Akash J. Patel

A Protein–Protein Interaction Network for Human Inherited Ataxias and Disorders of Purkinje Cell Degeneration

Many human inherited neurodegenerative disorders are characterized by loss of balance due to cerebellar Purkinje cell (PC) degeneration. Although the disease-causing mutations have been identified for a number of these disorders, the normal functions of the proteins involved remain, in many cases, unknown. To gain insight into the function of proteins involved in PC degeneration, we developed an interaction network for 54 proteins involved in 23 inherited ataxias and expanded the network by incorporating literature-curated and evolutionarily conserved interactions. We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen; of 75 pairs tested, 83% of the interactions were verified in mammalian cells. Many ataxia-causing proteins share interacting partners, a subset of which have been found to modify neurodegeneration in animal models. This interactome thus provides a tool for understanding pathogenic mechanisms common for this class of neurodegenerative disorders and for identifying candidate genes for inherited ataxias.

The AXH Domain of Ataxin-1 Mediates Neurodegeneration through Its Interaction with Gfi-1/Senseless Proteins

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an expanded glutamine tract in human Ataxin-1 (hAtx-1). The expansion stabilizes hAtx-1, leading to its accumulation. To understand how stabilized hAtx-1 induces selective neuronal degeneration, we studied Drosophila Atx-1 (dAtx-1), which has a conserved AXH domain but lacks a polyglutamine tract. Overexpression of hAtx-1 in fruit flies produces phenotypes similar to those of dAtx-1 but different from the polyglutamine peptide alone. We show that the Drosophila and mammalian transcription factors Senseless/Gfi-1 interact with Atx-1s AXH domain. In flies, overexpression of Atx-1 inhibits sensory-organ development by decreasing Senseless protein. Similarly, overexpression of wild-type and glutamine-expanded hAtx-1 reduces Gfi-1 levels in Purkinje cells. Deletion of the AXH domain abolishes the effects of glutamine-expanded hAtx-1 on Senseless/Gfi-1. Interestingly, loss of Gfi-1 mimics SCA1 phenotypes in Purkinje cells. These results indicate that the Atx-1/Gfi-1 interaction contributes to the selective Purkinje cell degeneration in SCA1.

Epidemiology of Metastatic Brain Tumors

Metastatic tumors are the most common brain tumors in adults, and their incidence is increasing. An accurate understanding of the epidemiology of metastatic brain tumors is useful for health care professionals to allocate appropriate clinical, diagnostic, therapeutic, and research resources. Reported incidences in the literature are derived from epidemiologic population-based studies; clinical studies from surgical, radiological, and autopsy series; and reviews of hospital and clinical medical records. Despite these various sources of information, an accurate incidence of metastatic brain tumors is difficult, and current figures are estimates at best. Here, we review the available data regarding the epidemiology of metastatic brain tumors.

Factors influencing the risk of local recurrence after resection of a single brain metastasis

OBJECT Local recurrence (LR) of a resected brain metastasis occurs in up to 46% of patients. Postoperative whole-brain radiation therapy (WBRT) reduces that incidence. To isolate factors associated with the risk of LR after resection, the authors only studied patients who did not receive adjuvant radiotherapy. METHODS The authors reviewed data from 570 cases involving patients who had undergone resection of a previously untreated single brain metastasis at The University of Texas M. D. Anderson Cancer Center between 1993 and 2006 without receiving postoperative WBRT. All tumors were measured preoperatively on MR images. The resection method (en bloc resection [EBR] or piecemeal resection [PMR]) was noted at the time of surgery. Predictors of LR were assessed using the Cox proportional hazards model. RESULTS The median patient age was 58 years, 55% were male, and 88% had a Karnofsky Performance Scale Score > or = 80. The most common primary cancers were those of the lung (28%), skin (melanoma, 21%), kidney (19%), and breast (11%). Piecemeal resection was performed in 201 patients (35%) and EBR in 369 (65%). Local recurrence developed in 84 patients (15%). The histological type of the primary cancer did not significantly predict LR; however, 7 of 22 patients with sarcoma developed LR (p = 0.16). The authors identified 2 variables that increased the risk of LR. Undergoing PMR carried a significantly higher LR risk than EBR (crude hazard ratio [HR] 1.7, 95% CI 1.1-2.6, p = 0.03). Tumors exceeding the median volume (9.7 cm(3)) had a significantly higher LR risk than those that were < 9.7 cm(3) (crude HR 1.7; 95% CI 1.1-2.6; p = 0.02). In the multivariate analysis, small tumors removed by EBR had a significantly lower LR risk. CONCLUSIONS The LR risk of a single brain metastasis is influenced by biological factors (such as tumor volume) and treatments (such as the resection method). Early administration of postoperative WBRT may be particularly warranted when such negative tumor-related prognostic factors are noted or when treatment-related ones such as PMR are unavoidable.

