Postoperative Cognitive Dysfunction in Patients with Preoperative Cognitive Impairment: Which Domains Are Most Vulnerable?

Background: The authors explored the database of the first International Study of Postoperative Cognitive Dysfunction study to specify the domains of cognitive function that were most vulnerable and to determine the pattern of deterioration in patients with preoperative cognitive impairment.

Methods: One thousand two hundred eighteen patients were included in the first International Study of Postoperative Cognitive Dysfunction, where neuropsychological testing was performed at entry to the study, at 1 week, and at 3 months after surgery. The authors' analyses determined the extent to which seven neuropsychological measures changed after surgery with focus on the relation with preoperative cognitive impairment, defined as a preoperative score 1.5 SD below healthy controls in the memory test.

Results: Preoperative cognitive impairment was found in 74 patients at baseline. At 1 week, cognitive deterioration was seen in all tests, but in particular in the Letter Digit Coding and the time of the Stroop interference test, with 14% and 16% of the total sample (n = 1,016) exceeding 2 SD, respectively. At 3 months, deterioration was more uniform. Significantly fewer in the preoperative cognitive impairment group had deterioration in the memory test, both at 1 week and at 3 months, with no patient displaying a deterioration exceeding 2 SD.     

Construction and validation of a Parkinson's disease mutation genotyping array for the Parkin gene.

Parkin mutations account for the majority of familial and sporadic early onset Parkinson's disease (EOPD) cases with a known genetic association. More than 100 mutations have been described in the Parkin gene that includes homozygous, compound heterozygous, and single heterozygous mutations. We have designed a Parkin mutation genotyping array (gene chip) that includes published Parkin sequence variants and allows their simultaneous detection. The chip was validated by screening 85 PD cases and 47 controls previously tested for Parkin mutations. Similar genotyping microarrays have been developed for other genetically heterogeneous diseases including age-related macular degeneration. Here, we show the utility of a genotyping array for Parkinson's disease by analysis of 60 subjects from the Genetic Epidemiology of Parkinson Disease (GEPD) study that includes 15 early-onset PD case probands and 45 relatives.     

WAVE1 and regulation of actin nucleation in myelination.

The myelin sheath can be compared to the neuronal growth cone in that the unfurled sheath looks like a giant lamellum. The authors recently tested this hypothesis by examining the importance of WAVE1, a regulator of lamellipodia formation in neurons and other cells, in myelinogenesis. They found that WAVE1 is critical for formation of oligodendrocyte lamellae and myelin sheaths. They review the regulation of WAVE1 and how WAVE1 is transported and localized to lamellipodia. Because they found that some but not all myelination was impaired by knockout of WAVE1 function, they hypothesize that other regulators of actin nucleation help oligodendrocytes produce myelin in parallel with WAVE1 function. Interestingly, they found that oligodendrocyte maturation also is disturbed with WAVE1 knockout and propose that proper localization and transport of signaling molecules relevant to the integrin signaling cascade are disrupted by loss of WAVE1 function.     

Gonadal steroid preservation of central synaptic input to hamster facial motoneurons following peripheral axotomy

In recent work, we have demonstrated that testosterone propionate accelerates recovery from facial nerve injury in the adult male hamster. Central synaptic stripping following peripheral motor neuron damage is a well-established component of the injury response. Gonadal steroids regulate synaptogenesis in the normal nervous system. In this study, we tested the hypothesis that testosterone propionate administration at the time of facial nerve transection alters the synaptic connectivity of injured facial motoneurons. Adult hamsters were subjected to right facial nerve transection at the level of the stylomastoid foramen. Half the animals received subcutaneous implants of testosterone propionate; the other half were sham implanted. At 5 days postoperative, the animals were killed by intracardiac perfusion-fixation, and the control and axotomized facial nuclear groups from the brainstems of nonhormone- and testosterone propionate-treated animals processed for routine transmission electron microscopy. Quantiative analysis of the synaptic ratio (percent somal membrane covered by synaptic profiles) and the average length of axosomatic synapses was accomplished. The results indicate that axotomy alone resulted in an 81% reduction in the synaptic ratio and a 26% decrease in the average synaptic length of axosomatic synapses. Exposure to testosterone propionate from the time of facial nerve transection resulted in only a 48% reduction in the synaptic ratio and a 16% decrease in the average synaptic length of axosomatic synapses following injury. Thus, testosterone propionate significantly attenuated the amount of synaptic stripping that occurred at 5 days postoperative and the decrease in average length of the remaining synapses as well. It is concluded that gonadal steroids modulate central synaptic plasticity following peripheral nerve injury. The results are discussed in light of our recent findings of steroidal effects on the central astrocyctic response to facial nerve injury as well.     

Absence of structural alterations of the multidrug resistance genes in transitional cell carcinoma

Summary Tumor DNA from 27 patients with treated or untreated transitional cell carcinomas of the urinary tract was screened for genomic alterations of the multidrug resistance genes in order to determine whether structural changes of these genes are important in primary urothelial tumors. None of the tumors showed evidence of amplification or rearrangements of either mdr1 or mdr2. The lack of amplification or rearrangements observed in these tumors suggests that structural alterations of the mdr1 and mdr2 genes are not important mediators of drug resistance in TCC.Supported in part by grant CA-34775 from the National Institutes of Health and by a grant from the Heckscher Foundation for ChildrenDr. Klein is a fellow of the American Cancer Society