Metabolic disorders with clinical and radiologic features of sporadic Creutzfeldt-Jakob disease.

Two patients with metabolic disorders presented with clinical and radiologic features suggestive of sporadic Creutzfeldt-Jakob disease (sCJD). Case 1 was a 50-year-old man with rapid decline in cognitive, behavioral, and motor function following new-onset seizures. MRI was read as consistent with CJD, and he was referred for a treatment trial, but it was determined that he recently experienced rapid correction of hyponatremia resulting in extrapontine myelinolysis. Case 2 was a 66-year-old woman with poorly controlled diabetes mellitus who was found unconscious after a suspected insulin overdose. Examination showed altered mental status and neuroimaging was remarkable for cortical/striatal hyperintensities suggestive of sCJD. On autopsy, she had hypoglycemic/hypoxic nerve cell loss. Although characteristic MRI findings have high sensitivity and specificity for sCJD, potentially reversible metabolic disorders sometimes present rapidly and can resemble sCJD both clinically and radiologically. These cases highlight the importance of establishing a broad differential diagnosis when evaluating a patient with suspected sCJD.

Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: This NIH/National Institute on Aging-funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. RESULTS: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. CONCLUSION: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.

Differential diagnosis of Jakob-Creutzfeldt disease.

OBJECTIVES: To identify the misdiagnoses of patients with sporadic Jakob-Creutzfeldt disease (sCJD) during the course of their disease and determine which medical specialties saw patients with sCJD prior to the correct diagnosis being made and at what point in the disease course a correct diagnosis was made. DESIGN: Retrospective medical record review. SETTING: A specialty referral center of a tertiary academic medical center. PARTICIPANTS: One hundred sixty-three serial patients over a 5.5-year period who ultimately had pathologically proven sCJD. The study used the subset of 97 patients for whom we had adequate medical records. MAIN OUTCOME MEASURES: Other diagnoses considered in the differential diagnosis and types of medical specialties assessing patients with sCJD. RESULTS: Ninety-seven subjects' records were used in the final analysis. The most common disease categories of misdiagnosis were neurodegenerative, autoimmune/paraneoplastic, infectious, and toxic/metabolic disorders. The most common individual misdiagnoses were viral encephalitis, paraneoplastic disorder, depression, vertigo, Alzheimer disease, stroke, unspecified dementia, central nervous system vasculitis, peripheral neuropathy, and Hashimoto encephalopathy. The physicians who most commonly made these misdiagnoses were primary care physicians and neurologists; in the 18% of patients who were diagnosed correctly at their first assessment, the diagnosis was almost always by a neurologist. The mean time from onset to diagnosis was 7.9 months, an average of two-thirds of the way through their disease course. CONCLUSIONS: Diagnosis of sCJD is quite delayed. When evaluating patients with rapidly progressive dementia with suspected neurodegenerative, autoimmune, infectious, or toxic/metabolic etiology, sCJD should also be included in the differential diagnosis, and appropriate diagnostic tests, such as diffusion brain magnetic resonance imaging, should be considered. Primary care physicians and neurologists need improved training in sCJD diagnosis.

Pathologic evidence that the T188R mutation in PRNP is associated with prion disease.

Human prion diseases can be caused by mutations in the prion protein gene PRNP. Prion disease with mutations at codon 188 has been reported in 6 cases, but only 1 had the T188R mutation and it was not pathologically confirmed. We report the clinical, neuropsychologic, imaging, genetic, and neuropathologic features of a patient with familial Creutzfeldt-Jakob disease, associated with a very rare PRNP mutation at T188R. The patient presented with prominent behavioral changes in addition to the more typical cognitive and motorimpairments seen in sporadic Creutzfeldt-Jakob disease. The autopsy confirmed prion disease pathology. This case supports the pathogenicity of the T188 PRNP mutation, demonstrates the variability of clinical phenotypes associated with certain mutations, and emphasizes the importance of testing for genetic prion disease in cases of apparently sporadic atypical dementia.

Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt-Jakob disease.

Recent cases of prion transmission in humans following transfusions using blood donated by patients with asymptomatic variant Creutzfeldt-Jakob disease (CJD) implicate the presence of prion infectivity in peripheral blood. In this study, we examined the levels of the normal, cellular prion protein (PrPC), and the disease-causing isoform (PrPSc) in subpopulations of circulating white blood cells (WBCs) from patients with sporadic (s) CJD, age-matched neurological controls and healthy donors. Though widely distributed, the highest levels of PrPC were found in a subpopulation of T lymphocytes: approximately 12,000 PrPC molecules were found per CD4+CD45RA-CD62L- effector memory T helper cell. Although platelets expressed low levels of PrPC on their surface, their high abundance in circulation resulted in the majority of PrPC being platelet associated. Using quantitative fluorescence-activated cell sorting analysis, we found that neither WBC composition nor the amount of cell-surface PrPC molecules was altered in patients with sCJD. Eight different WBC fraction types from the peripheral blood of patients with sCJD were assessed for PrPSc. We were unable to find any evidence for PrPSc in purified granulocytes, monocytes, B cells, CD4+ T cells, CD8+ T cells, natural killer cells, nonclassical gamma delta T cells, or platelets. If human WBCs harbor prion infectivity in patients with sCJD, then the levels are likely to be low.

