June 2005 • www.clinicalpsychiatrynews.com Neuropsychiatric Medicine 59 MRI Opens Thrombolysis Window After Stroke

BY MITCHEL L. ZOLER rhage. Desmoteplase also has very high specifici- Philadelphia Bureau ty and selectivity for fibrin and a long serum half- life of 4 hours. This last property means that it can N EW O RLEANS — The presence of a favorable pat- be given as a bolus dose and may also help pre- tern of cerebral perfusion on magnetic resonance imag- vent acute reocclusion of newly opened arteries. ing may tell physicians which patients with acute ischemic Desmoteplase is being developed in the United stroke stand to benefit from thrombolysis even hours af- States by Forest Laboratories and in Europe by ter the onset of symptoms. PAION, a German drug company. Dr. Furlan is a Findings from two phase II studies using MRI show that consultant to both companies, and he received some patients were able to safely receive a thrombolytic compensation from both for acting as a principal drug as long as 9 hours after the onset of their stroke investigator in these and ongoing studies. symptoms. Results from the most recent of these stud- The U.S. study involved enrollment of 37 pa- ies were reported at the 30th International Stroke Con- tients who all met the entry MR criteria. After ference. randomization, 14 of the patients were treated Results from the prior study, which was conducted in with 90 mcg/kg desmoteplase, 15 received 125 NIVERSITY

Europe, were published in January. mcg/kg desmoteplase, and 8 received placebo. U

“These are the first trials to test the hypothesis that se- The average time to treatment was 7 hours. Al- ON lecting patients with favorable imaging patterns can ex- though patients could enter treatment as long as tend treatment beyond the current 3-hour window,” said 9 hours after the onset of their stroke symptoms, ASHINGT W T

Anthony J. Furlan, M.D., head of the section of stroke and the top reason for excluding patients from the A neurologic intensive care at the Cleveland Clinic and prin- study was that they had gone beyond the 9-hour cipal investigator of the new study. window. ENTER “If this hypothesis is borne out, it could have an enor- The U.S. study’s primary end point was the rate C

mous impact on how we use thrombolytic therapy for of symptomatic, intracranial hemorrhage (sICH), TROKE stroke,” he added. “It has the potential to at least triple which occurred in none of the patients. In the pri- S the number of acute stroke patients who are eligible for or European study, one sICH occurred among 15 NTERNET thrombolytic therapy.” patients treated with 90 mcg/kg and none among I Like the study done in Europe, Dr. Furlan’s research 15 patients treated with 125 mcg/kg. Thus, the In this T1-weighted MRI, a large infarct is clearly visible in used a combination of perfusion-weighted and diffusion- overall rate of sICH in these two studies at these the middle cerebral artery of an 18-year-old woman. weighted imaging by MR to identify patients with at two doses was one among 59 treated patients, a least a 20% mismatch between the two. 1.7% rate that was lower than the 6% rate with TPA in and 60% of those in the high-dose arm. There was no The mismatch is a marker for patients with a signifi- routine practice, noted Dr. Furlan at the conference, spon- reduction of safety or efficacy in the patients treated 6- cant penumbra region in their brain, tissue that might be sored by the American Stroke Association. 9 hours after their stroke onset, compared with those salvageable by thrombolytic therapy because it is still vi- In the European study, 30 patients received substantially treated 3-6 hours after onset, Dr. Furlan reported. able despite being hypoperfused. “Most patients who higher doses of desmoteplase, and they had a 27% rate The results were promising enough for a phase III study made it to MR were eligible,” Dr. Furlan said. “The MR of sICH. In this higher-dose group, the lowest to start this spring, retesting both desmoteplase doses criteria did not exclude a lot of patients.” desmoteplase dose associated with intracranial hemor- against placebo in a total of 186 patients, Dr. Furlan said. The other novel feature of both the European and U.S. rhage was 294 mcg/kg. The next study will also test perfusion CT imaging as well studies was the thrombolytic drug used: desmoteplase, a The new study was not powered to show significant dif- as MR imaging because some centers have easier access plasminogen activator derived from vampire bat saliva. ferences in clinical outcomes. to CT scanners. Desmoteplase has several potential advantages over tissue The reperfusion rate was 38% in the control group, If study results continue to document the safety and plasminogen activator (TPA). 18% among those who received 90 mcg/kg, and 53% efficacy of desmoteplase paired with imaging to identi- In animal studies, desmoteplase showed no neurotox- among those who received 125 mcg/kg. Improved clin- fy appropriate patients, eventually desmoteplase will icity, and it did not activate β-amyloid, a process that’s ical outcomes at 90 days were seen in 25% of those in have to be compared with TPA in a head-to-head study, been linked to an increased risk of intracranial hemor- the placebo group, 29% of those in the low-dose arm, he said. I Genetic Variant Increases Risk of Late-Onset Alzheimer’s

