ALZHEIMER’S DISEASE LINKED WITH VARIANTS IN UBQLN1

Variants in the UBQLN1 gene on chromosome 9q22 increase the risk of Alzheimer’s disease, according to Lars Bertram, MD, and colleagues. In a report in the March 3 New England Journal of Medicine, the researchers suggested that these genetic variants increase the risk of Alzheimer’s disease by influencing alternative splicing of the UBQLN1 gene in the brain.

Researchers evaluated 19 single-nucleotide polymorphisms in three genes (APBA1, UBQLN1, and ABCA1) within the chromosome 9q linkage region in 1,439 individuals from 437 families with Alzheimer’s disease (National Institute of Mental Health Genetics Initiative Alzheimer’s disease study sample). Next, they tested the single-nucleotide polymorphisms that had positive results in an additional set of 489 individuals from 217 sibling groups (Consortium on Alzheimer’s Genetics study sample). Researchers then assessed the functional effect of an implicated single-nucleotide polymorphism in the brain tissue of 25 patients with Alzheimer’s disease and 17 controls.

When evaluating the National Institute of Mental Health sample, Dr. Bertram and his colleagues observed a significant association between Alzheimer’s disease and various single-nucleotide polymorphisms in UBQLN1. These associations were confirmed in the Consortium on Alzheimer’s Genetics study sample. “The risk-conferring haplotype in both samples was defined by a single intronic, single-nucleotide polymorphism located downstream of exon 8,” researchers said. They also found increased levels of an alternatively spliced UBQLN1 transcript in RNA extracted from the brains of carriers of the UBQ-8i risk allele.

“Additional genetic studies involving both family-based and large case–control samples, along with more extensive functional testing of UBQLN1, will be required to characterize the potential effect of this gene on the risk of Alzheimer’s disease,” concluded the researchers.

Bertram L, Hiltunen M, Parkinson M, et al. Family-based association between Alzheimer’s disease and variants in UBQLN1. N Engl J Med. 2005;352:884-894.

MIGRAINE ASSOCIATED WITH RISK FACTORS FOR CARDIOVASCULAR DISEASE

Individuals with migraine, particularly with aura, have a higher cardiovascular risk profile than those without migraine, suggested a study in the February 22 Neurology.

Ann Scher, PhD, of Uniformed Services University of the Health Sciences and the National Institute on Aging in Bethesda, Maryland, and colleagues compared the cardiovascular risk profile of 620 adults with migraine to that of 5,135 adults without migraine. Of the participants with migraine, 31% had aura, 64% did not have aura, and 5% were unclassified. Overall, the mean age of the participants was 42, and 53% were female.

Researchers found that individuals with migraine were less likely to drink alcohol and to participate in sports, and were more likely to smoke cigarettes than were controls. In addition, those with migraine with aura had higher adjusted total cholesterol and lower adjusted high-density lipoprotein (HDL) levels, a higher total/HDL ratio, and higher diastolic blood pressure than controls.

Among women, those with migraine were more likely to report a history of gestational hypertension. Women with migraine with aura were also more likely to have high total cholesterol levels and to be current users of oral contraceptives than were the women without migraine.

Migraine was also found to be associated with parental history of early myocardial infarction. They said this finding “suggests the influences of genetic factors that predispose toward both migraine and coronary heart disease.”

Researchers noted that patients with migraine with aura who were 45 or younger were at increased risk of either coronary heart disease or stroke compared with controls. No increased risk was seen in patients with or without aura after age 45. Researchers said these findings are consistent with previous reports indicating associations between migraine with aura and early-onset stroke. “Understanding the role of classic risk factors for cardiovascular disease in migraine sufferers might help to understand why people with migraine with aura are at increased risk for early-onset stroke,” said Dr. Scher.

The researchers said they could not determine whether cardiovascular risk factors are modified by migraine or vice versa. “However, the practical implication of our findings should be noted. For reasons that are not yet clear, migraineurs—particularly those with aura—may be more likely to present with clinically relevant risk factors that are associated with cardiovascular disease,” they said.

“Further research is warranted to determine why migraineurs have these risk factors more frequently than nonmigraineurs and the nature of the additional mechanism that predisposes these individuals to early-onset cardiovascular disease,” Dr. Scher and her colleagues concluded.

Scher AI, Terwindt GM, Picavet HSJ, et al. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology. 2005;64:614-620.

“ZASPOPATHY”—A NOVEL FORM OF MUSCULAR DYSTROPHY

Researchers have identified a previously unknown form of muscular dystrophy, known as “zaspopathy,” according to a report in the February Annals of Neurology. According to Duygu Selcen, MD, and Andrew G. Engel, MD, “the spectrum of zaspopathy encompasses both distal and proximal myopathies, as well as cardiomyopathy and peripheral neuropathy.”

