Mette Møller

Dynamic changes in corticospinal tracts after stroke detected by fibretracking

Background and aims: The integrity of motor pathways and functional connectivity patterns are important in assessing plastic changes related to successful recovery, to obtain prognostic information and to monitor future therapeutic strategies of stroke patients. We tested the following hypotheses: (1) that changes in axonal integrity along the corticospinal tract after stroke can be detected as a reduction in fractional anisotropy; and (2) that sustained low fractional anisotropy is indicative of axonal loss and therefore is correlated with poor motor outcome, as measured by specific neurological motor scores. Methods: We developed a segmentation tool based on magnetic resonance diffusion tensor imaging in conjunction with three dimensional fibretracking for longitudinal studies of the corticospinal tract, and used specific neurological motor scores to test the hypotheses in five stroke patients within the first week and 30 and 90 days after the stroke. Results: Reduction in fractional anisotropy within the first weeks after stroke reflected a decline in axonal integrity, leading to Wallerian degeneration, and demonstrated a correlation between the temporal evolution of fractional anisotropy and motor function in patients with poor motor outcome. Conclusion: The study demonstrated the feasibility of fibretracking as a segmentation tool for mapping distal parts of the corticospinal motor pathways and showed that fractional anisotropy in the segmented corticospinal tract is a sensitive measure of structural changes after stroke.

Parametric and regional maps of free serotonin 5HT1A receptor sites in human brain as function of age in healthy humans.

Serotonin 5HT1A-binding sites can be detected in living human brain with the positron-emitting antagonist [11C]WAY-100635. Previous measurements of the availability of [11C]WAY-binding sites in normal aging are equivocal, in part because of the greatly variable binding of this ligand. To test the null hypothesis that the binding potential (pB) of 5HT1A sites remains constant with age; 19 healthy volunteers aged 23–73 years (8 women, 11 men) underwent positron emission tomography. To determine pBs, we applied a novel tissue reference method of analysis, Estimation of Reversible Ligand Binding and Receptor Density (ERLiBIiRD) (Gjedde, 2003; Rosa-Neto et al, 2004), which extrapolates measures of specific binding to an estimated steady-state. We compared these estimates in the two age groups with results obtained with the conventional Logan Plot and Simplified Reference Tissue Method (SRTM) applied to both regions of interest-based as parametric analyses. The regional distribution of specific binding of free sites [11C]WAY-100635 was similar to that reported in previous studies, with the highest pBs in limbic structures and the raphé nuclei. Although the results of the three methods differed, pBs in the elderly subjects consistently were lower than those of young subjects. Thus, the correlation between pB and age applied to regions-of-interest revealed significant decline of pB at the rate of 3 or 4% per decade, and a 10% decline of the global mean 5HT1A receptor-pB in elderly relative to young subjects. The results demonstrate that the number of available 5HT1A-binding sites declines with age.

Serotonin 5HT1A receptor availability and pathological crying after stroke

Objectives –  Post‐stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (pB) of the 5‐HT1A receptor antagonist [carbonyl–11C]WAY‐100635, which is reversible by selective serotonin re‐uptake inhibitor (SSRI) treatment.

Parametric Mapping of 5HT1A Receptor Sites in the Human Brain with the Hypotime Method: Theory and Normal Values

