Iron deficiency and cognitive functioning in kidney transplant recipients: findings of the TransplantLines biobank and cohort study.

BACKGROUND: Neurocognitive impairment is common in kidney transplant recipients (KTRs). Adequate brain functioning requires energy and neurotransmitter activity, for which iron is essential. We aimed to investigate iron deficiency (ID) as a potentially modifiable risk factor for cognitive impairment in KTRs. METHODS: We analyzed stable KTRs participating in the TransplantLines Biobank and Cohort study. Participants underwent neuropsychological tests for memory, mental speed, and attention and executive functioning. ID was defined as ferritin <100 µg/mL or 100-299 µg/mL with transferrin saturation (TSAT) ≤20%. Associations between iron status and norm scores of neurocognitive outcomes, corrected for age, sex and education, were assessed using multivariable linear regression analyses adjusted for potential confounders including hemoglobin. RESULTS: We included 166 KTRs [median (IQR) age 57 (45-65) years, 59% male, estimated glomerular filtration rate 51±18 mL/min/1.73 m2]. Time since transplantation was 5.8 (1.0-12.0) years. Prevalence of ID was 65%. ID was independently associated with lower scores for mental speed (std.ß = -0.19, P = .02) and attention and executive functioning (std.ß = -0.19, P = .02), and tended to be associated with worse memory (std.ß = -0.16, P = .07). Lower plasma ferritin levels were associated with worse memory (std.ß = 0.23, P = .007), mental speed (std.ß = 0.34, P < .001), and attention and executive functioning (std.ß = 0.30, P = .001). Lower TSAT was associated with worse memory (std.ß = 0.19, P = .04) and mental speed (std.ß = 0.27, P = .003), and tended to be associated with worse attention and executive functioning (std.ß = 0.16, P = .08). CONCLUSIONS: Iron-deficient KTRs performed worse on neurocognitive tasks measuring memory, mental speed, and attention and executive functioning. These findings set the stage for prospective studies addressing whether ID correction restores cognitive function after kidney transplantation.

Long-term cognitive impairments in kidney transplant recipients: impact on participation and quality of life.

BACKGROUND: Cognitive impairment is often present shortly after transplantation in kidney transplant recipients (KTR). To date, it is unknown whether these impairments persist in thelong term, to what extent they are associated with disease-related variables and whether they affect societal participation and quality of life (QoL) of KTR. METHOD: This study was part of the TransplantLines Biobank & Cohort Study in the University Medical Center Groningen. A total of 131 KTR, with a mean age of 53.6 years (SD = 13.5) transplanted ≥1 year ago (M = 11.2 years, range 1-41.7 years), were included and compared with 306 healthy controls (HC). KTR and HC were well matched; there were no significant differences regarding age, sex and education. All participants were assessed with neuropsychological tests measuring memory, mental speed, attention and executive functioning, and with questionnaires examining societal participation and QoL. RESULTS: Compared with HC, KTR performed significantly worse on memory, mental speed and measures of executive functioning (all P-values <0.05). Moreover, 16% of KTR met the criteria for mild cognitive impairment (MCI), compared with 2.6% of the HC. MCI in KTR was not significantly correlated with age- and disease-related variables. Poorer cognitive functioning was significantly related to lower levels of societal participation and to lower QoL (all P-values <0.01). CONCLUSIONS: This study shows long-term cognitive impairments in KTR, which are not related to disease-related variables. Neuropsychological assessment is important to timely signal these impairments, given their serious negative impact on societal participation and QoL.

Association of Endogenous Erythropoietin Levels and Iron Status With Cognitive Functioning in the General Population.

