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The Year in Neurology


BOSTON -- Clinical and research developments in neurology in 2006 seemed to be as much about prevention as treatment.

BOSTON, Jan. 8 -- Clinical and research developments in neurology in 2006 seemed to be as much about prevention as treatment.

Among the highlights were the return to the market of Tysabri (natalizumab) for multiple sclerosis, a treatment for Parkinson's dementia, the ongoing struggles to understand the causes and treatment of autism spectrum disorders, and new evidence about the influence of diet in preventing cognitive decline.

The following summary reviews some of the major events of the year in neurologyy. For fuller accounts, links to the individual articles published in MedPage Today have been provided.


Fish Really is Brain Food

Patients with higher plasma levels of docosahexaenoic acid (DHA), a fatty acid found in fish, had a significant 47% reduction in the risk of all-cause dementia and a 39% reduced risk of Alzheimer's, researchers at Tufts in Boston reported.

The researchers found a link between fish intake, an important source of DHA, and a reduction in dementia, Ernst Schaefer, M.D., and colleagues, reported in the November issue of Archives of Neurology.

After adjustment for age, sex, apolipoprotein E ?4 allele, plasma homocysteine concentration, and education level, those in the upper quartile of baseline plasma DHA levels, compared with those in the lower three quartiles, had a relative risk of 0.53 for developing all-cause dementia (95% confidence interval, 0.29-0.97; P=0.04). The relative risk of developing Alzheimer disease was 0.61 (CI, 0.31-1.18; P=0.14), they reported.

According to Columbia University researchers, a Mediterranean-style diet -- spare on red meat and heavy on fruits, vegetables, and olive oil -- may help to fend off Alzheimer's.

The effect was strongest in people who followed a Mediterranean-type diet most religiously, reported Nikolaos Scarmeas, in the December issue of Archives of Neurology.

Also, the effect appeared to be independent of vascular risk factors, suggesting that the diet had non-vascular protective benefits, such as antioxidant or anti-inflammatory properties, they wrote.

And in a separate study, published by Swedish researchers in the October issue of Archives of Neurology, there was also evidence that dietary supplements containing a prominent Mediterranean diet component -- omega-3 fatty acids -- may reduce the rate of cognitive decline in people with the mildest Alzheimer's disease. Omega-3 didn't seem to slow the progression of more advanced forms of the dementia, they added.

Aricept Indications Expanded

Aricept (donepezil), one of the few available agents against Alzheimer's disease, received an expanded indication from the FDA in October.

A cholinesterase inhibitor on the market for mild to moderate Alzheimer's disease, Aricept became the first of its class to win FDA approval for severe disease, and the action made Aricept the only drug approved to treat all stages of Alzheimer's.

The FDA decision was based on efficacy demonstrated in two randomized, placebo-controlled 24-week trials in Sweden and Japan. The trials enrolled more than 500 patients with severe Alzheimer's dementia. Both trials evaluated Aricept's efficacy with standard measures that assessed cognitive function including memory, language, orientations, and attention as well as overall functioning. The patients randomized to Aricept had better scores than patients in the placebo arms of both studies.


Autism Tips Its Hand Early

A diagnosis of autism in a two-year old child stands a pretty good chance of holding up when that child is nine, according to researchers from North Carolina, England, and Israel.

On the other hand, a two-year-old diagnosed with pervasive developmental disorder not otherwise specified (PDD-NOS) is more likely to be re-classified as having autism or another disorder seven years down the road, according to Catherine Lord, Ph.D., and colleagues.

Getting the early diagnosis right may be important for researchers developing therapies for autism, and for educators developing early intervention programs targeted at the social, behavioral and adaptive deficits of children with autism, the authors suggested in the June issue of the Archives of General Psychiatry.

Older Dads Have More Autistic Kids

Men in their 40s are nearly six times more likely than men in their 20s to father children with autism spectrum disorders, according to researchers in the U.S. and Israel.

An analysis of medical records of more than 300,000 men and women reporting for the draft in Israel revealed that autism spectrum disorders were significantly more prevalent among recruits whose fathers were 40 or older at the time of their birth, found Abraham Reichenberg, Ph.D., of Mount Sinai in New York, and colleagues.

There was no association, however, between the mothers' ages at the time of their offspring's birth and autism, the investigators reported in the September issue of the Archives of General Psychiatry.

Autism 'Epidemic' Debunked

An apparent increase over the past decade in the prevalence of children labeled as autistic in special education programs may be a phantom conjured by diagnostic substitution, according to an investigator at the University of Wisconsin.

"My research indicates that the increase in the number of kids with an autism label in special education is strongly associated with a declining usage of the mental retardation and learning disabilities labels in special education during the same period," said Paul T. Shattuck Ph.D., MSSW, a pediatrics researcher.