Enhanced neuronal excitability in rat CA1 pyramidal neurons following trace eyeblink conditioning acquisition is not due to alterations in I M.

Previous work done by our laboratory has demonstrated a reduction of the post-burst afterhyperpolarization (AHP) and accommodation following trace eyeblink conditioning in rabbit CA1 pyramidal neurons. Our laboratory has also demonstrated a reduction in the AHP in rat CA1 pyramidal neurons following spatial learning. In the current study we have extended our findings in rabbits by showing a reduction in both the AHP and accommodation in F344 X BN rat CA1 pyramidal neurons following acquisition of trace eyeblink conditioning. A component current of the AHP, I(M), was evaluated with a specific blocker of this current, and showed no apparent contribution to the learning-related increase in neuronal excitability. Rather, a reduction in an isoproterenol-sensitive component of the AHP, presumably sI(AHP), was observed to underlie the learning-specific change.

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning.

A common cellular alteration, reduced post-burst afterhyperpolarization (AHP) in CA1 neurons, is associated with acquisition of the hippocampus-dependent tasks trace eyeblink conditioning and the Morris water maze. As a similar increase in excitability is correlated with these two learning paradigms, we sought to determine the interactive behavioral effects of training animals on both tasks by using either a consecutive or simultaneous training design. In the consecutive design, animals were trained first on either the trace eyeblink conditioning task for six sessions, followed by training on the water maze task for six sessions, or vice versa. The simultaneous design consisted of six or 11 training days; animals received one session/day of both trace eyeblink conditioning and water maze training. Separate groups were used for consecutive and simultaneous training. Animals trained on both tasks simultaneously were significantly facilitated in their ability to acquire the trace eyeblink conditioning task; no effect of simultaneous training was seen on the water maze task. No effect was seen on acquisition for either task when using the consecutive training design. Taken together, these findings provide insight into how the hippocampus processes information when animals learn multiple hippocampus-dependent tasks.

GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator.

We previously created a monoclonal antibody (MAb), B6B21, that acts as a partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor [Moskal, J.R., Schaffner, A.E., 1986. Monoclonal antibodies to the dentate gyrus: immunocytochemical characterization and flow cytometric analysis of hippocampal neurons bearing a unique cell-surface antigen. J. Neurosci. 6, 2045-2053.]. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [(3)H]MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of NMDA receptor [Moskal, J.R., Yamamoto, H., Colley, P.A., 2001. The use of antibody engineering to create novel drugs that target N-methyl-d-aspartate receptors. Curr. Drug Targets 2, 331-345.]. Peptides that were able to increase [(3)H]MK-801 binding in a dose-dependent manner under these conditions were named Glyxins. Here we report that GLYX-13, a tetrapeptide (TPPT-amide), was found to readily cross the blood-brain barrier and modulate the NMDA receptor in a glycine-like fashion when examined pharmacologically and electrophysiologically. When GLYX-13 was administered to rats at 0.5-1.0mg/kg i.v., a significant enhancement in learning was observed using a hippocampus-dependent trace eye blink conditioning paradigm. These data indicate that the Glyxins are a new class of NMDA receptor modulators that may have therapeutic potential. Based on the broad agonist range in vitro and the potent cognitive-enhancing properties in a valid in vivo model of learning, GLYX-13 is a new drug candidate with potential for the treatment of cognitive disorders.

Watermaze learning enhances excitability of CA1 pyramidal neurons.

The dorsal hippocampus is crucial for learning the hidden-platform location in the hippocampus-dependent, spatial watermaze task. We have previously demonstrated that the postburst afterhyperpolarization (AHP) of hippocampal pyramidal neurons is reduced after acquisition of the hippocampus-dependent, temporal trace eyeblink conditioning task. We report here that the AHP and one or more of its associated currents (IAHP and/or sIAHP) are reduced in dorsal hippocampal CA1 pyramidal neurons from rats that learned the watermaze task as compared with neurons from control rats. This reduction was a learning-induced phenomenon as the AHP of CA1 neurons from rats that failed to learn the hidden-platform location was similar to that of neurons from control rats. We propose that reduction of the AHP in pyramidal neurons in regions crucial for learning is a cellular mechanism of learning that is conserved across species and tasks.