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Kumar et al. carried out a series of experi-ments in mice with JEV or WNV encephalitis. The researchers identified a cross-species conserved sequence within the region encoding domain II of the viral envelope protein that, when targeted with a synthetic siRNA (siFvEJW), resulted in protection against encephalitis from either JEV or WNV.

Mice were given a single intracranial injection of siFvEJW or control siRNA (siLuc) 30 min or 6 h after intracranial injection with JEV or WNV. All control mice died, whereas all mice given an siFvEJW injection 30 min after flavivirus infec-tion survived. Of the mice injected with siFveJW 6 h after infection, 100% of those administered WNV survived, and 80% of those challenged with JEV survived.

The authors suggest that siRNA has the potential to be developed into a therapeutic drug for flavivirus-induced encephalitis. They note, however, that improved delivery methods are needed to ensure that siRNA is present throughout the brain, to combat the spread of virus that has occurred by the time clinical symptoms are evident.

Christine Kyme

Original article Kumar P et al. (2005) A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Medicine 3: e96

Safety of clopidogrel in children with arterial ischemic stroke

Antiplatelet therapy with aspirin is widely used for the secondary prevention of stroke in patients who have experienced an arterial ischemic stroke (AIS). Long-term use of aspirin, how-ever, can cause gastric and respiratory adverse effects, and resistance to therapy often occurs. Researchers in Canada have investigated the safety and toler ability of clopidogrel, an alternative antiplatelet treatment, in children with AIS.

This study included 17 children (mean age 8.8 years) recruited at time of initial AIS diag-nosis. Children in whom aspirin intolerance or failure occurred began clopidogrel therapy; eight children received clopidogrel alone and seven received clopidogrel in conjunction with aspirin.

No major side effects were reported during clopidogrel treatment alone. Complications were reported in four patients, but two of these—hand numbness and headaches—were unlikely to be clopidogrel-related, as they started before

clopi dogrel treatment commenced, and per-sisted when clopidogrel was discontinued. Two patients on clopidogrel plus aspirin suf-fered intracranial hemorrhage. Both of these patients had potential risk factors for hemor-rhage—one patient had undergone surgery recently and the other had hypertension, and both had cerebral atrophy.

The authors conclude that clopidogrel seems to be well tolerated in children resistant to aspirin, but that the combination of aspirin plus clopi dogrel should be used with caution in children who have risk factors for hemorrhage. AIS did not recur in any patient in the study, but no conclusions can be drawn from this as the sample size was small and the study was not designed to assess effectiveness of clopidogrel in stroke prevention.

Rebecca Ireland

Original article Soman T et al. (2006) The risks and safety of clopidogrel in pediatric arterial ischemic stroke. Stroke 37: 1120–1122

An amyloid-β protein assembly in the brain is linked with impaired memory

In a letter published in Nature, Lesné and co-workers have described a novel mechanism of memory impairment that could contribute to the cognitive deficits associated with Alzheimer’s disease. This mechanism, which involves extra-cellular accumulation of a 56 kDa soluble amyloid-β (Aβ) assembly, dubbed Aβ*56, has been shown to induce memory deficit in middle-aged Tg2576 MICE, independently of plaques or neuronal loss.

The authors quantified and compared four pools of transgene-derived Aβ species extracted from Tg2576 mice aged 4–25 months. Aβ*56 and its 40 kDa equivalent (Aβ*40) both appeared at 6 months of age—coinciding with onset of memory decline—and remained at stable levels in aging mice, implicating these assemblies as possible inducers of memory deficit. Aβ*56, however, was found at higher levels than the 40 kDa complex and correlated more strongly with memory impairment. Purified Aβ*56 taken from the brains of impaired Tg2576 mice was sub sequently injected into young, healthy rats, which underwent a series of tests in the MORRIS

WATER MAZE. Aβ*56 impaired long-term memory but did not affect acquisition of spatial memory; memory impairment was reversed when Aβ*56

GLOSSARYTg2576 MICETg(APPSWE)2576Kahs mice; these mice express a human amyloid-β precursor protein variant that is linked to Alzheimer’s disease

MORRIS WATER MAZEA behavioral neurological test for assessing spatial learning and memory

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administration ceased. The authors conclude that Aβ*56 induces memory impairment through transient physiological, rather than permanent neuropathological, brain alterations.