Many of the children now being counted in the autism category would probably have been counted in the mental retardation or learning disabilities categories if they were being labeled 10 years ago instead of today, Dr. Shattuck added. He outlined his case in the April issue of Pediatrics.


Eat Your Vegetables, Granny

Vegetables help older patients keep their wits about them, but fruit appears to have no effect on preventing cognitive decline, according to researchers from Rush Medical Center in Chicago.

Two servings of vegetables a day averted the equivalent of five years of mental aging in people older than 65, Martha Clare Morris, Sc.D., and colleagues, reported in the Oct. 24 issue of Neurology.

Those who ate at least 2.8 servings of vegetables a day effectively slowed their rate of cognitive change by about 40% compared with those who consumed less than one serving a day. But for fruit, the cognitive decline rate difference between the higher and lower intake quintile groups was not significant.

Put a Stopper on Dietary Copper

On the flip side of the dietary coin, a diet high in saturated and trans fats along with a high intake of dietary copper may be associated with an accelerated decline in thinking, learning, and memory.

In a study of 3,718 participants, ages 65 and older, enrolled in the Chicago Health and Aging Project (CHAP), high copper intake from food and supplements was linked to a significantly faster rate of cognitive decline. However, the association held only for those who also consumed a diet high in saturated and trans fats, found a study in the August issue of the Archives of Neurology.

Organ meats, such as liver, and shellfish are foods with the highest copper levels, followed by nuts, seeds, legumes, whole grains, potatoes, chocolate, and some fruits. Drinking water delivered through copper pipes may also add trace amounts of the metal. The recommended dietary allowance of copper for adults is 0.9 mg/d, said Martha Clare Morris, Sc.D., of Rush Medical College in Chicago, and colleagues.

A lifetime of infections with rhinoviruses, enteroviruses, or other members of the picornavirus family could lead to cumulative memory loss, according to Mayo Clinic researchers.

"Our findings suggest that picornavirus infections throughout the lifetime of an individual may chip away at the cognitive reserve, increasing the likelihood of detectable cognitive impairment as the individual ages," they wrote in the November issue of Neurobiology of Disease.

The investigators hypothesize that mild memory loss and cognitive impairment could be caused by cumulative insults to the hippocampus and loss of hippocampal neurons from repeated infection with picornaviruses, which comprise the most common viral infectious agents in humans.

Researchers Steal Lou Gehrig's Signals

An international team of researchers has identified the misfolded protein that causes both amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, and a less well-known condition, frontotemporal lobar degeneration, according to Virginia Lee, Ph.D., of the University of Pennsylvania.

It is TAR DNA-binding protein 43 (TDP-43), which has several functions and is found in the nucleus of many cell types, Dr. Lee and colleagues reported in the Oct. 6 issue of Science.

Misfolded proteins are a common motif in neurodegenerative diseases. They are tagged for recycling by the protein ubiquitin, but instead of being broken down they are dumped in the neurons. Yet the specific ubiquitinated protein involved in ALS and frontotemporal lobar degeneration had not been identified previously, Dr. Lee said. The finding "resolves a long-standing enigma," she and colleagues noted.

  • Awareness in Presumed Vegetative State?

In news that made headlines worldwide and stirred memories of the Terri Schiavo case, a woman thought to be in a persistent vegetative state showed evidence of awareness of herself and her environment in response to verbal commands, said English and Belgian researchers.

As Adrian M. Owen, Ph.D., and colleagues at Cambridge University and the University of Liege in Belgium reported in the Sept. 8 issue of Science, they used functional MRI to evaluate a 23-year-old woman's brain activity, if any, during the presentation of simple spoken sentences. The scans were compared with others taken when the patient was presented with acoustically-matched noise sequences.

The woman had been unresponsive since emerging from a coma after a traffic accident and met all the criteria for a persistent vegetative state. When she was presented with spoken sentences she had increased activity in speech comprehension centers in the brain, as seen on functional MRI. When she was asked to imagine herself playing tennis and walking through the rooms of her house, brain areas governing visiospatial and motor function lit up on the imaging screen, in patterns similar to those seen in normal volunteers, the investigators reported.

It's a spectacular result," said neurologist Nicholas D. Schiff, M.D., of Weill Cornell Medical College in New York, in a news article in the same issue of Science. It's not clear, however, whether the results could be reproduced in other patients diagnosed as being in persistent vegetative states, Dr. Schiff said.


One Headache the Pill Doesn't Prevent

Migraine related to menstruation may be exacerbated by hormonal birth control measures, with more use of analgesics and more recurrences, reported researchers at the American Headache Society meeting.

"Women taking birth control could potentially benefit from taking a combination of triptans and NSAIDs to reduce migraine recurrence," said Brenda Pinkerman, Ph.D., a psychology resident at the James A. Haley Veterans' Hospital in Tampa.

