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Wednesday, July 27, 2016

BY PETER SILLS

Estradiol, an estrogen-containing hormone therapy, may not affect the cognitive abilities of healthy postmenopausal women, regardless of whether treatment begins within six years of — or ten or more years after — menopause, according to a study published in the July 15 online issue of Neurology.

During a mean treatment period of 57 months, 1 mg oral 17b-estradiol daily compared to placebo had no effect on cognitive composite change scores in either postmenopausal group, the research team at Stanford University and University of Southern California reported.

Earlier studies have proposed that the effects of hormonal therapy on cognition can vary by age or by timing in relation to menopause, but the results have been inconsistent, study authors wrote. But the so-called "timing hypothesis" — that estradiol benefits memory and thinking in women soon after but not later menopause — had not been addressed in a randomized trial in both younger and older postmenopausal women.

The Early vs Late Intervention Trial with Estradiol (ELITE) randomized 567 healthy women between the ages of 41 and 84 within six years of menopause or 10 years after menopause to oral 17b-estradiol 1 mg daily or placebo for an average of five years. All participants underwent cognitive tests of verbal memory, executive function, or global cognition: 567 women provided cognitive outcomes after 2.5 years; 455 women provided outcomes after five years.

The researchers found no significant differences in cognitive outcomes between the two groups of women. Compared to their baseline scores, both groups of women improved in verbal memory due to practice. Scores were the same for women with and without hot flashes, and for women who had a uterus and those who had a hysterectomy.

"This study fails to confirm the timing hypothesis," said the lead study author Victor W. Henderson, MD, FAAN, professor of health research & policy and of neurology & neurological sciences at Stanford University, in a news release. "Our results suggest that healthy women at all stages after menopause should not take estrogen to improve memory. At the same time, women need not particularly be concerned about negative effects of postmenopausal estrogen supplements on memory when used for less than five years."

But the study authors offered this caveat: "Results do not generalize to women of reproductive age or in the menopausal transition, to women with primary ovarian insufficiency or premature menopause induced by surgery or cancer chemotherapy."

They added that among limitations, "the study lacked power to exclude small treatment effects in participant subgroups. It was not designed to assess short- term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease."

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Monday, July 18, 2016

Top: segmented hippocampi shown in 3 orientations (arrows). Bottom: Log p value maps of the brain regions showing age-by-genotype interactions. Credit: Chang L, Douet V, Bloss C, et al.

BY SARAH OWENS

Children who carry the apolipoprotein E (APOE) e2 and e4 genotypes showed differences in gray matter maturation and had worse performance on cognitive tests, according to a new study published online July 13 ahead of the print edition of Neurology.

Prior studies have evaluated the association between APOE genotypes and cognitive outcomes, but they assessed only groups of individuals with one or two genotypes – for instance, APOE e4 and APOE e2 – or specific cognitive outcomes, such as IQ and academic achievements. Researchers sought to study group differences across all six APOE genotypes in both gray matter changes and cognitive outcomes in children.

"This large sample of children validated and extended prior small studies that showed altered brain development in e4 carriers," the study's authors, led by Linda Chang, MD, professor of medicine and program director of neuroscience and MR research at the University of Hawaii, wrote. The findings suggest that "studying APOE polymorphism in young children may provide early indications of risk of future brain injuries and dementia."

Researchers evaluated 1,187 healthy children ranging in age from 3 to 20 years who had one of six APOE genotypes and were enrolled in the cross-sectional Pediatric Imaging Neurocognition and Genetics Study. They analyzed MRI scans to assess several aspects of gray matter changes, including morphometry and fractional anisotrophy. They also analyzed the study subjects' results on the NIH Toolbox Cognition Battery, which comprises seven tests that assess eight cognitive domains, including executive function, visual attention, episodic memory, and working memory.

They found that children with each variation of the e4 genotype – e2e4 and e4e4 – showed the greatest differences in gray matter maturation. Children with e2e4 had the smallest hippocampi; children with e4e4 had the lowest hippocampal fractional anisotrophy; and children with e4e4 showed age-dependent thinning of the entorhinal cortex.

They also found differences in cognitive function across ages. Younger children with the e2e4 genotype had larger parietal gyri, and younger children with the e4e4 genotype had thinner temporal and cingulate isthmus cortices or smaller hippocampi, which were associated with poorer performance on tests of attention and working memory in the NIH Toolbox.

The results, the study's authors wrote, show that "the e4e4 and e2e4 genotypes may negatively influence brain development and brain aging at the extremes of age."

The study's authors noted several limitations of the study, however. Among them, they noted that the "cohort effect" – in which individuals in a cohort share similar experiences because, for example, they are born around the same time and have similar environmental exposures – and the cross-sectional nature of the study may have biased the age-related brain measures, and that longitudinal follow-ups may be required to confirm the "true developmental trajectories" of children with e2 and e4 genotypes. They also noted that some children were not able to complete all the tests in the NIH Toolbox, and that the study sample could have been more ethnically diverse.

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Thursday, July 14, 2016

BY SARAH OWENS

For up to five years after an initial stroke, stroke survivors had an increased risk of a recurrent stroke and of post-stroke dementia, according to a new study published online on July 14 in Stroke. Cardiovascular risk factors that existed before the first stroke were associated with a substantial number of recurrent strokes, and to a lesser extent with post-stroke dementia, researchers found.

Previous studies have established that recurrent stroke risk is strongly associated with cardiovascular risk factors at the time of the first stroke. But the researchers, led by Marileen L. P. Portegies, MD, professor of epidemiology and neurology at Erasmus University Medical Center in Rotterdam, Netherlands, wanted to investigate the association of recurrent stroke and post-stroke dementia with risk factors that existed before the first stroke.

"The main novelty of our study is that we showed that a substantial proportion of recurrent strokes and dementia cases after stroke is attributable to prestroke cardiovascular risk factors," the study's authors wrote. The findings emphasize "the need of optimizing both primary and secondary preventions" of cardiovascular disease, they concluded.

Between 1990 and 2012, researchers followed 1,237 participants who had a first-ever stroke in the population-based Rotterdam Study  and matched them by sex, age, and other factors with 4,928 stroke-free participants. They found that the risk of recurrent stroke and post-stroke dementia was highest in the first year after the incident stroke. However, after that first year, patients had a threefold increased risk of recurrent stroke (incidence rate ratio: 3.16) and an almost twofold increased risk of post-stroke dementia (incidence rate ratio: 1.73) compared to stroke-fee people. The elevated risk remained statistically significant until the fifth year, researchers found.

Pre-stroke cardiovascular risk factors – including hypertension, low high-density lipoprotein (HDL) cholesterol, BMI of at least 25, and diabetes – were associated with recurrent stroke risk, researchers said. Overall, 39 percent of recurrent strokes and 10 percent of post-stroke dementia cases could be attributed to pre-stroke cardiovascular risk factors. However, no significant association was found between pre-stroke cardiovascular risk factors and dementia.

These percentages were similar for first-ever stroke and dementia cases in the matched stroke-free population, researchers added.

The researchers noted that the known modifiable risk factors used in the study – including hypertension, high cholesterol, low HDL cholesterol, BMI of at least 25, and diabetes – only contributed to a part of recurrent stroke and post-stroke dementia cases.  Further research into novel modifiable risk factors – including genetic factors, biomarkers, and response to treatment – may be necessary, they said.

The authors pointed out several study limitations. Among them were the lack of data on stroke severity – which they noted was a "possible mediator" in the association with recurrent stroke and post-stroke dementia risk – and that pre-stroke cardiovascular risk factors were only measured once.

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  • Portegies M L P, Wolters F J, Hofman A, et al. Prestroke vascular pathology and the risk of recurrent stroke and poststroke dementia. Stroke; Epub 14 July 2016.​

Tuesday, July 12, 2016

 

TBI with loss of consciousness was associated with an increased risk for Lewy body accumulation (shown here).

Credit: Murat Gokden

BY SARAH OWENS

Traumatic brain injury (TBI) with a loss of consciousness (LOC) was associated with an increased risk later in life for Parkinson's disease, progression of parkinsonism, and accumulation of Lewy bodies, but not with dementia or Alzheimer's disease (AD), according to a review of data from three prospective cohort studies published online July 11 in JAMA Neurology.

The data from the three studies — which included the Religious Orders Study (ROS), Adult Changes in Thought  (ACT) study, and the Memory and Aging Project  (MAP)— included clinical outcomes and post-mortem neuropathological analyses.

"Several previous studies have suggested associations between TBI with LOC and AD," wrote the authors of the study, led by Paul K. Crane, MD, MPH, professor of medicine at the University of Washington in Seattle. "To our knowledge this study is by far the greatest ever on this topic. With more than adequate power to detect an association between TBI with LOC and AD, we found none. We found that TBI with LOC was associated with Lewy body accumulation, progression of parkinsonian features, and the risk for incident PD."

Researchers evaluated a total of 7,130 participants for a total of 45,190 person-years of follow-up. Of these participants, 865 reported a history of TBI with LOC. Researchers analyzed data for both clinical outcomes – including dementia, Alzheimer's disease, Parkinson's disease, parkinsonism, and mild cognitive impairment – and neuropathologic outcomes, including neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis.

The authors noted that the total autopsy sample size – 1,682 autopsies – was more than seven times that of a previous evaluation of associations between TBI and pathologic findings of Alzheimer's disease.

