Stopping Familial Alzheimer's—Woman at Risk Has Healthy Twins
Would-be parents from families carrying devastating genetic mutations face a formidable decision: Should they have children and risk passing on the disease? It is even more complicated when the at-risk parent doesn’t know his or her genetic status, and wants to keep it that way. There is a procedure that enables them to circumvent these concerns. At the 139th annual meeting of the American Neurological Association, held October 12-14 in Baltimore, Murali Doraiswamy of Duke University, Durham, North Carolina, described the first such case from a family carrying a presenilin 1 (PS1) mutation. The woman, who chose to remain anonymous, now has 2-year old twins who have almost zero chance of carrying a familial AD mutation.
For the past two decades, doctors have used a combination of in vitro fertilization and preimplantation genetic diagnosis (PGD) to implant only embryos they know to have escaped the particular family mutation. Doctors can perform the procedure without revealing whether the parent carries the harmful gene (see Jul 2014 news story). However, even after 20 years, PGD remains relatively unknown, especially among families carrying alleles for familial Alzheimer’s disease (FAD). Not even a dozen couples from such families have used the procedure to conceive, in part because few know about it (see Jul 2014 news story).
While this 30-year-old woman wanted to spare her children the prospect of early onset Alzheimer’s, she did not want to know if she carried the mutant PS1 herself. To conceal her status, a team headed by Svetlana Rechitsky of Reproductive Genetics Institute, Northbrook, Illinois, performed what’s called indirect linkage analysis on cells from nine embryos conceived by in vitro fertilization. This was to ensure the woman passed on a normal copy of the PS1 gene, inherited from her father, rather than a mutant copy, which would have come from her mother, who had a confirmed diagnosis of AD. Rechitsky and colleagues conducted genetic testing on the couple and their parents to identify genetic markers that lay near PS1. Then they screened the embryos to identify those that contained the unaffected grandfather's copy of the gene, then implanted only those embryos. The point of this process is that the researchers never looked for the mutant PS1 allele itself. If a chromosome had markers around PS1 from the woman’s affected mother, that embryo was considered “at risk” of containing the mutated PS1 allele, and was not implanted.
PGD is not widely recognized as a potential solution for families who carry early onset AD mutations. Some of the few couples who have undergone PGD for FAD know about it from their own professional experience as doctors, geneticists, or neuroscientists, or they found out about it while seeking in vitro fertilization for other reasons, Doraiswamy told Alzforum. Some who learned about it in later years say they would have considered it before having children, but only a trickle of FAD cases comes through the door, said Doraiswamy. “Doctors and patients need to be educated,” he said.
Another problem is that few insurance companies in the United States, and only some in other countries, cover in vitro fertilization for fertile couples, while PGD is not covered for any conditions in the United States, according to Doraiswamy. The expense for combined PGD and in vitro fertilizations, which can run to $30,000 or more, deters couples, he said. On the other hand, a young woman from a different family who is similarly at risk of FAD but was not connected to this case told Alzforum, on condition of anonymity, that even if her insurance did cover PGD, she would not trust that her information would be kept confidential. So long as cost and genetic privacy remain obstacles, PGD may well remain a high-tech option for the affluent few.—Gwyneth Dickey Zakaib
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A New Drug to Calm Agitation, Uncontrollable Laughing and Crying, in Alzheimer’s?
At the 139th annual meeting of the American Neurological Association, held October 12-14 in Baltimore, researchers from Avanir Pharmaceuticals in Aliso Viejo, California, presented positive results from two studies of a drug in Alzheimer’s disease. AVP-923 is approved in the United States and European Union for the treatment of pseudobulbar affect (PBA). In this strange phenomenon, people with certain primary neurologic diseases frequently burst into uncontrollable, extended spells of laughter or are overcome by crying. PBA itself is rare in Alzheimer’s disease, but agitation is common. In a new Phase 2 trial, AVP-923, marketed as Nuedexta, reduced agitation scores in patients with Alzheimer’s. In a separate open-label study, the drug dampened the emotional outbursts of laughing and crying that sometimes afflict patients with dementia.
