which this may occur is via inflammation resulting from the activation of transforming growth factor-b (TGF-b). This TGF-b acti- vation can lead to up-regulation of factors promoting fibroblast proliferation and, ulti- mately, subarachnoid fibrosis. In turn, these changes impair CSF egress, resulting in communicating hydrocephalus. Botfield et al. hypothesized that inhibition of TGF- b activity could disrupt this cascade of events leading to subarachnoid fibrosis and thereby prevent the development of hydrocephalus. Decorin is a naturally occurring proteoglycan that, amongst other functions, is known to inhibit TGF-b activity. To test their hypoth- esis, these investigators induced communi- cating hydrocephalus in juvenile rodents. Using a promising model, kaolin, an alumi- num silicate substance, was injected into the basal cisterns. Decorin was then con- tinuously infused for 14 days into the lateral ventricles of a subset of the rodents. Immunohistochemical testing demonstrated that decorin infusion inhibited the TGF-b pathway. Specifically, rodents treated with decorin showed decreased TGF-b staining in the ependyma of the ventricles. Downstream signaling induced by TGF-b was also sup- pressed, as evidenced by decreased intensity of ependymal phosphorylated Smad2/3 protein staining. This inhibition of the TGF-b was shown to be associated with decreased accumulation of neutrophils, mac- rophages, and eosinophils in the subarach- noid space, when compared to untreated rodents. These events seemed to be associ- ated with decreased subarachnoid fibrosis, as the decorin group demonstrated meaning- fully less laminin and fibronectin deposition in the extracellular matrix. In addition, there was less reactive gliosis in the corpus callos- um and periventricular white matter, as demonstrated by decreased levels of GFAP immunostaining. Most importantly, Botfield et al. noted that decorin-mediated inhibition of TGF-b also prevented the development of ventriculomegaly. Conversely, in the absence of decorin treatment, significant ventriculomegaly was triggered by the kaolin injection. Taken together, this study by Botfield et al. has important implications for the continued study and treatment of hydrocephalus. First, these researchers confirmed the robustness of this useful model of communicating hydro- cephalus by powerfully demonstrating that activation of a TGF-b-mediated cascade re- sulted in the development of both the char- acteristic cellular and radiographic changes associated with this condition. Moreover, they established that there are potential ways for inhibiting critical inflammatory pathways that can potentially prevent the development of hydrocephalus. Although further research needs to be done to determine the applicability of this animal model to humans, this study offers hope that there will be non-surgical treatments to prevent the development of this common and often devastating neurosurgical disease. PHILIP LEE EDWARD A. MONACO, III ROBERT M. FRIEDLANDER Neuropathology Indicates a Need for Earlier Neurorestorative Intervention in Parkinson’s Disease P arkinson’s disease (PD) is character- ized by dysfunction in the dopami- nergic nigrostriatal system. It previously has been accepted that by the time of diagnosis, a significant amount of degeneration in dopaminergic fibers projec- ting from the substantia nigra pars compacta to the striatum has already occurred. How- ever, surprisingly little is known about the extent and time course of this deterioration in humans. This information is important, as it has direct bearing on the optimal timing for interventions that aim to prevent further neuronal loss or to rescue neuronal dysfunctional. In the recent report Disease duration and the integrity of the nigrostriatal system in Parkinson’ s disease, Kordower et al. (Brain 2013: 136; 2419-2431) evaluated the post- mortem brains of 28 patients who had been diagnosed with Parkinson’s disease over a range of 1-27 years before death. In each case, the diagnosis of PD had been made by a movement disorders neurologist and con- firmed by a neuropathologist. The authors then studied brain sections using tyrosine hydroxylase and dopamine transporter im- munostaining to investigate dopamine fiber density in the putamen, and stereology to estimate numbers of tyrosine hydroxylase expressing and melanin containing cells in the substantia nigra. Comparing these pa- tients to age-matched controls, the investi- gators sequentially examined the extent of dopaminergic terminal degeneration and cell loss throughout the course of the disease. Their findings revealed a previously unre- ported substantial reduction in dopamine terminals early on in the disease. Dopamine markers in the dorsal putamen of PD patients were significantly but variably reduced (35-75%) at 1-3 years after diagnosis, and severely reduced (70-90%) by 5 years after diagnosis, exhibiting stable levels thereafter. Similarly, profound loss of tyrosine hydroxy- lase expressing neurons was found in the pars compacta (50-90%) beginning at the earliest time points, suggesting that compensatory sprouting may transiently occur in the stria- tum during the earliest stage of the disease to offset neuronal loss in the nigra. Interestingly, at all time points there were more melanin- containing than tyrosine hydroxylase-expressing neurons, indicating that a window exists during which dopaminergic function is lost but cells survive. Although previous studies have examined histologic changes in the nigrostriatal system of PD patients, this is the largest pathology study to date that examines multiple post- diagnosis time points using modern stereological technique. Several points are important for neurosurgeons interested in developing or implementing neurorestorative therapies, such as gene therapy, direct drug delivery of therapeutic molecules, or cell transplantation. In light of these data, neuroprotective thera- pies targeted to individuals with greater than 4 years of disease duration may have missed the optimal window for preventing loss of dopa- minergic function in the majority of surviving neurons. On the other hand, trophic or regenerative therapies may still have value in later stages of the disease, due to the persis- tence of populations of melanin-containing neurons in which the dopaminergic pheno- type potentially may be restored. This study also emphasizes the need to develop bio- markers that would allow the diagnosis of patients before the onset of motor symptoms, after which significant nigrostriatal degenera- tion has already occurred. Future restorative neurosurgical clinical trials, therefore, should consider enrolling patients earlier in the course of their disease, rather than as a “last resort” following long disease duration and failure of medical management. NATHAN T. ZWAGERMAN R. MARK RICHARDSON SCIENCE TIMES N14 | VOLUME 73 | NUMBER 6 | DECEMBER 2013 www.neurosurgery-online.com Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited. 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