Drs. Selcen and Engel searched for mutations of the ZASP gene in 54 patients with myofibrillar myopathy with no mutations in desmin, αB-crystallin, or myotilin. They focused on ZASP for several reasons: (1) ZASP (a Z-band alternatively spliced PDZ motif-containing protein) is expressed in cardiac and skeletal muscle; (2) ZASP binds to α-actinin; (3) targeted deletion of ZASP in mice causes skeletal and cardiac myopathy; (4) mutations in ZASP cause dilated cardiac myopathy in humans; and (5) a dominant form of myofibrillar myopathy has been linked to the ZASP locus at chromosome 10q22.3-q23.2.

The researchers found three heterozygous mutations in 11 of the 54 patients. Ten of the 11 patients carried one of two mutations in exon 6—the A147T mutation was found in seven patients and the A165V mutation was found in three patients. One patient had the R268C mutation in exon 9. Of the 11 patients with mutations, nine were male and two were female. Age at onset of myofibrillar myopathy ranged from 44 to 73, and age at diagnosis ranged from 45 to 78. According to Drs. Selcen and Engel, “Seven patients had family histories consistent with autosomal dominant inheritance.”

The researchers also found that distal weakness was more predominant than proximal weakness in five patients, with one patient having only distal weakness. Two patients had only proximal weakness and three had both proximal and distal weakness. Cardiac involvement without signs of coronary artery disease was present in three patients. In addition, “peripheral nerve involvement by clinical, electromyographic, or histological criteria was present in five patients,” noted the researchers.

Drs. Selcen and Engel concluded that “the association of mutations in ZASP with a pathologically and clinically progressive myopathy warrants classifying zaspopathy as a muscular dystrophy.”

Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005;57:269-276.

ORAL TRANSMISSION OF BOVINE SPONGIFORM ENCEPHALOPATHY IN PRIMATES

A new study has provided insight into interspecies transmission of bovine spongiform encephalopathy (BSE). According to Corinne Ida Lasmézas, DrMedVet, of the Atomic Energy Commission in France, and colleagues, the incubation period for interspecies transmission of BSE can be more than a third longer than that of intraspecies transmission. Their study was published in the February 26 Lancet.

The researchers investigated oral transmission of BSE to two 4-year-old primates. The macaques were given a 5-g oral dose of brain homogenate from a BSE-infected cow. Macaques were chosen because they “have a digestive physiology similar to that of human beings, are methionine homozygous at codon 129 of the PRNP gene, and have a BSE neuropathology similar to that of variant Creutzfeldt-Jakob disease (vCJD).”

One macaque developed neurologic disease 60 months after exposure. “Histopathological examination of the brain of this animal showed the typical pathology of vCJD and an accumulation of PrP^res associated with the follicular dendritic cells in tonsils, spleen, and intestine. A western blot showed similar patterns of PrP^res,” said the researchers. The other macaque showed no clinical signs 76 months after exposure, and a tonsil biopsy taken at 72 months was negative.

Because two macaques in a previous study—which were given a 5-g dose of brain homogenate from a macaque with BSE—became ill after 44 and 47 months, the researchers suggested that the incubation period for interspecies transmission of BSE is significantly longer than that of intraspecies transmission. When comparing the 60-month incubation period in the present study to the 44- and 47-month incubation periods in the previous study, researchers found a 36% to 28% increase in the length of incubation periods for interspecies transmission.

The researchers also estimated that the efficiency of bovine-to-primate transmission is seven to 20 times lower than that of bovine-to-bovine transmission, suggesting an interspecies barrier. On the basis of their findings, the researchers extrapolated to human beings a maximum incubation period for transmission of BSE (50 years) and a predicted oral dose of BSE-infected tissue required for transmission (150 g).

Dr. Lasmézas and colleagues concluded that although their study does “not provide a definitive minimum infective dose for transmission of cattle BSE to primates,” it does offer enough data for a preliminary assessment of the adequacy of existing measures to protect the human food chain. “Our results provide reassurance that BSE screening procedures combined with central nervous system tissue removal are effective measures,” they added.

In an accompanying editorial, Mark W. Head and James W. Ironside said the study by Lasmézas et al is limited due to the small number of animals used, as well as the fact that “the level of infectivity in the inoculum was not titrated.”

They commented, “There remain fundamental problems about comparing likely human exposure to BSE with experiments of this type, even in primates that mimic vCJD pathology after oral BSE exposure. Multiple oral-exposure events over a period of years seem likely in the UK, and vCJD occurs predominantly in young adults, raising the possibilities of age-related susceptibility or exposure.” They also added that “more data will be forthcoming on some of these points from a larger primate study funded by the European Union, but it will be several years before they are likely to emerge.”

