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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1-/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1-/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1-/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.

JC virus (JCV) is a human polyomavirus that infects the central nervous system (CNS) of immunocompromised patients. JCV granule cell neuronopathy (JCV-GCN) is caused by infection of cerebellar granule cells, causing ataxia. A 77-year-old man with iatrogenic lymphopenia presented with severe ataxia and was diagnosed with JCV-GCN. His ataxia and cerebrospinal fluid (CSF) improved with intravenous immunoglobulin, high-dose intravenous methylprednisolone, mirtazapine, and mefloquine. Interleukin-7 (IL-7) therapy reconstituted his lymphocytes and reduced his CSF JCV load. One month after IL-7 therapy, he developed worsening ataxia and CSF inflammation, which raised suspicion for immune reconstitution inflammatory syndrome. Steroids were restarted and his ataxia stabilized.

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 [NAD.sup.+]-synthetase activity. We generated a mouse model to mirror the human syndrome and found that [Nmnat2.sup.V98M/R232Q] compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in [Nmnat2.sup.V98M/R232Q] mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation., Introduction Axon loss is one of the earliest pathological hallmarks--and likely the initiating event--in many common neurodegenerative disorders (1-3). Programmed axon degeneration is an active, genetically encoded, subcellular, self-destruction pathway [...]

We report the capture of 10 Symphurus plagiusa (Blackcheek Tonguefish) in 2022 and 2023 at the northern end of their range. These specimens are the first records from the tidal Hudson River, and we document other tonguefish specimens from New York waters from previous records. We establish the identification of juveniles based on caudal fin ray counts and discuss the benefits of community education networks in detecting and monitoring fish species. [ABSTRACT FROM AUTHOR]

Collections of vertebrates and macroinvertebrates over two years from 26 lentic temporary water bodies each surveyed 1–4 times, in Ulster and Dutchess counties in the Hudson Valley of New York, USA, resulted in identifications of 166 species. These included species resident in temporary waters that have life stages resistant to drying and freezing, species that reproduce in temporary waters that need to mature before drying occurs, predatory species that visit temporary waters, and highly aquatic species that move overland to temporary waters. Temporary waters sampled had a range of hydroperiods from a few weeks to almost a year. Of the macroinvertebrates we identified to species, 75 were each collected in a single pool-survey (n = 62 pool-surveys). Pools with greater volume, more vegetation cover, lower pH and turbidity, and more sodium yielded greater species richness of macroinvertebrates, and species richness of certain taxa (eg Mollusca) were correlated with additional elements. We briefly discuss several unusual animal occurrences. [ABSTRACT FROM AUTHOR]

We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.SignificanceIt is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230-6. ©2016 AACR.See related commentary by Snyder and Wolchok, p. 1210This article is highlighted in the In This Issue feature, p. 1197.

Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal-dominant disorders of early to middle-age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl-terminus of three prime exonuclease-1 (TREX1), the major mammalian 3' to 5' DNA exonuclease on chromosome 3p21.1-p21.3, result in a systemic vasculopathy that follows an approximately 5-year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.