Trafficking of AMPA receptors (AMPARs) is regulated by specific interactions of the subunit intracellular C-terminal domains (CTDs) with other proteins, but the mechanisms involved in this process are still unclear. We have found that the GluR1 CTD binds to cGMP-dependent protein kinase II (cGKII) adjacent to the kinase catalytic site. Binding of GluR1 is increased when cGKII is activated by cGMP. cGKII and GluR1 form a complex in the brain, and cGKII in this complex phosphorylates GluR1 at S845, a site also phosphorylated by PKA. Activation of cGKII by cGMP increases the surface expression of AMPARs at extrasynaptic sites. Inhibition of cGKII activity blocks the surface increase of GluR1 during chemLTP and reduces LTP in the hippocampal slice. This work identifies a pathway, downstream from the NMDA receptor (NMDAR) and nitric oxide (NO), which stimulates GluR1 accumulation in the plasma membrane and plays an important role in synaptic plasticity.

Parkinson's disease (PD), a late-onset condition characterized by dysfunction and loss of dopaminergic neurons in the substantia nigra, has both sporadic and neurotoxic forms. Neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite 1-methyl-4-phenylpyridinium (MPP؉) induce PD symptoms and recapitulate major pathological hallmarks of PD in human and animal models. Both sporadic and MPP؉-induced forms of PD proceed through a ''dying-back'' pattern of neuronal degeneration in affected neurons, characterized by early loss of synaptic terminals and axonopathy. However, axonal and synaptic-specific effects of MPP؉ are poorly understood. Using isolated squid axoplasm, we show that MPP؉ produces significant alterations in fast axonal transport (FAT) through activation of a caspase and a previously undescribed protein kinase C (PKC␦) isoform. Specifically, MPP؉ increased cytoplasmic dynein-dependent retrograde FAT and reduced kinesin-1-mediated anterograde FAT. Significantly, MPP؉ effects were independent of both nuclear activities and ATP production. Consistent with its effects on FAT, MPP؉ injection in presynaptic domains led to a dramatic reduction in the number of membranous profiles. Changes in availability of synaptic and neurotrophin-signaling components represent axonal and synaptic-specific effects of MPP؉ that would produce a dying-back pathology. Our results identify a critical neuronal process affected by MPP؉ and suggest that alterations in vesicle trafficking represent a primary event in PD pathogenesis. We propose that PD and other neurodegenerative diseases exhibiting dying-back neuropathology represent a previously undescribed category of neurological diseases characterized by dysfunction of vesicle transport and associated with the loss of synaptic function.is the second most common neurodegenerative disease after Alzheimer's disease with 1% of people Ͼ50 and 5% of those Ͼ85 developing PD (1). First described in 1817, PD is associated with a dying back of axons projecting from substantia nigra pars compacta (SNpC) to the striatum. When Ͼ80% of striatal dopaminergic synapses from nigral neurons no longer function, a shortage of dopamine in the striatum causes the movement defects that characterize PD (2). Although the proximate cause of PD is well understood, molecular pathogenesis in PD remained unknown. Approximately 95% of PD cases are sporadic, with an undetermined fraction resulting from environmental factors like 1-methyl-4-phenylpyridinium (MPTP) and other toxins (3). Ideally, treatments that prevent loss of affected neurons and maintain neuronal function will be developed, but this requires a better understanding of underlying molecular pathogenesis in PD (2).PD is unique among adult-onset neurodegenerative diseases in the existence of toxin-mediated forms of the disease that mirror the neuropathology observed in sporadic PD. MPTP and its metabolite 1-methyl-4-phenylpyridinium (MPPϩ) is the best-characterized example of a toxin-induced PD (4), although others such as p...

Purpose To assess the diagnostic performance of the callosal angle (CA) and Evans index (EI) measures and to determine their role versus automated volumetric methods in clinical radiology. Materials and Methods Magnetic resonance (MR) examinations performed before surgery (within 1-5 months of the MR examination) in 36 shunt-responsive patients with normal-pressure hydrocephalus (NPH; mean age, 75 years; age range, 58-87 years; 26 men, 10 women) and MR examinations of age- and sex-matched patients with Alzheimer disease (n = 34) and healthy control volunteers (n = 36) were studied. Three blinded observers independently measured EI and CA for each patient. Volumetric segmentation of global gray matter, white matter, ventricles, and hippocampi was performed by using software. These measures were tested by using multivariable logistic regression models to determine which combination of metrics is most accurate in diagnosis. Results The model that used CA and EI demonstrated 89.6%-93.4% accuracy and average area under the curve of 0.96 in differentiating patients with NPH from patients without NPH (ie, Alzheimer disease and healthy control). The regression model that used volumetric predictors of gray matter and white matter was 94.3% accurate. Conclusion CA and EI may serve as a screening tool to help the radiologist differentiate patients with NPH from patients without NPH, which would allow for designation of patients for further volumetric assessment. RSNA, 2017.

