Faculty Bibliography

Background/UNASSIGNED:The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. Purpose/UNASSIGNED:In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. Methods/UNASSIGNED:In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. Results/UNASSIGNED:A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24-2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74-2.04)). Conclusions/UNASSIGNED:After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

PrP^Sc is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. PrP^Sc replicates by binding to the cellular conformer of the prion protein (PrP^C) expressed by host cells and rendering its secondary structure a likeness of itself. PrP^C is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since PrP^Sc engages PrP^C along this trafficking pathway, its replication process is often referred to as "recycling propagation." Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of PrP^Sc from prion-infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the PrP^Sc conformer and has been shown to permanently clear prion-infected cells from PrP^Sc presence. We determined that 6D11 mAb engages and sequesters PrP^C and PrP^Sc at the cell surface. PrP^C/6D11 and PrP^Sc/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent PrP^Sc back to the cell surface. Targeting PrP^Sc by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between PrP^Sc formation and degradation. Ongoing translation of PrP^C allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of PrP^Sc and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor-independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1^F/F; CDX2-cre) and crossed them with Apc^Min/+ mice (Apc^Min/+; Gfi1^F/F; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (Apc^Min/+; Gfi1^F/F; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon.Implications: These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis.

The authors describe the case of a 19-year-old female who suffered posttraumatic emphysema of the optic nerve sheath. She suffered massive head trauma requiring emergent neurosurgery and was incidentally found to have air in her optic nerve sheath on CT scan. At 6 weeks follow up, her visual acuity (20/25 uncorrected) and color perception in the affected eye were excellent. Her examination was notable for an afferent pupillary defect, mild disc pallor, and optic nerve atrophy on optical coherence tomography. This is a case of a patient with posttraumatic optic nerve sheath emphysema who recovered excellent visual function and received follow-up ophthalmic imaging.

AIM:This study aims to investigate selective attention in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. METHOD:The sample included 28 females with Rett syndrome (RTT) and 32 age-matched typically developing controls. We used a classic search task, in conjunction with eye-tracking technology. Each trial included the target and several distractors. The distractors varied in number and differed from targets in either a "single feature" (color or shape), creating a pop-out effect, or in a "conjunction of features" (color and shape), requiring serial search. Children searched for the target in arrays containing five or nine objects; trials ended when the target was fixated (or 4000 ms elapsed). RESULTS:Children with Rett syndrome had more difficulty finding the target than typically developing children in both conditions (success rates less than 50% versus 80%) and their success rates were little influenced by display size or age. Even when successful, children with RTT took significantly longer to respond (392 to 574 ms longer), although saccadic latency differences were observed only in the single-feature condition. Both groups showed the expected slowing of saccadic reaction times for larger arrays in the conjunction-feature condition. Search failures in RTT were not related to symptom severity. CONCLUSIONS:Our findings provide the first evidence that selective attention, the ability to focus on or select a particular element or object in the environment, is compromised by Rett syndrome. They reinforce the notion that gaze-based tasks hold promise for quantifying the cognitive phenotype of RTT.

BACKGROUND AND PURPOSE/OBJECTIVE:Impaired distal perfusion predicts neurological deterioration in large artery atherosclerosis. We aim to determine the optimal threshold of Tmax delay on perfusion imaging that is associated with neurological deterioration in patients with symptomatic proximal anterior circulation large artery stenosis. METHODS:Data were abstracted from a prospective ischemic stroke database of consecutively enrolled patients with symptomatic proximal intracranial stenosis (internal carotid artery or M1 segment of the middle cerebral artery) who underwent magnetic resonance perfusion imaging within 24 hours of symptom onset during a 15-month period. Tissue volumes of perfusion delay Tmax 0-4 seconds, Tmax > 4 seconds, Tmax > 6 seconds, and Tmax > 8 seconds were calculated using an automated approach. A target mismatch (penumbra-core) was defined as ≥15mL of brain tissue using each of the Tmax threshold categories. The outcome was neurological deterioration at 30 days defined as new or worsening neurological deficits that are not attributed to a nonvascular etiology. RESULTS:Among 52 patients with symptomatic intracranial stenosis, 26 patients met inclusion criteria. Neurological deterioration was associated with target mismatch profile defined according to Tmax > 6 seconds (66.7% [6/9] vs. 5.9% [1/17], P < .01) and Tmax >8 seconds (57.1% [4/7] vs. 15.8% [3/19], P = .05] but not according to Tmax > 4 seconds (27.3% [6/17] vs. 11.1% [1/9], P = .35]. CONCLUSIONS:A target mismatch profile using Tmax > 6 seconds may define tissue at risk in patients with acute symptomatic proximal anterior circulation intracranial stenosis. More studies are needed to confirm our findings.

Background and Purpose- It is uncertain whether heart transplantation decreases the risk of stroke. The objective of our study was to determine whether heart transplantation is associated with a decreased risk of subsequent stroke among patients with heart failure awaiting transplantation. Methods- We performed a retrospective cohort study using administrative data from New York, California, and Florida between 2005 and 2015. Individuals with heart failure awaiting heart transplantation were identified using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for heart failure in combination with code V49.83 for awaiting organ transplant status. Individuals with prior stroke were excluded. Our primary exposure variable was heart transplantation, modeled as a time-varying covariate and defined by procedure code 37.51. The primary outcome was stroke, defined as the composite of ischemic and hemorrhagic stroke. Survival statistics were used to calculate stroke incidence, and Cox proportional hazards analysis was used to determine the association between heart transplantation and stroke while adjusting for demographics, stroke risk factors, Elixhauser comorbidities, and implantation of a left ventricular assist device. Results- We identified 7848 patients with heart failure awaiting heart transplantation, of whom 1068 (13.6%) underwent heart transplantation. During a mean follow-up of 2.7 years, we identified 428 strokes. The annual incidence of stroke was 0.7% (95% CI, 0.5%-1.0%) after heart transplantation versus 2.4% (95% CI, 2.2%-2.6%) among those awaiting heart transplantation. After adjustment for potential confounders, heart transplantation was associated with a lower risk of stroke (hazard ratio, 0.4; 95% CI, 0.2-0.6). Conclusions- Heart transplantation is associated with a decreased risk of stroke among patients with heart failure awaiting transplantation.

With the rapid growth of modern technology, many biomedical studies are being conducted to collect massive datasets with volumes of multi-modality imaging, genetic, neurocognitive, and clinical information from increasingly large cohorts. Simultaneously extracting and integrating rich and diverse heterogeneous information in neuroimaging and/or genomics from these big datasets could transform our understanding of how genetic variants impact brain structure and function, cognitive function, and brain-related disease risk across the lifespan. Such understanding is critical for diagnosis, prevention, and treatment of numerous complex brain-related disorders (e.g., schizophrenia and Alzheimer's disease). However, the development of analytical methods for the joint analysis of both high-dimensional imaging phenotypes and high-dimensional genetic data, a big data squared (BD2) problem, presents major computational and theoretical challenges for existing analytical methods. Besides the high-dimensional nature of BD2, various neuroimaging measures often exhibit strong spatial smoothness and dependence and genetic markers may have a natural dependence structure arising from linkage disequilibrium. We review some recent developments of various statistical techniques for imaging genetics, including massive univariate and voxel-wise approaches, reduced rank regression, mixture models, and group sparse multi-task regression. By doing so, we hope that this review may encourage others in the statistical community to enter into this new and exciting field of research.