Eric Salmon

Associative memory in aging: The effect of unitization on source memory

In normal aging, memory for associations declines more than memory for individual items. Unitization is an encoding process defined by creation of a new single entity to represent a new arbitrary association. The current study tested the hypothesis that age-related differences in associative memory can be reduced by encoding instructions that promote unitization. In two experiments, groups of 20 young and 20 older participants learned new associations between a word and a background color under two conditions. In the item detail condition, they had to imagine that the item is the same color as the background-an instruction promoting unitization of the associations. In the context detail condition, which did not promote unitization, they had to imagine that the item interacted with another colored object. At test, they had to retrieve the color that was associated with each word (source memory). In both experiments, the results showed an age-related decrement in source memory performance in the context detail but not in the item detail condition. Moreover, Experiment 2 examined receiver operating characteristics in older participants and indicated that familiarity contributed more to source memory performance in the item detail than in the context detail condition. These findings suggest that unitization of new associations can overcome the associative memory deficit observed in aging, at least for item-color associations.

Attention Supports Verbal Short-Term Memory via Competition between Dorsal and Ventral Attention Networks

Interactions between the neural correlates of short-term memory (STM) and attention have been actively studied in the visual STM domain but much less in the verbal STM domain. Here we show that the same attention mechanisms that have been shown to shape the neural networks of visual STM also shape those of verbal STM. Based on previous research in visual STM, we contrasted the involvement of a dorsal attention network centered on the intraparietal sulcus supporting task-related attention and a ventral attention network centered on the temporoparietal junction supporting stimulus-related attention. We observed that, with increasing STM load, the dorsal attention network was activated while the ventral attention network was deactivated, especially during early maintenance. Importantly, activation in the ventral attention network increased in response to task-irrelevant stimuli briefly presented during the maintenance phase of the STM trials but only during low-load STM conditions, which were associated with the lowest levels of activity in the dorsal attention network during encoding and early maintenance. By demonstrating a trade-off between task-related and stimulus-related attention networks during verbal STM, this study highlights the dynamics of attentional processes involved in verbal STM.

Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity.

Normal aging is characterized by brain glucose metabolism decline predominantly in the prefrontal cortex. The goal of the present study was to assess whether this change was associated with age-related alteration of white matter (WM) structural integrity and/or functional connectivity. FDG-PET data from 40 young and 57 elderly healthy participants from two research centers (n=49/48 in Center 1/2) were analyzed. WM volume from T1-weighted MRI (Center 1), fractional anisotropy from diffusion-tensor imaging (Center 2), and resting-state fMRI data (Center 1) were also obtained. Group comparisons were performed within each imaging modality. Then, positive correlations were assessed, within the elderly, between metabolism in the most affected region and the other neuroimaging modalities. Metabolism decline in the elderly predominated in the left inferior frontal junction (LIFJ). LIFJ hypometabolism was significantly associated with macrostructural and microstructural WM disturbances in long association fronto-temporo-occipital fibers, while no relationship was found with functional connectivity. The findings offer new perspectives to understand normal aging processes and open avenues for future studies to explore causality between age-related metabolism and connectivity changes.

Multiclass classification of FDG PET scans for the distinction between Parkinson's disease and atypical parkinsonian syndromes

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinsons disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration.

Metabolic and structural connectivity within the default mode network relates to working memory performance in young healthy adults.

Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 ± 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n=18) and high (n=17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p=0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions.

Differential effects of aging on the neural correlates of recollection and familiarity.

The present experiment aimed to investigate age differences in the neural correlates of familiarity and recollection, while keeping performance similar across age groups by varying task difficulty. Twenty young and 20 older adults performed an episodic memory task in an event-related functional magnetic resonance imaging (fMRI) design. At encoding, participants were presented with pictures, either once or twice. Then, they performed a recognition task, with a Remember/Know paradigm. A similar performance was observed for the two groups in the Easy condition for recollection and in the Hard condition for familiarity. Imaging data revealed the classic recollection-related and familiarity-related networks, common to young and older groups. In addition, we observed that some activity related to recollection (left frontal, left temporal, left parietal cortices and left parahippocampus) and familiarity (bilateral anterior cingulate, right frontal gyrus and left superior temporal gyrus) was reduced in older compared to young adults. However, for recollection processes only, older adults additionally recruited the right precuneus, possibly to successfully compensate for their difficulties, as suggested by a positive correlation between recollection and precuneus activity.

Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for 18F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on Vt was measured. In control animals the whole-brain Vt was 9.76 ± 0.52 mL/cm3 (mean ± SD; n = 4; test–retest), and the reproducibility in test–retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1–100 mg/kg intravenously). Conclusion: Our results indicated that 18F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [18F]UCB-H: First-in-Human Study

Purpose[18F]UCB-H is a novel radiotracer with a high affinity for synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a “first-in-class” antiepileptic drug with a distinct but still poorly understood mechanism of action. The objective of this study was to determine the biodistribution and radiation dosimetry of [18F]UCB-H in a human clinical trial and to establish injection limits according to biomedical research guidelines. Additionally, the clinical radiation dosimetry results were compared to estimations in previously published preclinical data.ProceduresDynamic whole body positron emission tomography/X-ray computed tomography (PET/CT) imaging was performed over approximately 110xa0min on five healthy male volunteers after injection of 144.5u2009±u20097.1xa0MBq (range, 139.1–156.5xa0MBq) of [18F]UCB-H. Major organs were delineated on CT images, and time–activity curves were obtained from co-registered dynamic PET emission scans. The bladder could only be delineated on PET images. Time-integrated activity coefficients were calculated as area under the curve using trapezoidal numerical integration. Urinary excretion data based on PET activities including voiding was also simulated using the dynamic bladder module of OLINDA/EXM. The radiation dosimetry was calculated using OLINDA/EXM.ResultsThe effective dose to the OLINDA/EXM 70-kg standard male was 1.54u2009×u200910−2u2009±u20096.84u2009×u200910−4xa0millisieverts (mSv)/MBq, with urinary bladder wall, gallbladder wall, and the liver receiving the highest absorbed dose. The brain, the tracer’s main organ of interest, received an absorbed dose of 1.89u2009×u200910−2u2009±u20092.32u2009×u200910−3xa0mGy/MBq.ConclusionsThis first human dosimetry study of [18F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672xa0MBq for US practice and 649xa0MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.

Exploration of the Mechanisms Underlying the ISPC Effect: Evidence from Behavioral and Neuroimaging Data

The item-specific proportion congruent (ISPC) effect in a Stroop task - the observation of reduced interference for color words mostly presented in an incongruent color - has attracted growing interest since the original study by Jacoby, Lindsay, and Hessels [(2003) Psychonomic Bulletin & Review, 10(3), 638-644]. Two mechanisms have been proposed to explain the effect: associative learning of contingencies and item-specific control through word reading modulation. Both interpretations have received empirical support from behavioral data. Therefore, the aim of this study was to investigate the responsible mechanisms of the ISPC effect with the classic two-item sets design using fMRI. Results showed that the ISPC effect is associated with increased activity in the anterior cingulate (ACC), dorsolateral prefrontal (DLPFC), and inferior and superior parietal cortex. Importantly, behavioral and fMRI analyses specifically addressing the respective contribution of associative learning and item-specific control mechanisms brought support for the contingency learning account of the ISPC effect. Results are discussed in reference to task and procedure characteristics that may influence the extent to which item-specific control and/or contingency learning contribute to the ISPC effect.

Verbal learning in Alzheimer's disease and mild cognitive impairment: fine-grained acquisition and short-delay consolidation performance and neural correlates

The aim of this study was to examine correlations between acquisition and short-delay consolidation and brain metabolism at rest measured by fluorodeoxyglucose positron emission tomography (FDG-PET) in 44 Alzheimers disease (AD) patients, 16 patients with mild cognitive impairment (MCI) who progressed to dementia (MCI-AD), 15 MCI patients who remained stable (MCI-S, 4-8 years of follow-up), and 20 healthy older participants. Acquisition and short-delay consolidation were calculated respectively as mean gained (MG) and lost (ML) access to items of the California Verbal Learning Task. MG performance suggests that acquisition is impaired in AD patients even at predementia stage (MCI-AD). ML performance suggests that short-delay consolidation is deficient only in confirmed AD patients. Variations in acquisition performance in control participants are related to metabolic activity in the anterior parietal cortex, an area supporting task-positive attentional processes. In contrast, the acquisition deficit is related to decreased activity in the lateral temporal cortex, an area supporting semantic processes, in patients at an early stage of AD and is related to metabolic activity in the hippocampus, an area supporting associative processes, in confirmed AD patients.