Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion.

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell­derived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels. Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

Cervical Diastematomyelia: A Case Presentation and Systematic Review.

Diastematomyelia is a rare congenital disorder characterized by the separation of the spinal cord by an osseocartilaginous or fibrous septum. While diastematomyelia has been reported to be more common in the thoracic and lumbar regions, the true incidence of cervical diastematomyelia is currently unknown. In this study, we conducted the most comprehensive systematic review to date of all other case reports of diastematomyelia to better characterize the incidence of cervical diastematomyelia and provide comprehensive statistics on the clinical characteristics of diastematomyelia generally. Ninety-one articles were included in our study, which comprised 252 males (27.9%) and 651 females (72.0%) (and one patient with unspecified gender). In 507 cases, the vertebral level of the diastematomyelia was described, and we recorded those levels as either cervical ( n = 8, 1.6%), thoracic ( n = 220, 43.4%), lumbar ( n = 277, 54.6%), or sacral ( n = 2, 0.4%). In 719 cases, the type of diastematomyelia was specified as either Type I ( n = 482, 67.0%) or Type II ( n = 237, 33.0%). Our study found that diastematomyelia has been reported in the cervical region in only 1.6% of cases, and we provide comprehensive data that this disorder occurs in female-to-male ratio of approximately 2.6:1 and Type I versus Type II diastematomyelia in an estimated ratio of 2:1.

Hearing preservation outcomes using direct cranial nerve eight and auditory brainstem response neuromonitoring in the resection of vestibular schwannomas.

OBJECTIVE: Advancements in microsurgical technique and technology continue to improve outcomes in patients with skull base tumor. The primary cranial nerve eight monitoring systems used in hearing preservation surgery for vestibular schwannomas (VSs) are direct cranial nerve eight monitoring (DCNEM) and auditory brainstem response (ABR), although current guidelines are unable to definitively recommend one over the other due to limited literature on the topic. Thus, further research is needed to determine the utility of DCNEM and ABR. The authors performed a retrospective cohort study and created an interactive model that compares hearing preservation outcomes based on tumor size in patients receiving ABR+DCNEM and ABR-only monitoring. METHODS: Twenty-eight patients received ABR+DCNEM and 72 patients received ABR-only monitoring during VS hearing preservation surgery at a single tertiary academic medical center between January 2008 and November 2022. Inclusion criteria consisted of adult patients with a preoperative American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification of A or B. Tumor size was measured as the maximal medial to lateral length, including the internal auditory canal component. RESULTS: Overall hearing preservation (word recognition score [WRS] > 0%) was achieved in 31 patients with ABR-only monitoring (43.1%) and in 18 patients with ABR+DCNEM (64.3%). Serviceable hearing preservation (AAO-HNS class A or B) was attained in 19 patients with ABR-only monitoring (26.4%) and in 11 patients with ABR+DCNEM (39.3%). There was no difference in overall hearing preservation between the two groups (p = 0.13). Change in tumor size was not associated with the odds of serviceable hearing preservation for the ABR-only group (p = 0.89); however, for ABR+DCNEM, there was some indication of an interaction between tumor size and the association of ABR+DCNEM versus ABR-only monitoring, with the odds of serviceable hearing preservation at p = 0.089. Furthermore, with ABR+DCNEM, every 0.5-cm increase in tumor size was associated with a decreased odds of serviceable hearing preservation on multivariable analysis (p = 0.05). For both overall and serviceable hearing preservation, a worse preoperative AAO-HNS classification was associated with a decreased odds of preservation (OR 0.43, 95% CI 0.19-0.97, p = 0.042; OR 0.17, 95% CI 0.053-0.55, p = 0.0031, respectively). CONCLUSIONS: The result of this interactive model study proposes that there may be a higher chance of hearing preservation when using ABR+DCNEM rather than ABR alone for smaller tumors, with that relationship reversing as tumor size increases.

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early-onset psychosis.

CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain-1 function. Here we illustrate a translational approach to the case of an 18-year-old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound-heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop-gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain-1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.