Women using birth control used significantly more analgesics: 3.5 pills per migraine versus 2.8 per migraine for those not on birth control (P=0.001). Those who used birth control medication also had a significantly higher proportion of their migraines return within 24 hours following a pain-free interval (38.6% versus 22.7%, P=0.026). Menstrually related migraines were also more likely to recur within 24 hours for women taking birth control (66.0% versus 30.4%), but the study was not sufficiently powered to show significance.

During the last three months of their tours of duty in Iraq, U.S. soldiers were prone to twice as many migraines as the general population, according to army researchers. This increased incidence persists for months after they return home, found a study presented at the American Headache Society meeting.

"Migraine headaches are unexpectedly common among military personnel serving in a combat zone," said Jay C. Erickson, M.D., a staff neurologist at Madigan Army Medical Center at Fort Lewis, Wash., and colleagues. "The results also suggest that migraine headaches are suboptimally managed in deployed military personnel."

Overall, 19% (524 of 2,697) survey respondents had definite migraine while in Iraq, while another 18% (480 of 2,697) had probable migraine for a total of 37% with episodes of either. Comparatively, an estimated 14% of Americans in the general population suffer migraine or probable migraine headaches.


Tysabri Returns -- With Caveats

The FDA cleared the way for Tysabri (natalizumab), the multiple sclerosis drug, to go back on the market but under a special restricted distribution program. Tysabri, a monoclonal antibody approved in November 2004 for relapsing forms of MS, was withdrawn by its maker, Biogen Idec, and distributor, Elan, in February 2005.

The drug was yanked after three patients in clinical trials developed progressive multifocal leukoencephalopathy (PML), a rare viral infection of the brain. Two of the cases were fatal.

To decrease the possibility of patients developing PML in the future, an FDA advisory committee recommended a risk-minimization program with mandatory patient registration and periodic follow-up to identify as early as possible, any cases of PML that may occur, and to try to determine the reason the infection occurs.

The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program. Tysabri will only be administered to patients who are enrolled in the program. Prior to initiating the therapy, health care professionals are to obtain the patient's MRI scan to help differentiate potential future multiple sclerosis symptoms from PML. Patients taking Tysabri are to be evaluated at three and six months after the first infusion and every six months after that, and their status will be reported regularly to Biogen Idec and Elan.

Lesion, Heal Thyself

The key to stopping or reversing the progression of multiple sclerosis may lie in or near the lesions themselves, reported researchers in Texas and New York in a review of the current understanding of multiple sclerosis pathogenesis, published in the March 2 issue of the New England Journal of Medicine.

A reservoir of oligodendrocyte precursor cells left over from development might be coaxed into maturing and directing repair processes that could help to knit severed nerves or restore myelin sheathing, wrote Elliot Frohman, M.D., Ph.D., of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

Intriguingly, there is now evidence to suggest that remyelination, albeit transient, is consistently found in MS lesions. The remyelination appears to occur when oligodendrocyte precursor cells are recruited to lesions by chemokines.

The remyelination process is impeded by several growth-inhibiting repressor proteins that could form targets for novel treatment strategies that would allow oligodendrocyte precursors to mature and get on with the work of myelin repair, the investigators suggested.


Exelon Gets Green light for Parkinson's dementia

The FDA gave Exelon (rivastigmine), already approved for treatment of mild-to-moderate Alzheimer's dementia, the added indication of mild-to-moderate Parkinson's dementia. The drug, marketed by Novartis, became the first agent approved for the Parkinson's condition.

Steven Galson, M.D., director of the FDA's Center for Drug Evaluation and Research, said dementia associated with Parkinson's disease differs from Alzheimer's dementia. The most common features of Parkinson's dementia are dysexecutive syndrome and impairment of visuospatial functions.

According to the FDA, 0.2% to 0.5% of those 65 or older are affected by Parkinson's dementia. "Until now, there has been no treatment that has been shown to be effective specifically for the dementia associated with Parkinson's Disease," Dr. Galson said.


Alcohol Prevents Death From Brain Injury? I'll Drink to That

Finally, in keeping with the spirit of the season, Canadian researchers reported that alcohol may protect the head as well as the heart by reducing the risk of death from a hard blow to the head.

They looked at blood alcohol levels in patients with severe traumatic brain injury following blunt head trauma, and found that those with low-to-moderate levels had a lower risk of dying compared with those with either no alcohol in the blood or too much.

"Overall, people are still at much greater risk of dying if they drive while intoxicated," wrote Homer C. N. Tien, M.D., of the University of Toronto, and colleagues in other Canadian centers, in the December issue of Archives of Surgery. "What our study implies is that there may be a role for an alcohol-based resuscitation fluid in improving outcomes in adequately resuscitated patients with severe head injury."

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