Peter D. Kim

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention. Getting to the Root of Parkinson’s Disease Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results in the loss of dopamine neurons in the substantia nigra of the brain. Degeneration of these movement-related neurons predictably causes rigidity, slowness of movement, and resting tremor, but patients also show cognitive changes. Although gene mutations have been identified in several families with PD, the cause of the more common sporadic form is not known. Certain environmental factors, such as exposure to the pesticide rotenone, combined with a genetic susceptibility, are thought to confer risk for developing PD. A key pathological feature seen in postmortem brain tissue from PD patients is Lewy bodies, neuronal inclusions containing clumps of the α-synuclein protein (which is mutated in familial PD), as well as damaged mitochondria. Taking a systems biology approach to pinpoint the root cause of PD, Zheng et al. now implicate altered activity of the master transcription factor PGC-1α and the genes it regulates in the early stages of PD pathogenesis. To detect new sets of genes that may be associated with PD, the investigators did a meta-analysis of 17 independent genome-wide gene expression microarray studies that had been performed on a total of 322 postmortem brain tissue samples and 88 blood samples. The samples came from presymptomatic and symptomatic PD patients, as well as from control individuals who did not show any neurological deficits at autopsy. Nine genome-wide expression studies were conducted either on dopaminergic neurons obtained by laser capture from substantia nigra (three studies) or on substantia nigra homogenates (six studies). The authors then used a powerful tool called Gene Set Enrichment Analysis to sift through 522 gene sets (a gene set is a group of genes involved in one biological pathway or process). At the end of this tour-de-force analysis, they identified 10 gene sets that were all associated with PD. The gene sets with the strongest association contained nuclear genes encoding subunits of the electron transport chain proteins found in mitochondria. These genes all showed decreased expression in substantia nigra dopaminergic neurons (obtained by laser capture) even in the earliest stages of PD. Furthermore, a second gene set associated with PD and also underexpressed in the earliest stages of PD encodes enzymes involved in glucose metabolism. These results are compelling because many studies have already implicated dysfunctional mitochondria and altered energy metabolism as well as defective glucose metabolism in PD. The authors realized that these gene sets had in common the master transcriptional regulator, PGC-1α, and surmised that disruption of PGC-1α expression might be a root cause of PD. They tested this hypothesis in cultured dopaminergic neurons from embryonic rat midbrain forced to express a mutant form of α-synuclein. Overexpression of PGC-1α in these neurons resulted in activation of electron transport genes and protection against neuronal damage induced by mutant α-synuclein. In other cultured neurons treated with rotenone, overexpression of PGC-1α also was protective, blocking pesticide-induced neuronal cell death. These exciting findings identify altered expression of PGC-1α and the genes it regulates as key players during early PD pathogenesis. This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs. Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Functional magnetic resonance imaging-guided brain tumor resection.

Objectives: We evaluated the safety and efficacy of using functional magnetic resonance imaging (fMRI) brain activation data obtained at both 1.5 and 3 T to guide brain tumor resections using 1.5-T intraoperative MRI (ioMRI) guidance. Materials and Methods: From January 1997 to March 2006, fMRI was performed on 29 patients before attempted brain tumor resection. Functional MRI was used to identify and coregister areas of brain activation for motor (n = 18), speech (n = 6), motor and speech (n = 4), and short-term memory and speech (n = 1) with respect to the tumor using a 1.5-T and two 3-T MRI scanners. Surgical resection was accomplished using 2 different 1.5-T ioMRI systems. The appropriate MRI scan sequences were obtained during surgery to determine and maximize the extent of the surgical resection depending on the tumor type. Results: Of 29 patients, 20 (69%) had radiographically complete fMRI-guided tumor resections and 2 (7%) had successful MRI-guided brain biopsy because of the proximity of their astrocytomas to the eloquent cortex. The tumors were oligodendrogliomas (n = 16), astrocytomas (n = 4), meningiomas (n = 3), glioblastomas multiforme (n = 2), a pleomorphic astrocytoma (n = 1), and a dysembryoplastic neuroepithelial tumor (n = 1). The preoperative fMRI data were accurate in all cases. After tumor resection, 7 patients (26%) had transient neurologic deficits that resolved completely within 1 month of the surgical procedure in all cases. No adverse events associated with ferromagnetic instrumentation occurred. Conclusions: Functional MRI was accurate for localizing areas of eloquent neurologic function before ioMRI-guided brain tumor resection.

Three-Tesla High-Field Applications

The authors believe that 3-T intraoperative MRI (iMRI) is likely to become the standard of care for a wide range of neurosurgical procedures. Although 3-T high-field image acquisition does pose challenges, the advantages of this field strength, such as superior visualization of soft tissue and clear delineation of any residual tumor tissue, are clearly optimized using this equipment. Additionally, the use of 3-T high-field scanning offers functional options, such as brain activation studies and complex vascular imaging, that are unavailable with low- and midfield iMRI systems. The authors believe that the cost and effort necessary to acquire and establish a 3-T high-field iMRI program represent the natural progression for image-guided neurosurgery.

Risk of cervical spine injury and other complications seen with skull fractures in the setting of mild closed head injury in young children: a retrospective study

We have reviewed records for patients under 2 years of age who presented at our hospital with mild closed head injuries and nondisplaced skull fractures, specifically to examine methods utilized for spine clearance, associated cervical injuries, involvement and findings of child protective services and delayed complications. Of 42 patients included in the series, none were found to have cervical spine injuries. Child protective services were involved in 12 cases with confirmatory findings and subsequent placement occurring in 2 cases. There were no serious delayed complications in this series of patients. AP and lateral plain films of the cervical spine are nonetheless recommended until larger prospective studies suggest otherwise.

Use of positron emission tomography scanning to evaluate pseudoresponse

Although an important part of the neuro-oncologists armamentarium, antiangiogenic chemotherapeutic agents can result in a pseudoresponse. This phenomenon occurs because the contrast enhancement that is used to measure tumor burden radiographically, depends upon the breakdown of the blood-brain barrier which may be restored after treatment with antiangiogenic agents, even without true eradication of the neoplasm. This occurrence may complicate attempts to determine an accurate prognosis for patients with malignant brain tumors as well as delay the initiation of more beneficial treatment strategies.