Researchers from the USA conclude that poor cognitive function is linked to poorer recovery.
High-density lipoprotein (HDL), homocysteine and diabetes have been linked to poorer cognitive function and greater disability after stroke. This supports the view that metabolic stress plays a significant role in the post-stroke period.
These conclusions were made by researchers from the USA and were published in the November 27 issue of Neurology. The results were drawn using data from the Vitamin Intervention for Stroke Prevention (VISP) trial, which used a linear mixed effects model. A total of 3680 subjects were analyzed; all over 35 years of age and entered into the VISP database between 1996 and 2003. Cognitive and motor function during a 2-year post-stroke period were assessed using scores from the Mini-Mental State Examination (MMSE) and modified Rankin Scale (mRS). Subjects with lower levels of both HDL and homocysteine were more likely to have memory difficulties and reduced motor activity following a stroke episode.
The aim of the study was, “To delineate factors associated with cognitive function following stroke and test the hypothesis that vascular risk factors associated with oxidative stress impair recovery.”
In addition to the metabolic stress factors, increased age, recurrent stroke and left hemisphere cortical lesions were independent predictors of less successful cognitive recovery.
George Newman, who worked on the study, commented that, “It’s currently unclear why these factors are contributing to a slower stroke recovery and more research is needed. We need to focus our attention on identifying and treating these vascular risk factors since they can be modified.”
Source: Newman GC, Bang H, Hussain SI, Toole JF. Association of diabetes, homocysteine and HDL with cognition and disability after stroke. Neurology 69, 2054–2062 (2007).
Progesterone shown to have mixed effects on Alzheimer’s disease neuropathology
A recent study has investigated the effect of progesterone on the development of Alzheimer’s disease (AD). Although falling estrogen levels in postmenopausal women are currently considered as a contributing factor to AD, the effect of progesterone has not been thoroughly investigated.
The researchers, from the Universities of California and Southern California (CA, USA), used a murine model to look at the effects of progesterone on AD-like neuropathology both alone and in combination with estrogen. Triple transgenic mice were predisposed to develop AD. The progression of AD was then charted by analyzing β-amyloid accumulation, tau hyperphosphorylation and hippocampal-dependent behavioral impairments; all signs of AD.
The transgenic mice with intact ovaries showed signs of AD within 3 months of age, which worsened in the following 9 months, reflecting their transgenic status. Also, as expected, ovarectomized transgenic mice significantly increased β-amyloid accumulation and reduced memory performance. Treating the ovarectomized mice with estrogen alone prevented the AD-like neuropathology. However, when treated with estrogen and progesterone, the ovarectomized mice showed no improvement on β-amyloid accumulation.
Unexpectedly, progesterone significantly reduced tau hyperphosphorylation both alone and when administered in combination with estrogen. Hyperphosphorylation of the tau protein is a feature of AD, resulting in the transformation of tau from a soluble molecule into an insoluble paired helical filament.
The authors conclude that, “These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.”
Source: Carroll JC, Rosario ER, Chang L et al. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J. Neurosci. 27(48), 13357–13365 (2007).
Potential new diagnostic tool for hemiplegic migraine
Researchers from The Netherlands have recently discovered that ATP1A2 has the potential to be used in the diagnosis of migraines.
Genes associated with familial hemiplegic migraine (FHM) have now also been linked with sporadic hemiplegic migraine (SHM). This is according to research by scientists in The Netherlands, who scanned the genes of hemiplegic migraine sufferers.
Both types of migraine can cause transient hemiparesis, partial paralysis of one side of the body. The migraine is classified as sporadic if the sufferer has no first-degree relative that also has hemiplegic migraines. In FHM, three genes have been identified that have a role in the pathophysiology of the disorder. The three genes encode the subunits of a calcium channel (CACNA1A), a sodium–potassium pump (ATP1A2) and a sodium channel (SCN1A). The study aimed to find a genetic basis for SHM, with a view to further the understanding of its connection with other types of migraine and to provide a staring point for diagnosis of the disease.
The genes of 39 SHM patients were scanned for the three FHM genes. Functional assays were performed for all new sequence variants. Seven SHM patients were found to have sequence variants; one CACNA1A mutation, five ATP1A2 mutations and one SCN1A polymorphism. Functional changes were seen in the cellular assays in all six of the mutations.
