Faculty Bibliography

INTRODUCTION/BACKGROUND:Neighborhood deprivation is associated with shorter survival, cognitive impairment, and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS:= 161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS:Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION/CONCLUSIONS:Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis. CLINICAL TRIAL REGISTRATION INFORMATION/BACKGROUND:N/A.

INTRODUCTION/BACKGROUND:Neighborhood deprivation is associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS:We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn FTD Center. In a subset (n=161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS:Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION/CONCLUSIONS:Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.

Primary age-related tauopathy (PART) and Alzheimer's disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in ß-amyloid burden and degree of p-tau severity and spread. Thus, PART provides a human model to understand the mechanisms of age and amyloid-independent modifiers of p-tau. Given the dynamics of DNA methylation over the lifespan, we (1) performed an epigenome-wide association study of PART that nominated 13 loci associated with p-tau; (2) developed two novel epigenetic clocks predictive of p-tau in age-, and ß-amyloid-independent manners: "TauSeverity" relates hippocampal p-tau severity in PART and AD and synaptic transmission genes; "TauSpread" relates to p-tau spread to frontal cortex of AD and neuroinflammatory genes; and (3) a machine learning classifier that identifies low- and high resilience individuals with overlapping neuropathological features but distinct epigenetic, transcriptomic, and clinical features. We conclude that the epigenome contributes to the severity and spread of p-tau pathology, guided by distinct pathways with cognitive consequences.

Patients with myotonic disorders are at risk for severe generalized muscle contraction, referred to as a "myotonic crisis." For those patients with nondystrophic myotonia (NDM), the most common trigger of a myotonic crisis is exposure to succinylcholine. In this case, a 10-year-old female patient with NDM secondary to an SCN4A pathogenic variant developed a severe myotonic crisis in the setting of an upper respiratory infection and asthma flare treated with a beta-adrenergic agonist (ß-agonist). She presented with generalized rigidity and features of hypermetabolism resembling an anesthetic-related malignant hyperthermia. Management necessitated multidisciplinary collaboration, a complex intubation strategy, and an extended course in the pediatric intensive care unit. We suspected that this crisis was precipitated in part by continuous ß-agonist use during her initial asthma management. Treatments targeting sequential steps of the myocyte activation cascade tempered the contractile apparatus leading to clinical improvement in rigidity.

OBJECTIVE:The apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem-cell-derived neurons predisposes them to injury and promotes the release of phosphorylated tau. METHODS:Induced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types. RESULTS:Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform-dependent manner by a heparin sulfate proteoglycan-dependent mechanism. INTERPRETATION:Our results demonstrate that endogenous expression of E4 by stem-cell-derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms. Ann Neurol 2019;85:726-739.

The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration.