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Wednesday, July 23, 2014
by Richard Robinson
Misfolded tau forms distinct strains that can be serially propagated both in vitro and in vivo, according to a study in the June 18 issue of Neuron. That faithful cell-to-cell transmission of misfolded tau brings tauopathies under the umbrella of prion diseases, according to lead author Marc Diamond, MD, a professor of neurology at the Washington University in Saint Louis School of Medicine in Missouri.
Furthermore, he said, different human tauopathies are characterized by different constellations of strains, suggesting that multiple anti-misfolding therapies may be required to successfully treat Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and other tauopathies.
The prion concept began with the recognition that certain proteins could act as templates to cause molecules of the same protein to fold into the same conformation, which could go on to template the folding of yet more protein. The first such proteins identified, called prion proteins (PrP), caused neurodegenerative diseases of humans and ungulates (including sheep and cows), and were transmissible to some extent within species, and to a much lesser extent between species.
Since then, the concept has been extended to include many of the proteins associated with neurodegenerative diseases, including amyloid-beta in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, and tau in the tauopathies. While there is little evidence to date suggesting that these proteins are spread between organisms, the strong similarities in templating and spreading between cells has led many in the field to use the term “prion” to describe them as well.
“From a cell biology standpoint, it is exactly like a prion,” Dr. Diamond said. A characteristic of PrP is the existence of strains, unique conformations that are passed on in the templating process.
While templating and cell-to-cell transmission have been previously shown for tau, faithful maintenance of strains has not, Dr. Diamond said. That led him to determine whether tau shared this characteristic with the PrPs. This is important, he said, because to the extent that prion mechanisms underlie the tauopathies, “only stably propagating strains can account for stereotyped clinical presentation” and spread through networks of brain neurons.
To test for the presence of strains in tau, Dr. Diamond used the aggregation-prone core of the protein, the repeat domain, bearing an aggregation-prone mutation, to transduce cells in culture. After several days, individual aggregate-containing cells were isolated and grown up separately. At the end of a month, Dr. Diamond analyzed the progeny cells to determine whether they contained identifiably different strains.
Based on aggregate morphology, he identified 20 different clones. Each clone maintained its inclusion type over the course of six months of cell culture, and thus, Dr. Diamond concluded, were true strains of tau aggregates.
Different strains induced different pathologies in mice expressing a mutant tau protein, and after two rounds of isolation and reinjection into naïve mice, the same strain as originally injected could be isolated again from the mouse brain. Within the brain, the tau aggregates spread from the site of injection to distant, synaptically connected regions.
Finally, Dr. Diamond searched for tau strains in the brains of 29 patients with tauopathies, including Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and others. He isolated tau aggregates from each brain, and used them to induce inclusions in cell culture, and then classified the inclusions based on morphology, similar to the earlier identification of the 20 clones.
Four of the six AD brains induced a single type of inclusion; the two remaining AD brains induced predominantly that same type, and small amounts of a second type. Several patients with corticobasal degeneration contained the same two strains as the mixed-type AD patients, but in opposite proportions. Other diseases were more heterogeneous, with multiple types of inclusions both within a single patient and between patients with the same diagnosis.
“We are moving toward understanding these diverse neurodegenerative diseases based on the structure of the pathogenic forms of the protein,” Dr. Diamond said. “By the time we are done, I hope we will be able to diagnose diseases based on molecular structure, and use that to make predictions of clinical course and potentially even response to therapy.”
Read more about this research and its implications for understanding and treating neurodegenerative disease in the August 7 issue of Neurology Today. Browse our archives on prions and neurodegenerative disease: http://bit.ly/NT-prions.
Tuesday, July 22, 2014
by Tom Valeo
Traumatic brain injury (TBI) increases the risk of dementia by 60 percent and accelerates onset by about two years, according to a study published in the June 25 online edition of Neurology.
However, the findings, based on medical records of 188,784 veterans with an average age of 68 when the study began, do not provide the fine-grained picture needed to differentiate the effects of milder from more severe TBIs, or the contributions from cardiovascular disease, diabetes, and other confounding factors for dementia, according to neurologists who analyzed the findings for Neurology Today.
Of the 1,229 vets diagnosed with a TBI, 196 (16 percent) developed dementia during the nine-year follow-up, compared with 18,255 (10 percent) who did not experience a TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35–1.83). And TBI victims who did not develop dementia died 2.3 years earlier than those not diagnosed with brain trauma.