Evidence suggests that normal pressure hydrocephalus (NPH) is underdiagnosed in day to day radiologic practice, and differentiating NPH from cerebral atrophy due to other neurodegenerative diseases and normal aging remains a challenge. To better characterize NPH, we test the hypothesis that a prediction model based on automated MRI brain tissue segmentation can help differentiate shunt-responsive NPH patients from cerebral atrophy due to Alzheimer disease (AD) and normal aging. Brain segmentation into gray and white matter (GM, WM), and intracranial cerebrospinal fluid was derived from pre-shunt T1-weighted MRI of 15 shunt-responsive NPH patients (9 men, 72.6 ± 8.0 years-old), 17 AD patients (10 men, 72.1 ± 11.0 years-old) chosen as a representative of cerebral atrophy in this age group; and 18 matched healthy elderly controls (HC, 7 men, 69.7 ± 7.0 years old). A multinomial prediction model was generated based on brain tissue volume distributions. GM decrease of 33% relative to HC characterized AD (P < 0.005). High preoperative ventricular and near normal GM volumes characterized NPH. A multinomial regression model based on gender, GM and ventricular volume had 96.3% accuracy differentiating NPH from AD and HC. In conclusion, automated MRI brain tissue segmentation differentiates shunt-responsive NPH with high accuracy from atrophy due to AD and normal aging. This method may improve diagnosis of NPH and improve our ability to distinguish normal from pathologic aging.

Purpose. We quantify the additional radiation exposure in terms of effective dose incurred by patients in the CT portion of SPECT/CT examinations. Methods. The effective dose from a variety of common nuclear medicine procedures is calculated and summarized. The extra exposure from the CT portion of the examination is summarized by examination and body part. Two hundred forty-eight scans from 221 patients are included in this study. The effective dose from the CT examination is also compared to average background radiation. Results. We found that the extra effective dose is not sufficient to cause deterministic effects. However, the stochastic effects may be significant, especially in patients undergoing numerous follow-up studies. The cumulative effect might increase the radiation exposure compared to patient management with SPECT alone. Conclusions. While the relative increase in radiation exposure associated with SPECT/CT is generally considered acceptable when compared with the benefits to the patient, physicians should make every effort to minimize this effect by using proper technical procedures and educating patients about the exposure they will receive.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration has been used, in various mammalian species, as an experimental model of Parkinson's disease. The pathogenesis for such pharmacologically induced Parkinson's disease involves 1-methyl-4-phenylpyridinium (MPP؉), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This metabolite produces rapid degeneration of nigrostriatal dopaminergic neurons, which causes the parkinsonian syndrome. In this work, we show that injection of MPP؉ into the presynaptic terminal of the squid giant synapse blocks synaptic transmission without affecting the presynaptic action potential or the presynaptic calcium currents. These effects of MPP؉ were mimicked by the injection of an active form of caspase-3 and prevented by inhibitors of caspase-3 and protein kinase C ␦. Ultrastructurally, MPP؉-injected synapses showed a dramatic reduction in the number of neurotransmitter vesicles at the presynaptic active zone, as compared with control synapses. Otherwise, normal docking and clathrincoated vesicles were observed, albeit at much reduced numbers. These results indicate that MPP؉ acutely reduces presynaptic vesicular availability, not release, and that MPP؉-induced pathogenesis results from presynaptic dysfunction that leads, secondarily, to dyingback neuropathy in affected neurons.

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BACKGROUND AND PURPOSE:Transmastoid sigmoid sinus wall reconstruction is a surgical technique increasingly used for the treatment of pulsatile tinnitus arising from sigmoid sinus wall anomalies. The imaging appearance of the temporal bone following this procedure has not been well-characterized. The purpose of this study was to evaluate the postoperative imaging appearance in a group of patients who underwent this procedure.