55 research outputs found
Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies
Blood oxygenation level dependent (BOLD) contrast fMRI is a widely used technique to map
brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology,
the neurovascular coupling between cerebral blood flow and neural activity may be altered,
resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose
of this study was to demonstrate the feasibility of using a recently validated breath-hold task
in patients with stroke, both to assess group level changes in cerebrovascular reactivity
(CVR) and to determine if alterations in regional CVR over time will adversely affect
interpretation of task-related BOLD signal changes. Three methods of analyzing the breathhold
data were evaluated. The CVR measures were compared over healthy tissue, infarcted
tissue, and the peri-infarct tissue, both sub-acutely (~two weeks) and chronically (~four
months). In this cohort, a lack of CVR differences in healthy tissue between the patients and
controls indicates that any group level BOLD signal change observed in these regions over
time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct
tissue but remained unchanged over time. Therefore, although a lack of activation in this
region compared to the controls may be confounded by a reduced CVR, longitudinal grouplevel
BOLD changes may be more confidently attributed to neural activity changes in this
cohort. By including this breath-hold based CVR assessment protocol in future studies of
stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal
reflect true alterations in neural activity
Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease
Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP(+)) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP(+) led to the sequential phosphorylation and activation of JNK kinase (MKK4), JNK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the JNK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of JNK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the JNK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases
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