Also, the authors, after adjusting for demographic factors and medical history, determined that risk of dementia increased among veterans with TBI if they also suffered from other risk factors such as depression, post-traumatic stress disorder (PTSD), or cerebrovascular disease.
The study helps to clarify conflicting evidence regarding the relationship between TBI and the risk of dementia, said the lead author Deborah E. Barnes, PhD, MPH, an associate professor of psychiatry and epidemiology and biostatistics at the University of California, San Francisco School of Medicine, and a researcher at the San Francisco Veterans Affairs Medical Center.
“Some studies have found an association, while others have found no association,” she said. “Our results come down on the side of head injury being associated with increased risk.”
Dr. Barnes acknowledged that the study did not distinguish different types of dementia. “For all-cause dementia, I think our findings are very strong, but we had limited power to look at dementia subtypes,” she said.
Also, the study relied on diagnoses made by clinicians, which could obscure the types of dementias acquired by the veterans. “We don’t know what criteria they used, so I have less confidence in the subtype data than I do in the all-cause dementia data,” she said.
A closer analysis of the medical records would yield more information about the severity and frequency of head trauma, “but it would be a time-intensive process,” Dr. Barnes said. “That is something we would like to do in the future, but it would be a massive undertaking, and we don’t have funding to do it now.”
An editorial in the same issue of Neurology praised the study for linking brain trauma to an increased risk of dementia, but also cited the need a more detailed analysis of the correlation.
Read the full discussion of these findings with commentary from outside experts in the August 7 issue of Neurology Today. See our previous coverage on the link between brain injury and dementia here: http://bit.ly/TBI-dmta.
Monday, July 21, 2014
by Olga Rukovets
For doctors treating advanced dementia patients—a population wholly unable to advocate for its own interests—the decision of whether or not to use feeding tubes can be an especially difficult one. Last week, the American Geriatrics Society (AGS) released an updated position statement to offer some guidance on this complex issue. Published in the July 17 issue of the Journal of the American Geriatrics Society, the statement reinforces the use of careful hand feeding in place of tube feeding in this patient group whenever possible. Tube feeding, according to the paper, is associated with agitation, increased use of physical and chemical restraints, and the development of pressure ulcers.
Caroline Vitale, MD, vice chair of the AGS Ethics Committee which published the recommendations along with the AGS Clinical Practice and Models of Care Committee, said in a press statement, "Patients with advanced dementia are dependent on others for all aspects of their care, and must rely on others to make decisions about the types of care they receive. Once persistent eating difficulties arise, family caregivers are often confronted with difficult decisions that typically include whether to continue hand feeding or initiate tube feeding." However, shared decision-making between medical staff and family or caregivers can help ensure a care plan that will reflect the individual’s needs and goals, the paper states.
The AGS recommendations include:
· Careful hand feeding should be offered; for persons with advanced dementia, hand feeding is at least as good as tube feeding for the outcomes of death, aspiration pneumonia, functional status and patient comfort.
· Efforts to enhance oral feeding by altering the environment and creating patient-centered approaches to feeding should be part of usual care for older adults with advanced dementia.
· A patient’s surrogate decision maker can decline or accept tube feeding as a medical therapy in accordance with advance directives, previously stated wishes, or what it is thought the patient would want.
· It is the responsibility of all members of the health care team caring for residents in long-term care settings to understand any previously expressed wishes of the patient (through review of advance directives and with surrogate caregivers) regarding tube feeding and incorporate these wishes into the care plan.
· Hospitals, nursing homes, and other care settings should promote choice, endorse shared and informed decision-making, and honor patient preferences regarding tube feeding. They should not impose obligations or exert pressure on patients or providers to institute tube feeding.
Read the full position statement from the AGS, which includes the rationale behind each of the five recommendations, here. Also, see Neurology Today’s previous coverage on the use of feeding tubes in older dementia patients: bit.ly/WqM04R.
Friday, July 18, 2014
by Olga Rukovets
New research published in the Journal of the American Medical Association (JAMA) offers some good news for members of the stroke community: Stroke incidence and mortality rates in the US have decreased in recent decades (from 1987 to 2011), according to the July 16 paper by Silvia Koton, PhD, of the Stanley Steyer School of Health Professions at Tel Aviv University, and colleagues. However, the reported decreases in incidence and mortality rates were attributed to two distinct age groups.
