Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA-BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging.

In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.

Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults: A Longitudinal Population-Based Study.

IMPORTANCE: Vitamin B12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia. OBJECTIVE: To investigate the association of circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults. DESIGN, SETTING, AND PARTICIPANTS: The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009. MAIN OUTCOMES AND MEASURES: The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume. RESULTS: In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, ß (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (ß [SE] per 1-SD increase, -0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (ß [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids. CONCLUSIONS AND RELEVANCE: This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.

Long-term test-retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [(11)C]raclopride and high-resolution PET.

We measured the long-term test-retest reliability of [(11)C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [(11)C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [(11)C]raclopride binding in the striatum. A novel finding is the relatively low variability of [(11)C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [(11)C]raclopride PET to be verified in future studies.

Alteration of the counterregulatory responses to insulin-induced hypoglycemia and of cognitive function after massive weight reduction in severely obese subjects.

The autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are reported as activated in excess in the morbidly obese state and, therefore, changes after weight loss can be anticipated. The aim of this study was to investigate the impact of a massive (approximately 30%) weight reduction on the activation of the HPA axis and the ANS following bariatric surgery. Eight (7 women, 1 man) severely obese (125+/-12 kg; body mass index [BMI], 45+/-4 kg/m2) nondiabetic subjects, underwent a 3-hour hyperinsulinemic (1,034 pmol/kg/h) glucose clamp study at hypoglycemia of arterial B-glucose concentration of 3.4 mmol/L. Cognitive function was evaluated by a visuospatial computerized problem-solving test, the Perceptual Maze Test (PMT). The mean weight loss was 40+/-9 kg approximately 12 months postsurgery when their weight was stabilized (85+/-6 kg; BMI, 31+/-3 kg/m2), and insulin sensitivity improved to an average increase of 376%+/-250% (P<.01) of initial value. Before weight reduction, all patients demonstrated brisk peak responses in glucagon, epinephrine, pancreatic polypeptide (PP), norepinephrine, and cortisol, indicative of preserved or exaggerated activation of ANS and HPA axis. In the reduced-obese state, all these responses were attenuated and most markedly so for glucagon, which was totally abolished. In contrast, the growth hormone (GH) response was increased after weight reduction. The cognitive function was clearly modified by weight reduction both during normoglycemia and hypoglycemia and was changed preferentially to a speed-preferring strategy in the reduced-obese state compared with a more accuracy preferred problem-solving process of PMT test presurgery. These results demonstrate a reduction of the glucose counterregulatory hormonal responses, increased insulin sensitivity, and perturbed cognitive function after massive weight reduction. It may be speculated on if the increased insulin sensitivity and reduced counterregulation to hypoglycemia could predispose to low plasma glucose concentrations.

Reference values for serum levels of vitamin B12 and folic acid in a population-based sample of adults between 35 and 80 years of age.

OBJECTIVES: To examine folic acid and vitamin B12 status in a group of 1000 persons sampled from the community of Umeå, Sweden, and aged 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80 years. Reference data for folate and age-stratified reference data for vitamin B12 are presented, together with an examination of potential confounders. MEASUREMENTS: All subjects participated in extensive health examinations and interviews, and laboratory blood testing was performed. RESULTS: A series of exclusion criteria were applied, and data from 961 subjects were analysed. Vitamin B12 levels were found to decrease with increasing age, whereas folate levels remained constant across the age span studied. None of the vitamins was found to vary with sex, education, smoking or alcohol consumption, body mass index, prescription-free vitamin supplements, level of haemoglobin, or mean cell volume of erythrocytes. Further, none of these factors was associated with the age-related decrease of vitamin B12 level. CONCLUSIONS: The offered reference ranges should be used only in order to rule out deficiency. For B12 levels, the age of the subject should be considered such that, for elderly people in particular, values above the medians should be considered as indicative of normal vitamin status.