Episodic memory decline in Parkinson' s disease: relation with white matter hyperintense lesions and influence of quantification method.

The relation of white matter hyperintense lesions to episodic memory impairment in patients with Parkinson's disease (PD) is still controversial. We aimed at evaluating the relation between white matter hyperintense lesions and episodic memory decline in patients with PD. In this multicentric prospective study, twenty-one normal controls, 15 PD patients without mild cognitive impairment (MCI) and 13 PD patients with MCI were selected to conduct a clinico-radiological correlation analysis. Performance during episodic memory testing, age-related white matter changes score, total manual and automated white matter hyperintense lesions volume and lobar white matter hyperintense lesions volumes were compared between groups using the Kruskal-Wallis and Wilcoxon signed-rank tests, and correlations were assessed using the Spearman test. MCI PD patients had impaired free recall. They also had higher total, left prefrontal and left temporal white matter hyperintense lesions volumes than normal controls. Free recall performance was negatively correlated with the total white matter hyperintense lesions volume, either manually or automatically delineated, but not with the age-related white matter changes score. Using automated segmentation, both the left prefrontal and temporal white matter hyperintense lesions volumes were negatively correlated with the free recall performance. Early episodic memory impairment in MCI PD patients may be related to white matter hyperintense lesions, mainly in the prefrontal and temporal lobes. This relation is influenced by the method used for white matter hyperintense lesions quantification. Automated volumetry allows for detecting those changes.

MRI volumetric morphometry in vascular parkinsonism.

Vascular parkinsonism is a difficult clinical differential diagnosis in elderly subjects. We aimed at identifying morphometric markers in the brain of elderly patients with vascular parkinsonism (VP) compared with age-matched patients with Parkinson's disease (PD) and healthy controls. In this multicenter prospective study, 46 patients (80 ± 5 years old; male 32) with parkinsonism (32 PD and 14 VP) and 29 controls (mean age 78 ± 3 years; male 21) underwent brain MRI on a 3-T scanner including T1 MPRAGE and FLAIR sequences. Volumetric morphometry was obtained using Morphobox software and compared between patients and controls. Receiver operating characteristics curve analysis with computation of area under the curve (AUC) was used to compare diagnostic values. Caudate nucleus and white matter hyperintense lesions (WMHL) volumes appeared significantly higher in patients with VP. Normalized caudate volume of at least 0.67% and normalized WMHL of at least 1.11% identified patients with VP from patients with PD and controls with similar performances (p > 0.25). Caudate nucleus and WMHL volumes were positively correlated (ρ = 0.74, p < 0.0001), suggesting vascular disease related remodelling in elderly subjects. Caudate nucleus and WMHL MRI volumes might be used as additional markers to help identify patients with VP in the initial workup of elderly subjects with parkinsonian symptoms.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects.

BACKGROUND AND PURPOSE: The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. MATERIALS AND METHODS: Thirty-five patients were prospectively included (multiple-system atrophy, n=5; Parkinson's disease, n=15; progressive supranuclear palsy, n=9; vascular parkinsonism, n=6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinson's disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. RESULTS: Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p=0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p=0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinson's disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. CONCLUSION: Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.

Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase.

Vitamin B12 (cobalamin, cbl) is a cofactor of methionine synthase (MTR) in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAM), which is involved in epigenomic regulatory mechanisms. We have established a neuronal cell model with stable expression of a transcobalamin-oleosin chimer and subsequent decreased cellular availability of vitamin B12, which produces reduced proliferation, increased apoptosis and accelerated differentiation through PP2A, NGF and TACE pathways. Anti-transcobalamin antibody or impaired transcobalamin receptor expression produce also impaired proliferation in other cells. Consistently, the transcription, protein expression and activity of MTR are increased in proliferating cells of skin and intestinal epitheliums, in rat intestine crypts and in proliferating CaCo2 cells, while MTR activity correlates with DNA methylation in rat intestine villi. Exposure to nitrous oxide in animal models identified impairment of MTR reaction as the most important metabolic cause of neurological manifestations of B12 deficiency. Early vitamin B12 and folate deprivation during gestation and lactation of a 'dam-progeny' rat model developed in our laboratory is associated with long-lasting disabilities of behavior and memory capacities, with persisting hallmarks related to increased apoptosis, impaired neurogenesis and altered plasticity. We found also an epigenomic deregulation of energy metabolism and fatty acids beta-oxidation in myocardium and liver, through imbalanced methylation/acetylation of PGC-1alpha and decreased expression of SIRT1. These nutrigenomic effects display similarities with the molecular mechanisms of fetal programming. Beside deficiency, B12 loading increases the expression of MTR through internal ribosome entry sites (IRES) and down-regulates MDR-1 gene expression. In conclusion, vitamin B12 influences cell proliferation, differentiation and apoptosis in brain. Vitamin B12 and folate combined deficiency impairs fatty acid oxidation and energy metabolism in liver and heart through epigenomic mechanisms related to imbalanced acetylation/methylation. Some but not all of these effects reflect the upstream role of vitamin B12 in SAM synthesis.

[Diagnostic approach for breast cancer classification]. / Démarche diagnostique dans cancer du sein, classification.

The pathologist is involved at various steps in the management of a patient with breast cancer and in the therapeutic decision. First, the pathologist confirms a diagnosis of malignancy on cytology specimens, microbiopsies and surgical specimens. During the surgery, through the frozen section, the pathologist specifies the surgical limits and collects specimens for research purposes. Then the pathologist evaluates the parameters needed to establish the final diagnosis, the prognosis and the identification of predictive factors, using ancillary techniques such as immunohistochemistry, in situ hybridization or molecular techniques. Mandatory elements to be included in the final pathological report are size, histological type, SBR grade modified by Elston and Ellis, the presence or absence of vascular or lymphatic peritumoral emboli (prognostic parameters), the status of resection margins (local relapse risk) and the status of hormonal receptor and HER2 (predictive parameters).