Helge Rootwelt

Increased Hippocampal Default Mode Synchronization during Rest in Middle-Aged and Elderly APOE ε4 Carriers: Relationships with Memory Performance

The apolipoprotein (APOE) ε4 allele is a strong genetic risk factor for Alzheimers disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the ε4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE ε4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect ε4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging-derived endophenotypes in the emerging field of imaging genetics.

Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E ɛ4

Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48-75 years. Fifty nine were APOE epsilon 4- (no epsilon 4 allele) and 37 were epsilon 4+ (1 or 2 epsilon 4 alleles). The genotype groups had similar age, sex and IQ. Two T(1)-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. epsilon 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the epsilon 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimers disease (AD), we conclude that APOE epsilon 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-beta aggregation (occipitotemporal and basal temporal cortex).

Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults

In the present study, we investigated age-related changes in interactions between efficiency of neuronal repair mechanisms and efficiency of cholinergic neurotransmission in the context of attentional orienting. In addition, we explored white matter volume changes as possible neuronal underpinnings. A sample of 230 healthy middle-aged (53–64 years) and older (65–75 years) adults was genotyped for polymorphisms of APOE and CHRNA4, a nicotinic receptor subunit gene. Participants were administered a visuospatial attention task involving letter discrimination with location cues of varying validity. Genotype effects on white matter volume were also investigated in a subset of participants who received MRI scans. APOE interacted with CHRNA4, such that APOE-ε4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. The interaction was stronger in the middle-aged participants than in the older participants. There was also a trend for individuals with combined APOE-ε4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task. The interaction of a neurotransmission gene (CHRNA4) and a susceptibility gene (APOE) suggests that the efficiency of neuronal repair mechanisms may modulate the cholinergic system to influence attentional function.

Hippocampal volumes are important predictors for memory function in elderly women

BackgroundNormal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).MethodsBrain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.ResultsAPOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.ConclusionGender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

Effects of APOE on brain white matter microstructure in healthy adults.

Objectives: APOE is related to cholesterol transport and clearance and brain white matter (WM) properties involving myelin, of which cholesterol is a major component. Diffusion tensor imaging enables in vivo investigations of brain WM, and could increase our understanding of the pathways leading to Alzheimer disease. The main objective was to investigate the association between APOE and diffusion tensor imaging–derived indices of WM microstructure. Methods: Healthy participants were assessed on a range of neuropsychological measures, genotyped, and underwent MRI. A total of 203 volunteers (aged 21.1–69.9 years, mean = 47.6, SD = 14.9) with APOE genotypes ϵ2/ϵ3 (n = 30), ϵ3/ϵ3 (n = 113), and ϵ3/ϵ4 (n = 60) were included. Results: There were widespread increases in mean and radial diffusion in carriers of the ϵ3/ϵ4 alleles compared with ϵ3/ϵ3 with medium to strong effect sizes (Cohens d = 0.77–0.79). No interactions between genotype and age were observed, indicating relatively stable differences from early adulthood. The results were independent of presence of dementia in close family. We also observed increased mean and radial diffusion and decreased fractional anisotropy in carriers of the ϵ2/ϵ3 alleles compared with ϵ3/ϵ3 carriers. No significant differences were found between ϵ2/ϵ3 and ϵ3/ϵ4. Conclusions: APOE affects microstructural properties of the brain WM from early adulthood, but the specific allelic effects do not directly reflect the associated risk of developing Alzheimer disease. The role of APOE in cholesterol transport, the high density of cholesterol in myelin, and the specific effects on radial diffusivity support a putative functional role of APOE in modulating myelin-related processes in the brain.

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype

Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O‐demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes.

Working memory deficits in healthy APOE epsilon 4 carriers

Studies on the cognitive effects of APOE allele variation in healthy persons have mainly focused on episodic memory performance as most sensitive to genetic effects. The present study focuses on working memory performance, measured both in an experimental paradigm, the AX-Continuous Performance Task (AX-CPT), and in neuropsychological test paradigms of span capacity and interference control. In a highly functioning healthy group (N=186) of mean age 64.5 years we found evidence of reduced working memory performance in APOE epsilon4 carriers, with sex and epsilon4 dose as modifying variables. Several aspects of capacity and control in working memory were affected, while genetic effects were not present for measures of episodic memory. The pattern of results suggests that response inhibition is sensitive to genetic effects. In healthy individuals the broad range of neurobiological mechanisms associated with APOE is consistent with effects on non-memory cognitive subsystems, and gender effects may be modulated by interaction of APOE with myelination, androgen mechanisms, or broad patterns of age-related changes in gene expression.

Individual variation in a cholinergic receptor gene modulates attention.

Cholinergic influences on attention are well documented and recent evidence indicates that genetic variation in the alpha4beta2 nicotinic receptor affects attentional networks of the brain. Several behavioral and electrophysiological studies have shown that a common polymorphism in the CHRNA4 gene (rs1044396) affects aspects of visual and auditory attentional processing. We examined genetic effects on neuropsychological measures of memory and attention in an adult life-span sample (N=488). TT homozygotes perform speed and attention tasks more slowly than TC or CC allele carriers, with stronger effects on complex attention tasks in participant 70-79 years of age. There are no parallel effects on memory function. The results are consistent with clinical studies indicating that reduction in nicotinic receptor efficiency affects attention and speed, but not memory. Both normal age-related changes in receptor function and incipient pathology may have contributed to the results.

Expression of IMPDH1 and IMPDH2 after transplantation and initiation of immunosuppression.

Background. Mycophenolic acid (MPA) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase (IMPDH). Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy. Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated. Methods. Whole blood, CD4+ cell, and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation. The expressions of two IMPDH isoforms, type 1 and 2, were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index. The IMPDH activity was determined by ultraviolet high-performance liquid chromatography. Results. Transplantation and the initiation of immunosuppressive therapy was associated with increased IMPDH1 (50–88%, P<0.0005) and decreased IMPDH2 (42–56%, P<0.0005) expression. In CD4+ cells, however, IMPDH2 increased (15%, P=0.009). These changes are probably related to glucocorticoid effects. Two weeks posttransplant, MPA-treated patients displayed elevated IMPDH 1 and 2 in reticulocytes, suggesting enzyme induction in these cells during prolonged MPA therapy. Patients with acute rejection during follow-up demonstrated higher IMPDH2 expression in CD4+ cells pretransplant than nonrejecting patients (median expression 1.26 vs. 0.87 respectively, P=0.017). Conclusions. Knowledge of changes in IMPDH 1 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of MPA on IMPDH and the potential for pharmacodynamic monitoring of MPA by measuring IMPDH activity. The expression of IMPDH2 in CD4+ cells pretransplant may be an indicator of immune activation.

Apolipoprotein E genotype and risk for development of cataract and age‐related macular degeneration

Purpose:  To study whether apolipoprotein E (APOE) genotypes are associated with risk for developing cataract and age‐related macular degeneration (AMD).