Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease.

Neurofibrillary tangles (NFTs), a marker of neuronal alterations in Alzheimer's disease (AD) and other tauopathies, are comprised of aggregates of hyperphosphorylated tau protein. We recently studied the formation of NFTs in the entorhinal cortex (EC) and their subsequent propagation through neural circuits in the rTgTauEC mouse model (de Calignon et al., 2012). We now examine the consequences of suppressing transgene expression with doxycycline on the NFT-associated pathological features of neuronal system deafferentation, NFT progression and propagation, and neuronal loss. At 21 months of age we observe that EC axonal lesions are associated with an abnormal sprouting response of acetylcholinesterase (AChE)-positive fibers, a phenotype reminiscent of human AD. At 24 months, NFTs progress, tau inclusions propagate to the dentate gyrus, and neuronal loss is evident. Suppression of the transgene expression from 18 to 24 months led to reversal of AChE sprouting, resolution of Gallyas-positive and Alz50-positive NFTs, and abrogation of progressive neuronal loss. These data suggest that propagation of NFTs, as well as some of the neural system consequences of NFTs, can be reversed in an animal model of NFT-associated toxicity, providing proof in principle that these lesions can be halted, even in established disease.

Intraspinal cervicothoracic junction chondrosarcoma: illustrative case.

BACKGROUND: Chondrosarcoma is an uncommon spinal tumor that can present as an extraskeletal mass. Rarely, these tumors present as dumbbell tumors through the neural foramina, mimicking schwannomas or neurofibromas. OBSERVATIONS: A 46-year-old female presented with 2 years of worsening right-arm radiculopathy. Magnetic resonance imaging of the thoracic spine revealed a peripherally enhancing extramedullary mass through the right T1 foramen and compressing the spinal cord. Computed tomography showed the mass to be partially calcified. She underwent C7-T2 laminectomy and C6-T3 posterior instrumented fusion with gross-total resection of an extradural mass. Pathology revealed a grade I chondrosarcoma. Her symptoms improved postoperatively, with some residual right-arm radicular pain. LESSONS: Intraspinal extradural dumbbell conventional chondrosarcoma is rare, with only 9 cases, including ours, reported. Patient ages range from 16 to 72 years old, and male sex is more common in these cases. The most common location is the thoracic spine, and our case is the only reported one in the cervicothoracic junction. These tumors often mimic schwannomas on imaging, but chondrosarcoma should remain in the differential diagnosis, because management of these tumors differs. Chondrosarcoma may benefit from more aggressive resection, including en bloc resection, and may require adjuvant radiotherapy.

Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-ß.

The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer's disease, but the link between this gene and neurodegeneration remains unclear. Using array tomography, we analysed >50000 synapses in brains of 11 patients with Alzheimer's disease and five non-demented control subjects and found that synapse loss around senile plaques in Alzheimer's disease correlates with the burden of oligomeric amyloid-ß in the neuropil and that this synaptotoxic oligomerized peptide is present at a subset of synapses. Further analysis reveals apolipoprotein E ε4 patients with Alzheimer's disease have significantly higher oligomeric amyloid-ß burden and exacerbated synapse loss around plaques compared with apolipoprotein E ε3 patients. Apolipoprotein E4 protein colocalizes with oligomeric amyloid-ß and enhances synaptic localization of oligomeric amyloid-ß by >5-fold. Biochemical characterization shows that the amyloid-ß enriched at synapses by apolipoprotein E4 includes sodium dodecyl sulphate-stable dimers and trimers. In mouse primary neuronal culture, lipidated apolipoprotein E4 enhances oligomeric amyloid-ß association with synapses via a mechanism involving apolipoprotein E receptors. Together, these data suggest that apolipoprotein E4 is a co-factor that enhances the toxicity of oligomeric amyloid-ß both by increasing its levels and directing it to synapses, providing a link between apolipoprotein E ε4 genotype and synapse loss, a major correlate of cognitive decline in Alzheimer's disease.

Real-life consequences of cognitive dysfunction in Parkinson's disease.

While motor symptoms are the most recognized features of Parkinson's disease (PD), cognitive dysfunction is a key determinant of consequences of PD in real-life. In this chapter we review important domains where cognitive dysfunction negatively impacts the lives of people with PD (PwPD), such as difficulties in occupational and social life, and instrumental ADLs such as driving. Early loss of employment has important effects for PwPD, their families, and society. PwPD experience higher rates of family and social discord as well as important changes in their social roles. These processes are largely mediated through cognitive dysfunction, particularly difficulties processing and understanding emotions, decreased attention, and executive dysfunction. Cognitive dysfunction is also an important mediator of driving impairments, which contributes to decreased independence in PwPD. Finally, we briefly review the costs associated with cognitive impairment in PD. Both indirect and direct costs for PwPD with cognitive impairment are substantially higher than for PwPD with normal cognition.

Non-Fibrillar Oligomeric Amyloid-ß within Synapses.

Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-ß (Aß) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aß associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aß and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aß oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aß inside synaptic terminals. Further, we tested a panel of Aß antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aß species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aß antibodies in brain tissue.

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes.

One of the hallmarks of Alzheimer's disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRDΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation.

Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration.

Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.

Tau-amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid-induced disruption of axonal projections and exacerbated axonal pathology.

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle-bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau-expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau-containing axons. Moreover, human P301L tau-containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau-containing neurons profoundly impacts their normal connectivity.

Studying synapses in human brain with array tomography and electron microscopy.

Postmortem studies of synapses in human brain are problematic because of the axial resolution limit of light microscopy and the difficulty in preserving and analyzing ultrastructure with electron microscopy (EM). Array tomography (AT) overcomes these problems by embedding autopsy tissue in resin and cutting ribbons of ultrathin serial sections. Ribbons are imaged with immunofluorescence, allowing high-throughput imaging of tens of thousands of synapses to assess synapse density and protein composition. The protocol takes ~3 d per case, excluding image analysis, which is done at the end of the study. Parallel processing for transmission electron microscopy (TEM) using a protocol modified to preserve the structure in human samples allows complementary ultrastructural studies. Incorporation of AT and TEM into brain banking is a potent way of phenotyping synapses in well-characterized clinical cohorts in order to develop clinicopathological correlations at the synapse level. This will be important for research in neurodegenerative disease, developmental disease and psychiatric illness.

Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice.

Although age remains the main risk factor to suffer Alzheimer's disease (AD) and vascular dementia (VD), type 2 diabetes (T2D) has turned up as a relevant risk factor for dementia. However, the ultimate underlying mechanisms for this association remain unclear. In the present study we analyzed central nervous system (CNS) morphological and functional consequences of long-term insulin resistance and T2D in db/db mice (leptin receptor KO mice). We also included C57Bl6 mice fed with high fat diet (HFD) and a third group of C57Bl6 streptozotocin (STZ) treated mice. Db/db mice exhibited pathological characteristics that mimic both AD and VD, including age dependent cognitive deterioration, brain atrophy, increased spontaneous hemorrhages and tau phosphorylation, affecting the cortex preferentially. A similar profile was observed in STZ-induced diabetic mice. Moreover metabolic parameters, such as body weight, glucose and insulin levels are good predictors of many of these alterations in db/db mice. In addition, in HFD-induced hyperinsulinemia in C57Bl6 mice, we only observed mild CNS alterations, suggesting that central nervous system dysfunction is associated with well established T2D. Altogether our results suggest that T2D may promote many of the pathological and behavioral alterations observed in dementia, supporting that interventions devoted to control glucose homeostasis could improve dementia progress and prognosis.

Successful treatment of primary pulmonary melanoma.

Presented is a rare case of a primary melanoma of the lung in an 89 year old male patient. Primary melanoma of the lung has been previously reported in the English literature in about 30 patients. Surgical resection either with lobectomy of pneumonectomy and a lymph node dissection has been shown to be the best chance of long term survival. This is the oldest patient on record where surgical resection was successful.

Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain.

Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Aß. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain.

Endoscopic hemostasis by using the TriClip for peptic ulcer hemorrhage: a pilot study.

BACKGROUND: The feasibility, efficacy, and safety of the TriClip in the management of peptic ulcer hemorrhage in human beings are scarcely reported in the literature. OBJECTIVE: A pilot study was conducted to assess the feasibility, efficacy, and safety of the TriClip endoscopic clipping device in the control of peptic ulcer hemorrhage. DESIGN: Prospective evaluation. SETTING: Regional government hospital. PATIENTS: From July 2004 to January 2005, patients older than 16 years and with Forrest type I and IIa peptic ulcer hemorrhages were included in the study. INTERVENTIONS: TriClips were used for initial hemostasis. Salvage procedures, including adrenalin injection, heat probe application, argon plasma coagulation, or surgery will be carried out appropriately if TriClip failed to control bleeding alone. An endoscopy was repeated 24 hours later for the security of the TriClip and for any endoscopic evidence of recurrent bleeding. A follow-up endoscopy was performed 8 weeks later to assess ulcer healing. MAIN OUTCOME MEASUREMENTS: Procedure time, successful hemostatic rate, number of clips used, ulcer recurrent bleeding rate, complications, and ulcer healing rate were measured. LIMITATIONS: No comparative arm; pilot study only. RESULT: A total of 27 cases (11 women, 16 men) were included in the study, with a median age of 70 years (range 18-88 years). There were 19 cases of duodenal ulcer and 8 cases of gastric ulcer, with median size of 8 mm (range 2-20 mm). The rate of successful hemostasis in the first endoscopy by TriClips alone was 81.5% (22/27), with a median procedure time of 10 minutes (range 3-30 minutes). In the second endoscopy, the endoscopic recurrent bleeding rate was 14.8% (4/27) and the TriClips were found dislodged in 11 patients (40.7%). The permanent hemostasis rate was 67% (18/27). The overall failure rate was 33% (9/27). Three patients required blood transfusion before the first endoscopy. There was no morbidity or mortality observed in all cases. All ulcers healed after 8 weeks. CONCLUSIONS: The use of the TriClip is feasible in the initial control of peptic ulcer hemorrhage. However, we could not detect any obvious advantages in arresting bleeding vessels by using this new clipping device.