Process-specific training can improve performance on untrained tasks, but the magnitude of gain is variable and often there is no transfer at all. We demonstrate transfer to a 3-back test of working ...memory after 5 weeks of training in updating. The transfer effect was based on a joint training-related activity increase for the criterion (letter memory) and transfer tasks in a striatal region that also was recruited pretraining. No transfer was observed to a task that did not engage updating and striatal regions, and age-related striatal changes imposed constraints on transfer. These findings indicate that transfer can occur if the criterion and transfer tasks engage specific overlapping processing components and brain regions.
Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG‐degrading enzyme of Streptococcus pyogenes (IdeS imlifidase) were assessed in a single‐center, open‐label ascending‐dose study in ...highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 n = 3; 0.25 mg/kg ×1 n = 3, or 0.25 mg/kg ×2 n = 2). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti‐HLA was abolished. IdeS also cleaved the IgG‐type B cell receptor on CD19+ memory B cells. Anti‐IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA‐B7), detected by complement‐dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA‐incompatible donor (HLA‐B7+) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.
In highly sensitized patients with chronic kidney disease, the immunoglobulin G–degrading enzyme of Streptococcus pyogenes (imlifidase) degrades plasma IgG efficiently, reduces HLA antibodies substantially, and abolishes C1q binding to anti‐HLA, thus enabling HLA‐incompatible kidney transplantation.
The possibilities of computer-based cognitive training (CCT) in postponing the onset of dementia are currently unclear, but promising. Our aim is to investigate older adults´ adherence to a long-term ...CCT program, and which participant characteristics are associated with adherence to the CCT. This study was part of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were 60-77-year-old individuals with increased dementia risk, recruited from previous population-based studies. The participants included in this study (n = 631) had been randomized to receive a multi-domain lifestyle intervention, including CCT. The measure of adherence was the number of completed CCT sessions (max = 144) as continuous measure. Due to a substantial proportion of participants with 0 sessions, the zero inflated negative binomial regression analyses were used to enable assessment of both predictors of starting the training and predictors of completing a higher number of training sessions. Several cognitive, demographic, lifestyle, and health-related variables were examined as potential predictors of adherence to CCT. Altogether, 63% of the participants participated in the CCT at least once, 20% completed at least half of the training, and 12% completed all sessions. Previous experience with computers, being married or cohabiting, better memory performance, and positive expectations toward the study predicted greater odds for starting CCT. Previous computer use was the only factor associated with a greater number of training sessions completed. Our study shows that there is a large variation in adherence to a long-lasting CCT among older adults with an increased risk of dementia. The results indicate that encouraging computer use, and taking into account the level of cognitive functioning, may help boost adherence to CCT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, ...exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.
•Higher iron load was linked to lower D1-like receptor availability across the adult lifespan.•The interplay between high iron, low D1DR and older age explained lower task-related brain ...response.•Lower brain response was related to deficient task performance.•The iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration.
Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
Updating of working memory has been associated with striato-frontal brain regions and phasic dopaminergic neurotransmission. We assessed raclopride binding to striatal dopamine (DA) D2 receptors ...during a letter-updating task and a control condition before and after 5 weeks of updating training. Results showed that updating affected DA activity before training and that training further increased striatal DA release during updating. These findings highlight the pivotal role of transient neural processes associated with D2 receptor activity in working memory.
Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, ...prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.
Within-person, moment-to-moment, variability in behavior increases with advancing adult age, potentially reflecting the influence of reduced structural and neurochemical brain integrity, especially ...that of the dopaminergic system. We examined the role of dopamine D2 receptor (D2DR) availability, grey-, and white-matter integrity, for between-person differences in cognitive variability in a large sample of healthy older adults (n = 181; 64-68 years) from the Cognition, Brain, and Aging (COBRA) study. Intra-individual variability (IIV) in cognition was measured as across-trial variability in participants' response times for tasks assessing perceptual speed and working memory, as well as for a control task of motor speed. Across the whole sample, no associations of D2DR availability, or grey- and white-matter integrity, to IIV were observed. However, within-person variability in cognition was increased in two subgroups of individuals displaying low mean-level cognitive performance, one of which was characterized by low subcortical and cortical D2DR availability. In this latter group, fronto-striatal D2DR availability correlated negatively with within-person variability in cognition. This finding suggests that the influence of D2DR availability on cognitive variability may be more easily disclosed among individuals with low dopamine-system integrity, highlighting the benefits of large-scale studies for delineating heterogeneity in brain-behavior associations in older age.
Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian ...bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand 11CSCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.
Individual differences in working memory (WM) performance have rarely been related to individual differences in the functional responsivity of the WM brain network. By neglecting person-to-person ...variation, comparisons of network activity between younger and older adults using functional imaging techniques often confound differences in activity with age trends in WM performance. Using functional magnetic resonance imaging, we investigated the relations among WM performance, neural activity in the WM network, and adult age using a parametric letter
-back task in 30 younger adults (21–31 years) and 30 older adults (60–71 years). Individual differences in the WM network's responsivity to increasing task difficulty were related to WM performance, with a more responsive BOLD signal predicting greater WM proficiency. Furthermore, individuals with higher WM performance showed greater change in connectivity between left dorsolateral prefrontal cortex and left premotor cortex across load. We conclude that a more responsive WM network contributes to higher WM performance, regardless of adult age. Our results support the notion that individual differences in WM performance are important to consider when studying the WM network, particularly in age-comparative studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
