Despite recognition that Alzheimer's disease (AD) is a polygenic and heterogeneous dementing neurodegenerative disorder, there is continued merit in defining the AD phenotype by the presence of progressive cognitive impairments and the pathological brain lesions (senile plaques, neurofibrillary tangles) as originally formulated by Alois Alzheimer. This position paper discusses the rationale for emphasizing the detection of both beta amyloid-rich plaques and tau-rich tangles in the next iteration of the neuropathological criteria for the postmortem diagnosis of AD that has been recommended by the Working Group on Consensus Criteria for the Postmortem Diagnosis of AD. Further, it also underlines the need to exploit continuing advances in understanding the pathobiology of plaques and tangles in subsequent iterations of these criteria. It is expected that such efforts, now and in the future, will hasten the development of strategies for the early and accurate antemortem diagnosis of AD as well as the discovery of effective treatments for this common dementing illness of the elderly.

Aged↗

PubMedDate not supplied

Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders.

The presence of the biomarkers of oxidative damage, protein carbonyl formation and the inactivation of oxidatively sensitive brain creatine kinase (CK BB, cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from patients with different age-related neurodegenerative diseases: Alzheimer's disease (AD), Pick's disease (PkD), diffuse Lewy body disease (DLBD), Parkinson's disease (PD), and age-matched control subjects. The CK activity was significantly reduced in the frontal lobe of AD, PkD and DLBD subjects, and CK BB-specific mRNA was significantly reduced in AD and DLBD. Protein carbonyl content was significantly increased in AD, PkD and DLBD. The results of this study confirm that the presence of biomarkers of oxidative damage is related to the presence of histopathological markers of neurodegeneration. Our data suggest that oxidative damage contributes to the development of the symptoms of frontal dysfunction in AD, PkD and DLBD. The development of frontal dysfunction in idiopathic PD might be secondary to oxidative damage and neuronal loss primarily located in the nigrostriatal system. The results of CK BB expression analysis demonstrate that the loss of the isoenzyme in different neurodegenerative diseases is likely the consequence of its posttranslational modification, possibly oxidative damage. Changes in CK BB expression may be an early indicator of oxidative stress in neurons.

Aged↗

PubMedDate not supplied

Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the novoseven emergency-use program.

Activated recombinant human coagulation factor VII (rFVIIa) is a promising new therapeutic agent for patients with hemophilia A or B with inhibitors who experience serious bleeding episodes or who need coverage during surgical procedures. This open-label, uncontrolled, emergency-use study evaluated the efficacy and safety of rFVIIa in 11 hemophiliac patients and 1 FVII-deficient patient with life-threatening intracranial hemorrhage previously unresponsive to one or more alternative therapies. rFVIIa effectively controlled intracranial hemorrhage in 10 of the 12 patients. Patients with hemophilia A or B received an average of 96.9 rFVIIa injections over 14.7 days with a mean total administration of 153.3 mg, corresponding to 8.1 mg/kg. Most reported adverse events were considered to be unrelated to rFVIIa therapy. These findings suggest that rFVIIa is an effective and well-tolerated therapeutic option in the management of central nervous system bleeding in patients with hemophilia A or B with inhibitors.

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PubMedDate not supplied

Evidence for molecular heterogeneity in human ganglioneuroblastoma.

Ganglioneuroblastomas are tumors of sympathetic cell origin that contain both primitive neuroblastomatous and mature ganglioneuromatous elements. It is thought that these tumors arise from a single cellular clone and that the morphologically distinct components of ganglioneuroblastomas represent cells in different stages of differentiation. Two pathologic variants of this tumor, composite and diffuse, have been described; metastasis is more commonly seen with composite ganglioneuroblastomas. We analyzed a composite ganglioneuroblastoma for N-myc copy number at initial resection and 2 years later after progressive disease. In the second sample the more differentiated portion of the tumor was analyzed separately from the neuroblastic foci for N-myc copy number and DNA ploidy. The DNA content and N-myc copy number differed in the two morphologically discrete areas of the tumor, suggesting that at least two clones were present. More composite ganglioneuroblastomas need to be examined to determine whether these tumors are largely composed of tumor cell populations with molecular heterogeneity.

Aneuploidy↗