The authors concluded that, “our findings reinforce the hypothesis that FHM, SHM and ‘normal’ migraine are part of a disease spectrum with shared pathogenetic mechanisms. The results also indicate that screening of ATP1A2 has the potential to be used in the diagnosis of SHM. This would be a useful tool as currently this type of migraine is often mistaken for epilepsy, stroke or other disorders and therefore often patients do not receive the most appropriate treatment.”
Source: de Vries B, Freilinger T, Vanmolkot KRJ et al. Systemic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology 69, 2170–2176 (2007).
Positive Phase III results for Keppra XR™ in the treatment of adults with refractory epilepsy
Drug: Levetiracetam
Tradename: Keppra XR™
Manufacturer: UCB, Belgium
Indication: An adjunctive therapy for adults with refractory epilepsy
Structure:
Presented at the 61st annual meeting of the American Epilepsy Society (PA, USA), UCB (Brussels, Belgium) has announced the positive results of its Phase III trial of Keppra XR™ (levetiracetam) as an adjunctive therapy in the treatment of partial-onset seizures in patients with refractory epilepsy.
The Phase III, multicenter, randomized, placebo-controlled study evaluated the efficacy, safety and tolerability of extended release (XR) Keppra (two-times 500 mg) once daily as an add-on therapy. A total of 158 refractory epilepsy patients aged 12–70 years who suffered from partial-onset seizures participated in the study.
Over a 12-week period, treatment with Keppra XR resulted in a median 46.1% decrease in partial-onset seizures, compared with only a 33.4% reduction in patients who received a placebo. In addition, the seizure frequency was cut by 75–100% in 24% of participants receiving Keppra XR, compared with 11.4% in the placebo group.
Patients who received Keppra XR showed a 10.1% reduction in the frequency of partial-onset seizures and an 8.9% reduction in seizures overall, compared with only 2.5 and 1.3%, respectively, in the placebo group.
“In this study with a new formulation of Keppra about one in ten patients with refractory partial onset epilepsy achieved seizure freedom,” explained Jukka Peltola from the Department of Neurology, Tampere University Hospital, Finland. “There is an ongoing need for new antiepileptic drug options and XR formulations offer the potential advantages of convenience and improved patient compliance.”
The drug was generally well-tolerated, with the most common side effects being influenza, irritability, somnolence, nasopharyngitis, nausea and dizziness.
“These data show that the once-daily, XR formulation of Keppra reduced the frequency of partial-onset seizures in patients with uncontrolled epilepsy and was generally well tolerated,” commented Iris Loew-Friedrich, Global Head of Development at UCB.
Source: UCB News Release www.ucb-group.com/investor_relations/2811.htm
“My memory’s not what it used to be”
Study suggests why our brains deteriorate as we get older.
A recent study, published in the December 6 issue of Neuron, has demonstrated that deteriorating neural connections are linked to normal cognitive decline. This decline was shown to occur even in the absence of serious pathologies such as Alzheimer’s disease.
“Our study now shows that cognitive decline in aging may be linked to disruption of communication between different regions of the brain,” commented Randy Buckner, coauthor of the study. Using functional MRI, the researchers investigated the connectivity between frontal and posterior regions – associated with high-level cognitive functions – of the participants’ brains. “The crosstalk between the different parts of the brain is like a conference call,” explained Jessica Andrews-Hanna, lead author of the study. “We were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another.”
A total of 93 healthy individuals, aged 18–93 years, were divided into two groups: young adults, aged 18–34 years (n = 38) and old adults, aged 60–93 years (n = 55). The researchers found that reduced correlation between the brain regions was associated with lower performance on cognitive tests.
“We found that in young adults, the front of the brain was pretty well in sync with the back of the brain,” explained Andrews-Hanna. “In older adults this was not the case. The regions became out of sync and they were less correlated with each other. Interestingly, the older adults with normal, high correlations performed better on cognitive tests.”
The cause of this loss of synchrony was shown to be deterioration in the brain’s white matter, resulting in disrupted connectivity between the brain regions.
“It may help explain why some people are just as sharp in their 90s as they were in their 40s,” commented Andrews-Hanna. “We all age differently and cognitive abilities vary considerably among individuals.”