Head MW, Ironside JW. Mad cows and monkey business: the end of vCJD? Lancet. 2005;365:730-731.
Lasmézas CI, Comoy E, Hawkins S, et al. Risk of oral infection with bovine spongiform encephalopathy agent in primates. Lancet. 2005;365:781-783.

RADIOTHERAPY PLUS TEMOZOLOMIDE INCREASES SURVIVAL IN PATIENTS WITH GLIOBLASTOMA

The addition of a novel chemotherapy agent, temozolomide, to radiation therapy increases survival in patients with glioblastoma, according to Roger Stupp, MD, and colleagues. Furthermore, molecular analysis of tumors allows for the identification of patients most likely to benefit from this type of treatment. Results of their study were published in the March 10 issue of the New England Journal of Medicine.

A total of 573 patients with newly diagnosed glioblastoma were randomly assigned to receive radiotherapy alone or radiotherapy plus continuous daily temozolomide (75 mg/ m² of body surface area, from the first to the last day of radiotherapy) followed by six cycles of adjuvant temozolomide (150 to 200 mg/m² for five days during each 28-day cycle).

According to researchers, the patients who received radiotherapy plus temozolomide also concomitantly received “prophylaxis against Pneumocystis carinii pneumonia, consisting of either inhaled pentamidine or oral trimethoprim–sulfamethoxazole. Antiemetic prophylaxis with metoclopramide or a 5-hydroxytryptamine3 antagonist was recommended before the initial doses of concomitant temozolomide and was required during the adjuvant five-day courses of temozolomide,” they noted.

At a median follow-up of 28 months, the median survival was 14.6 months following treatment with radiotherapy plus temozolomide and 12.1 months following radiotherapy alone. The two-year survival rate was 26.5% following treatment with radiotherapy plus temozolomide and 10.4% following treatment with radiotherapy alone.

Researchers noted that during concomitant treatment with temozolomide, 7% of patients had any type of grade 3 or 4 hematologic toxic effect; during adjuvant treatment with temozolomide, 14% of patients had any type of grade 3 or 4 hematologic toxic effect.

Dr. Stupp and his colleagues concluded that “the addition of chemotherapy to radiotherapy significantly prolongs survival among patients with newly diagnosed glioblastoma, with a median increase in survival of 2.5 months or a relative reduction in the risk of death of 37%.”

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.

RASAGILINE AS AN ADJUNCTIVE TREATMENT FOR PATIENTS WITH PARKINSON'S DISEASE

Once-daily rasagiline reduces daily periods of poor or absent motor function and improves Parkinson’s symptoms in patients with motor fluctuations, an effect similar to that of therapy with entacapone, suggested a study in the March 12 Lancet.

Olivier Rascol, MD, and colleagues randomized 687 patients to receive oral rasagiline (1 mg once daily), entacapone (200 mg with every levodopa dose) or placebo for 18 weeks. Eighty-eight patients did not complete the study. According to the researchers, dopamine agonists were the most common class of concomitant drugs for Parkinson’s disease treatment, used in approximately 60% of patients. About 30% and 10% of patients used amantadine and anticholinergics, respectively.

Results indicated that both rasagiline and entacapone reduced periods of poor or absent motor function by more than one hour per day—almost three times more than the reduction seen with placebo—and increased periods of improved motor function, without raising the frequency of troublesome dyskinesia. Researchers also observed that treatment with rasagiline and entacapone was associated with mean improvements in Clinical Global Improvement scores and Unified Parkinson’s Disease Rating Scale scores for activities of daily living and motor function, compared with treatment with placebo.

The researchers concluded that rasagiline is effective and safe and is “a favorable candidate for the adjunct treatment of Parkinson’s disease.”

In an accompanying editorial, Carl E. Clarke questioned the reliability of the study results. “The treatment duration of 18 weeks is relatively short for this chronic disease…. 12 months’ follow-up would be more useful to assess long-term effects, such as tolerance, but keeping patients with deteriorating disease on placebo for this length of time is unethical,” wrote Dr. Clarke.

However, he noted that unlike many previous Parkinson’s disease trials that have focused on an unrepresentative young population of patients, more than 25% of the study participants in Dr. Rascol’s study were 70 or older. This “will be of particular interest to geriatricians because older patients with Parkinson’s disease are more likely to have adverse events with the addition of new medication,” he pointed out.

Clarke CE. Rasagiline for motor complications in Parkinson’s disease. Lancet. 2005;365:914-916.
Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet. 2005;365:947-954.

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