John W. Gilbert

Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers

A pathological hallmark of Alzheimer’s disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40–42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer’s-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-β oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer’s disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-β oligomers on neurons—one that is central to the pathophysiological process in Alzheimer’s disease. Here we identify the cellular prion protein (PrPC) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPC is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

Phospholemman Is a Substrate for Myotonic Dystrophy Protein Kinase

The genetic abnormality in myotonic muscular dystrophy, multiple CTG repeats lie upstream of a gene that encodes a novel protein kinase, myotonic dystrophy protein kinase (DMPK). Phospholemman (PLM), a major membrane substrate for phosphorylation by protein kinases A and C, induces Cl currents (ICl(PLM)) when expressed in Xenopusoocytes. To test the idea that PLM is a substrate for DMPK, we measuredin vitro phosphorylation of purified PLM by DMPK. To assess the functional effects of PLM phosphorylation we compared ICl(PLM) in Xenopus oocytes expressing PLM alone to currents in oocytes co-expressing DMPK, and examined the effect of DMPK on oocyte membrane PLM expression. We found that PLM is indeed a good substrate for DMPK in vitro. Co-expression of DMPK with PLM in oocytes resulted in a reduction in ICl(PLM). This was most likely a specific effect of phosphorylation of PLM by DMPK, as the effect was not present in oocytes expressing a phos(−) PLM mutant in which all potential phosphorylation had been disabled by Ser → Ala substitution. The biophysical characteristics of ICl(PLM) were not changed by DMPK or by the phos(−) mutation. Co-expression of DMPK reduced the expression of PLM in oocyte membranes, suggesting a possible mechanism for the observed reduction in ICl(PLM) amplitude. These data show that PLM is a substrate for phosphorylation by DMPK and provide functional evidence for modulation of PLM function by phosphorylation.

Mice lacking synapsin III show abnormalities in explicit memory and conditioned fear

Synapsin III is a neuron‐specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety‐ and depressive‐like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 h and 10 days after training and in social transmission of food preference at 20 min and 24 h. In addition, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 h after conditioning. The synapsin III knockout mice also showed aberrant responses in fear‐potentiated startle. As synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders.

Atraumatic headache in US emergency departments: recent trends in CT/MRI utilisation and factors associated with severe intracranial pathology

Objectives To estimate recent trends in CT/MRI utilisation among patients seeking emergency care for atraumatic headache in the USA and to identify factors associated with a diagnosis of significant intracranial pathology (ICP) in these patients. Design/setting/participants Data were obtained from the USA National Hospital Ambulatory Medical Care Survey of emergency department (ED) visits between 1998 and 2008. A cohort of atraumatic headache-related visits were identified using preassigned ‘reason-for-visit’ codes. Sample visits were weighted to provide national estimates. Results Between 1998 and 2008 the percentage of patients presenting to the ED with atraumatic headache who underwent imaging increased from 12.5% to 31.0% (p<0.01) while the prevalence of ICP among those visits decreased from 10.1% to 3.5% (p<0.05). The length of stay in the ED was 4.6 h (95% CI 4.4 to 4.8) for patients with headache who received imaging compared with 2.7 (95% CI 2.6 to 2.9) for those who did not. Of 18 factors evaluated in patients with headache, 10 were associated with a significantly increased odds of an ICP diagnosis: age ≥50 years, arrival by ambulance, triage immediacy <15 min, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg and disturbance in sensation, vision, speech or motor function including neurological weakness. Conclusions The use of CT/MRI for evaluation of atraumatic headache increased dramatically in EDs in the USA between 1998 and 2008. The prevalence of ICP among patients who received CT/MRI declined concurrently, suggesting a role for clinical decision support to guide more judicious use of imaging.

A Duplication in Chromosome 4q35 Is Associated with Hereditary Benign Intraepithelial Dyskeratosis

Hereditary benign intraepithelial dyskeratosis (HBID) is an autosomal dominant disorder characterized by elevated epithelial plaques on the ocular and oral mucous membranes. It has been reported primarily, but not exclusively, in individuals of American Indian heritage in North Carolina. We have examined and obtained DNA on two large families affected by HBID. Using genetic linkage analysis we have localized the HBID gene to chromosome 4 (4q35) with a peak LOD score of 8.97. Molecular analysis of these data reveals that all individuals affected with HBID in both families demonstrate the presence of three alleles for two tightly linked markers, D4S1652 and D4S2390, which map to the telomeric region of 4q35. This suggests the presence of a duplication segregating with the disease phenotype that is most likely involved in its causation.

Loeys-Dietz syndrome: cardiovascular, neuroradiological and musculoskeletal imaging findings

Loeys-Dietz syndrome (LDS) is an increasingly recognized autosomal-dominant connective tissue disorder with distinctive radiological manifestations, including arterial tortuosity/aneurysms, craniofacial malformations and skeletal abnormalities. LDS exhibits a more aggressive course than similar disorders, such as Marfan or the vascular subtype of Ehlers-Danlos syndrome, with morbidity and mortality typically resulting from complications of aortic/arterial dissections. Early diagnosis, short-interval follow-up imaging and prophylactic surgical intervention are essential in preventing catastrophic cardiovascular complications. This review focuses on the cardiovascular, neuroradiological and musculoskeletal imaging findings in this disorder and recommendations for follow-up imaging.