Identification of diverse astrocyte populations and their malignant analogs

Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting–based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.

Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis

OBJECTIVETo test the hypothesis that differential risks of developing leptomeningeal disease (LMD) exist in patients having a single supratentorial brain metastasis resected via a piecemeal or en bloc approach or treated with stereotactic radiosurgery (SRS). METHODSBetween 1993 and 2006, 827 patients with a supratentorial brain metastasis underwent resection or SRS at The University of Texas M.D. Anderson Cancer Center. The primary outcome was the incidence of LMD. RESULTSResection was performed piecemeal in 191 patients and en bloc in 351 patients; 285 patients received SRS. LMD occurred in 33 patients, 29 in the resection group and 4 in the SRS group. Risk of LMD was significantly higher with piecemeal tumor resection than with other procedures (SRS: hazard ratio [HR] for piecemeal, 5.8; 95% confidence interval [CI], 1.9–17.2; P = 0.002; en bloc, HR for piecemeal, 2.7; 95% CI, 1.3–5.6; P = 0.009). The difference between piecemeal and en bloc was particularly pronounced in patients with a melanoma primary (HR, 8.4; 95% CI, 1.8–39.2; P = 0.007). The risk of LMD was not significantly different between en bloc resection and SRS (HR for en bloc, 2.1; 95% CI, 0.7–6.4; P = 0.21). Similar results were obtained when comparing effects of SRS and both resection approaches after limiting the sample to patients with tumors in a specific volume range. CONCLUSIONPiecemeal resection of a supratentorial brain metastasis carries a higher risk of LMD than en bloc resection or SRS. Further assessment of the role of the 2 surgical resection approaches and SRS in a controlled prospective setting with large numbers of patients is warranted.

Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review.

Abstract:  Propionic acidemia is a rare metabolic disorder that often results in episodic hyperammonemia, basal ganglia infarction, mental retardation, and cardiomyopathy. OLT has been used as a treatment for propionic acidemia, but its benefit in patients with this disease is unclear. The current study was undertaken to clarify the role of OLT in the management of this disease. The medical literature, a national registry of US OLT recipients, and a single institution liver transplant experience were reviewed for cases of OLT for propionic acidemia. Accumulated cases demonstrate that OLT has resulted in clear evidence of clinical improvement in several patients, often obviating the need for dietary restriction or other forms of medical management. OLT appears to halt the decline in neurocognitive function often associated with propionic acidemia. In total, 12 patients with propionic acidemia have undergone a total of 14 OLTs. A quantitative analysis of outcomes shows an overall patient survival rate of 72.2% at one year after OLT. In conclusion, OLT should be considered a treatment option for patients with propionic acidemia who continue to experience episodes of hyperammonemia in spite of maximal medical therapy. Early OLT may limit the development of mental retardation and/or cardiomyopathy.

Pineal cyst apoplexy: case report and review of the literature.