Scientists do not know exactly how AVP-923 works for agitation. It is a stable combination of two old drugs: dextromethorphan hydrobromide, the active ingredient in cough medicines such as Robitussin, and the arrhythmia drug quinidine sulfate. The former is an uncompetitive antagonist of NMDA-type glutamate receptors and an agonist of the sigma-1 receptor, a protein chaperone that resides in the endoplasmic reticulum membranes. The latter blocks cytochrome P450 2D6, a liver enzyme that metabolizes dextromethorphan hydrobromide, increasing its plasma concentration (Cruz, 2013).
A previous Phase 3 trial reported that AVP-923 improved pseudobulbar affect in people with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) (see Pioro et al., 2010). Trials are ongoing for neuropathic pain and for levodopa-induced movements in Parkinson’s, as well as for autism, migraine, and depression.
To see if AVP-923 treated agitation in Alzheimer’s, researchers at 44 sites, including Jeffrey Cummings of the Cleveland Clinic, Luo Ruvo Center for Brain Health in Las Vegas, enrolled 220 adults aged 50 to 90, all of whom had probable AD with clinical agitation. The researchers used a sequential, parallel comparison design developed for indications that are particularly prone to placebo effects (see Ivanova et al., 2011). These trials have two stages. Scientists first randomize subjects to receive drug or placebo. After some time, they separate the placebo group into those who improve and those who did not, and re-randomize them to receive either drug or placebo. This allows researchers to compare the two treatments among people who exhibit a minimal placebo response.
The researchers divided the double-blind trial into two five-week periods. For the first, 93 people were randomized to receive AVP-923 twice daily; 127 got placebo. Because this drug combination has known side effects, doses started at 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate, and then rose to 30 mg and 10 mg, respectively. For the second stage, people already on the drug stayed on it, but the placebo group was re-randomized such that 15 of the 30 who had had a strong placebo response were switched to the drug and 15 stayed on placebo. Of the 89 placebo participants whose scores stayed stable, 44 now got the drug and 45 stayed on placebo. This brought the total number of people who received the drug to 152.
The agitation/aggression domain of the neuropsychiatric inventory (NPI) served as the primary outcome measure; secondary outcomes included the other subdomains and the total NPI score. As an exploratory outcome, the researchers measured change in the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog).
At the end of the first stage, AVP-923 improved the NPI agitation score by 3.3 points, compared with 1.7 points in the placebo group. At the end of the second stage, the researchers assessed the 44 people in the initial placebo group who had demonstrated no strong placebo effect and began taking AVP-923 after five weeks. In them, the drug reduced agitation and aggression. Scores fell by 2 points, compared with 0.8 points for the 45 people still on placebo. Overall, NPI total and subdomain scores also improved more for the drug treatment group. In both stages, caregivers reported that their own stress abated, and both they and clinicians reported that the patient was less agitated.
Adverse events occurred in 61 percent of people taking AVP-923, versus 43 percent on placebo. They included falls, diarrhea, urinary-tract infections, dizziness, agitation, contusion, back pain, and peripheral edema, and are in line with the drug’s known safety profile, said co-author Joao Siffert of Avanir. Serious adverse events occurred in 12 people on the drug and six on placebo. Twenty-six people dropped out of the trial; 17 from the AVP-923 group, nine from placebo. Eight and four, respectively, stopped because of adverse events. No one died during the trial.
AVP-923’s safety profile is not benign. It is contraindicated for people with heart problems such as prolonged QT interval, atrioventricular block, and others, as well as people with a history of thrombocytopenia, hepatitis, bone-marrow depression, or lupus-like syndrome. People who are overly sensitive to dextromethorphan-containing common cough medicines also should not take AVP-923. Drug interactions with other CNS drugs, such as monoamine oxidase inhibitors (MAOs) and serotonin reuptake inhibitors (SSRIs) are also known (see Cruz, 2013; Schoedel et al., 2014).
