Faculty Bibliography

PURPOSE/OBJECTIVE:To assess the potential biologic significance of variations in burst-suppression patterns (BSPs) after cardiac arrest in relation to recovery of consciousness. In the context of recent theoretical models of BSP, bursting frequency may be representative of underlying network dynamics; discontinuous activation of membrane potential during impaired cellular energetics may promote neuronal rescue. METHODS:We reviewed a database of 73 comatose post-cardiac arrest patients who underwent therapeutic hypothermia to assess for the presence of BSP and clinical outcomes. In a subsample of patients with BSP (n = 14), spectral content of burst and suppression periods were quantified using multitaper method. RESULTS:Burst-suppression pattern was seen in 45/73 (61%) patients. Comparable numbers of patients with (31.1%) and without (35.7%) BSP regained consciousness by the time of hospital discharge. In addition, in two unique cases, BSP initially resolved and then spontaneously reemerged after completion of therapeutic hypothermia and cessation of sedative medications. Both patients recovered consciousness. Spectral analysis of bursts in all patients regaining consciousness (n = 6) showed a prominent theta frequency (5-7 Hz) feature, but not in age-matched patients with induced BSP who did not recover consciousness (n = 8). CONCLUSIONS:The prognostic implications of BSP after hypoxic brain injury may vary based on the intrinsic properties of the underlying brain state itself. The presence of theta activity within bursts may index potential viability of neuronal networks underlying recovery of consciousness; emergence of spontaneous BSP in some cases may indicate an innate neuroprotective mechanism. This study highlights the need for better characterization of various BSP patterns after cardiac arrest.

Alzheimer's disease (AD) is the most common type of dementia in the elderly with no effective treatment currently. Recent studies of noninvasive neuroimaging, resting-state functional magnetic resonance imaging (rs-fMRI) with graph theoretical analysis have shown that patients with AD and mild cognitive impairment (MCI) exhibit disrupted topological organization in large-scale brain networks. In previous work, it is a common practice to threshold such networks. However, it is not only difficult to make a principled choice of threshold values, but also worse is the discard of potential important information. To address this issue, we propose a threshold-free feature by integrating a prior persistent homology-based topological feature (the zeroth Betti number) and a newly defined connected component aggregation cost feature to model brain networks over all possible scales. We show that the induced topological feature (Integrated Persistent Feature) follows a monotonically decreasing convergence function and further propose to use its slope as a concise and persistent brain network topological measure. We apply this measure to study rs-fMRI data from the Alzheimer's Disease Neuroimaging Initiative and compare our approach with five other widely used graph measures across five parcellation schemes ranging from 90 to 1,024 region-of-interests. The experimental results demonstrate that the proposed network measure shows more statistical power and stronger robustness in group difference studies in that the absolute values of the proposed measure of AD are lower than MCI and much lower than normal controls, providing empirical evidence for decreased functional integration in AD dementia and MCI.

OBJECTIVES/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C- reactive protein, yearly frequency of hyper-adrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body Mass Index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower Inspiratory Capacity (IC) (42.7% predicted vs 62.8% predicted; p=0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

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.

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

Bilateral thalamic strokes due to Artery of Percheron (AOP) occlusion are rare but have been previously reported in the literature. It is due to a rare anatomic variant where a solitary arterial trunk from the proximal segment of either posterior cerebral artery (PCA) supplies bilateral thalami and midbrain. Despite its description in the literature, these strokes are usually missed and patient's symptoms are not thought to be secondary to a vascular etiology. Through this report we aim to describe the clinical and radiographic features seen in these patients. We describe a series of 6 patients who present with varying levels of somnolence and oculomotor nerve palsies who had an occlusion of the AOP with bilateral thalamic infarcts with midbrain involvement. These clinical presentations, combined with the "V" sign on MRI are important in making the diagnosis.

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/OBJECTIVE:Patients with intracerebral hemorrhage (ICH) frequently present with hypertension, but it is unclear if this is due to pre-existing hypertension (prHTN) or to the bleed itself or associated pain. We sought to assess the relationship between prHTN and admission systolic blood pressure (aBP) and bleed severity. METHODS:We retrospectively assessed the relationship between prHTN and aBP and NIHSS in patients with ICH at 3 institutions. RESULTS:Of 251 patients, 170 (68%) had prHTN based on history of hypertension/antihypertensive use. Median aBP was significantly higher in those with prHTN (155 mm Hg (IQR 135-181) versus 139 mm Hg (IQR 124-158), P < .001). Patients with left ventricular hypertrophy (LVH) on electrocardiogram (ECG) or transthoracic echocardiogram (TTE) had significantly higher aBP than those without LVH (median aBP 195 mm Hg (IQR 155-216) for patients with LVH on ECG versus 147 mm Hg (IQR 129-163) for patients with no LVH on ECG, P < .001; median aBP 181 mm Hg (IQR 153-214) for patients with LVH on TTE versus 152 mm Hg (IQR 137-169) for patients with no LVH on TTE, P = .01). prHTN was associated with a higher median NIHSS (11 (IQR 3-20) for patients with history of hypertension/antihypertensive use versus 6 (IQR 1-14) for patients without this history (P = .02); 9 (IQR 3-19) versus 5 (IQR 2-13) for patients with/without LVH on ECG (P = .085); and 10 (IQR 5-18) versus 5 (IQR 1-13) for patients with/without LVH on TTE (P = .046). CONCLUSIONS:Patients with ICH who have prHTN have higher aBP and NIHSS, suggesting that prHTN may worsen reactive hypertension in the setting of ICH.

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.