The researchers acknowledge that more research is required, however, they are hopeful that their work will aid in our understanding of ‘normal’ aging, as Buckner pointed out. “We can use this new approach (correlating the activities of different regions of the brain) as a tool to understand variation between individuals. We can also explore risk factors for breakdowns (in these pathways) like cardiovascular health.”
Source: Andrews-Hanna JR, Snyder AZ, Vincent JL et al. Disruption of large-scale brain systems in advanced aging. Neuron 56, 924–935 (2007).
Abilify® approved by the US FDA for add-on treatment of major depressive disorder
Drug: Aripiprazole
Tradename: Abilify®
Manufacturer: Bristol-Myers Squibb company and Otsuka Pharmaceutical Co., Ltd
Indication: Adjunctive treatment of MDD
Abilify® (aripiprazole) has become the first drug to be approved for adjunctive treatment of major depressive disorder (MDD) in adults. The US FDA approved the supplemental New Drug Application of the drug, produced by Bristol-Myers Squibb Company (NY, USA) and Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan) on 20th November.
“This approval is a reflection of our ongoing commitment to provide innovative therapies, such as Abilify, to help adults living with depression” commented Elliott Sigal, Bristol-Myers Squibb.
The approval was based on the positive results of two 6-week double-blind, randomized, placebo-controlled multicenter studies. Patients were first treated for 8 weeks with antidepressant therapy (ADT) plus a single-blind placebo in order to confirm inadequate response to ADT. Following this, the 743 patients continued their ADT but also received double-blind adjunctive placebo or adjunctive Abilify for a 6-week period. Those patients who received adjunctive Abilify demonstrated a significant improvement in depressive symptoms.
“We are pleased that Abilify has achieved this important milestone as the first medication approved as adjunctive treatment for adults with MDD,” Taro Iwamoto, Otsuka Pharmaceutical Development and Commercialization, Inc., commented. “This new add-on treatment option for depression represents hope for many adults suffering from this debilitating illness.”
According to the NIMH, in the USA, MDD is the leading cause of disability for people aged 15–44 years. Approximately 14.8 million American adults (6.7% of the population aged over 18 years) suffer from MDD. It is clear that any improvement in the treatment of this disorder could vastly improve the quality of millions of patients’ lives, as Madhukar Trivedi, University of Texas Southwestern Medical School (TX, USA), pointed out, “The approval of this new add-on treatment option is critical for adults suffering from depression who cannot find sufficient relief for their symptoms with antidepressants alone. Now physicians have a proven new option they can add to their patients’ antidepressant treatments to help them feel better and relieve unresolved depressive symptoms.”
Source: Bristol-Myers Squibb Newsroom. US Food and Drug Administration approves ABILIFY® (aripiprazole) as the first medication for add-on treatment of major depressive disorder (MDD) http://newsroom.bms.com/index.php?s=press_releases&item=324
Newly identified exercise gene could help in the treatment of depression
Scientists from Yale University discover mechanism for the antidepressive effect of exercise.
Insight into the mechanism behind the well-known antidepressive effect of exercise has been gained by scientists from Yale University (CT, USA). Their study indicates that exercise stimulates a neurotrophic factor signaling cascade thought to be involved in the action of antidepressants. The gene encoding this VGF nerve growth factor is one of the most highly regulated target genes of exercise.
This discovery was made by investigating exercise-regulated genes in the mouse hippocampus, thought to be involved in controlling mood and in the antidepressant response. Genes were analyzed using a custom microarray that indicated slight changes to gene expression. The array analysis highlighted 27 new hippocampal exercise-related genes, adding to the six already identified previously. Running wheels were used to determine the amount of exercise and the extent of depression in the mice.
In support of the idea that VGF is involved in depression, the researchers found that mice treated with a synthetic VGF-derived peptide display an antidepressant response. Furthermore, mutation of VGF in mice is associated with depressive responses.
Crucially, the findings in this study may lead to a new antidepressant drug target. The authors write, “The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.” Ronald Duman, author of the study, believes that, “the VGF exercise-related gene and target for drug development could be even better than chemical antidepressants because it is already present in the brain.” One problem with current antidepressants is the length of time they take to start working.
Source: Hunsberger JG, Newton SS, Bennett A et al. Antidepressant actions of the exercise-regulated gene VGF. Nat. Med. DOI:10.1038/nm1669 (2007) (Epub ahead of print).