Background: Emerging data suggest that erythropoietin (EPO) promotes neural plasticity and that iron homeostasis is needed to maintain normal physiological brain function. Cognitive functioning could therefore be influenced by endogenous EPO levels and disturbances in iron status. Objective: To determine whether endogenous EPO levels and disturbances in iron status are associated with alterations in cognitive functioning in the general population. Materials and Methods: Community-dwelling individuals from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a general population-based cohort in Groningen, Netherlands, were surveyed between 2003 and 2006. Additionally, endogenous EPO levels and iron status, consisting of serum iron, transferrin, ferritin, and transferrin saturation were analyzed. Cognitive function was assessed by scores on the Ruff Figural Fluency Test (RFFT), as a reflection of executive function, and the Visual Association Test (VAT), as a reflection of associative memory. Results: Among 851 participants (57% males; mean age 60 ± 13 years), higher endogenous EPO levels were independently associated with an improved cognitive function, reflected by RFFT scores (ß = 0.09, P = 0.008). In multivariable backward linear regression analysis, EPO levels were among the most important modifiable determinants of RFFT scores (ß = 0.09, P = 0.002), but not of VAT scores. Of the iron status parameters, only serum ferritin levels were inversely associated with cognitive function, reflected by VAT scores, in multivariable logistic regression analysis (odds ratio, 0.77; 95% confidence interval 0.63-0.95; P = 0.02 for high performance on VAT, i.e., ≥11 points). No association between iron status parameters and RFFT scores was identified. Conclusion: The findings suggest that endogenous EPO levels and serum ferritin levels are associated with specific cognitive functioning tests in the general population. Higher EPO levels are associated with better RFFT scores, implying better executive function. Serum ferritin levels, but not other iron status parameters, were inversely associated with high performance on the VAT score, implying a reduced ability to create new memories and recall recent past. Further research is warranted to unravel underlying mechanisms and possible benefits of therapeutic interventions.

The cerebral metabolic topography of spinocerebellar ataxia type 3.

Introduction: We aimed to uncover the pattern of network-level changes in neuronal function in Spinocerebellar ataxia type 3 (SCA3). Methods: 17 genetically-confirmed SCA3 patients and 16 controls underwent structural MRI and static resting-state [18F]­Fluoro­deoxyglucose Positron Emission Tomography (FDG-PET) imaging. A SCA3-related pattern (SCA3-RP) was identified using a multivariate method (scaled subprofile model and principal component analysis (SSM PCA)). Participants were evaluated with the Scale for Assessment and Rating of Ataxia (SARA) and with neuropsychological examination including tests for language, executive dysfunction, memory, and information processing speed. The relationships between SCA3-RP expression and clinical scores were explored. Voxel based morphology (VBM) was applied on MRI-T1 images to assess possible correlations between FDG reduction and grey matter atrophy. Results: The SCA3-RP disclosed relative hypometabolism of the cerebellum, caudate nucleus and posterior parietal cortex, and relatively increased metabolism in somatosensory areas and the limbic system. This topography, which was not explained by regional atrophy, correlated significantly with ataxia (SARA) scores (ρ = 0.72; P = 0.001). SCA3 patients showed significant deficits in executive function and information processing speed, but only letter fluency correlated with SCA3-RP expression (ρ = 0.51; P = 0.04, uncorrected for multiple comparisons). Conclusion: The SCA3 metabolic profile reflects network-level alterations which are primarily associated with the motor features of the disease. Striatum decreases additional to cerebellar hypometabolism underscores an intrinsic extrapyramidal involvement in SCA3. Cerebellar-posterior parietal hypometabolism together with anterior parietal (sensory) cortex hypermetabolism may reflect a shift from impaired feedforward to compensatory feedback processing in higher-order motor control. The demonstrated SCA3-RP provides basic insight in cerebral network changes in this disease.

Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients.

INTRODUCTION: In the past decades, short-term results after solid organ transplantation have markedly improved. Disappointingly, this has not been accompanied by parallel improvements in long-term outcomes after transplantation. To improve graft and recipient outcomes, identification of potentially modifiable risk factors and development of biomarkers are required. We provide the rationale and design of a large prospective cohort study of solid organ transplant recipients (TransplantLines). METHODS AND ANALYSIS: TransplantLines is designed as a single-centre, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. Data will be collected from transplant candidates before transplantation, during transplantation, at 3 months, 6 months, 1 year, 2 years and 5 years, and subsequently every 5 years after transplantation. Data from living organ donors will be collected before donation, during donation, at 3 months, 1 year and 5 years after donation, and subsequently every 5 years. The primary outcomes are mortality and graft failure. The secondary outcomes will be cause-specific mortality, cause-specific graft failure and rejection. The tertiary outcomes will be other health problems, including diabetes, obesity, hypertension, hypercholesterolaemia and cardiovascular disease, and disturbances that relate to quality of life, that is, physical and psychological functioning, including quality of sleep, and neurological problems such as tremor and polyneuropathy. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the relevant local ethics committee. The TransplantLines cohort study is designed to deliver pioneering insights into transplantation and donation outcomes. The study design allows comprehensive data collection on perioperative care, nutrition, social and psychological functioning, and biochemical parameters. This may provide a rationale for future intervention strategies to more individualised, patient-centred transplant care and individualisation of treatment. TRIAL REGISTRATION NUMBER: NCT03272841.