal (excitatory) and sham transcranial direct current stimulation (tDCS) over the left M1 (with reference electrode over the contralateral supraorbital region) during a gestural-verbal integration task where subjects had to make a decision about the semantic congruency of the gesture (prime) and the word (target). We used a cross-over within-subject design in young subjects. Attentional load and simple reaction time (RT) tasks served as control conditions, applied during stimulation (order of three tasks was counterbalanced). Our results showed that anodal (atDCS) compared to sham tDCS (stDCS) reduced RTs in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, with no effect on control task performance. Our findings provide evidence for the involvement of the sensorimotor system in gestural-verbal integration performance. Further, our results suggest that functional modulation induced by sensorimotor tDCS may be specific to gestural-verbal integration. Future studies should now evaluate the modulatory effect of tDCS on semantic congruency by using tDCS over additional brain regions and include assessments of neural connectivity.

Role of the Retinoblastoma protein, Rb, during adult neurogenesis in the olfactory bulb.

Adult neural stem cells (aNSCs) are relatively quiescent populations that give rise to distinct neuronal subtypes throughout life, yet, at a very low rate and restricted differentiation potential. Thus, identifying the molecular mechanisms that control their cellular expansion is critical for regeneration after brain injury. Loss of the Retinoblastoma protein, Rb, leads to several defects in cell cycle as well as neuronal differentiation and migration during brain development. Here, we investigated the role of Rb during adult neurogenesis in the olfactory bulb (OB) by inducing its temporal deletion in aNSCs and progenitors. Loss of Rb was associated with increased proliferation of adult progenitors in the subventricular zone (SVZ) and the rostral migratory stream (RMS) but did not alter self-renewal of aNSCs or neuroblasts subsequent migration and terminal differentiation. Hence, one month after their birth, Rb-null neuroblasts were able to differentiate into distinct subtypes of GABAergic OB interneurons but were gradually lost after 3 months. Similarly, Rb controlled aNSCs/progenitors proliferation in vitro without affecting their differentiation capacity. This enhanced SVZ/OB neurogenesis associated with loss of Rb was only transient and negatively affected by increased apoptosis indicating a critical requirement for Rb in the long-term survival of adult-born OB interneurons.