Still, Siffert interpreted the latest trial results to mean that overall, AVP-923 was well-tolerated. The researchers found no evidence of treatment-related cognitive decline on the MMSE or ADAS-cog. This is important, he said, because other drugs aimed at treating agitation have been associated with cognitive decline (see Feb 2014 news story).
The results justify larger Phase 3 trials, claimed Siffert, who said that the company would begin talks with the FDA early next year. “The study shows potential for this drug to be helpful,” agreed Lon Schneider, University of Southern California, Los Angeles, who was not involved in this trial but saw the poster. Schneider noted that the relatively small sample was heterogeneous in age, MMSE score, and both level and type of agitation. Patients also differed on the drugs they were already taking, such as acetylcholinesterase inhibitors, memantine, antidepressants, and antipsychotics. Since quinidine sulfate is a potent inhibitor of cytochrome P450 2D6 and slows the metabolism of several drugs, it may affect other drugs, and that could contribute to efficacy as well as adverse events, he told Alzforum. Schneider noted that larger trials will be needed to discern how well the drug works in which type of patient.
A second AVP-923 study was also presented on a poster at the AAN conference. This study followed 134 patients with AD, vascular or frontotemporal dementia, or dementia with Lewy bodies who took AVP-923. They constituted the dementia cohort, led by Rachelle Doody, Baylor College of Medicine, Houston, of the larger PRISM-II study. Conducted at more than 100 centers in the United States, PRISM-II used no placebo control, but simply evaluated safety, tolerability, and the effect of AVP-923 in 750 people whose PBA accompanied primary conditions such as stroke or a traumatic brain injury. “The purpose of this investigation was to gain more experience with the use of AVP-923 in patients whose PBA was related to disorders that were not well-represented in the trials used for regulatory approval,” Doody wrote to Alzforum.
Participants received the 20 mg/10 mg combination twice daily for 12 weeks, and were assessed for change in the Center for Neurologic Study-Lability Scale (CNS-LS). The Center for Neurologic Study is the not-for-profit organization in La Jolla, California, that originally developed this drug combination. CNS-LS is a questionnaire to measure uncontrollable tearfulness or laughter (see Moore et al., 1997). Other endpoints included how often participants had such episodes, their MMSE score, and clinicians’ and caregivers’ global impression of change.
Patients improved on the CNS-LS. Episodes dropped by half at day 30 compared to baseline, by two-thirds at day 60, and three-quarters of clinicians and caregivers reported that symptoms improved at day 90. Overall, MMSE scores remained steady.
Forty-nine patients had mild to moderate adverse events, such as headache, urinary-tract infection, diarrhea, nausea, falls, dizziness, and sleepiness; a third were considered possibly related to AVP-923. Fourteen people had serious side effects, but Doody and colleagues considered these unrelated to the drug. Seventeen patients dropped out because of adverse events. The authors wrote that the results suggest that AVP-923 treats PBA regardless of the underlying neurological condition.
John (Wes) Ashford of Stanford University Medical Center in California wrote to Alzforum that PBA is uncommon in Alzheimer’s. Ashford suggested that other off-patent drugs could work as well or better than AVP-923 if they were competitively tested against one another. As examples, he mentioned the antidepressants nortriptyline and citalopram, the antipsychotic olanzapine, and the anticonvulsants lamotrigine, valproic acid, and topiramate. The study was funded by Avanir; both Cummings and Doody have consulted for this company.—Gwyneth Dickey Zakaib
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- Parkinson’s Antipsychotic Looks Good in Phase 3 Trial
- Citalopram Calms Agitation in Alzheimer’s, but Carries Risks
- Warning on Antipsychotics Heeded, But What’s the Alternative?
- CADRES Trial—Tempering Agitation by Non-pharmacological Means
- Antipsychotics on Trial Again—DART-AD Confirms Increased Mortality
Does Shining Laser Light on Blood Reflect Alzheimer’s?