BY SUSAN The mean age at disease onset was 72 Findings from the second investigation, sage. They found a relationship between LAWRENCE VOLKMAR years, the investigators said (N. Engl. J. the Consortium on Alzheimer’s Genetics the UBQ-8i allele and a UBQLN1 transcript Contributing Writer Med. 2005;352:884-94). study, showed that the rate of transmis- lacking exon 8 in the 25 samples from pa- Evaluation of 19 single-nucleotide poly- sion of the H3 haplotype was increased tients with Alzheimer’s disease. trategies for the prevention and treat- morphisms in three within the chro- among subjects with Alzheimer’s disease. In an accompanying editorial, Thomas Sment of late-onset Alzheimer’s disease mosome 9q linkage region showed that Investigators found no association with D. Bird, M.D., called UBQLN1 “intriguing may be improved by the identification of Alzheimer’s disease was significantly as- rs1411483 in APBA1. as a candidate because of its poten- a gene variant that seems to increase sociated with two single-nucleotide poly- Specimen collection began in 1999 and tial role in the degradation of Alzheimer’s disease, according to a report morphisms in UBQLN1 and one in APBA1. has been completed for 224 Alzheimer’s and its interaction with PS1 and by Lars Bertram, M.D., of MassGeneral Haplotype block patients and 265 un- PS2.” Institute for Neurodegenerative Diseases, structure estimates Most genetic analyses of affected siblings. Af- “As always, this new association requires Charlestown, Mass., and his associates. showed that the sin- fected participants replication and confirmation in addition- Variants in the ubiquilin 1 (UBQLN1) gle haplotype (H3), Alzheimer’s were at least 50 years al populations,” commented Dr. Bird, gene, located on 9, may almost exclusively have been done on groups old at disease onset; who is professor of neurology, medicine, substantially increase the risk of late-on- defined by the risk mean age at onset and psychiatry at the University of Wash- set Alzheimer’s disease, which accounts allele of UBQ-8i, was too small to demonstrate was 71 years. ington, Seattle, and a research neurologist for over 90% of the disease, other inves- associated with a sig- moderate genetic effects Analyses by Dr. at the Veterans Affairs Medical Center in tigators have reported. nificantly increased Bertram and col- Seattle (N. Engl. J. Med. 2005;352:862-4). Dr. Bertram and his associates examined rate of transmission like that of UBQLN1. leagues on data Dr. Bertram’s group observed that “the two groups of patients; the first consisted to affected subjects. merged from the two rampant inconsistencies encountered in of 1,439 subjects from 437 families with The testing of APBA1 polymorphisms did family groups showed the most pro- genetic analyses of putative candidate Alzheimer’s disease who participated in not indicate such transmission. nounced single-local signals for UBQ-8i genes for Alzheimer’s disease in the liter- the National Institute of Mental Health Ubiquilin 1 encodes the followed by rs2781002 and rs2780995. ature to date” may stem from the fact that multiplex family study between 1991 and ubiquilin 1, regulates protein degradation, Dr. Bertram’s group also studied RNA most studies are done on groups too 1997. Of that group, 994 patients had interacts with 1 and presenilin extracts from neocortical brain tissue sam- small to show moderate genetic effects Alzheimer’s, 411 were unaffected, and 34 2, and promotes the accumulation of pre- ples to see if the risk allele UBQ-8i affects like that of UBQLN1, instead of the more had unknown phenotypes. senilin in vitro, they said. the splicing of exon 8 in the UBQLN1 mes- pronounced effects of APOE. I