A new study shows a significant reduction in the incidence of Alzheimer's disease (AD) and dementia among subjects taking angiotensin receptor blockers (ARBs) compared with those taking angiotensin-converting enzyme (ACE) inhibitors or other cardiovascular drugs.

Further, there appeared to be a reduction in rates of disease progression, indicated by the time to admission to a nursing home or death, among those taking ARBs, the study authors note.

The people who did the best appeared to be those who were taking ARBs together with ACE inhibitors. They had a 55% lower incidence of Alzheimer's or dementia, and a 70% decrease in nursing home admissions.

The report was published online January 12 in the British Medical Journal.

ARBs selectively inhibit the AT1 receptor, and although slightly less effective at lowering blood pressure than ACE inhibitors, they have been shown in an increasing number of studies to be related to preservation of cognitive function through a mechanism independent of their antihypertensive action, the study authors write.

In this study, Dr. Wolozin and colleagues used data from the US Veterans Affairs administrative database to look at time to incident AD or dementia during a 4-year period in 3 prospective cohorts. Participants were predominantly male and 65 years and older, with a diagnosis of cardiovascular disease. One group included subjects taking an ARB, a second included those taking the ACE inhibitor lisinopril, and a third comparator group were taking other cardiovascular drugs, excluding ARBs, ACE inhibitors, and statins.

Among those with a previous diagnosis of AD or dementia, disease progression was defined for these purposes as the time to admission to a nursing home or death.

After adjustment for age, diabetes, stroke and cardiovascular disease, incident AD, and particularly incident dementia were reduced with the ARB vs both the ACE inhibitor and the cardiovascular comparator group.

Table 1. Risk for Incident Alzheimer's Disease and Dementia With ARB Treatment vs Lisinopril and a Cardiovascular Comparator

ARB = angiotensin receptor blocker; CI = confidence interval

Among those who already had AD, treatment with an ARB was associated with a significantly lower risk of admission to a nursing home or death during the follow-up period.

"Angiotensin receptor blockers exhibited a dose response as well as additive effects in combination with angiotensin-converting enzyme inhibitors," the study authors note. Compared with the ACE inhibitor alone, the combination was associated with a significantly reduced risk of incident AD and dementia and admission to a nursing home.

Table 2. Risk for Dementia and Nursing Home Admission With Combined ARB and ACE Inhibitors vs ACE Inhibitor Alone

ACE = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval

"Because vascular dysfunction and stroke are associated with cognitive decline, our data raise the possibility that combined use of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might confer superior protection against cognitive decline (compared with other cardiovascular drugs) by reducing neuronal damage associated with stroke and vascular dysfunction," the study authors speculate.

Neuropsychological impairment is an important early indicator of multiple sclerosis, even among patients with clinically isolated syndrome, report researchers in the January issue of Multiple Sclerosis. A routine assessment of neuropsychological functioning can provide, on the one hand, a more comprehensive picture of the disease status and, on the other, additional cues on the prognosis of the disease.

The finding, the study authors say, will have important implications for therapeutic decision making.

A second paper, published in the January 26 issue of Neurology, suggests that this early cognitive dysfunction in patients with multiple sclerosis may be the result of cortical thinning in the brain (2010;74:321-328).

Investigators led by Massimiliano Calabrese, MD, from the University Hospital of Padova in Italy, propose that cognitive impairment might be an expression of more aggressive and widespread cortical disease.

In the present analysis, researchers led by Valentina Zipoli, MD, at the University of Florence, studied all patients consecutively referred to their center and followed up for at least a year. Investigators evaluated 56 people with clinically isolated syndrome, a first demyelinating episode.

At baseline, 57% fulfilled McDonald’s magnetic resonance imaging criteria for dissemination in space. During follow-up, 46% converted to a diagnosis of multiple sclerosis.

Investigators conducted neuropsychological assessments using Rao's Battery and the Stroop test. They found that failure of at least 3 cognitive tests and the presence of McDonald's dissemination in space at baseline significantly predicted conversion to multiple sclerosis.

Table. Converted From Clinically Isolated Syndromes to Multiple Sclerosis

This is not the first time this research team has suggested that cognitive impairment can predict multiple sclerosis. In July, they published another paper showing that people who failed more than 2 cognitive tests were 20% more likely to progress over time. That small study published in Neurology included 63 patients (2009;73:498-503).

In an accompanying editorial, Dr. Ralph Benedict, from the State University of New York in New York City, and Dr. Franz Fazekas, from the Medical University of Graz in Austria, applauded the work for offering a valuable observation. "It confirms neuropsychological functioning as another important measure of brain integrity," they noted.

Treadmill training can lead to more improved gait parameters for patients with Parkinson's disease (PD) than for those who do not participate in exercise treatment, according to a new systematic review from Germany.

In fact, the training group showed increases in stride length, walking speed, and walking distance.

"Acceptability of treadmill training for study participants was also good and adverse events were rare," write Jan Mehrholz, MPH, professor at the Leiter Wissenschaftliches Institut at the Private Europaische Medizinische Akademie der Klinik Bavaria in Kreischa, Germany, and colleagues.

This study was published in the first 2010 issue of the Cochrane Database of Systematic Reviews.