Among their findings, TBI with LOC was positively associated with incident Parkinson's disease in the ACT study (hazard ratio of 3.56 for a TBI with LOC lasting longer than one hour) and with progression of parkinsonism signs in the ROS and MAP (odds ratio of 2.23 for TBI lasting longer than one hour). They also found that TBI with LOC was associated with presence of Lewy bodies (relative risk of 2.64 for TBI with LOC lasting longer than one hour in the ACT study) and with cerebral microinfarcts (relative risk of 2.12 for TBI with LOC lasting longer than one hour in ROS and MAP).

However, no association was found between TBI with LOC and incident dementia (HR of 1.03 for TBI with LOC lasting one hour or less; HR of 1.18 for TBI with LOC lasting longer than one hour).

Researchers included the apolipoprotein genotype – associated with Alzheimer's disease risk – in their analysis, but they found it had a "negligible" effect on the results.

The authors pointed out several limitations in their analysis, however.  Among them, they did not enroll ethnically diverse populations and there were systematic differences in research practices. They noted, too, the lack of available data to analyze associations between TBI with LOC and early-onset Alzheimer's disease.

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Monday, July 11, 2016

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Bickley LS, Szilagyi P. Bates' Guide to Physical Examination and History Taking, 8th Ed. Philadelphia: Lippincott Williams & Wilkins 2003

BY SARAH OWENS

Deutetrabenazine appeared to control chorea associated with Huntington's disease over the course of 12 weeks, according a study published July 5 in the Journal of the American Medical Association.

Chorea – an involuntary, sudden movement that can affect any muscle and can flow randomly across regions of the body – carries safety risks and can interfere with daily function. The Food and Drug Administration approved tetrabenazine in 2008 for treating Huntington's disease-associated chorea, but there have been concerns about tetrabenazine-associated adverse effects at peak concentration, including somnolence, depression, anxiety, and nausea.

Deutetrabenazine, which is structurally related to tetrabenazine, contains deuterium, a nontoxic form of hydrogen that offers the advantages of a longer half-life and reduced metabolic variability. Researchers hypothesized that these properties would allow less frequent and lower daily doses while reducing adverse treatment effects, resulting in an improved risk-benefit profile.

Researchers from the Huntington Study Group enrolled 90 ambulatory adults with manifest HD from 34 Huntington Disease Group investigational sites in the US and Canada . They randomized 45 participants to receive deutetrabenazine and 45 participants to receive placebo. Over the first eight weeks, participants were titrated to an optimal dosage level; dosage began at 6 mg daily, and increased by 6 mg daily each week until chorea was adequately controlled, the patient experienced a clinically significant adverse event, or the 48-mg maximum allowable dose was reached. Over the following four weeks, participants received a maintenance dose twice a day, followed by a one-week washout period.

The researchers' primary end point was a 2.7-unit difference in total maximal chorea score – a standardized assessment that measures the frequency and severity of chorea in seven body regions, with a range from 0 to 28; higher scores indicate worse chorea. They found that mean total maximal chorea scores in the deutetrabenazine group improved from 12.1 to 7.7, compared to an improvement from 13.2 to 11.3 in the placebo group, resulting in an average between-group difference of 2.5 units (p<0.001).

The findings indicate that deutetrabenazine treatment significantly improved chorea control as measured by the total maximal chorea score and by three other secondary end points, the researchers wrote.  Although the observed 2.5-unit treatment effect fell short of the trial's 2.7-unit goal, the study authors nonetheless suggested that the findings may be of clinical relevance. They noted that the safety profile of deutetrabenazine was similar to that of placebo; neither drug showed worsening of depression, and rates of anxiety and parkinsonism were not significantly different between the two drugs.

The study authors noted a number of limitations. Among them, they cited the short duration of the trial and the fact that the study design did not allow for a detailed safety assessment. They noted, as well, that only a small proportion of participants were stratified based on prior exposure to tetrabenazine.

"Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety," they concluded.

In an accompanying editorial, Michael D. Geschwind, MD, PhD, FAAN, professor of neurology, and Nick Paras, PhD, associate adjunct professor of neurology, both of the University of California at San Francisco, said the study was well-done and clearly presented. But they added: "As the authors note, the minimally clinically important difference for the primary outcome of the change in total maximal chorea score has not been determined, so the clinical relevance of the findings is not definitive."

They pointed out, as well, that the trial did not directly compare the safety and efficacy of deutetrabenazine with tetrabenazine. "From a clinician's standpoint, an ideal trial might have had 3 groups comparing deutetrabenazine, tetrabenazine, and placebo," they wrote, adding that the short, 12-week trial duration meant that the "sustainability of benefit" remains an unknown. The editorialists note that an ongoing trial, the Alternatives for Reducing Chorea in Huntington Disease (ARC-HD) trial, may address some of these issues.

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