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Background and Purpose: Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene. Our hypothesis was that regional analysis of cortical brain degeneration may identify brain regions that are affected earliest and most severely by the disease., Materials and Methods: Fifty-two high-resolution 3T MR imaging datasets were prospectively acquired on 38 subjects with CLN2. A retrospective cohort of 52 disease-free children served as a control population. The FreeSurfer software suite was used for calculation of cortical thickness., Results: An increased rate of global cortical thinning in CLN2 versus control subjects was the primary finding in this study. Three distinct patterns were observed across brain regions. In the first, subjects with CLN2 exhibited differing rates of cortical thinning versus age. This was true in 22 and 26 of 34 regions in the left and right hemispheres, respectively, and was also clearly discernable when considering brain lobes as a whole and Brodmann regions. The second pattern exhibited a difference in thickness from healthy controls but with no discernable change with age (9 left hemispheres, 5 right hemispheres). In the third pattern, there was no difference in either the rate of cortical thinning or the mean cortical thickness between groups (3 left hemispheres, 3 right hemispheres)., Conclusions: This study demonstrates that CLN2 causes differential rates of degeneration across the brain. Anatomic and functional regions that degenerate sooner and more severely than others compared with those in healthy controls may offer targets for directed therapies. The information gained may also provide neurobiologic insights regarding the mechanisms underlying disease progression., (© 2016 by American Journal of Neuroradiology.)

Purpose: Whereas T2 hyperintensities known as NF-associated bright spots are well described in patients with neurofibromatosis type I (NF-1), there is a paucity of data on incidental findings in patients with neurofibromatosis type II (NF-2). We aim to characterize unexplained imaging findings in the brains of patients with NF-2., Materials and Methods: This study is retrospective, HIPAA-compliant and approved by the institutional review board. 34 patients with NF-2 underwent brain magnetic resonance imaging (MRI) between January 2000 and December 2012. T2 and T1-weighted imaging characteristics, diffusion weighted imaging (DWI) characteristics, and enhancement patterns were analyzed by visual inspection. Clinical information at time of imaging was available for all patients. Neuropathologic data was available for one patient., Results: We found unexplained T2 hyperintensities present on initial imaging in 23/34 patients (67%). Of the 23 patients with unexplained MRI findings, 15 (65%) had wedge-shaped T2 hyperintensities in the subcortical white matter extending to the cortex suggestive of a cortical dysplasia. 3 additional cases (17%) had a lesion within the cerebellum suggestive of a neuronal migration anomaly. In one patient where the MRI was suggestive of focal cortical dysplasia, histopathologic analysis revealed dysplastic glial foci without other alterations of cortical architecture or other cytologic abnormalities., Conclusion: Unexplained T2 hyperintensities occur frequently in patients with NF-2. While they may not be the NF-2 equivalent of NF-associated bright spots seen in NF-1, some of these T2 hyperintensities in patients with NF-2 may represent underlying disorders of neuronal migration. Further studies are needed to validate our findings.

Background and Purpose: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease-severity score., Materials and Methods: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5-8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity., Results: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R2=0.76, P<.001)., Conclusions: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired.

Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, lysosomal storage disorder caused by mutations in the CLN2 gene, results in a deficiency of tripeptidyl-peptidase I (TPP-I) activity in neurons. Our prior studies showed that delivery of the human CLN2 cDNA directly to the CNS, using an adeno-associated virus serotype 2 (AAV2) vector, is safe in children with LINCL. As a second-generation strategy, we have demonstrated that AAVrh.10hCLN2, a rhesus-derived AAV vector, mediates wide distribution of TPP-I through the CNS in a murine model. This study tests the hypothesis that direct administration of AAVrh.10hCLN2 to the CNS of rats and nonhuman primates at doses scalable to humans has an acceptable safety profile and mediates significant CLN2 expression in the CNS. A dose of 10(11) genome copies (GC) was administered bilaterally to the striatum of Sprague Dawley rats with sacrifice at 7 and 90 days with no significant impact except for mild vector-related histopathological changes at the site of vector administration. A dose of 1.8×10(12) GC of AAVrh.10hCLN2 was administered to the CNS of 8 African green monkeys. The vector-treated monkeys did not differ from controls in any safety parameter except for mild to moderate white matter edema and inflammation localized to the administration sites of the vector. There were no clinical sequelae to these localized findings. TPP-I activity was >2 SD over background in 31.7±8.1% of brain at 90 days. These findings establish the dose and safety profile for human clinical studies for the treatment of LINCL with AAVrh.10hCLN2.

The number of high vocal center (HVC) neurons labeled in adult male canaries by systemic injections of [3H]thymidine depended on season and survival time. This was true for HVC neurons projecting to the robust nucleus of the archistriatum and for other HVC neurons that could not be retrogradely filled from the robust nucleus of the archistriatum. Birds injected in October and killed 40 days later had twice as many labeled HVC neurons as birds injected in May and killed 40 days later. However, this difference became much larger (5 times) when the birds were allowed to survive for 4 months. Whereas more than half of the spring-born neurons disappeared between 40 days and 4 months, there was no reduction in the number of fall-born neurons present at the 4-month survival point. We infer that seasonal variables affect the life span of HVC neurons born in adulthood.