OBJECTIVE AND IMPORTANCE:Although most pineal cysts are clinically benign and asymptomatic, some can become symptomatic. Of the various symptomatic presentations, apoplexy is the rarest and most ill-defined. A comprehensive search of publications in the English language yielded 18 cases of pineal cyst apoplexy. We reviewed the literature to compare symptomatology and management strategies and their outcomes. CLINICAL PRESENTATION:A 29-year-old woman with a 1-month history of headaches presented with an acute worsening of her symptoms with a severe occipital headache and trouble focusing when reading. Her neurological examination was otherwise normal. Magnetic resonance imaging showed pineal cyst apoplexy and accompanying hydrocephalus. INTERVENTION:A left paramedian craniotomy with a transcallosal, transchoroidal approach using an intraoperative neuronavigation system was used to resect a pineal cyst. Postoperative imaging showed complete removal of the cyst and resolution of the hydrocephalus. Follow-up imaging at 12 months demonstrated no evidence of recurrence or any hydrocephalus. The patient has remained asymptomatic for 18 months. CONCLUSION:Pineal cyst apoplexy should always be considered when following a patient with a pineal cyst that becomes symptomatic. The most common symptom was severe headache of sudden onset or acute worsening. Other signs of hydrocephalus may or may not be present. Magnetic resonance imaging is essential to making a diagnosis. Although we believe that surgical resection is the most effective approach because it minimizes the risk for recurrence and complication, stereotactic aspiration has been used successfully to treat this condition.

Publication patterns of oral and poster presentations at the annual meetings of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons

OBJECT National and international meetings, such as the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS) meetings, provide a central location for the gathering and dissemination of research. The purpose of this study was to determine the publication rates of both oral and poster presentations at CNS and AANS meetings in peer-reviewed journals. METHODS The authors reviewed all accepted abstracts, presented as either oral or poster presentations, at the CNS and AANS meetings from 2003 to 2005. This information was then used to search PubMed to determine the rate of publication of the abstracts presented at the meetings. Abstracts were considered published if the data presented at the meeting was identical to that in the publication. RESULTS The overall publication rate was 32.48% (1243 of 3827 abstracts). On average, 41.28% of oral presentations and 29.03% of poster presentations were eventually published. Of those studies eventually published, 98.71% were published within 5 years of presentation at the meeting. Published abstracts were published most frequently in the Journal of Neurosurgery and Neurosurgery. CONCLUSIONS Approximately one-third of all presentations at the annual CNS and AANS meetings will be published in peer-reviewed, MEDLINE-indexed journals. These meetings are excellent forums for neurosurgical practitioners to be exposed to current research. Oral presentations have a significantly higher rate of eventual publication compared with poster presentations, reflecting their higher quality. The Journal of Neurosurgery and Neurosurgery have been the main outlets of neurosurgical research from these meetings.

Analysis of the risk of shunt failure or infection related to cerebrospinal fluid cell count, protein level, and glucose levels in low-birth-weight premature infants with posthemorrhagic hydrocephalus

OBJECT Premature, low-birth-weight infants with posthemorrhagic hydrocephalus have a high risk of shunt obstruction and infection. Established risk factors for shunt failure include grade of the hemorrhage and age at shunt insertion. There is anecdotal evidence that the amount of red blood cells or protein levels in the CSF may affect shunt performance. However, this has not been analyzed specifically for this cohort of high-risk patients. Therefore, the authors performed this study to examine whether any statistical relationship exists between the CSF constituents and the rate of shunt malfunction or infection in this population. METHODS A retrospective cohort study was performed on premature infants born at Riley Hospital for Children from 2000 to 2009. Inclusion criteria were a CSF sample analyzed within 2 weeks prior to shunt insertion, low birth weight (< 1500 grams), prematurity (birth prior to 37 weeks estimated gestational age), and shunt insertion for posthemorrhagic hydrocephalus. Data points included the gestational age at birth and shunt insertion, weight at birth and shunt insertion, history of CNS infection prior to shunt insertion, shunt failure, shunt infection, and the levels of red blood cells, white blood cells, protein, and glucose in the CSF. Statistical analysis was performed to determine any association between shunt outcome and the CSF parameters. RESULTS Fifty-eight patients met the study entry criteria. Ten patients (17.2%) had primary shunt failure within 3 months of insertion. Nine patients (15.5%) had shunt infection within 3 months. A previous CNS infection prior to shunt insertion was a statistical risk factor for shunt failure (p = 0.0290) but not for shunt infection. There was no statistical relationship between shunt malfunction or infection and the CSF levels of red blood cells, white blood cells, protein, or glucose before shunt insertion. CONCLUSIONS Low-birth-weight premature infants with posthemorrhagic hydrocephalus have a high rate of shunt failure and infection. The authors did not find any association of shunt failure or infection with CSF cell count, protein level, or glucose level. Therefore, it may not be useful to base the timing of shunt insertion on CSF parameters.