Researchers have been trying, with limited success, to pinpoint blood markers that herald Alzheimer’s. At the 139th annual meeting of the American Neurological Association, held October 12-14 in Baltimore, one presentation suggested that a laser-based measurement can do the job. In Raman spectroscopy, researchers shine laser light at a sample and measure the energies of the scattered photons. The spectrum that emerges depends on the molecules in the sample with which the photons interact. Taking Raman spectra of blood samples, researchers led by Igor Lednev, University at Albany, State University of New York, and Earl Zimmerman, Albany Medical Center, distinguished people with Alzheimer’s disease from healthy controls, and from people with other forms of dementia. “We don’t limit our search to a specific class of biomolecule,” Lednev told Alzforum. “It could be picking up a specific protein, or equally multiple components.” The results appeared in online in the Journal of Biophotonics on September 25.
When laser light hits a sample, some photons bounce back. Most return unchanged, but a tiny fraction lose some energy by causing molecules in the sample to vibrate. The difference in energy is known as the Raman shift, and varies depending on the electron properties and bonds in the molecules the photons encounter. Every molecule has its own unique Raman spectrum, or “fingerprint.” Raman spectroscopy is used to identify the chemical structure and composition of solids, liquids, and gases. It has also been explored as a way to analyze blood for breast cancer, pre-eclampsia, oxidative stress, and low glucose (see Pichardo-Molina et al., 2007; Schipper et al., 2008; Koo et al., 1999). Researchers led by Pedro Carmona, Instituto de Estructura de la Materia, CSIC, Madrid, have reported that it differentiated blood samples of 35 Alzheimer’s patients from those of 12 healthy controls with about 92 percent specificity and 89 percent sensitivity (see Carmona et al., 2013). Others have reported similar success on small numbers of patient as well (Burns et al., 2009; Peuchant et al., 2008).
Lednev and colleagues wanted to know if the technology could also distinguish AD from other forms of dementia. First author Elena Ryzhikova aimed a faint laser beam of near-infrared photons at blood samples from 18 healthy controls, 10 patients each with mild and moderate AD, and 18 people who had other forms of dementia, including two with progressive supranuclear palsy, 10 with dementia due to Parkinson’s disease, five who had dementia with Lewy bodies, and three with frontotemporal dementia.
Blood contains many different proteins, lipids, and carbohydrates. Raman spectra reflect that complexity, showing dozens of peaks and troughs. The researchers used a series of computer programs to determine which spectral features best separated people with AD from healthy controls or from people with other dementias. The algorithms distinguished mild or moderate Alzheimer’s from healthy controls and people with other dementias with about 95 percent accuracy. “The data were surprisingly good in terms of their ability to differentiate stages of AD from healthy people and other dementias," said David Teplow, University of California, Los Angeles.
Though the technique does not identify individual blood components that distinguish AD spectra from others, most of the spectral peaks arise when photons interact with proteins, as opposed to lipids, DNA, or other molecules that may be floating around in the blood. “We can conclude that the composition of these blood samples differs in protein makeup,” said Lednev. In the future, he plans to validate this test in a larger cohort of patients and look for the effects of additional factors, such as patient medication, and other illnesses. Preliminary evidence suggests measurements are unaffected by the AD drug donepezil, which is taken by many AD patients and ends up in their blood. To see if this method picks up evidence of AD in the presymptomatic phase, Lednev will also analyze blood samples given by patients five to 10 years before they developed symptoms.
While the ideal test would pinpoint the exact biomolecular changes taking place in a person with AD, that is not essential, Teplow said “It is more important that they can differentiate one patient group from another,” he told Alzforum. While the study used only a small number of patients, and needs to be validated with a larger sample set, Teplow noted that the new test is unbiased, which is a potential advantage over other methods that reach similar sensitivity and specificity. That is especially true if it could help tell one type of dementia from another, he said.
Though some scientists expressed skepticism that a blood test of any kind is in the cards for AD, Carmona told Alzforum that the routine clearance of cerebrospinal fluid solutes into the blood makes the latter a potential source of biomarkers. “Infrared and Raman spectroscopy are rapid, reagent-free, non-destructive, high-throughput, and relatively inexpensive methods that require a minimal amount of background training,” he wrote in an email.—Gwyneth Dickey Zakaib
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