Absolute CBF and CBV measurements by MRI bolus tracking before and after acetazolamide challenge: repeatabilily and comparison with PET in humans

Bolus tracking magnetic resonance imaging (MRI) is a powerful technique for assessing cerebral perfusion, but its capability to measure absolute cerebral blood flow (CBF) and volume (CBV) values is still debated. To validate the MRI technique, absolute CBF and CBV values in healthy humans obtained by echo planar gradient echo MRI were compared to H(2)(15)O and (11)CO positron emission tomography (PET) before and after acetazolamide (ACZ) (n = 8) or saline (n = 4) administration. The repeatability of CBF and CBV measurements was moderate with both methods, and slightly lower with MRI than with PET. At rest, the mean CBF values were similar with both techniques except in the cortex where they were moderately higher with MRI. CBV was higher with MRI than with PET in all areas, which may reflect an underestimation of the arterial input function (AIF). After ACZ, a significant CBF increase was observed in gray matter with both MRI and PET, suggesting that MRI might be used to assess the cerebrovascular reserve. In individual subjects, the correlation between MRI and PET measurements was good for both CBF and CBV (R(2) between 0.70 and 0.84). However, when all results were considered as a group, R(2) was lower (0.40 to 0.65), and the limits of agreement between the two methods (SD of the difference) were large. Our data suggest that physiologic CBF values and systematically overestimated CBV values may be obtained with MRI in healthy humans, but that an individual scale factor should be applied to MRI measurements to improve the agreement with PET.     

Apolipoprotein E and LRP1 Increase Early in Parkinson's Disease Pathogenesis

Parkinson's disease (PD) is characterized by α-synuclein-containing Lewy bodies (LBs) and loss of melanized neurons in the substantia nigra (SN). Recently, a link between apolipoprotein E (ApoE) expression, α-synuclein aggregation, and neurodegeneration was suggested. Here, we report on ApoE expression appearing in melanized neurons of the SN and in LBs in both PD and incidental LB disease cases. Interestingly, increased expression of the low-density lipoprotein receptor-related protein 1 (the receptor for ApoE) was also observed in incidental LB disease and PD. Our data suggest that alterations in lipoprotein homeostasis/signaling in melanized neurons of the SN are an early event during PD pathogenesis.     

Changes in the proteome and infectivity of Leishmania infantum induced by in vitro exposure to a nitric oxide donor

Leishmania species are protozoan parasites that exhibit an intracellular amastigote form within mammalian macrophages and an extracellular promastigote form inside the sandfly vector. The generation of nitric oxide (NO) upon activation of macrophages is surely the principal killing effector of intracellular amastigotes but little is known about the potential action of NO against the promastigote phase during its multiplication inside the digestive tract of the sandfly vector. Therefore, we have approached this issue by using an in vitro model to study the effect of an NO donor, 3-morpholinosydnonimine (SIN-1), on the proteome and infectivity of promastigotes of Leishmania infantum. Exposure of promastigotes to SIN-1 during its logarithmic growth phase caused a dramatic effect on parasite protein expression and viability, consequently killing about 60-70% of the promastigotes. The significant changes in the proteome included the over-expression of enolase, peroxidoxin precursors, and heat-shock protein 70 (HSP70), under-expression of 20S proteasome alpha 5 unit, and phosphomannomutase and induced expression of 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) synthase and prostaglandine f2-alpha (PGD2) synthase. Interestingly, promastigotes that resisted treatment showed enhanced infectivity to J774 macrophages in comparison to the controls. This finding together with the appearance of the PGD2S and an over-expression of HSP70 isoforms in treated promastigotes led us to speculate the existence of NO-mediated programmed cell death (PCD) events as a potential mechanism of population regulation and selection of properly infecting forms that predominantly operate on the promastigote stage.     

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.     

Appearance of Tissue Transglutaminase in Astrocytes in Multiple Sclerosis Lesions: A Role in Cell Adhesion and Migration?

Multiple Sclerosis (MS) is a neuroinflammatory disease mainly affecting young adults. A major pathological hallmark of MS is the presence of demyelinated lesions in the central nervous system. In the active phase of the disease, astrocytes become activated, migrate and contribute to local tissue remodeling that ultimately can result in an astroglial scar. This process is facilitated by extracellular matrix proteins, including fibronectin. Tissue Transglutaminase (TG2) is a multifunctional enzyme with a ubiquitous tissue distribution and it has been shown that inflammatory cytokines can induce TG2 activity. In addition, TG2 is known to mediate cell adhesion and migration. We therefore hypothesized that TG2 is present in MS lesions and plays a role in cell adhesion and/or migration. Our studies showed that TG2 immunoreactivity appeared in astrocytes in active and chronic active MS lesions. These TG2 positive astrocytes partly co‐localized with fibronectin. Additional in vitro studies showed that TG2 mediated astrocytoma adhesion to and migration on the extracellular matrix protein fibronectin. We therefore speculate that TG2 mediates the enhanced interaction of astrocytes with fibronectin in the extracellular matrix of MS lesions, thereby contributing to astrocyte adhesion and migration, and thus in tissue remodeling and possibly glial scarring.