The radioligand [carbonyl-11C]WAY-100635 (11C-WAY) is a PET tracer of the serotonin 5HT1A receptors in the human brain. It is metabolized so rapidly in the circulation that it behaves more as a chemical microsphere than as a tracer subject to continuous exchange between the circulation and brain tissue. Although reference tissue methods are useful as analyses of uptake of some radioligands with indeterminate arterial input functions, their use to analyze 11C-WAY uptake and binding is challenged by the rapid plasma metabolism, which violates the assumption that regions of interest and reference regions continue to exchange radioligand with the circulation during the entire uptake period. Here, we proposed a method of calculation (Hypotime) that specifically uses the washout rather than the accumulation of 11C-WAY to determine binding potentials (BPND), without the use of regression analysis. Methods: A total of 19 healthy volunteers (age range, 23–73 y) underwent PET to test the Hypotime application of the chemical microsphere properties of 11C-WAY to identify regions of binding and nonbinding on the exclusive basis of the rate of washout of 11C-WAY. Results: The results of the Hypotime method were compared with the simplified but multilinearized reference tissue method (MLSRTM). The distribution of receptor BPND obtained with Hypotime was consistent with previous autoradiography of postmortem brain tissue, with the highest values of BPND recorded in the medial temporal lobe and decline of receptor availability with age. The values in the basal ganglia and cerebellum were negligible. The MLSRTM, in contrast, yielded lower BPND in all regions and only weakly revealed the decline with age. Conclusion: The simple and computationally efficient Hypotime method gave reliable values of BPND without the use of regression. The MLSRTM, on the other hand, appeared to be affected by the early disappearance of the radioligand from the circulation and the associated uncertain late presence of 11C-WAY in the circulation.

Trends in stage-specific incidence of prostate cancer in Norway, 1980–2010: a population-based study

To estimate changes in the stage distribution of prostate cancer during the time period where opportunistic prostate‐specific antigen (PSA) testing was introduced.

Effect of organized mammography screening on breast cancer mortality: A population-based cohort study in Norway: Mammography screening and breast cancer mortality

We aimed to estimate the effect of organized mammography screening on incidence‐based breast cancer mortality by comparing changes in mortality among women eligible for screening to concurrent changes in younger and older ineligible women. In a county‐wise balanced, open‐cohort study, we used birth cohorts (1896–1982) to construct three age groups in both the historical and screening period: women eligible for screening, and younger or older women ineligible for screening. We included women diagnosed with breast cancer who died within the same age‐period group during 1987–2010 (n = 4,903). We estimated relative incidence‐based mortality rate ratios (relative MRR) comparing temporal changes in eligible women to concurrent changes in ineligible women. Additionally, we conducted analyses comparing the change in eligible women to younger, ineligible women with either continued accrual and follow‐up period (eligible women only) or continued follow‐up period. All three age groups experienced a reduction in mortality, but the decrease among eligible women was about the same among ineligible women (relative MRR = 1.05, 95% CI: (0.94–1.18)). Varying the definition of follow‐up yielded similar results. Mammography screening was not associated with a larger breast cancer mortality reduction in women eligible relative to ineligible women.

The Screening Illustrator: separating the effects of lead-time and overdiagnosis in mammography screening

Background Mammography screening increases incidence because cancers are detected earlier in time and because of overdiagnosis. We developed an Excel-based model to visualize the expected increase from lead-time amplified by increasing background incidence. Subsequently, we added overdiagnosis to the model. Methods We constructed two hypothetical populations of women aged 50-79 in 5-year age and calendar groups: one with screening for women aged 50-69 and one without. The user enters information on population at risk, number of breast cancers, trends in background incidence, average length of lead-time and, optionally, overdiagnosis. The model computes incidence rate ratios (IRRs) comparing incidence changes with screening to changes without in open and closed cohorts. Results We entered information from Norway from 1990 to 1994, the period preceding the gradual introduction of a national mammography screening programme. As expected, the Screening Illustrator showed prevalence peaks and compensatory drops. Only the closed cohort approach remained unaffected by increasing background incidence. The model showed a 20% sustained increase in incidence (IRR: 1.20) from lead-time and increasing background incidence in the open cohort approach for women aged 50-69. However, real life Norwegian data show a corresponding 38% increase. For the model to achieve the observed incidence, 10-14% overdiagnosis had to be added. Conclusion The observed breast cancer incidence increase in Norway after screening implementation could not be obtained from an average lead-time of 2.5 years and empirical background incidence trends, but had to incorporate overdiagnosis.