Leucoaraiosis, nigrostriatal denervation and motor symptoms in Parkinson's disease.

Leucoaraiosis is associated with motor symptoms in otherwise normal older adults. Comorbid leucoaraiosis is predicted to contribute also to motor features in Parkinson's disease but previous studies of white matter changes in Parkinson's disease show variable results. No prior studies have compared directly the effects of both leucoaraiosis and the degree of nigrostriatal dopaminergic denervation on motor features. We investigated the effect of leucoaraiosis severity on motor impairment independent of the degree of nigrostriatal dopaminergic denervation in Parkinson's disease. Seventy-three subjects with Parkinson's disease (Hoehn and Yahr stages 1-3) underwent brain magnetic resonance and [(11)C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography imaging. Automated assessment of supratentorial fluid-attenuated inversion recovery magnetic resonance hyperintense white matter voxels was performed using cerebellar white matter as the intensity reference. White matter signal hyperintensity burden was log-transformed and normalized for brain volume. Unified Parkinson's Disease Rating Scale total and subscore ratings were assessed to determine motor impairment. Subjects receiving dopaminergic medications were examined in the clinically defined 'OFF' state. Multivariate regression analysis with measures of white matter signal hyperintensity burden and nigrostriatal denervation as independent variables demonstrated a significant overall model for total motor Unified Parkinson's Disease Rating Scale scores (F = 11.4, P < 0.0001) with significant regression effects for both white matter signal hyperintensity burden (t = 2.0, ß = 0.22, P = 0.045) and striatal monoaminergic binding (t = -3.5, ß = -0.38, P = 0.0008). Axial motor impairment demonstrated a robust association with white matter signal hyperintensity burden (t = 4.0, ß = 0.43, P =0.0001) compared with striatal monoaminergic binding (t = -2.1, ß = 0.22, P = 0.043). White matter signal hyperintensity burden regression effects for bradykinesia had borderline significance. No significant white matter signal hyperintensity burden effects were found for rigidity or tremor subscores. White matter signal hyperintensity burden was significantly higher in the subgroup with postural instability and gait difficulties compared with the tremor-predominant subgroup despite no significant differences in age or duration of disease. These findings indicate that increased white matter signal hyperintensity burden is associated with worse motor performance independent of the degree of nigrostriatal dopaminergic denervation in Parkinson's disease. Comorbid white matter disease is a greater determinant of axial motor impairment than nigrostriatal dopaminergic denervation.

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis.

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI(Tie2) (71% ± 0.9%, P < .001) and TFPI(LysM) (19% ± 0.6%, P < .001) compared with TFPI(Flox) littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased ferric chloride-induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.

Incremental value of diagnostic 131I SPECT/CT fusion imaging in the evaluation of differentiated thyroid carcinoma.

OBJECTIVE: The purpose of this study was to determine the incremental value of (131)I SPECT/CT over traditional planar imaging of patients with differentiated thyroid carcinoma. MATERIALS AND METHODS: Fifty-six planar and SPECT/CT scans were obtained for 53 patients. Forty-eight scans were diagnostic (131)I studies before first radioiodine therapy, four were diagnostic (131)I studies with recombinant human thyroid-stimulating hormone stimulation, and four scans were posttherapy (131)I studies. Two nuclear physicians interpreted central neck and distant activity on planar scans and reviewed SPECT/CT images to assess the incremental diagnostic value with respect to localization and characterization of focal activity and to evaluate reader confidence. One of the readers was unblinded and had access to clinical, imaging, histologic, and biochemical information. RESULTS: Planar scans depicted 130 neck foci and 17 distant foci. At SPECT/CT these foci were further characterized as thyroglossal duct and thyroid bed remnant (n = 98), cervical nodal metastasis or local residual disease (n = 26), physiologic activity (n = 11), and distant metastasis (n = 12). Interobserver disagreement occurred on eight of 147 foci (5%). Because of superior lesion localization and additional anatomic information derived from the low-dose CT component, incremental diagnostic value with SPECT/CT over planar imaging was found for 70 of 147 foci (47.6%), including 53 of 130 neck foci (40.8%) and all 17 (100%) distant foci. Reader confidence increased regarding 104 of 147 foci (70.7%). CONCLUSION: Iodine-131 SPECT/CT is useful for accurate evaluation of regional and distant activity in characterization of foci as residual thyroid tissue or nodal, pulmonary, or osseous metastasis. Suspected physiologic mimics of disease can be confirmed with increased reader confidence.