Lesné et al. propose that the targeting of soluble Aβ memory-disrupting assemblies in humans could be a potential mechanism for halting Alzheimer’s disease before permanent structural damage is incurred. Their results sug-gest that other soluble protein assemblies could also have a role in inducing brain dysfunction.

Pippa Murdie

Original article Lesné S et al. (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440: 352–357

Intensive patient education improves clinical outcome in migraine patients

Migraine patients, it has been reported, are among those most dissatisfied with their stan-dard of medical care. A wide range of therapies for migraine are now available, but demands on clinician time make it difficult to educate patients to derive maximum benefit from these treatments. Rothrock et al. sought to determine whether the addition of an intensive patient edu-cation program to routine patient management might improve the clinical outcome for migraine patients. The researchers randomly allocated 100 consecutive patients to receive either rou-tine care (controls) or a standardized course of instruction on migraine bio genesis and manage-ment. The course of instruction involved three 90 min classes taught by migraine sufferers who had previously undergone intensive instruction by a neurologist.

At 6 months, the intervention group had a significantly greater reduction in mean MIGRAINE

DISABILITY ASSESSMENT (MIDAS) score than did the control group. There was a threefold greater frequency of prescription drug use and more analgesic overuse in the control group compared with the intervention group, and there were four times as many headache-related calls to a doc-tor and twice as many unscheduled visits for acute headache medication by patients in the control group.

The authors state that their education pro-gram, costing US$5,000/year, improved clinical outcome and patient compliance, and reduced demand for medical resources. They conclude

that traditional management is inadequate to meet the needs of migraine patients and call for further initiatives to improve patient care.

Jim Casey

Original article Rothrock JF et al. (2006) The impact of intensive patient education on clinical outcome in a clinic-based migraine population. Headache [doi: 10.1111/j.1526-4610.2006.00428.x]

Glucose mediates cognitive dysfunction in type 2 diabetes

Older adults with type 2 diabetes are known to be at an increased risk for cognitive dysfunc-tion. It is unknown if this is related to chroni-cally elevated glucose levels or insulin levels; however, the available evidence suggests that elevated insulin levels might be to blame. A US team has compared the effects of rosiglitazone (which increases insulin sensitivity) and gliben-clamide (which encourages insulin production, and is also known as glyburide) on cognition in older patients with type 2 diabetes.

In total, 145 patients (mean age 60 years) were randomly assigned to 24 weeks of daily therapy with either rosiglitazone or glibenclamide. Doses were titrated throughout the study to achieve equal glycemic control for all patients (range 4–8 mg for rosiglitazone and 2.5–15 mg for gliben-clamide). The patients completed seven cogni-tive tests at baseline and again at week 24. The tests fell into three categories: working memory, learning ability, and cognitive efficiency.

Performance changed significantly only on one of the three tests that assessed working memory, the CANTAB PAL TEST. Both rosiglitazone and glibenclamide were associated with simi-lar improvements in patient performance from baseline (P <0.0001 and P <0.001, respectively). No relationship was observed between circu-lating insulin levels and performance; however, a fall in fasting plasma glucose was correlated with improvement, regardless of treatment group.

Although the mechanism is currently unknown, high peripheral glucose levels are thought to adversely affect cerebral glucose, which has been shown to be important in animal studies of working memory. These results indicate that glucose, rather than insulin, mediates cognitive dysfunction in diabetic adults.

Katherine Sole

Original article Ryan CM et al. (2006) Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care 29: 345–351

GLOSSARYMIGRAINE DISABILITY ASSESSMENT (MIDAS)A questionnaire that measures headache-related disability by counting the number of days of lost and limited activity due to migraine

CANTAB PAL TESTThe Cambridge Neuropsychological Test Automated Battery Paired Associates Learning test; it assesses memory and new learning

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