The prospective cohort analysis included more than 14,300 participants (about 282,100 person-years) from four different US communities who were enrolled in the Atherosclerosis Risk in Communities (ARIC) study and free of stroke at baseline. Using interviews and physical examinations, the participants were recruited between 1987 and 1989; follow-up continued until 2011 with examinations, annual phone interviews, hospital discharge reports, and linkage with the National Death Index. All possible strokes were identified and classified them as definite or probable ischemic or hemorrhagic events by physician reviewers.
Dr. Koton and investigators identified 1,051 participants with incident stroke (7 percent): 929 had incident ischemic stroke, 140 had incident hemorrhagic stroke, and 18 participants had both during the study period. The stroke incidence rates were about 3.73 per 1000 person-years for total stroke: 3.29 per 1000 person-years for ischemic stroke, and 0.49 per 1000 person-years for hemorrhagic stroke, the researchers wrote.
Over time, the incidence of stroke decreased significantly in both white and black participants of both sexes (age-adjusted incidence rate ratio per 10-year period: 0.76, or an absolute decrease of 0.93 per 1000 person-years overall). However, the decrease in incidence was only evident in participants over the age of 65 (with an age-adjusted incidence rate ratio per 10-year period of 0.69, or absolute decrease of 1.35 per 1000 person-years), they said.
Mortality after stroke also decreased over time (HR, 0.80, or an absolute decrease of 8.09 per 100 strokes after 10 years). This decrease, on the other hand, was explained by the significant drop in mortality only among younger stroke patients (less than 65 years of age): HR, 0.65, the authors said.
Overall, Dr. Koton and colleagues found that stroke incidence and mortality rates decreased significantly from 1987 to 2011 in both men and women among white and black participants, due to a combination of different decreases in stroke incidence and mortality across age.
See our collection of stories on stroke research here: http://bit.ly/strokeNT.
Thursday, July 17, 2014
by Tom Valeo
With and without the use of a selective serotonin reuptake inhibitor (SSRI), a form of cognitive behavioral therapy reduced psychogenic non-epileptic seizures (PNES), according to the results of a pilot randomized clinical trial reported in the July 2 online edition of JAMA Psychiatry.
In the trial, 38 patients were divided into four groups. One received only sertraline (Zoloft), a common SSRI. Another received only cognitive behavior therapy-informed psychotherapy (CBT-ip), which was devised for this study. A third group received a combination of sertraline and CBT-ip, and a fourth received treatment as usual, which usually involved tapering antiepileptic medication and referral to a psychiatrist or psychologist.
CBT-ip alone produced a 51.4 percent reduction in seizures (p=.01) — the primary outcome measure — as well as improvement in quality of life, social interactions, and comorbidities such as depression and anxiety (p<.001). CBT-ip combined with sertraline produced the largest reduction in seizures — 59.3 percent (p=.08) — as well as improvements in secondary outcome measures, including global functioning (p=.007). Neither sertraline alone nor treatment as usual produced a significant reduction in seizures.
The participants received 12 one-hour sessions of CBT-ip from therapists who followed a treatment workbook designed to promote more effective behaviors.
“Before the therapy the participants would communicate only in a passive or an aggressive manner,” said the study’s lead author W. Curt LaFrance, Jr., MD, MPH, FAAN, director of neuropsychiatry and behavioral neurology at Rhode Island Hospital, and an assistant professor of psychiatry and neurology at Brown University’s Alpert Medical School in Providence, RI. “They learned to practice assertive communication, which improves their relationships with others. Some learned to identify the aura that precedes a seizure so they could take action to avoid it. Some kept a thought record so they could look at their thoughts and moods from a different perspective.”
The CBT-ip also was used to teach mindfulness techniques to patients with a history of trauma and abuse. The patients in this group showed significant reductions in their seizures and improvement in other symptoms, as well as in quality of life.
“It’s more than just supportive talk therapy,” said Dr. LaFrance. “I think the power of this version of psychotherapy is that it gets down to the core beliefs, and helps people go from feeling like a victim to feeling empowered, and they take control of their seizures. It's really exciting to see this transformation occur in patients.”
The treatment workbook used in the study, Taking Control of Your Seizures: A Workbook, will be published by Oxford University Press later this year, he added.
Read more about Dr. LaFrance’s research on PNES and cognitive behavioral therapy in the Aug. 7 issue of Neurology Today. For our previous coverage of CBT for the treatment of neurological disorders, browse our archives: http://bit.ly/CBT-NT.