Gait hypokinesia, characterized by slowness of movement, is one of the primary movement disorders associated with PD, according to the study authors. Currently, exercise is often incorporated into treatment regimens for these patients as a useful complement to traditional drug therapies, and past studies have looked at using electromechanical devices, such as treadmills, to facilitate gait rehabilitation.

"Small trials have shown improvements but have been inconclusive," said Dr. Mehrholz. "Therefore, we were interested in a systematic evaluation [that provided] strong evidence about this type of therapy to give clear advice going forward."

His team sought to compare the effects of treadmill training vs no treadmill training on the gait of patients with PD, as well as its acceptability and safety, by evaluating data on 203 patients (mean age, 66.25 years) from 8 randomized controlled and randomized controlled crossover trials from the Cochrane Library. They measured gait improvement by analyzing walking speed, stride length, number of steps per minute (cadence), and walking distance.

"We hoped that treadmill training as a nonpharmaceutical approach would lead to clear improvements of gait," explained Dr. Mehrholz.

Improvements in All Outcomes but Cadence

Results showed that the group receiving treadmill training had improvements in all gait parameter measurements except for cadence compared with those in the other group. The training also did not increase the risk of patients dropping out, signalling patient acceptability.

Table. Treadmill Training Effects on Gait Parameters

"Treadmill training appears to be a safe and effective way of improving gait in patients with [PD]," the study authors write. "Crucially, we saw very few adverse effects or drop outs ... given this type of rehabilitation therapy."

However, the study authors caution that these findings are based on only 8 small studies, and the persistence of the gait improvements is unknown. Dr. Mehrholz reported that his team hopes to follow up in 1 year on the individual patient data from the trials evaluated.

On January 22, 2010, the US Food and Drug Administration (FDA) announced approval for dalfampridine extended-release tablets to improve walking in patients with multiple sclerosis (MS).

The drug, a potassium channel blocker, was shown in clinical trials to improve walking speeds vs placebo. It is the first drug approved for this use, an FDA statement notes; currently approved MS drugs are indicated to decrease relapse rates or in some cases to prevent accumulation of disability.

“Trouble with walking is one of the most debilitating problems people with MS face,” Russell Katz, MD, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, said in a statement.

The drug was previously known as fampridine sustained release with the proposed brand name Amaya, but is now called dalfampridine (Ampyra). The change was made to avoid potential confusion with other marketed products, a spokesperson for the FDA confirmed. It will be manufactured under licenses from Elan of Dublin, Ireland, and distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Given at doses greater than the recommended 10 mg twice a day, dalfampridine can cause seizures, the statement adds. The most common adverse events reported in clinical trials were urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching of skin.

A new Practice Parameter from the American Academy of Neurology (AAN) and the Child Neurology Society provides new guidance on how to treat spasticity in children with cerebral palsy (CP).

For localized and segmental spasticity, the study authors concluded that botulinum toxin type A is generally safe and effective and gave it a Level A recommendation, although they acknowledge that the US Food and Drug Administration (FDA) is currently investigating cases of serious adverse events, including death, with use of this agent to treat spasticity in children.

The new Practice Parameter is published in the January 26 issue of Neurology.

CP affects more than 10,000 infants born each year in the United States. It is the most common cause of spasticity in children, and most children with CP have spasticity, the study authors note.

However, CP is a complex motor disorder, and spasticity is only 1 feature of it. The decision to treat spasticity should be made by a multidisciplinary medical and surgical team. It is important that doctors, patients, and caregivers together set a goal for measuring the success of medication use or any other spasticity treatment.

In some cases, for example, spasticity can be used by the patient to their advantage, and treating it might actually reduce their function. In others, reducing spasticity can ease pain and muscle spasms, facilitate the use of a brace, improve posture, minimize contractures and deformity, facilitate mobility and dexterity, and improve a patient's ability for self-care.

For this review, they limited themselves to pharmacologic treatments. A panel of specialists, including a pediatric and an adult neurologist, developmental pediatricians, physiatrists, and an orthopedic surgeon, reviewed the literature from 1966 to 2008 and classified treatments according to the AAN classification system.

Their recommendations were as follows:

• For localized and segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment, they write; "however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes." (Level A);
• There were insufficient data, they note, to support or refute use of phenol, alcohol, or botulinum toxin type B as regional treatments (Level U);
• For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment (Level B) and tizanidine may be considered (Level C); and
• Again, there were insufficient data to draw conclusions about dantrolene, oral baclofen, or continuous intrathecal baclofen in generalized spasticity (Level U).

"That doesn't mean they don't work, I'm just saying there is no scientific evidence," Dr. Delgado noted of these Level U classifications in both regional and generalized spasticity. "I think it's important to understand that the lack of scientific evidence doesn't mean that we're against it."

More Research Critical

"I think the exercise of reviewing the literature is important because it allows us to review what we have and what we don't have, and I think the fact that we don't have scientific evidence for some of these medications that we use in clinic on a regular basis basically opens the door to do more research," Dr. Delgado said. "Many of the treatments that we use in pediatrics have been approved and tested in adults, and we translate that into children."

In addition, some of these older drugs, such as dantrolene and baclofen, were never formally tested in children. More research is needed to understand proper doses and ways to use these agents more safely, he added, as well as providing evidence that treating the spasticity will translate into improved function for these children.