Lumbar Stenosis Rates in Symptomatic Patients Using Weight-Bearing and Recumbent Magnetic Resonance Imaging

OBJECTIVE The purpose of this study was to determine the rate of lumbar stenosis detected via magnetic resonance imaging (MRI) in patients with symptomatic foraminal stenosis, lateral recess stenosis, or central stenosis. METHODS A retrospective review was performed on 1983 MRI scans from a 2-year period on 1486 symptomatic patients. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II; Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright sitting position using midfield (0.6 T) open Upright MRI (Fonar Corp, Melville, NY). In total, 986 serial scans (recumbent) and 997 serial scans (weight-bearing) were performed. RESULTS Of scans performed in the recumbent position, stenoses were identified in 382 scans (38.8%), central stenosis in 119 scans (12%), lateral recess stenosis in 91 scans (9.2%), and foraminal stenosis in 327 scans (33.2%). Of scans performed in a weight-bearing position, stenoses were identified in 565 scans (56.7%), central stenosis in 136 scans (13.6%), lateral recess stenosis in 206 scans (20.7%), and foraminal stenosis in 524 scans (52.6%). CONCLUSIONS The stenosis rates as indicated by MRI interpretation ranged between 38.5% (recumbent) and 56.7% (weight-bearing). These rates are higher than those reported in the medical literature for asymptomatic patients. Further study is needed to determine whether weight-bearing, compared with recumbent, MRI better informs the clinician in the diagnosis of spinal stenosis.

Lumbar Disk Protrusion Rates of Symptomatic Patients Using Magnetic Resonance Imaging

OBJECTIVE The purpose of this study was to determine the rate of disk protrusions detected via magnetic resonance imaging (MRI) in patients symptomatic for spine pain, radiculopathy, or other spine-related pain. METHODS A retrospective review of 1983 MRI scans was performed over a 2-year period on 1486 patients, each of whom was symptomatic for spine pain, radiculopathy, or other noncancer, spine-related pain. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II, Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright, sitting position using mid-field (0.6 T) open Upright MRI (Fonar, Melville, NY). In total, 986 serial scans were performed on patients in the recumbent position and 997 serial scans on patients in the weight-bearing position. RESULTS One or more disk protrusions were identified in 73.3% of scans performed in the sitting position and in 50.1% of scans performed in the recumbent position. Most disk protrusions occurred at L5-S1 (52.3% and 29.8%), L4-L5 (42.6% and 26.7%), and L3-L4 (26.7% and 13.1%) in upright and recumbent positions, respectively. CONCLUSIONS The disk protrusion rate in this group of patients ranged between 50.1% (recumbent) and 73.3% (weight-bearing). These rates are higher than rates reported in the medical literature for asymptomatic patients, a finding that supports the decision to further evaluate patients with persistent spine-related pain.

Suicidality in Chronic Noncancer Pain Patients

Patients with chronic pain have high rates of suicide. To examine whether our practice guidelines are effective in decreasing suicidality among chronic noncancer pain patients, we performed a retrospective review. From June 2003 through June 2005, approximately 50,000 patients were subjected to a set of universal precautions for chronic noncancer pain management. Approximately 20% underwent psychological assessments. Fewer than five suicide attempts could be identified, and no patient completed suicide. Our results suggest that universal precautions used in treating chronic noncancer pain patients may help reduce suicidality in this patient population.

Repeat Upright Positional Magnetic Resonance Imaging for Diagnosis of Disorders Underlying Chronic Noncancer Lumbar Pain

OBJECTIVE Cases of chronic noncancer pain are both the most frequent and the most difficult that the spine care professional is called upon to treat. We use this case to illustrate the potential effectiveness of repeat positional upright, weight-bearing magnetic resonance (MR) imaging to diagnose disorders and to detect changes in disorders. CLINICAL FEATURES We present the case of a 35-year-old man referred to our neurosurgical clinic with complaints of chronic, noncancer lower back pain and right-greater-than-left sciatica. Traditional recumbent MR imaging had revealed degenerative disk disease at L5-S1 and a 2.2-mm (grade 1) degenerative spondylolisthesis. The patient had not improved after more than a year of conservative treatments and, moreover, had been prescribed opiates for pain management that were potentially masking changes in his condition. INTERVENTION AND OUTCOMES After referral to our clinic, we ordered repeat lumbar MR imaging in an upright weight-bearing position (sitting) 14 months after the patients recumbent MR imaging. The weight-bearing MR imaging revealed a 9.13-mm (grade 1) degenerative spondylolisthesis at L5-S1. The patient underwent arthrodesis. His leg pain and back were significantly and clinically improved. CONCLUSION When patients with noncancer, lower back pain worsen, fail to improve, or require opiates to manage their pain, updated clinical diagnosis including repeat positional imaging may be an effective diagnostic strategy.